PYRROLIDINES AS INHIBITORS OF NEURAMINIDASES

PYRROLIDINES UTILISES COMME INHIBITEURS DE NEURAMINIDASES

English Abstract

Disclosed are compounds of formula (I) which are useful for inhibiting
neuraminidases from disease-causing microorganisms, especially, influenza
neuraminidase. Also disclosed are compositions and methods for preventing and
treating diseases caused by microorganisms having a neuraminidase, processes
for preparing the compounds and synthetic intermediates used in these
processes.

French Abstract

L'invention concerne les composés représentés par la formule (I). Ces composés servent à inhiber les neuraminidases dans des micro-organismes pathogènes, en particulier la neuraminidase de la grippe. L'invention concerne également des compositions et des procédés permettant de prévenir et de traiter les maladies causées par des micro-organismes comprenant une neuraminidase, des procédés de préparation de ces composés et des intermédiaires de synthèse utilisés dans ces procédés.

Claims

CLAIMS
What is claimed is:
1. A compound of the formula:
<IMG>
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein R1 is selected from the group consisting of
(b) -CO2H, (b) -CH2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO2H,
(g) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, (j) -CH2PO2H,
(l) tetrazolyl, (l) -CH2-tetrazolyl, (m) -C(=O)-NH-S(O)2-R11,
(o) -CH2C(=O)-NH-S(O)2-R11, (o) -SO2N(T-R11)R12 and
(p) -CH2SO2N(T-R11)R12
wherein T is selected from the group consisting of
(i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v)
-C(=O)NR3,
(vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR36-,
R11 is selected from the group consisting of
(i) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv)
(cycloalkyl)alkyl,
(w) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl,
(ix) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi)
(aryl)alkenyl,
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(xvii) heterocyclic, (xiii) (heterocyclic)alkyl and
(xviii) (xiv) (heterocyclic)alkenyl; and
R12 and R36 are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) C2-C12 alkenyl, (iv) cycloalkyl,
(v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl,
(viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl,
(xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic,
(xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of
(a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-,
(e) -N(R*)-SO2-, and (f) -SO2-N(R*)- wherein R* is hydrogen, C1-C3 loweralkyl
or
cyclopropyl;
R2 is selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl,
(e) C5-C6 cycloalkenyl, (f) halo C1-C6 alkyl and (g) halo C2-C6 alkenyl;
or R2-X- is
<IMG>
wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(R aa)(R bb)-
wherein
R aa and R bb are indepedently selected from the group consisting of hydrogen,
C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl,
1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl,
methoxymethyl,
N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from the group consisting of
(a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and
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(f) -Z-R14
wherein Z is
(ii) -C(R37a)(R37b)-, (ii) -C(R47)=C(R48)-, (iii) -C~C, (IV) -C(-O)-,
(v) -C(=S)-, (vi) -C(=NR15)-, (vii) -C(R37a)(OR37c)-, (viii)-
C(R37a)(SR37c)-
(ix) -C(R37a)(N(R37b)(R37c))- (x) _C(R37a)(R37b)-O-,
(xi) =C(R37a)(R37b)-N(R37c)- (XII) -C(R37a)(R37b)-N(O)(R37c)-
(xiii) -C(R37a)(R37b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-
(xv) -C(R37a)(R37b)-S(O)-, (xvi) -C(R37a)(R37b)-S(O)2-,
(xviii) -C(R37a)(R37b)-C(=O)-, (xviii) -C(R37a)(R37b)-C(=S)-
(xxi) _C(R37a)(R37b)-C(=NR15)-, (xx) -C(R37a)(OR37c)-C(=O)-,
(xxi) -C(R37a)(SR37c)-C(=O)-, (xxii) -C(R37a)(OR37c)-C(=S)-,
(xxiii) -C(R37a)(SR37c)-C(=S)-, (xxiv) -C(=O)-C(R37a)(OR37c)-,
(xxv) -C(=O)-C(R37a)(SR37c)-, (xxvi) -C(=S)-C(R37a)(OR37c)-,
(xxvii) -C(=S)-C(R37a)(SR37c)-, (xxviii) -C(R37a)(OR37c)-C(R37a)(OR37c)-,
(xxix) -C(R37a)(SR37c)-C(R37a)(OR37c)-,
(xxx) -C(R37a)(OR37c)-C(R37a)(SR37c)-,
(xxxi) -C(R37a)(SR37c)-C(R37a)(SR37c)-, (xxxii) -C(=O)-C(=O)-,
(xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-. (xxxv) -C(=O)-S-,
(xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R37a)-,
(xxxix) -C(=S)-N(R37a)-, (x~) -C(R37a)(R37b)-C(=O)-N(R37a)-,
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(x~i) -C(R37a)(R37b)-C(=S)-N(R37a)-, (x~ii)-C(R37a)(R37b)-C(=O)-O-,
(X~iii) -C(R37a)(R37b)-C(=O)-S-, (x~iv) -C(R37a)(R37b)-C(=S)-O-,
(x~v) -C(R37a)(R37b)-C(=S)-S-, (x~vi) -C(R37a)(R37b)-N(R37b)-C(=O)-,
(x~vii) -C(R37a)(R37b)-N(R37b)-C(=S)-, (x~viii) -C(R37a)(R37b)-O-C(=O)-,
(x~iv) -C(R37a)(R37b)-S-C(=O)- (~) -C(R37a)(R37b)-O-C(=S)-,
(~i) -C(R37a)(R37b)-S-C(=S)-, (~ii) -C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-,
(~iii) -C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-,
(~iv) -C(R37a)(R37b)-N(R37b)-C(=O)-O-,
(~v) -C(R37a)(R37b)-N(R37b)-C(=O)-S-,
(~vi) -C(R37a)(R37b)-N(R37b)-C(=S)-O-,
(~vii) -C(R37a)(R37b)-N(R37b)-C(=S)-S-,
(~viii) -C(R37a)(R37b)-O-C(=O)-N(R37a)-,
(~ix) -C(R37a)(R37b)-S-C(=O)-N(R37a)-,
(~x) -C(R37a)(R37b)-O-C(=S)-N(R37a)-,
(~xi) -C(R37a)(R37b)-S-C(=S)-N(R37a)-, (~xii) -C(R37a)(R37b)-O-C(=(O)-O-,
(~xiii) -C(R37a)(R37b)-S-C(=O)-S-, (~xiv) -C(R37a)(R37b)-O-C(=O)-S-,
(~xv) -C(R37a)(R37b)-S-C(=O)-S-, (~xvi) -C(R37a)(R37b)-O-C(=S)-O-,
(~xvii) -C(R37a)(R37b)-S-C(=S)-O-, (~xviii) -C(R37a)(R37b)-O-C(=S)-S-,
(~xix) -C(R37a)(R37b)-S-C(=S)-S- or (~xx) -C(R37a)(R37b)-C(R37a)(OR37c)-,
R14 is
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
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(v) thiol-substituted alkyl, (vi) R37c O-substituted alkyl,
(vii) R37c S-substituted alkyl, (viii) aminoalkyl,
(ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-susbstituted alkyl,
(xi) R37a O-(O=)C-substituted alkyl, (xii) R37a S-(O=)C-substituted
alkyl, (xiii) R37a O-(S=)C-substituted alkyl,
(xix) R37a S-(S=)G-substituted alkyl,
(xx) (R37a O)2-P(=O)-substituted alkyl, (xvi) cyanoalkyl,
(xxi) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl,
(xxii) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl,
(xxiv) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl,
(xxv) (cycloalkenyl)alkyl,
(xxvii) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii)
aryl,
(xxx) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl,
(xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl,
(xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl,
with the proviso that R14 is other than hydrogen when Z is
-C(R37a)(R37b)-N(R37b)-G(=O)-O- -C(R37a)(R37b)-N(R37b)-C(=S)-O-
-C(R37a)(R37b)-N(R37b)-G(=O)-S- -C(R37a)(R37b)-N(R37b)-C(=S)-S-
-C(R37a)(R37b)-O-G(=O)-O- -C(R37a)(R37b)-O-C(=S)-O-
_G(R37a)(R37b)-S-C(=O)-O- _C(R37a)(R37b)-S-G(=S)-O-
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-C(R37a)(R37b)-O-C(=O)-S-, C(R37a)(R37b)-O-C(=S)-S-
-C(R37a)(R37b)-S-C(=O)-S- or -C(R37a)(R37b)-S-C(=S)-S-.
R37a R37b R47, and R48 at each occurrence are independently selected
from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl,
(viii) C2-C12 alkynyl, (ix) cycloalkyl,
(x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl,
(xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)-alkenyl,
(xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl,
(xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic,
(xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and
(xxiv) (heterocyclic)alkynyl;
R37c at each occurrence is independently selected from the group
consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl,
(v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl,
(viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl,
(xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl,
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(xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl,
(xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic,
(xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl,
(xxiv) (heterocyclic)alkynyl, (xxiii) -C(=O)-R14, (xxiv) -C(=S)-R14,
(xxv) -S(O)2-R14 and (xxvi) hydroxyalkyl;
or when Z is -C(R37a)(R37b)-N(R37c)-, then N(R37c) and R14 when
taken together are an azido group;
or when Z is -C(R37a)(R37b)-N(O)(R37c)-, then N(O)(R37c) and R14
when taken together are an N-oxidized 3-7 membered heterocyclic
ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R37a)(OR37c)-, -C(R37a)(SR37c)- or
-C(R37a)(N(R37b)(R37c))-, then R37a, R14 and the carbon atom to
which they are bonded when taken together form a cyclopentyl,
cyclopentenyl, cyclohexyl or cyclohexenyl ring;
R15 is selected from the group consisting of
(i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C1-C12 alkyl, (v) haloalkyl,
(vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl,
(ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl,
(xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl,
(xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic,
(xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
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or R3 and R4 taken together, with the atom to which they are attached, form a
carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R5 is selected from the group consisting of
(a) hydrogen, (b) -CH(R38)2, (c) -O-R40, (d) C2-C4 alkynyl, (e) cyclopropyl,
(f) cyclobutyl, (g) -C(=Q1)-R17, and (h) -N(R19)2
wherein Q1 is O, S, or N(R18);
R17 and R18 are independently selected, at each occurrence, from the
group consisting of hydrogen, methyl, and ethyl;
R19, R38, and R40 are independently selected, at each occurrence, from the
group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl,
(v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl,
(viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl,
(xi) (cycioalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv)
(aryl)alkenyl,
(xv) heterocyclic, (xvi) (heterocyclic)alkyl and
(xvii) (heterocyclic)alkenyl;
Y is selected from the group consisting of
(a) hydrogen, (b) C1-C5 alkyl, (c) C1-C5 haloalkyl, (d) C2-C5 alkenyl,
(e) C2-C5 haloalkenyl, (f) C2-C5 alkynyl, (g) C3-C5 cycloalkyl,
(h) C3-C5 cycloalkyl-C1-to-C3-alkyl, (i) C5 cycloalkenyl, (j) C5 cycloalkenyl-
C1-to-
C3-alkyl, (k) C5 cycloalkenyl-C2-to-C3-alkenyl, (I) -(CHR39)n OR20, (m) -
CH(OR20)-
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CH2(OR20), (n) -(CHR39)n SR21, (o) -(CHR39)n CN, (p) -(CHR39)n N3, (q) phenyl,
(r) halo-substituted phenyl, (s) -(CHR39)n C(=Q2)R22, (t) -(CHR39)n N(=Q3),
(u) -N(O)=CHCH3, (v) -(CHR39)n NR23R24, (w) halo and (x) a heterocyclic ring
having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42;
R20 at each occurrence is independently
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) C,-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl,
(x) allyl, (xi) C2-C3 haloalkenyl, (xii) amino, (xiii) -NHCH3, (xiv) -N(CH3)2,
(xv) -NHCH2CH3, (xvi) -N(CH3)(CH2CH3), (xvii) -N(CH2CH3)2 or
(xviii) -N(=CH2);
R21 is
hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x)
allyl or (xi) C2-C3 haloalkenyl;
R22 is
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy,
(xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio,
(xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii)
vinyl,
(xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R28a)(R28b),
(xxv) -CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl,
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(xxvi) thioimethyl, (xxvii) -NHNH2, (xxviii) -N(CH3)NH2 or
(xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R41 and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of
(i) hydrogen, (ii) C1-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl,
(v) cyclopropyl, (vi) -C(=Q4)-R30, (v) -OR31, and (vi) -N(R32)2,
wherein Q4 is O, S, or N(R33);
R25 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R26 group is hydrogen, methyl or ethyl ;
R28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2,
methoxy, ethoxy, or -CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together
represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy,
ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R30 group is hydrogen, methyl, ethyl, -OR34, -SR34, -N(R35)2, -NHOH,
-NHNH2, -N(CH3)NH2, or -N(CH2CH3)NH2;
R31 and R32 substituents, at each occurrence, are independently
hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
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R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2 is CHR26 then R22 is selected from the group
consisting of hydrogen, -CH3, -C2H5, -C3H7, -OCH3, -SCH3, -O-C2H5, and
-S-C2H5,
and with the proviso that when R3 and R4 are each hydrogen, then Y is other
than hydrogen;
R6 and R7 are independently selected from the group consisting of
(c) hydrogen, (b) C1-C12 alkyl, (c) C2-C12 alkenyl, (d) cycloalkyl,
(e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h)
(cyclo-alkenyl)alkyl,
(j) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (l) (aryl)alkenyl, (m)
heterocyclic,
(o) (heterocyclic)alkyl and (o) (heterocyclic)alkenyl; and
R8, R9, and R10 are independently selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl,
(e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total
number of
atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
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2. The compound according to Claim 1 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
3. The compound according to Claim 1 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
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4. The compound according to Claim 1 wherein
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-
wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo
C2-C3
alkenyl or -X-R2 is
<IMG>
wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)(Rbb)-
wherein
Raa and Rbb are independently selected from the group consisting of hydrogen,
C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl,
1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl,
methoxymethyl,
N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4
is
other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen, fluoro or loweralkyl;
R10 is hydrogen, fluoro or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22,
-N(=Q3), -N(O)=CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 ring
atoms, wherein R22, R23, R24, Q2 and Q3 are as defined therein.
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5. The compound according to Claim 4 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
6. The compound according to Claim 4 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
7. The compound according to Claim 1 wherein wherein
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-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-
wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo
C2-C3
alkenyl or -X-R2 is
<IMG>
wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)(Rbb)- wherein Raa and Rbb are
independently selected from the group consisting of hydrogen,
C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4
is
other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22,
-N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also
containing one or two double bonds, wherein R22, Q2 and Q3 are as defined
therein.
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8. The compound according to Claim 7 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
9. The compound according to Claim 7 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
10. A compound according to Claim 1 wherein
-573-

-X-R2 is R2-C(=O}-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-
wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo
C1-C3
alkenyl or -X-R2 is
<IMG>
wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)(Rbb)- wherein Raa and Rbb are
independently selected from the group consisting of hydrogen,
C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4
is
other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring
atoms
and also containing one or two double bonds.
-574-

11. The compound according to Claim 10 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
12. The compound according to Claim 10 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
13. A compound according to Claim 1 wherein
R1 is -CO2H;
-575-

-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-
wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4
is
other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are hydrogen independently hydrogen or loweralkyl;
R8 and R9 are hydrogen independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring
atoms and also containing one or two double bonds.
14. The compound according to Claim 13 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
-576-

15. The compound according to Claim 13 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein and wherein R3 and R4 are not both the same.
16. The compound according to Claim 1 wherein
R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-
wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is heterocyclic or -Z-R14 wherein Z
and R14 are as defined therein;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring
atoms and also containing one or two double bonds.
-577-

17. The compound according to Claim 16 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
18. The compound according to Claim 16 having the relative
stereochemistry depicted by formula
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein and wherein R3 and R4 are not both the same.
19. The compound according to Claim 1 wherein
R1 is -CO2H;
-578-

-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or
R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic (b) alkyl,
(d) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=O)-R14,
(h) -C(R37a)(OR37c)-R14 or (i) -C(R37a)(R37b)-N(O)(R37c)R14 wherein R14 is
(j) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v)
haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic
(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii)
cyanoalkyl,
(xiv) (R37a O)-(O=)C-substituted alkyl or (xv) (R37a O)2-P(=O)-substituted
alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) loweralkyl or (iii) loweralkenyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring
atoms and also containing one or two double bonds.
-579-

20. The compound according to Claim 19 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
21. The compound according to Claim 19 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein and wherein R3 and R4 are not both the same.
22. The compound according to Claim 1 wherein
R1 is -CO2H;
-580-

-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or
R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-
R14 wherein R14 is
(ii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v)
haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii)
cyanoalkyl,
(xiv) (R37a O)-(O=)C-substituted alkyl or (xv) (R37a O)2-P(=O)-substituted
alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen ;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring
atoms and also containing one or two double bonds.
-581-

23. The compound according to Claim 22 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
24. The compound according to Claim 22 having the relative
stereochemistry depicted by formula
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein and wherein R3 and R4 are not both the same.
25. The compound according to Claim 1 wherein
R1 is -CO2H;
-582-

-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or
halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-
R14
wherein R14 is
(i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or
(iv) alkoxy-substituted loweralkyl;
R37a is
(i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and
R37c is
(i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring
atoms and also containing one or two double bonds.
-583-

26. The compound according to Claim 25 having the relative
stereochemistry depicted by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
27. The compound according to Claim 25 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein and wherein R3 and R4 are not both the same.
28. The compound according to Claim 1 wherein
R1 is -CO2H;
-584-

-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or
halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is -C(R37a)(OR37c)-R14 wherein R14 is
loweralkyl or loweralkenyl;
R37a is
loweralkyl or loweralkenyl; and
R37c is
hydrogen, C1-C3 loweralkyl or allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring
atoms and also containing one or two double bonds.
29. The compound according to Claim 28 having the relative
stereochemistry depicted by the formula:
<IMG>
-585-

wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein
and wherein R3 and R4 are not both the same.
30. The compound according to Claim 29 having the relative
stereochemistry depicted by formula:
<IMG>
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined
therein and wherein R3 and R4 are not both the same.
31. A compound selected from the group consisting of:
(~)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R, 3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-
1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;
-586-

(~)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-
carboxylate Ammonium Salt;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-
carboxylic Acid;
(~)-(2 R, 3S, 5 R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-
oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-
3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-
pyrrolidine-5-carboxylic Acid;
-587-

(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2 R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid;
-588-

(~)-(2R,3S,5R,1'R.2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R, 3S,5 R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-
5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-
carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-
carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-
carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-
carboxylic Acid;
(~)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
-589-

(~)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-
5-
carboxylic Acid;
(~)-(2R,3S.5R,1'S,3'R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-
5-
carboxylic Acid;
(~)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-
2-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-
carboxylic
Acid;
(~)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-
5-
carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-
5-
carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-
5-
carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-
5-
Carboxylic Acid;
-590-

(~)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-
5-
carboxylic Acid; and
(~)-(2S,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-
carboxylic Acid; or a pharmaceutically acceptable salt, ester or prodrug
thereof.
32. A compound selected from the group consisting of:
(~)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;
(~)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-
pyrroiidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-
carboxylate Ammonium Salt;
(~)-(2R,3S,5R,1'R.2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
-591-

(~)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-
carboxylic Acid;
(~)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-
oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-
3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid;
-592-

(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R, 3S, 5R, 1'R,2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl) propyl-3-(cis-
propen-1-
yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid ; and
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid ;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
33. A pharmaceutical composition for inhibiting influenza neuraminidase
comprising a pharmaceutical carrier and a therapeutically effective amount of
a
compound of Claim 1.
34. A pharmaceutical composition for treating an influenza infection
comprising a pharmaceutical carrier and a therapeutically effective amount of
a
compound of Claim 1.
-593-

35. A pharmaceutical composition for preventing an influenza infection
comprising a pharmaceutical carrier and a therapeutically effective amount of
a
compound of Claim 1.
36. A pharmaceutical composition for inhibiting influenza neuraminidase
comprising a pharmaceutical carrier and a therapeutically effective amount of
a
compound of Claim 31.
37. A pharmaceutical composition for treating an influenza infection
comprising a pharmaceutical carrier and a therapeutically effective amount of
a
compound of Claim 31.
38. A pharmaceutical composition for preventing an influenza infection
comprising a pharmaceutical carrier and a therapeutically effective amount of
a
compound of Claim 31.
39. A method for inhibiting neuraminidase from a disease-causing
microorganism comprising administering to a human or other mammal in need
thereof, a therapeutically effective amount of a compound of Claim 1.
40. The method of Claim 39 wherein the disease-causing microorganism
is a virus.
41. The method of Claim 40 wherein the virus is influenza virus.
42. A method for treating a disease caused by a microorganism which
has a neuraminidase, comprising administering to a human or other mammal in
need thereof, a therapeutically effective amount of a compound of Claim 1.
43. The method of Claim 42 wherein the disease-causing microorganism
is a virus.
44. The method of Claim 43 wherein the virus is influenza virus.
-594-

45. A method for preventing a disease caused by a microorganism
which has a neuraminidase, comprising administering to a human or other
mammal in need thereof, a therapeutically effective amount of a compound of
Claim 1.
46. The method of Claim 45 wherein the disease-causing microorganism
is a virus.
47. The method of Claim 46 wherein the virus is influenza virus.
48. A method for inhibiting neuraminidase from a disease-causing
microorganism comprising administering to a human or other mammal in need
thereof, a therapeutically effective amount of a compound of Claim 31.
49. The method of Claim 48 wherein the disease-causing microorganism
is a virus.
50. The method of Claim 49 wherein the virus is influenza virus.
51. A method for treating a disease caused by a microorganism which
has a neuraminidase, comprising administering to a human or other mammal in
need thereof, a therapeutically effective amount of a compound of Claim 31.
52. The method of Claim 51 wherein the disease-causing microorganism
is a virus.
53. The method of Ciaim 52 wherein the virus is influenza virus.
54. A method for preventing a disease caused by a microorganism which
has a neuraminidase, comprising administering to a human or other mammal in
need thereof, a therapeutically effective amount of a compound of Claim 31.
55. The method of Claim 54 wherein the disease-causing microorganism
is a virus.
-595-

56. The method of Claim 55 wherein the virus is influenza virus.
-596-

Description

CA 02329422 2000-10-19
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTS PART1E DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME_
CECI EST LE TOME ~ 02 DE
~10TE: Pour les tomes additionels, veuiilez contacter le Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS _ ~,
THiS SECT10N OF THE APPUCATIONlPATENT CONTAINS MORE
THAN ONE VOLUME
THIS !S VOLUME OF
' NOTE: For additional volumes-phase contact the Canadian Patent Ofifica . ~'

CA 02329422 2000-10-19
WO 99!54299 PCT/US99/07945
!_',
CH3
AcHN. N>.,~OH
HH O
OH TFA
Ph
67B (t)-~2R 3S 5R.1'R 2'S -2-) (1-Acetamido-2-hydroxy-2-(phenylacetylen-1-
yl~ ethy~cis-~ropen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid
Salt
The title compound is prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-(phenylacetyien-1-yl))ethyl-3-(cis-propen-1-yl)-
pyrrolidine-
5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-f-
butoxycarbonyl-2-{ 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic acid t butyl ester.
Example 68
(t)-(2R.3S.5R.1'R 2'R)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-
3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
i- ,
CH3
AcHN. N~.,~OH
H H
/ ~OH O
P h TFA
68A (t)-(2R,3S.5R.1'R.2'R)-2-(1-Acetamido-2-h dr~roxy-~phenylacetyien-1-
yl))ethyl-3-(cis-propen-1-yi)-pyrrolidine-5-carboxylic Acid Trifluoroacetic
Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-(phenyiacetyien-1-yl))ethyl-3-(cis-propen-1-yl)-
pyrrolidine-
-249-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-2-( 1-acetamido-2-hyd roxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-
carboxylic acid t-butyl ester (yield: 0.0034 g, 100%).
'H NMR (DMSO-ds) b 9.2 (bs, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.45-7.35 (m,
5H), 5.50 (m, 1 H), 5.29 (m, 1 H), 4.64 (d, J=4.9, 1 H), 4.5-4.4 (m, 2H), 3.81
(m,
1 H), 3.22 (quint., J=8.5Hz, 1 H), 2.45 (dt, J=12.8,7.3Hz, 1 H), 1.89 (s, 3H),
1.74
(dt, J=12.7, 1 O.OHz, 1 H), 1.58 (dd, J=7.3,1.BHz, 3H).
MS: (M+H)+ = 357, (M+Na)+ = 379, (M-H)- = 355.
Example 69
(t)-(2R.3S,5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy-3-ethyl)pen I-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN_ N~_,~ tBu
H Boc
~O
69A (t)-(2R.3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-
ether;pentyl-3-(cis-propen-1-y~~yrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 42A, substituting (t)-(2R,3S,5R,1'R,2',R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid f-butyl ester in place of (2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester (yield: 8 mg, 81 %).
MS: (M+H}+=481, (M-H)- =479
-250-

CA 02329422 2000-10-19
WO 99/54299 PCT/CJS99/07945
~OtBu
O
69B (t)-(2R,3S.5R.1'R,2'S)-1-t Butoxycarbonyl-2-(1-Acetamido-2-hydrox~3-
ethy~eentYl-3-(cis-propen-1-yl)-pyrrolidine-5-carbo~rlic Acid t Butyl Ester.
The title compound was prepared according to the method described in
Example 42B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-
2-oxo-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester
in place of (2R,3S,5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-
(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 5 mg, 63%).
MS: (M+H)+=483, (M-H)- =481
/ _',
CH3
AcH N
N
H Boc
OH
,~ H
O
CH3
AcHN.
H N
H
OH
TFA
69C (t~-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-eth~)pentyl-3-(cis-
rp open-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl}-pyrrolidine-5-carboxylic acid t
butyl
ester (yield: 4 mg, 95%).
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WO 99/54299 PCT/US99/07945
' H NMR (DMSO-ds) s 7.67(d, J=8.9Hz, 1 H), 5.48(m, 1 H), 5.23(m, 1 H),
4.42(m, 1 H), 4.21 (m, 1 H), 3.58(m, 2H), 3.22(m, 1 H), 2.43(m, 1 H), 1.82(s,
3H),
1.74(m, 1 H), 1.58(dd, J=6.71, 1.23 Hz, 3H), 1.52(m, 1 H), 1.38(m, 1 H),
1.29(m,
2Hz), 1.13(m, 1 H), 0.80(m, 6H)
MS: (M+H)+=327, (M-H)- =325
Example 70
(t)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hydroxy-3-ethyl pentyl-3-~cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
~OtBu
O
70A (t)-(2R.3S.5R,1'R,2'R)-1-tButoxycarbonyl-2-(1-Acetamido-2-hydroxr-~3-
ethyl)aentyl-3-(cis-proyen-1-yl)-p)rrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 41 B, substituting 3-pentyl magnesium bromide in place of ethyl
magnesium bromide (yield: 13mg, 45%).
MS: (M+H)+=483, (M-H)- =481
i= ,
CH3
AcHN
N
H Boc
~OH
-252-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
,~OH
O
70B (t)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hydrox -~thyl)pentyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid TrifluoroaceticAcid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-ethyl)pentyi-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t butyl ester in place of (t}-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f
butyl
ester (yield: 3 mg, 96%).
'H NMR (DMSO-ds} 8 7.85 (d, J=9.2 Hz, 1H), 5.47 (m, 1H), 5.30 (m, 1H),
4.28 (m, 1 H}, 4.19 (m, 1 H), 3.67 (m, 1 H), 3.58 (m, 1 H), 3.17 (rn, 1 H),
2.43 (m,
1 H), 1.81 (s, 3H), 1.63 (m, 1 H), 1.58 (dd, J=6.71, 1.82 Hz, 3H), 1.40 (m,
2H), 1.28
(m, 1 H), 1.10 (m, 1 H), 1.05 (m, 1 H), 0.83 (m, 6H)
MS: (M+H)+=327, (M-H)- =325
/'=',
CH3
AcH N
H N
H
~OH
TFA
-253-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
Example 71
{t)-(2R.3S,5R,1'R.2'R)-2-(1-Acetamido-2-h~~phenyl)eth~~cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
tBu
O
71A (t)-(2R,3S,5R,1'R.2'R)-1-t-Buto~carbonyl-2-(1-Acetamido-2-hydrox
phen~ ethy~cispropen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 41 B, substituting phenyl magnesium bromide in place of ethyl
magnesium bromide (yield: 36 mg, 60%).
MS: (M+H)'= 489, (M+Na)+= 511, (M-H)- = 487.
,~OH
O
71 B (t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydrox rL-2~henyi)ethYl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yi)-pyrrolidine-5-
carboxylic
acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
CH3
AcHN. ,.
N
H Boc
~OH
w
CH3
AcHN. >..
H N
H
~OH
/ TFA
-254-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester (yield: 5.5 mg, 100%).
'H NMR (DMSO-ds) d 7.79 (d, J= 9.2Hz, 1 H), 7.36 (m, 2H), 7.31 (m, 2H),
7.22 (m, 1 H), 5.49 (m, 1 H), 5.22 (m, 1 H), 4.94 (d, J= 3.OHz, 1 H), 4.52 (m,
1 H),
4.35 (m, 1 H), 3.62 (t, J= 8.5Hz, 1 H), 3.22 (m, 1 H), 2.46 (m, 1 H), 1.77 (m,
1 H),
1.fi5 (s, 3H), 1.57 (dd, J= 6.7, 0.8Hz, 3H).
MS: (M+H)+= 333, (M+Na)+ = 355, {M-H)- = 331.
Example 72
,(t)-(2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-
1-
ylLpyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
,~OH
O
72A _(t)-(2R 3S 5R 1'R~1-t-Butox c~ony~1-Acetamido-2-oxo-2-
phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 42A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid f-butyl ester in place of (2R,3S,5R,1'R,2'R)-1-t butoxycarbonyl 2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-
butyl
ester (yield: 24 mg, 84%).
MS: (M+H}+= 487, {M+Na}+= 509, (M-H)- = 485.
CH3
AcH N .
' N
H Boc
O
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CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
,~OH
O
72B (t)-(2R.3S.5R,1'R,2'S)-1-t Butoxycarbonyi-2-~1-Acetamido-2-hydrox
phenyl)ethyl-3-(cis-propen-1-~)-pyrrolidine-5-carboxylic Acid t Butter.
The title compound was prepared according to the method described in
Example 42B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-
2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester
in place of (2R,3S,5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-
(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 7.9 mg, 52%).
MS: (M+H)+= 489, (M+Na)+= 520, (M-H)- = 487.
/-= ,
CH3
AcH N .
N
H Boc
OH
CH3
AcHN. N~.,~OH
H H
w OH O
TFA
72~t)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-phenyl ethyl-3-(cis-
proaen-1-yl)-p~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-{2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid f-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 7.5 mg, 100%).
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CA 02329422 2000-10-19
WO 99154299 PCT/US99/07945
'H NMR (DMSO-ds) d 7.83 (d, J= 9.2Hz, 1H), 7.36 (m, 2H), 7.32 (m, 2H),
7.25 (m, 1 H), 5.47 (m, 1 H), 5.33 (m, 1 H), 4.54 (d, J= 9.8Hz, 1 H), 4.36 (m,
1 H),
4.23 (m, 1 H), 3.78 (m 1 H), 3.20 (m, 1 H), 2.43 (m, 1 H), 1.63 (m, 1 H), 1.56
(dd, J=
6.7, l.2Hz, 3H), 1.53 (s, 3H).
MS: (M+H)+= 333, (M+Na)+= 355, (M-H)- = 331.
Example 73
Lt)-(2R.3S,5R.1'R.2'R)-2-(1-Acetamido-2-h~x~-2-(thiophen-2-yl))ethyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N~.,~O
H'Boc /7~'O
r OOH
S
73~t)-(2R,3S.5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-h~xy-2-
thio hen-2-yl))ethyl-3-(~cispropen-1-~pyrrolidine-5-carboxylic Acid t-Butt
Ester.
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (40 mg, 0.098
mmol) in
THF (2 mL) was added dropwise to a solution of 2-thienyllithium (1 M in THF,
0.505 mmol, 5 equivalents) in THF (1 mL) at 25 °C and reacted for 20
minutes.
The reaction was quenched with saturated aqueous ammonium chloride (2 mL)
and water (5 mL) followed by extraction using dichloromethane (2 X 10 mL). The
organic layer was dried over magnesium sulfate, filtered and concentrated in
vacuo. The residue was purified by column chromatography on silica gel using
1/1: ethyl acetate/hexane to provide the title compound (yield: 9.5 mg, 20%).
MS: (M+H)+= 495, (M+Na)+= 517, (M-H)- = 493.
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CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
/_~,
CH3
AcHN_ N~.,~OH
w HH O
OH
S TFA
73B (t)-(2R.3S,5R,1'R.2'R)-2-(1-Acetamido-2-hydroxy-2-(thiophen-2-yl )ethyl-
3-(cis-propen-1-yl)-pyrrolidine-5-carbox lid c Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetam id o-2-hyd roxy-2-(th i ophen-2-yl))ethyl-3-(cis-p ropen-1-yl)-pyrrolid
ine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-
butyl ester (yield: 4.3 mg, 100%).
'H NMR (DMSO-ds) b 7.86 (d, J= 9.8Hz, 1H), 7.63 (dd, J= 5.4, 1.0 Hz, 1H),
7.07 (m, 1 H), 6.98 (m, 1 H), 5.58 (m, 1 H), 5.43 (m, 1 H), 4.55 (m, 1 H),
4.39 (m,
1 H), 3.72 (m, 1 H), 3.11 (m, 2H), 2.43 (m, 1 H), 2.04 (s, 3H), 1.80 (m, 1 H),
1.57 (m,
3H).
MS: (M+H)+= 339, (M+Na)+ = 361, (M-H)- = 337.
Example 74
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WO 99/54299 PCT/US99/07945
~-(2R.3S,5R,1'R,2'S)-2-(1-Acetamido-2-~droxy-3-~4-methylthiazol-2-yl~ prowl-
3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
i-, i-,
CH3 CH3
AcHN. ~, OtBu AcHN. ,., OtBu
H Boc ~ H Boc
~OH ~OH
N~ S N~ S
H3C H3C
74A (t)-(2R,3S.5R,1'R.2'S) and (t)~2R.3S,5R.1'R.2'R)-1-t-Butoxycarbonyl-2-
(1-Acetamido-2-h~idroxy 3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1- r~l -
wrrolidine-5-carbox liy c Acid t-Butyl Ester.
1.6 M n-Butyllithium (0.125 mL, 0.20 mmol, 4 equivalents) was added to a
solution of 2,4-dimethylthiazole (28.3 mg, 0.25 mmol, 5 equivalents) in 1 mL
of
THF at -78 °C and reacted for 30 minutes. ((t)-(2R,3S,5R,1'R)-1-t-
butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic acid t butyl ester (20.5 mg, 0.050 mmol) in THF (1 mL) was added
dropwise to the above solution and reacted for 30 minutes at -78 °C and
then for
30 minutes at room temperature. The reaction mixture was quenched with
saturated aqueous ammonium chloride (5 mL) and water (5 mL) followed by
extraction using dichloromethane (3 X 25 mL). The organic layer was dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue was
purified
by column chromatography on silica gel using 1/2: ethyl acetate/hexane to
provide (t)-(2R,3S,5R,1'R,2'S)-1-f butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-
(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-
butyl ester (yield: 3.3 mg, 13%) and (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-
2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7.5 mg, 29%).
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(2R,3S,5R,1'R,2'S) MS: (M+H)+=524, (M+Na)+=546, (2M+Na)+=1069, (M-
H)'=522.
(2R,3S,5R,1'R,2'R) MS: (M+H)+=524, (M+Na)+=546, (2M+Na)+=1069, (M-
H)-=522.
CH3
AcHN. N~.,~ H
H H
O
OH
N ~ S TFA
H3C
74B (tL,(~2R.3S,5R,1'R,2'S)-2-(1-Acetamido-2-h~droxy-3-{4-methylthiazol-2-
yl~prop~cis-proyen-1-y~-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid
Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-
1-t
butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic acid t-butyl ester (yield: 0.0030 g, 100%).
' H NMR (DMSO-ds) b 9.0 (bs, 1 H), 8.10 (d, J=8.3Hz, 1 H), 7.11 (d, J=1.0
Hz, 1 H), 5.48 (m, 1 H), 5.30 (m, 1 H), 4.30 (m, 1 H), 4.10 {m, 1 H), 3.88
(dt,
J=9.4,2.6Hz, 1 H), 3.78 (m, 1 H), 3.25-3.15 (m, 2H), 2.93 (dd, J=15.1,8.3Hz, 1
H),
2.41 (dt, J=12.3,7.3Hz, 1 H), 2.33 (d, J=1.OHz, 3H), 1.86 (s, 3H), 1.66 (dt,
J=12.7,
10.3Hz, 1 H), 1.61 (dd, J=6.8,1.SHz, 3H).
MS: (M+H)+= 368, (M+Na)+ = 390, (M-H)- = 366.
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Example 75
(t)-(2R 3S 5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-
yl)Zpropyl-
3-(cis-proyen-1-~~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
i= ,
CH3
AcHN. N,.,~OH
H H
O
OH
N ~ S TFA
H3C
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-{1-
acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-
1-t
butoxycarbonyl-2-( 1-acetam ido-2-hyd roxy)butyl-3-(cis-propen-1-yl)-pyrrolid
ine-5-
carboxylic acid t-butyl ester (yield: 0.0030 g, 100%).
' H NMR (DMSO-ds) d9.0 (bs, 1 H), 7.77 (d, J=9.3Hz, 1 H), 7.11 (s, 1 H),
5.47 (m, 1 H), 5.25 (m, 1 H), 4.45 (m, 1 H), 4.20 (m, 2H), 3.58 (t, J=9.1 Hz,
1 H),
3.19 (m, 1 H), 2.96 (m, 2H), 2.41 (m, 1 H), 2.33 (d, J=1.OHz, 3H), 1.85 (s,
3H),
1.73 (dt, J=12.7, 10.3Hz, 1H), 1.54 (dd, J=6.9,1.5Hz, 3H).
MS: (M+H)+= 368, (M+Na)+ = 390, (M-H)- = 366, (M+CF3COOH)-=480,
(2M-H)-=733.
Example 76
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(t)-(2R,3S.5R,1'R,2'RS)-2-(1-Acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-
(cis-propen-1-yl)-p~olidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N~., OH
H Boc
-OH
N~ S
U
76A (t)-(2R,3S,5R,1'R,2'RS)-1-t Butoxycarbonyi-2-{1-Acetamido-2-
hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
Acid
t-Butyl Ester
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (20.5 mg, 0.05
mmol)
in THF (1 mL) was added dropwise to a solution of the (thiazolin-2-yl)methyl
lithium (0.20 mmol, 4 equivalents, prepared from 0.025 g of 2-methylthiazoline
and 0.125 mL of 1.6 M n-BuLi at -78 °C) in THF (2 mL) at -78 °C
and reacted for
30 minutes. The reaction was quenched with saturated aqueous ammonium
chloride (5 mL) and water (5 mL) followed by extraction using dichloromethane
(3
X 20 mL). The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatography on
silica get using 1/1: ethyl acetate/hexane to provide the title compound as a
mixture of isomers (yield: 10 mg, 40%).
MS: (M+H)+= 512, (M+Na)+=534, (M-H)-=510.
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!_',
CH3
AcHN. N~.,~OH
H H O
-OH
N i $ TFA
U
76B (t)-(2R.3S.5R,1'R.2'RS)-2-(1-Acetamido-2-h rLdroxv-3-(thiazolin-2-
yl))propel-3-(cis-propen-1-yl)-pyrrolidine-5-carbox~ Acid Trifluoroacetic Acid
Salt
The title compounds were prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'RS)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic acid t-butyl ester n place of (t)-(2R,3S,5R,1'R,2'S)-1-t
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t
butyl ester {yield: 0.003 g, 100%).
Major isomer' H NMR (DMSO-ds) 8 8.88 (m, 1 H), 7.76 (d, J=8.8Hz, 1 H),
5.46 (m, 1 H), 5.19 (m, 1 H), 4.69 (m, 1 H), 3.90 (m, 1 H), 3.85 (m, 1 H),
3.49 (m,
2H), 3.35 (t, J=9.OHz, 1 H), 3.29 (dd, J=17.6,5.9Hz, 1 H), 3.04 (t, J=8.9Hz, 1
H),
2.78 (dd, J=17.6,8.1 Hz, 1 H), 2.7-2.55 (m, 2H), 1.75 (s, 3H), 1.70 (m, 1 H),
1.56
(dd, J=6.8,1.5Hz, 3H).
MS: (M+H)+= 356, (M+Na)+=378, (2M+Na)+=733, (M-H)'=354.
Example 77
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ft)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy-3 3-difluoro-3-vin I)pro y1;3-
~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
~OtBu
O
F
77A lt)-(2R.3S,5R.1'R,2'S)-1-t-Butox~rbonyl-2-(1-acetamido-2-h droxv-3 3-
difluoro-3-vinyl)aropyl-3-(cis-propen-1-~)-pyrrolidine-5-carbox~rlic Acid t-
Butyl
Ester
(t)-(2R,3S,5R,1'R)-1-f Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester {41 mg, 0.10
mmol)
and 1,1-difluoroallyl iodide (94 mg, 0.60 mmol, 6 equivalents) in TH1= (2 mL)
was
reacted with zinc dust (33 mg, 0.50 mmol, 5 equivalents) at 0°C for 5
minutes and
then at room temperature for 4 hours. The reaction mixture was quenched with
saturated aqueous ammonium chloride (15 mL) and water (15 mL) and extracted
with 3 X 25 mL dichloromethane. The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue was purified by
column
chromatography on silica gel using 1/3: ethyl acetate/hexane to provide the
title
compound (yield: 35 mg, 71 %}.
MS: (M+H)+=489, (M+Na)+=511, (2M+Na)+=999, (M-H)'=487.
CHI
3
AcHN.
H Boc
~OH
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,~OH
O
F TFA
77B (t)-(2R,3S,5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-
vinyl)propyl-3-~cis-propen-1- rL-pyrrolidine-5-carboxylic Acid Trif)uoroacetic
Acid
Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t}-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxylbutyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t
butyl ester (yield: 0.0026 g, 96%).
'H NMR (DMSO-ds) d7.68 (d, J=7.8Hz, 1 H), 5.97 (m, 1 H), 5.55-5.45 (m,
2H), 5.43 (m, 1 H), 5.23 (m, 1 H), 4.45 (m, 2H), 4.10 (m, 1 H), 3.16(quint.
J=9.1 Hz,
1 H), 2.41 (dt, J=12.8,7.3Hz, 1 H), 1.72 {s, 3H), 1.70 (dt, J=12.8, 10.3Hz, 1
H), 1.61
(dd, J=6.7,1.2Hz, 3H).
MS: (M+H)+=333, (M+Na)+=355, (M-H)-= 331, (2M-H)-=663.
Example 78
/_.',
CH3
AcH N .
H N
H
~O H
F
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(t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-h d~y~3,3-difluoro-3-vinyl)propyi-3-
(cis-propen-1- I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN _ N ~. , OtBu
H Boc
O
F
78A ~t~~2R,3S.5R,1'R)-1-t Butoxycarbonyl-2-(1-Acetamido-2-oxo-3.3-difluoro-
3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl
Ester.
The title compound was prepared according to the method described in
Example 42A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3, 3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolid
ine-5-
carboxylic acid t butyl ester in place of (2R,3S,5R,1'R,2'R)-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
to
provide (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-2-oxo-3,3-
difluoro-
3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid
t butyl
ester (yield: 0.00508, 44%).
MS: (M+H)+=487, (M+Na)+=509, (M-2F)+=448, (M-H)-=485.
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~Bu
O
F
78B (t)-y2R.3S.5R.1'R,2'R)-1-t Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3-3-
difluoro-3-vinyl)propyl-3~cis-proden-1-~pyrrolidine-5-carboxylic Acid f-Butyl
Ester.
The title compound is prepared according to the method described in
Example 42B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-
2-oxo-3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t
butyl ester in place of (2R,3S,5R,1'R)-2-(1-acetamido-2-oxo)butyl-3-(cis-
propen-
1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
CH3
AcHN_ N~.,~OH
H H
OH
F F TFA
78C (t)-ri2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-h d~ro -3,3-difluoro-3-
vinyl~propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carbox~ic Acid Trifluoroacetic
Acid
The title compound is prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3, 3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-
carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t
butyl ester.
Example 79
CH3
AcHN. ).
N
H Boc
OH
F
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(t)-(2R,3S.5R.1'R.2'R -2-) (1-Acetamido-2-hydrox~Lis-buten-2-yl))ethy~cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N~., OtBu
H Boc
H3C ~~ 'OH
CH3
79A (tZ~2R.3S,5R.1'R.2'R)-1-t-Butox~arbon~rl-2-(1-Acetamido-2-hydrox r-L2-
(cis-buten-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-
Butyl
Ester.
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (30 mg, 0.073
mmol)
in THF (5 mL) was reacted with cis-2-buten-2-yl lithium (0.75 mL (0.5M), 0.37
mmol) at 25°C for 45 min. The reaction was quenched with saturated
aqueous
ammonium chloride (5 mL) and water (5mL) followed by extraction using
dichloromethane (2 X 10 mL). The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue was purified by
column
chromatography on silica gel using 1/1: ethyl acetatelhexane to provide the
title
compound (yield: 20 mg, 59%).
' H NMR (CDC13) 8 6.19(d, J=8.9 Hz, 1 H), 5.61 (m, 1 H), 5.35(m, 1 H),
5.27(m, 1 H), 4.48(m, 1 H), 4.18(m, 1 H), 4.77(m, 2H), 3.10(m, 1 H), 2.72(m, 1
H),
1.99(s, 3H), 1.82(m, 1 H), 1.73(m, 3H), 1.55(m, 6H), 1.47(s, 9H), 1.44(s, 9H)
MS: (M+H)+= 467, (M-H)-= 465
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,
CH3
AcHN. N~.,~OH
H H
O
HsC ~ ~OH
CH3 TFA
79B (t)-(2R 3S 5R 1'R 2'R)-2-(1-Acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-
3-(cis'propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxyiic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-
butyl ester (yield: 4 mg, 96%).
' H NMR (DMSO-ds) 8 8.09(d, J=9.0 Hz, 1 H), 5.50(m, 1 H), 5.32(m, 1 H),
5.16(m, 1 H), 4.50(m, 1 H), 4.38(m, 1 H), 4.19(m, 1 H), 3.43(m, 1 H), 3.20(m,
1 H),
2.43(m, 1 H), 1.88(s, 3H), 1.74(m, 1 H), 1.70(s, 3H), 1.62(m, 3H), 1.58(m, 3H)
MS: (M+H)+=311, (M-H)- =309
Example 80
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(t)-(2R.3S,5R.1'R,2'R,3'R) and t,~-(2R,3S,5R.1'R,2'R,3'S)-2-(1-Acetamido-2-
hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid
Trifluoroacetic Acid Salt
=, i=,
CH3 CH3
AcHN_ ~., OtB~ AcHN_ ~., OtBu
H Boc ~ H Boc
~OH ~OH
80A (tl-12R.3S.5R.1'R,2'R,3'R and (t)-~2R,3S.5R,1'R.2'R,3'S)-1-t
Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1 yl)-
pyrrolidine-5-carbox~c Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (60 mg, 0.15
mmol) in
THF (1 mL) was added dropwise to a solution of 2-butylmagnesium bromide (3M
in ether) (0.45 mL, 0.85 mmol) at room temperature and reacted for 40 minutes.
The reaction was quenched with saturated NH4C1 (1 mL) followed by extraction
using dichloromethane (3 x 1 mL). The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue was purified by
column
chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the
title
compounds (t)-(2R,3S,5R,1'R,2'R,3'S)-1-t-butoxycarbonyl 2-(1-acetamido-2-
hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester Rf= 0.65 (1:1 ethyl acetate: hexanes) (yield: 19 mg, 27%) and (t)-
(2R, 3S, 5R,1' R,2'R, 3'R)-1-t-butoxycarbonyl 2-( 1-acetamido-2-hydroxy-3-
methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
Rf=
0.5) (1:1 ethyl acetate: hexanes) (yield: 19 mg, 27%).
Rf= 0.65 'H NMR (CDC13) 8 5.98 (d, J=8.8Hz, 1H), 5.62 (t, J=10.5Hz,
1 H), 5.35 (m, 1 H), 4.66 (d, J=4.4Hz, 1 H), 4.16 (d, J=9.5Hz, 1 H), 3.78 (m,
3H),
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3.12(m, 2H), 2.73 (m, 1 H), 2.0 (s, 3H), 1.81 (d, J=13.2Hz, 1 H), 1.54 (br s,
3H),
1.47 (s, 9H), 1.44 (s, 9H), 1.25 (m, 1 H), 0.81 {m, 6H)
MS: (M-H)- = 467; (M+H)+ = 469.
Rf= 0.5 'H NMR (CDC13) 8 6.00 (d, J=10.2Hz, 1H), 5.61 (br t, 1H),
5.36 (m, 1 H), 4.58 (d, J=4.7Hz, 1 H), 4.14 (d, J=8.8Hz, 1 H), 3.82 (m, 3H),
3.13 (m,
2H), 2.73 (m, 1 H), 1.99 (s, 3H), 1.80 (d, J=13.9Hz, 1 H), 1.54 (br s, 3H),
1.46 (s,
9H), 1.44 (s, 9H), 1.43 (m, 1 H), 0.97 (d, J=6.8Hz, 3H), 0.81 (t, J=7.2Hz, 3H)
MS: (M-H)- = 467; (M+H)+ = 469.
CH3
AcHN_ N~.,~OH
H H
~OH O
TFA
80B ft)-(2R,3S,5R.1'R,2'R,3'S)-2-(1-Acetamido-2-hydrox r-~3-methyl)pentyl-3-
~cis-propen-1-yIZ eyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
(t)-(2R,3S,5R,1'R,2'R,3'S}-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-
3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester (2.5
mg, 0.005 mmol) was reacted with trifluoroacetic acid (0.8 mL) in
dichloromethane (0.2 mL) at room temperature for 6 hrs. The reaction was
concentrated in vacuo overnight and triturated with acetonitrile (2 x 1 mL) to
provide the title compound (yield: 2.0 mg, 100%).
1 H NMR (DMSO-d6) 8 7.68 (d, J=8.8Hz, 1 H), 5.45 (m, 1 H), 5.23 (t,
J=7.3Hz, 1 H), 4.24 {br t, 1 H), 4.18 (m, 1 H), 3.52 (t, J=7.3Hz, 1 H), 3.45
(m, 1 H),
3.16 (m, 1 H), 2.38 (m, 1 H), 1.83 (s, 3H), 1.68 (m, 1 H), 1.58 (dd, J=2.0,
4.8Hz,
3H), 1.37 (m, 2H), 0.99 (m, 1 H), 0.89 (d, J=6.8Hz, 3H), 0.79 (t, J=7.4Hz, 3H)
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MS: (M-H)- = 311; (M+H)+ = 313, (M+Na)+ = 335.
Example 81
~t - 2R 3SL5R 1'R 2'R,3'R?-2-l1-Acetamido-2-h dy roxy-3-methvi)penty~cis-
propen-1-yl)-eyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Sait
CH3
AcHN. N~.,~OH
H H
~OH O
TFA
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R,3'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t butyl ester (Rf= 0.5, 1:1, ethyl acetate:hexanes) in place of (t)-
(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1.6 mg, 76%).
' H NMR (DMSO-ds) 8 7.55 (d, J=9.3Hz, 1 H), 5.45 (m, 1 H), 5.23 (m, 1 H),
4.31 (br t, ~ H), 4.20 (t, J=8.3Hz, 1 H), 3.51 (t, J=9.3Hz, 1 H), 3.43 (d,
J=7.4Hz,
1 H), 3.17 (m, 1 H), 2.40 (m, 1 H), 1.80 (s, 3H), 1.70 (m, 1 H), 1.55 (dd,
J=1.4,
5.4Hz, 3H), 1.36 (m, 2H), 1.14 (m, 1 H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d,
J=6.9Hz,
3H)
MS: (M-H)- = 311; (M+H)+ = 313, (M+Na)+ = 335.
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Example 82
(tL(2R,3S 5R 1'R 2'S 3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-
propen-1-y~-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
~0~8u
O
82A (t)-(2R 3S 5R 1'R 3'RS)-1-t Butox,~,rcarbon~-2-(1-acetamido-2-oxo-3-
methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 42A, substituting (t)-(2R,3S,5R,1'R,2'R,3'RS}-1-t butoxycarbonyl-2-(1-
acetamido-2-hyd roxy-3-methyl)pentyl-3-(cis-grope n-1-yl)-pyrrolid ine-5-
carboxylic
acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'R) 1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-
butyl
(yield: 12 mg, 63%).
i= ,
CH3 CH3
AcHN. ~., OtBu AcHN. ~.. O~Bu
H Boc ~ H Boc'
OH ; OH
82~t -(2) R 3S 5R 1'R 2'S 3'S) and (t~-{2R,3S,5R.1'R.2'S.3'R)-1-t
Butoxycarbonvl-2-( 1-acetamido-2-hid roxy-3-meths,pentyl-3-(cis-propen-1-vl)-
pyrrolidine-5-carboxylic Acid t Butyl Ester.
The title compounds were prepared according to the method described in
Example 42B, substituting (t)-{2R,3S,5R,1'R,3'RS)-1-t butoxycarbonyl-2-(1-
acetamido-2-oxo-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid
CH3
AcHN_
' N
H Boc
O
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t-butyl ester (Rf= 0.5 and 0.65, 1:1, ethyl acetate: hexanes) in place of
(2R,3S,5R,1'R)-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic acid t-butyl ester to give (t)-(2R,3S,5R,1'R,2'S,3'S)-1-t-
butoxycarbonyl-2-( 1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid t butyl ester (Rf= 0.15, 1:1, ethyl acetate:
hexanes)
(yield: 6.0 mg, 50%) and (t)-(2R,3S,5R,1'R,2'S,3'R)-1-t-butoxycarbonyi-2-(1-
acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester(Rf= 0.10, 1:1, ethyl acetate: hexanes) (yield: 2.5 mg,
63%).
,~ H
O
TFA
82~t)-~2R,3S.5R.1'R,2'S.3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pent)rl-3-
(cis-propen-1-Yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S,3'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hyd roxy-3-methyl) pentyl-3-(cis-p ro pen-1-yl)-pyrrolid i ne-5-
carboxylic
acid t-butyl ester (Rf= 0.15, 1:1, ethyl acetate: hexanes) in place of (t)-
(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 6.0 mg,
100%).
'H NMR (DMSO-ds) 8 7.78 (d, J=9.2Hz, 1 H), 5.42 (m, 1 H), 5.29 (t,
J=10.3Hz, 1 H), 4.08 (m, 1 H), 3.96 (br t, 1 H), 3.51 (m, 2H), 3.08 (m, 1 H),
2.33 (m,
1 H), 1.78 (s, 3H), 1.56 (d, J=6.3Hz, 3H), 1.52 (m, 1 H), 1.40 (m, 1 H), 1.29
(m, 1 H),
1.21 (m, 1 H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d, J=6.9Hz, 3H)
MS: (M-H)~ = 311; (M+H)+ = 313, (M+Na)+ = 335.
CH3
AcH N .
H N
H
OH
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Example 83
(t)-~2R 3S 5R 1'R 2'S 3'R~-2~1-Acetamido-2-h~drox~-3-methyllpentyl-3-(cis-
propen-1-yl) pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN_ N~.,~ H
H H O
OH
TFA
The title compound was prepared according to the method described in
Example 41C, substituting(t)-(2R,3S,5R,1'R,2'S,3'R)-1-f-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t butyl ester (Rf= 0.10, 1:1 ethyl acetate: hexanes) in place of (t)-
(2R, 3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.5 mg,
100%).
'H NMR (DMSO-dfi) 8 7.85 (d, J=8.7Hz, 1 H), 5.45 (m, 1 H), 5.29 (t,
J=9.3Hz, 1 H), 4.20 (m, 2H), 3.63 (t, J=8.3Hz, 1 H), 3.42 (br d, 1 H), 3.14
(m, 1 H),
2.41 (m, 1 H), 1.79 (s, 3H), 1.62 (m, 1 H), 1.58 (d, J=5.4Hz, 3H), 1.43 (m,
2H), 1.0
(m, 1 H), 0.88 (d, J=6.8Hz, 3H), 0.80 (t, J=7.3Hz, 3H)
MS: (M-H)' = 311; (M+H)+ = 3'13, (M+Na)+ = 335.
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Example 84
(t)-(2R,3S,5R.1'R,2'S)-2-(1-Acetamido-2-methoxy)but~cis-propen-1- rLl)-
pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N)., O=Bu
H Boc
OCH3
84A (t)-(2R.3S.5R,1'R.2'S~-1-t Butoxycarbonyl-2-(1-acetamido-2-
methoxy)butyl-3-(cis-propen-1-~)-pYrrolidine-5-carboxylic Acid t-Butyl Ester
(t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
(22
mg, 0.05 mmole) was reacted with methyl iodide (0.016 mL, 0.25 mmole),
potassium hydroxide (14 mg, 0.25 mmole) and 18-crown-6 (0.7 mg, 0.0025
mmole) in N,N-dimethylformamide {2 mL) at room temperature for 23 hours.
Water (5 mL) was then added to the reaction mixture, followed by extraction
with
ether (2 x 10 mL). The organic layer was washed with water, and brine, dried
over MgS04, filtered and concentrated in vacuo. The residue was purified by
chromatography on silica gel using 66% ethyl acetate/hexanes to provide the
title
compound, as a colorless oil (yield: 5.2 mg, 23%).
MS: (M+H)+= 455, (M-H)- = 453.
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CH3
AcHN. N~.,~OH
H\ H
OCH3 O
TFA
84B (t;~~2R 3S 5R.1'R.2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-
yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting {t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester
(yield: 4.7 mg, 98%).
'H NMR {DMSO-d6) 8 7.96 (d, J= 9.2Hz, 1 H), 5.50 (m, 1 H), 5.24 (m, 1 H),
4.25 (m, 2H), 3.70 (m, 1 H), 3.23 (s, 3H), 3.19 (m, 2H), 2.40 (m, 2H), 1.86
(s, 3H),
1.68 (m, 2H), 1.62 (dd, J= 7.0, 1.BHz, 3H), 1.39 (m, 1 H), 0.77 (t, J= 7.3Hz,
3H).
MS: (M+H)+= 299, (M+Na)+= 321, (M-H)- = 297
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Exam_,ple 85
St)-(2R~ 3S.5R.1 'R.2'R~-2 ~ 1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-vl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N~., O~Bu
H Boc
~OCH3
85A (tl-(2R,3S,5R,1'R.2'R)-1-t-ButoxycarbonLrl-2-(1-acetamido-2-
methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(t)-(2R, 3S, 5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
(17
mg, 0.04 mmole) was reacted with methyl iodide (28 mg, 0.19 mmole), potassium
hydroxide (8 mg, 0.19 mmole) and 18-crown-6 ( 0.002 mrnole) in N,N-
dimethylformamide {1.5 mL) at room temperature for 6 hours. Water (5 mL) was
then added to the reaction mixture, followed by extraction with ether (2 x 10
mL).
The organic layer was washed with water, and brine, dried over MgS04, filtered
and concentrated in vacuo. The residue was purified by chromatography on
silica gel using 50% ethyl acetate/hexanes to provide the title compound,
(yield: 5
mg, 29%).
MS: (M+H)+=455, (M-H)- =453
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/= ,
CH3
AcHN. N~-,~ H
H H
~OCH3 O
TFA
85B (t)-(2R 3S,5R 1'R 2'Rl-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-
yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester
(yield: 4 mg, 95%).
1 H NMR (DMSO-d6) d 8.00(d, J=9.8HZ, 1 H), 5.57(m, 1 H), 5.35(m, 1 H),
4.42(m, 1 H), 4.28(m, 1 H),3.95(m, 1 H), 3.54(m, 1 H), 3.28(s, 3H), 2.80(m, 1
H),
2.30(m, 1 H), 1.92(s, 3H), 1.65(m, 1 H), 1.60(m, 3H), 1.43(m, 2H), 0.82(t,
J=7.31 HZ, 3H).
MS: (M+H)+=299, (M-H)- =297
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Example 86
(~2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
i- ,
CH3
AcHN. N~., OH
H Boc
-OCH3
86~t~~2R 3S 5R 1'R 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3-
methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound is prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t butyl ester in place of (~)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester.
CH3
AcHN_ N~.,~OH
H H
O
OCH3
TFA
86B (t)-(2R 3S 5R 1'R.2'S)-2-l1-Acetamido-2-methoxy-3-methvl)butyl-3-(cis-
propen-1_yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-~-butoxycarbonyl-2-(1-
acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester.
Example 87
(t~-(2R.3S,5R 1'R 2'R)-2-(1-Acetamido-2-methoxy-3-methyl~tyl-3-(cispropen-
1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N~., OH
H Boc
~OCH3
86A (t)-(2R.3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3-
meth Iy )bu_,tyl-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 6.8 mg, 33%).
MS: (M+H)+= 469, (M+Na)+= 491, (M-H)- = 467.
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CH3
AcHN_ N>.,~OH
H H
~OCH3 O
TFA
87B (t)-(2R 3S.5R 1'R.2'R)-2-~1-Acetamido-2-methoxy-3-methvl)butyl-3-(cis-
~ropen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolid ine-5-
carboxylic
acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester. ester (yield: 6.6 mg, 100%).
' H NMR (DMSO-ds) 8 7.65 (d, J= 9.2Hz, 1 H), 5.43 (m, 1 H), 5.23 (m, 1 H),
4.42 (m, 1 H), 4.37 (m, 1 H), 3.56 (m, 1 H), 3.46 (s, 3H), 3.17 (m, 2H), 2.44
(m, 1 H),
1.80 s, 3H), 1.78 (m, 1 H), 1.70 (m, 1 H), 1.57 (dd, J= 6.7, 1.2Hz, 3H), 0.94
(d, J=
6.7Hz, 3H), 0.82 (d, J= 6.7Hz, 3H).
MS: (M+H)+= 313, (M+Na)+ = 335, (M-H)- = 311.
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Example 88
(~2R 3S 5R.1'R 2'S)-2-(1-Acetamido-2-methoxy~pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
H
OCH3 O
CH3
AcHN.
N
H Boc
88A (t)~2R.3S.5R 1'R.2'S~1-t-Butoxycarbonyl-2-(1-acetamido-2-
methoxy)pentyl-3-(cis propen-1-yl)-pyrrolidine-5-carboxylic Acid t Butyl Ester
The title compound was prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester
(yield: 11.9 mg, 36%).
MS: (M+H)+= 469, (M+Na)+= 491, (M-H)- = 467.
CH3
AcHN. N~.,~ H
H H
OCH3 O
TFA
88B fit)-12R.3S.5R.1'R.2'S~ 2-(1-Acetamido-2-methoxv)pent~,(cis-~~~ropen-1-
yl)-pyrrolidine-5-carboxYic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
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2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester.
(yield: 11.5 mg, 100%).
' H NMR (DMSO-ds) s 7.95 (d, J= 9.8Hz, 1 H), 5.49 (m, 1 H), 5.23 (m, 1 H),
4.25 (m, 2H), 3.68 (m, 1 H), 3.24 (s, 3H), 3.22 (m, 1 H), 3.18 (m, 1 H), 2.40
(m, 1 H),
1.85 (s, 3H), 1.66 (m, 1 H), 1.62 (m, 3H), 1.58 (m, 1 H), 1.38 (m, 1 H), 1.27
(m, 2H),
0.86 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 313, (M+Na)+=335, (M-H)- = 311.
Example 89
-(2R,3S.5R,1'R,2'R~2-(1-Acetamido-2-methoxy)pent rLl-3-(cis-propen-1-y~-
gyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
~OH
O
OCH3
89A (t)-(2R,3S.5R,1'R.2'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-
methoxy)pentyl-3-(cis-propen-1~r1~-pyrrolidine-5-carboxylic Acid t Butyl Ester
The title compound was prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl
ester
(yield: 4.3 mg, 21 %).
MS: (M+H)+= 469, (M+Na)+= 491, (M-H)-= 467.
CH3
AcHN .
N
H Boc
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/-',
CH3
AcHN_ N~.,~OH
H H
~OCH3 O
TFA
89B (t)-(2R,3S~5Ry1'R,2'R)-2-(1-Acetamido-2-methoxy~pentyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-
acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester
(yield: 4.8 mg, 100%).
' H NMR (DMSO-ds) 8 7.70 (d, J= 9.8Hz, 1 H), 5.45 (m, 1 H), 5.24 (m, 1 H),
4.40 (m, 1 H), 4.25 (m, 1 H), 3.57 (t, J= 8.5Hz, 1 H), 3.40 (m, 1 H), 3.35 (s,
3H),
3.17 (m, 1 H), 2.42 (m, 1 H), 1.82 (s, 3H), 1.69 (m, 1 H), 1.56 (dd, J= 7.1,
1.2Hz,
3H), 1.24 (m, 4H), 0.88 (t, J= 7.OHz, 3H).
MS: (M+H)+= 313, (M+Na)+= 335, (M-H)- = 311
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Example 90
(t)-(2R,3S~5R.1'R.2'S)-2-(1-Acetamido-2-methoxy-2-all ly )ethyl-3-(cis-propen-
1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N~., OtBu
H Boc
OCH3
90A (t~~2R.3S.5R.1'R,2'Sl-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-
allyl)ethyl-3-(cis-aropen-1-yl)-pyrrolidine-5-carboxylic Acid t-Bu I Ester
The title compound was prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid
t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester (yield: 8 mg, 31 %).
MS: (M+H)+=467, (M-H)-=465
90~t)-(2R.3S.5R.1'R,2'S)-2-(1-Acetamido-2-methox -~yl)ethyl-3~cis-
propen-1 yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl}-pyrrolidine-5-carboxylic
acid t-butyl ester in place of {t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid f-
butyl
ester. ester (yield: 6 mg, 96%).
' H NMR (DMSO-d6) 8 8.02{d, J=8.6HZ, 1 H),5.75 (m, 1 H), 5.51 (m, 1 H),
5.24(m, 1 H), 5.05(m, 2H), 4.27(m, 1 H), 4.22{m, 1 H), 3.74(m, 2H), 3.26(s,
3H),
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3.18(m, 1 H), 2.47(m, 1 H), 2.39(m, 1 H), 2.17(m, 1 H), 1.87(s, 3H), 1.67{m,
1 H),1.63(dd, J=6.71, 1.23 HZ, 3H).
MS: (M+H)+=311, (M-H)-=309
Example 91
{t)-(2R,3S.5R,1'R.2'R)-2-(1-Acetamido-2-methoxy-2-aIILrI ethyl-3-(cis-propen-1-
I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN_ ~., OtBu
N
~, H Boc
OCH3
91A ~t~2R.3S.5R,1'R.2'R~1-t Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-
aIILrI)et~l-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid
f-butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 4.0 mg, 16%).
MS: (M+H)+=467, (M-H)- =465
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/= ,
CH3
AcHN. N~.,~OH
H H
/ O
~OCH3
91 B (~-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-
propen-1- r~l -pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxy-2-aliyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 3 mg, 96%).
' H NMR (DMSO-ds) 8 7.75 (d, J=9.2 HZ, 1 H), 5.75(m, 1 H), 5.47(m, 1 H),
5.24(m, 1 H), 5.06(m, 2H), 4.42(m, 1 H), 4.25(m, 1 H), 3.58(m, 1 H), 3.50(m, 1
H),
3.37(s, 3H), 3.17(m, 1 H), 2.42(m, 1 H), 2.36(m, 1 H), 1.83(s, 3H), 1.71 (m, 1
H),
1.55(dd, J=6.73, 1.83 HZ, 3H)
MS: (M+H)+=311, (M-H)- =309
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Example 92
(t)-(2R,3S.5R,1'R.2'S)-2-(1-Acetamido-2-h drox -~inyl)butyl-3-(cis-propen-1-
yl~p rLrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
CH3 CH3
AcHN. ~., O~B~ AcHN. ,., OtBu
H Boc ~ H Boc
~OH ~OH
\ \
92A (t)-(2R.3S,5R.1'R.2'S and (t)-(2R,3S,5R 1'R.2'R)-1-t-Butoxycarbonyl-2-
~1-acetamido-2-hydroxy-4-vin~~buty~cis-eropen-1- r~l)=pyrrolidine-5-carboxylic
Acid t Butyl Ester.
The title compounds were prepared according to the method described in
Example 41 B, substituting 1-buten-4.-yl magnesium bromide for ethyl magnesium
bromide to provide (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-{1-acetamido-2-
hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl ester
(yield: 0.0030 g, 6%) and (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t butyl ester (yield: 0.0145 g, 28%).
(t)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=467, (M+Na)+=489,
(2M+Na)+=955, (M-H)-=465.
(t)-(2R,3S,5R,1'R,2'R)- MS: (M+H)+=467, (M+Na)+=489,
(2M+Na)+=955, (M-H)~=465.
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/= ,
CH3
AcHN. N~,~OH
\ HH
OH O
ZFA
92B (t)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-4-vinyl)butyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 0.0027 g, 100%).
~ H NMR (DMSO-ds) 8 8.93 (bs, 1 H), 7.90 (d, J=9.2 Hz, 1 H), 5.80 (m, 1 H),
5.48 (m, 1 H), 5.28 (m, 1 H), 5.00 (dd, J=17.1, 1.BHz, 1 H), 4.94 (dd,
J=10.4,1.8Hz,
1 H), 4.29 (bt, J=8.3Hz, 1 H), 4.03 (m, 1 H), 3.71 (m, 1 H), 3.49 (m, 1 H),
3.15
(quint., J=8.5Hz, 1 H), 2.41 (dt, J=12.8,7.3Hz, 1 H), 2.16 (M, 1 H), 2.05 (m,
1 H),
1.83 (s, 3H), 1.79-1.75 (m, 1 H), 1.64 (m, 1 H), 1.58 (dd, J=6.7,1.BHz, 3H),
1.34
(m, 2H).
MS: (M+H)+ = 311, (M+Na)+ = 333, (M-H)~ = 309, (M+CF3C00~)'=423
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Example 93
(t)-L2R,3S.5R,1'R.2'R)-2-(1-Acetamido-2-hYdroxy-4-vinyl)butyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
CH3
AcHN_ N~,~OH
H H
O
~OH
TFA
93A (t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-4-vinyl)but~(cis-
propen-1-yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hyd roxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrol id i ne-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester (yield: 0.0027 g, 100%).
' H NMR (DMSO-ds) 8 7.68 (d, J=9.6 Hz, 1 H), 5.81 (m, 1 H), 5.48 (m, 1 H),
5.25 (m, 1 H), 5.01 (dd, J=17.1, 1.BHz, 1 H), 4.95 (dd, J=10.3,1.7Hz, 1 H),
4.43 (t,
J=8.5Hz, 1 H), 4.10 (m, 1 H), 3.74 (m, 1 H), 3.56 (t, J=8.9Hz, 1 H), 3.16
(quint.,
J=8.9Hz, 1 H), 2.42 (dt, J=12.8,7.3Hz, 1 H), 2.11 (M, 1 H), 2.07 (m, 1 H),
1.83 (s,
3H), 1.72 (dt, J=12.8, 9.8Hz, 1H), 1.55 (dd, J=6.7,1.8Hz, 3H), 1.5-1.35 (m,
2H).
MS: (M+H)+= 311, (M+Na)+= 333, (M-H)-= 309, (M+CF3C00-)-=423,
(2M-H)-=619.
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Example 94
(t)-(2R 3S 5R 1'R.2'S.3'S)-2-(1-Acetamido-2-methoxv-3-methyl)penty~cis-
propen-1- rLl -pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
i= ,
CH3
AcHN.. N~., OH
H Boc
OCH3
94A (t)-(2R 3S.5R,1'R,2'S.3'S)-1-t-Butoxycarbony~1-acetamido-2-methox~
3-meth)pentyl-3-(cis-propen-1-YI)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound is prepared according to the method described in
Example 84A, substituting (t}-(2R,3S,5R,1'R,2'S,3'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-methyl}pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester.
,~OH
O
TFA
94B (t)-(2R.3S.5R.1'R.2'S,3'S -2-) (1-Acetamido-2-methoxy-3-methyl)pentyl-3-
(cis=prohen-1~r1)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S,3'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-methoxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester in place of {t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
i= ,
CH3
AcH N .
H N
H
OCH3
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acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester.
Example 95
(t)-(2R,3S.5R,1'RSV-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)eth !-~3-(cis-
propen-1- r~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN '. , ~~Bu
F F N
H Boc
F3C F~ ~O
F
95A (t~~2R,3S.5R.1'RS)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-
heptafluoroprop~rl)ethyl-3 ~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t
Butt
Ester.
The title compound was prepared according to the method described in
Example 42A, substituting (t)-(2R,3S,5R,1'R,2'RS)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic acid t butyl ester for (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-
(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 6.8 mg, 88%).
MS: (M+H)+=579, (M-H)'=577.
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,
CH3
AcHN ~., ~OH
F F H H
F3C O O
F F TFA
95B (t)-(2R.3S,5R,1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropv I)r_ethyl;3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'RS)-1-t-butoxycarbonyl-2-(1-
acetamido-2-oxo-3-heptafluoropropyl)ethyl-3-(cis-propen-1- yl)-pyrroiidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-
butyl ester (yield: 0.0037 g, 100%).
MS: (M+H)+=423, (M-H)~=421.
Exam~~le 96
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(t)-(2R 3S 5R 1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carbox rLlic Acid Trifluoroacetic Acid Salt
CH3
AcHN ~. , ~OtBu
F F ' N
H Boc O
F3C O
F F
96A (t)-(2R 3S 5R 1'RS)-1-t Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-
heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-
ButLrl
Ester.
The title compound was prepared according to the method described in
Example 42A, substituting (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic acid t-butyl ester for (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-
(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 6.8 mg, 88%).
MS: (M+H)+=579, (M-H)-=577.
CH3
AcHN ~.,~OH
F F H H
F3C ~ O
F F TFA
96B (t)-(2R 3S 5R 1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-
(cis-propen-1- r~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-{cis-propen-1-yl)-pyrrolidine-
5
carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl
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2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-
butyl ester (yield: 0.0037 g, 100%).
MS: (M+H)+=423, (M-H)'=421.
Example 97
~t)-~2R,3S,5R,1'R)-2~1-Acetamido-2-oxo~~entyi-3-(cis-propen-1- I~yrrolidine-
5-carboxylic Acid Trifluoroacetic Acid Salt.
CH3
AcHN N>., O~Bu
o Boc
97A (t)-(2R,3S 5R 1'R)-1-t-Butox)rcarbonYl-2-(1-acetamido-2-oxo)pen I-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid t Butyl Ester.
The title compound was prepared according to the method described in
Example 42A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hdroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester in place of (2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
(yield:
14 mg, 58%).
MS: (M+H)+ = 453, (M+Na)' = 475; (M-H)' = 451.
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/= ,
CH3
AcHN_ N~.,~ H
H~H
O O
TFA
97B (t)-(2R 3S 5R.1'R)-2-(1-Acetamido-2-oxo)pentyl-3-(cis-propen-1-YI)-
~~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in
Exampie41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
(yield:
1.4 mg, 28%).
' H NMR (DMSO-ds) 8 8.31 (d, J=8.3Hz, 1 H), 5.40 (m, 1 H), 5.19 (br t, 1 H),
4.26 (t, J=6.8Hz, 1 H), 3.63 (t, J=8.3Hz, 1 H), 3.35 (m, 1 H), 2.97 (m, 1 H),
2.45 (m, 1 H), 2.34 (dt, J=3.4, 7.4Hz, 1 H), 2.20 (m, 1 H), 1.84 (s, 3H), 1.58
(dd,
J=2, 4.3Hz, 3H), 1.43 (m, 3H), 0.82 (t, J=7.3Hz, 3H)
MS: (M-H)- = 295; (M+H)+ = 297, (M+Na)+ = 319.
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Example 98
(t)-(2R.3S,5R,1'R-,l-2-(1-Acetamido-2-oxo)butyl-3-~cis-propen-1-yi)-
pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt .
CH3
AcHN_ N~.,~OH
H H
O O
TFA
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester prepared in Example 42A in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-2-( 1-acetamid o-2-hyd roxy)b utyl-3-(cis-propen-1-yl)-pyrrolid
ine-5-
carboxyiic acid t butyl ester (yield: 5.0 mg, 100%).
1 H NMR (DMSO-d6) 8 8.52 (d, J= 8.6Hz, 1 H), 5.47 (m, 1 H), 5.15 (m, 1 H),
4.54 (m, 1 H), 4.39 (dd, J= 11.0, 6.7Hz, 1 H), 3.84 (t, J= 9.2Hz, 1 H), 3.17
(m, 1 H),
2.50 (m, 1 H), 2.38 (m, 1 H), 2.33 (m, 1 H), 1.83 (s, 3H), 1.63 (m, 1 H), 1.58
(dd, J=
6.7, l.BHz, 3H), 0.94 (t, J= 7.5Hz, 3H).
MS: (M+H)+= 283, (M+Na)+ = 305, (M-H)' = 281.
Examples 99-115
The title compounds were prepared according to the methods described in
Examples 20 and 40-42 by substituting the respective reactants.
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Example 99
CH3
AcHN. N~.,~OH
H H
/ O O
TFA
~L(2R.3S.5R.1' R)-2-( 1-Acetamido-2-oxo-2-all~)ethyl-3-(cis-prohen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 8.38 (d, J= 8.5Hz, 1 H), 5.73 (m, 1 H), 5.37 (m, 1 H),
5.05 (m, 3H), 4.32 (t, J= 7.9Hz, 1 H), 3.90 (m, 1 H), 3.49 (m, 1 H), 3.13 (m,
2H),
2.98 (m, 1 H), 3.18 (m, 1 H), 1.78 (s, 3H), 1.51 (dd, J= 5.5, 1.2Hz, 3H), 1.44
(m,
1 H).
MS: (M+H)+= 295, (M-H)- = 293.
Example 100
AcHN. N>..,~OH
H H
O O
TFA
(t)-(2R.3S.5R,1'R)-2-(1-Acetamido-2-oxo-3-methyl)butyl-3-vinyl-~yrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-dfi) a 8.64 (d, J= 8.5Hz, 1 H), 5.59 (m, 1 H), 5.08 (d, J=
17.1 Hz, 1 H), 5.02 (d, J= 9.8Hz, 1 H), 4.65 (t, J= 8.6Hz, 1 H), 4.32 (m, 1
H), 3.82 (t,
J= 9.2Hz, 1 H), 2.82 (m 2H), 2.36 (m, 1 H), 1.83 (s, 3H), 1.80 (m, 1 H), 1.03
(d, J=
6.7Hz, 3H), 0.97 (d, J= 6.7Hz, 3H).
MS: (M+H)+= 283, (M+Na)+ = 305, (M-H)- = 281.
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Example 101
AcHN. N~.,~OH
H H
O O
TFA
{t)-f2R 3S 5R 1'R)-2-(1-Acetamido-2-oxo}propyl-3-vinyl-pyrrolidine-5-
carboxylic
Acid Trifluoroacetic Acid Salt
'H NMR (DMSO-ds) 8 8.96 (d, J= 7.9Hz, 1 H), 5.71 (m, 1 H), 5.27 (d,
J=17.7Hz, 1 H), 5.97 (d, J= 11.OHz, 1 H), 4.38 {m, 1 H), 4.29 (m, 1 H), 3.81
(m, 1 H),
2.61 (m, 1 H), 2.22 (m, 1 H), 2.13 (s, 3H), 2.01 (s, 3H), 1.24 (m, 1 H).
MS: (M+H)+= 255, (M+Na)+ = 277, (M-H)- = 253.
Example 102
AcHN. \ OH
Fi Hue-.
O
O
TFA
{t~2R,3S.5R.1'R~-2-f 1-Acetamido-2-oxo)butyl-3-vinyl-pyrrolidine-5-carboxylic
Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 8.61 (d, J= 8.5Hz, 1 H), 5.60 (m, 1 H), 5.10 (d, J=
17.7Hz, 1 H), 5.03 (dd, J= 10.4, 1.2Hz, 1 H), 4.54 (t, J= 8.5Hz, 1 H), 4.38
(dd, J=
11.0, 6.7Hz, 1 H), 3.86 (m, 1 H), 2.84 (m, 1 H), 2.52 (m, 1 H), 2.37 (m, 2H),
1.85 (s,
3H), 1.82 (m, 1 H), 0.94 (t, J= 7.OHz, 3H).
MS: (M+H}+= 269, {M+Na)+ = 291, (M-H)- = 267.
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Example 103
AcHN. N~.,~OH
H H
O
O
TFA
jt~(2R 3S 5R 1'R)-2-(1-Acetamido-2-oxo pentyl-3-vinyl-pyrrolidine-5-carboxylic
Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 8.60 (d, J= 9.7Hz, 1 H), 5.60 (m, 1 H), 5.07 (m, 2H),
4.65 (m, 1 H), 4.54 (m, 1 H), 4.38 (m, 1 H), 3.86 (m, 1 H), 2.84 (m, 1 H),
2.45 (m,
1 H), 2.36 (m, 1 H), 1.86 (s, 3H), 1.82 (m, 1 H), 1.47 (m, 2H), 0.87 (t, J=
5.8Hz, 3H).
MS: (M+H)'= 283, (M+Na)+= 305, (M-H)- = 281.
Example 104
AcHN. ,~ H
O
TFA
Lt)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-hydroy)ethyl-3-vinyl-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 8.00 (d, J= 9.9Hz, 1 H), 5.63 (m, 1 H), 5.08 (m, 1 H),
4.98 (m, 1 H), 4.35 (m, 1 H), 4.25 (m, 1 H), 4.08 (m, 1 H), 3.55 (m, 1 H),
3.45 (m,
1 H), 3.38 (m, 1 H), 2.83 (m, 1 H), 2.33 (m, 1 H), 1.78 (s, 3H).
MS: (M+H)+= 243, (M+Na)+= 265, (M-H}- = 241.
N
H H
OH
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Example 105
AcHN. N~.,~ H
H H
OH O
TFA
(t}-(2R,3S.5R,1'R,2'S~2-(1-Acetamido-2-h droxy}propyl-3-vinyl pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) b 7.96 {d, J= 9.7Hz, 1 H), 5.74 {m, 1 H), 5.12 (m, 1 H),
5.03 (m, 1 H), 4.27 (m, 1 H), 3.96 (m, 1 H), 3.77 (m 1 H), 3.65 (m, 1 H), 2.87
(m, 1 H),
2.38 (m, 1 H), 1.82 (s, 3H), 1.80 (m, 1 H), 1.08 (d, J= 6.OHz, 3H).
MS: (M+H)+= 257, (M+Na)+= 279, (M-H)- = 255.
Example 106
AcHN. N>.,~OH
H
OH O
TFA
(t)-(2R,3S,5R.1'R.2'S}-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 87.99 (d, J= 9.OHz, 1 H), 5.75 (m, 1 H), 5.13 (d, J=
17.1 Hz, 1 H), 5.04 (d, J= 10.5Hz, 1 H), 4.27 (t, J= 8.4Hz, 1 H), 4.04 (m, 1
H), 3.78
(m, 1 H), 3.48 (m, 1 H), 2.89 (m, 1 H), 2.40 (m, 1 H), 1.88 (m, 1 H), 1.85 (s,
3H), 1.54
(m, 1 H), 1.28 (m, 1 H), 0.86 (t, J= 7.2Hz, 3H).
MS: (M+H)+= 271, (M+Na)+ = 293, (M-H)- = 269.
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Example 107
AcHN_ N~.,~OH
H H
OH O
TFA
St)-(2R 3S 5R 1'R 2'Sl-2-(1-Acetamido-2-h dy rox )Lpentyl-3-vin r~yrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
'H NMR (DMSO-ds) s 7.99 (d, J= 9.9Hz, 1 H), 5.75 (m, 1 H), 5.08 (m, 2H),
4.28 (m, 1 H), 4.03 (m, 1 H), 3.77 (m, 1 H), 3.52 (m, 1 H), 2.88 (m, 1 H),
2.40 (m,
1 H), 1.86 (s, 3H), 1.75 (m, 1 H), 1.45 (m, 2H), 1.25 (m, 2H), 0.87 (t, J=
5.9Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)- = 283.
Example 108
AcHN_ N~.,~OH
H H
OH O
TFA
(ty-(2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 7.97 (d, J= 9.3Hz, 1 H), 5.75 (m, 1 H), 5.12 (d, J=
17.1 Hz, 1 H), 5.04 (d, J= 11.2Hz, 1 H), 4.24 (m, 1 H), 4.13 (m, 1 H), 3.74
(dd, J=
9.8, 6.1 Hz, 1 H), 3.44 (dd, J= 10.3, 2.OHz, 1 H), 2.87 (m, 1 H), 2.40(m, 1
H), 1.84
(m, 1 H), 1.83 (s, 3H), 1.75 (m, 1 H), 0.89 (d, J= 6.8, 3H), 0.75 (d, J=
6.8Hz, 3H).
MS: (M+H)+= 285, (M+Na)+ = 307, (M-H)- = 283.
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Example 109
AcHN. N~. ~OH
H H
OH O
TFA
(t)-(2R.3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxY 2-cyclopropyl)ethyl-3-vi~l-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
'H NMR (DMSO-ds) 8 7.81 (d, J= 10.OHz, 1 H), 5.73 (m, 1 H), 5.05 (m, 2H),
4.39 {m, 1 H), 4.20 (m 1 H), 3.90 (m, 1 H), 3.61 (m, 1 H), 3.08 (m, 1 H), 2.86
(m, 1 H),
2.42 {m, 1 H), 1.85 (s, 3H), 0.88 (m, 1 H), 0.45 (m, 1 H), 0.35 (m, 2H), 0.11
(m, 1 H).
MS: (M+H)+= 283, (M+Na)+= 305, (M-H)- = 281.
Example 110
-,
AcHN. N~.,~OH
H
~OHH O
TFA
jt -) (2R,3S.5R.1'R,2'R)-2-(1-Acetamido-2-h~rdroxy)propel-3-vinyi-pyrrolidine-
5-
carbox~rlic Acid Trifluoroacetic Acid Salt
'H NMR (DMSO-ds) 8 7.77 {d, J= 9.7Hz, 1 H), 5.72 (m, 1 H), 5.07 (m, 2H),
4.40 (m, 1 H), 4.03 (m, 1 H), 3.95 (m 1 H), 3.57 (m, 1 H), 2.86 (m, 1 H), 2.43
(m, 1 H),
1.88 (m, 1 H), 1.84 (s, 3H), 1.04 (d, J= 6.OHz, 3H).
MS: (M+H)+= 257, (M+Na)+= 279, (M-H)- = 255.
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Exam~~le 111
AcHN. N~.,~OH
H H
~OH O
TFA
f t~~2R, 3S.5R.1'R,2'R)-2-( 1-Acetamido-2-hydrox~butyl-3-vin~yrrolidine-5-
carbo Ix iY c Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 87.72 (d, J= 9.8Hz, 1 H), 5.73 (m, 1 H), 5.08 (d, J=
17.1 Hz, 1 H), 5.03 (d, J= 10.4Hz, 1 H), 4.41 (m, 1 H), 4.13 (m, 1 H), 3.68
(m, 1 H),
3.63 (m, 1 H), 2.88 (m, 1 H), 2.44 (m, 1 H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.38
(m, 2H),
0.84 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 271, (M+Na)+ = 293, (M-H)- = 269.
Exam~~le 112
AcHN. N~.,~OH
H H
~OH O
TFA
(~2R.3S 5R.1'R.2'R)-2-f1-Acetamido-2-hydroxy)pent)rl-3-vinyl-pyrrolidine-5-
carbo Ix~ic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) s 7.72 (d, J= 9.9Hz, 1 H), 5.72 (m, 1 H), 5.06 (m, 2H),
4.42 (m, 1 H), 4.09 (m, 1 H), 3.77 (m, 1 H), 3.61 (m, 1 H), 2.87 (m, 1 H),
2.43 (m,
1 H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.37 (m, 2H), 1.27 (m, 2H), 0.87 (t, J=
5.9Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)- = 283.
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Example 113
AcHN. N~.,~ H
H H
~OH O
TFA
(t~~2R.3Sy5R.1'R,2'R -) 2!(1-Acetamido-2-hydroxy-3-meth~rl)butyl-3-vinyl-
pyrrolidine-5-carboxyiic Acid Trifluoroacetic Acid Salt
~ H NMR (DMSO-d6) 8 7.71 {d, J= 9.3Hz, 1 H), 5.70 (m, 1 H), 5.08 (d, J=
17.1 Hz, 1 H), 5.03 (d, J= 10.3Hz, 1 H), 4.42 (m, 1 H), 4.25 (m, 1 H), 3.61
(m, 1 H),
3.35 (dd, J= 8.3, 2.5Hz, 1 H), 2.90 (m, 1 H), 2.44 (m, 1 H), 1.92 (m, 1 H),
1.82 {s,
3H), 1.58 (m, 1 H), 0.95 (d, J= 6.8Hz, 3H), 0.79 (d, J= 6.4Hz, 3H).
MS: (M+H)+= 285, (M+Na)+ = 307, (M-H)- = 283.
Example 114
AcHN. N~.,~OH
H
~OH O
TFA
~2R,3S.5R.1'R.2'R)-2-(1-Acetamido-2-h droxy-2-cycloprop,~l)ethyl-3-vinyl-
Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) b 7.94 (d, J= 9.6Hz, 1 H), 5.76 (m, 1 H), 5.12 (m, 2H),
4.40 (m, 1 H), 4.21 (m, 1 H), 3.90 (m, 1 H), 3.53 (m, 1 H), 3.13 (m, 1 H),
2.81 (m,
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1 H), 2.25 (m, 1 H), 1.87 (s, 3H), 0.90 (m, 1 H), 0.47 (m, 1 H), 0.37 (m, 2H),
0.15 (m,
1 H).
MS: (M+H)+= 283, (M+Na)'= 305, (M-H)- = 281.
Example 115
AcHN. N~.,~ H
H
~OH O
TFA
(t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-4-meth~pentyl-3-vinyl-
pyrrolidine-5-carbox~rlic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 7.71 (d, J= 9.7Hz, 1 H), 5.83 (m, 1 H), 5.06 (d, J=
17.1 Hz, 1 H), 5.02 (d, J= 10.3Hz, 1 H), 4.41 (m, 1 H), 4.06 (m, 1 H), 3_83
(m, 1 H),
3.59 (t, J= 8.8Hz, 1 H), 2.84 (m, 1 H), 2.42 (m, 1 H), 1.90 (m, 1 H), 1.82 (s,
3H),
1.71 (m, 1 H), 1.34 (m, 1 H), 1.07 {m, 1 H), 0.89 (d, J= 6.8Hz, 3H), 0.86 (d,
J=
6.3Hz, 3H).
MS: (M+H)+= 299, (M+Na)+ = 321, (M-H)- = 297.
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Example 116
(t)-(2R,3S 5R.1'R)-2-(1-Acetamido-2-hydroxy-2-methyl)propel-3-vinyl-
pyrrolidine-
5-carboxylic Acid Trifluoroacetic Acid Salt
AcHN. N>., O~Bu
OHBcc
116A (t)-(2R.3S.5R,1'R)-f-Butoxycarbonyl-2-~-Acetamido-2-hydroxy-2-
methyl)propyl-3-vin rLl-pyrrofidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R, 3S,5R,1'R)-t-Butoxycarbonyl 2-(1-acetamido-2-oxo)propyl-3-vinyl-
pyrrolidine-5-carboxylic acid t-butyl ester (11 mg, 0.027 mmol) was reacted
with
methyl magnesium bromide (3 M) ( 0.05mL, 0.134 mmol) in THF (2 mL) at 25
°C
for 2 hours. The reaction was quenched with saturated aqueous ammonium
chloride (2 mL) and water (2 mL) followed by extraction using dichloromethane
(2
X 5 mL). The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel using 2/1: ethyl acetatelhexane to provide the title compound
(yield: 1.9
mg, 17%).
MS: (M+H)+=427, (M-H)- =425
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AcHN. N~.,~OH
H\ H
OH O
TFA
1168 (t)-(2R.3S.5R,1'R)-2-(1-Acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl
ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
(yield:
1.6 mg, 99%).
' H NMR (DMSO-ds) 8 7.70(d, J=9.9Hz, 1 H), 5.75(m, 1 H), 5.02(m, 2H),
4.37(m, 1 H), 4.15(m, 1 H), 3.61 (m, 1 H), 2.78(m, 1 H), 2.41 (m, 7 H), 1.81
(s, 3H),
1.20(s, 3H), 1.12(s, 3H)
MS: (M+H)+ =271, (M+23)+ =293, (M-H)- =269
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Example 117
(t)-(2R,3S.5R.1'R)-2-(1-Acetamido-2-hydroxy-2-ethyl)bu I-3-vinyl-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
AcHN. N,., O~Bu
OH ~c
117A (t)-(2R.3S.5R.1'R)-t Butoxycarbon)rl-2-(1-Acetamido-2-hydro~-2-
ethylLt~l-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Es-ter.
(t)-(2R, 3S,5R,1'R)-f-Butoxycarbonyl-2-( 1-acetamido-2-oxo)butyl-3-vinyl-
pyrrolidine-5-carboxylic acid t-butyl ester (37mg, 0.087 mmol) was reacted
with
ethyl magnesium bromide (3 M) ( 0.15mL, 0.44rnmol) in THF (5 mL) at 25
°C for
2 hours. The reaction was quenched with saturated aqueous ammonium chloride
mL) and water (5 mL) followed by extraction using dichloromethane (2 X 10
mL). The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel using 2/1: ethyl acetate/hexane to provide the title compound
(yield: 14
mg, 35%).
MS: (M+H)+= 455, (M-H)- =453
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AcHN. N~.,~ H
H H
OH O
TFA
1168 (t)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-hydrox -y 2-ethyl)butyl-3-viny(-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-ethyl)butyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl
ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
(yield:
5.8 mg, 98%).
' H NMR (DMSO-ds) 8 7.62(d, J=9.6HZ, 1 H), 5.75(m, 1 H), 5.03(m, 2H),
4.39(m, 1 H), 4.31 (m, 2H), 3.87(m, 1 H), 3.38(m, 1 H), 2.88( m, 1 H), 2.40(m,
1 H),
1.83(s, 3H), 1.55-1.30(m, 4H), 0.86(m, 6H)
MS: {M+H)+ =299, (M-H)- =297
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Example 118
(t~2R.3S.5R,1'S)-2-(1-Acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N~., O~Bu
H Boc
118A (t)-~2R.3S.5R,1'S)-1-t-Butox~carbonyl-2-(1-acetamidoLlly~cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 20K, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-
2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester in
place of (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-
formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 15.3 mg, 61.4%).
MS: {M+H)+= 409.
CH3
AcHN. N~.,~ H
/ H H O
TFA
1188 (t)-(2R.3S.5R,1'S~,2-(1-Acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-
acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester in
place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyi-2-(1-acetamido-2-
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hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
(yield:
13.1 mg, 100%).
'H NMR (DMSO-dg): 61.58 (dd, 3H), 1.74 (dt, 1H), 1.88 (s, 3H), 2.41 (dt,
1 H), 3.17 (m, 1 H), 3.56 (dd, 1 H), 4.35 (dd, 1 H), 4.70 (dd, 1 H), 5.22-5.30
(m, 3H),
5.51 (m, 1 H), 5.82 (m, 1 H), 8.15 (d, 1 H), 9.18 (br s, 2H).
MS: (M+H)+= 253.
Example 119
(t)-(2R 3S 5R 1'S~,-2-(1-Acetamido-2-(cis and traps)buten-1-yl)-3-(cis-propen-
1-
~~ pyrrolidine-5-carbox~rlic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N>., OtBU
H Boc
O
119A (t)-(2R 3S 5R 1'S)-1-t Butoxycarbonyl-2-(1-Acetamido-2-(cis and
traps)buten-1-yl)-3-(cis-pro.Len-1-yll ~wrrolidine-5-carboxylic Acid t-Butyl
Ester
The title compound was prepared according to the method described in
Example 20K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-
2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester in
place of (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-
formyl-pyrrolidine-5-carboxylic acid t-butyl ester and
ethyltriphenylphosphonium
bromide for methyltriphenylphosphonium bromide (yield: 12.4 mg, 48.2%).
MS: (M+H)+= 423
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/= ,
CH3
AcHN. N~.,~ H
H3C / N H p
TFA
119B (t)-(2R.3S,5R,1'S~-2-(1-Acetamido-2-(cis and trans)buten-1-yl)-3-(cis-
propen-1-yl~_pyrrolidine-5-carbox liy c Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-
2-(cis and traps)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid
t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester
(yield: 11.8 mg, 100%).
' H NMR (DMSO-ds): 81.63 (dd, 3H), 1.66 (dd, 3H), 1.74 (m, 1 H), 1.88 (s,
3H), 2.41 (dt, 1 H), 3.17 (m, 1 H), 3.50 (dd, 1 H), 4.34 (dd, 1 H), 4.95 (m, 1
H), 5.23
(m, 1 H), 5.39 (m, 1 H), 5.53 (m, 1 H), 5.68 (m, 1 H), 8.21 (d, 1 H), 9.18 (br
s, 2H).
MS: (M+H)+= 267
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Example 120
{t~2R.3S,5R,1'S~ 2-(1-Acetamido-3,3-dimethyl)allyl-3-(cis-propen-1- rLl~
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN_ N~., O~Bu
H Boc
120A (t)-(2R,3S,5R~1'S)-1-t Butox cy a~,rbonYl-2-(1-acetamido-3,3-dimethyl)all
~cis-propen-1-yl~-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in
Example 20K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-
2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester in
place of (t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-
formyl-pyrrolidine-5-carboxylic acid t-butyl ester and
isopropyitriphenylphosphonium bromide for methyltriphenylphosphonium bromide
(yield: 8.2 mg, 25.9%).
MS: {M+H)+= 437
CH3
AcHN_ N~.,~ H
/ H H
O
TFA
120B fit)-~2R,3S 5R.1'S)-2-(1-Acetamido-3.3-dimethyl)ally-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-
3,3-dimethyi)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester in
-3 3 5-

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place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetarnido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
ester
(yield: 7.5 mg, 100%).
'H NMR (DMSO-d6): 51.53 (dd, 3H), 1.57 (s, 3H}, 1.61 (s, 3H), 1.66 (m,
1 H), 1.77 (s, 3H), 2.32 (dt, 1 H), 3.07 (m, 1 H), 3.39 (dd, 1 H), 4.26 (m, 1
H), 4.75
(m, 1 H), 5.07 (d, 1 H), 5.15 (m, 1 H), 5.44 (m, 1 H), 8.06 (d, 1 H).
MS: (M+H)+= 281.
Example 121
(t) ~2R 3S 5R 1'S)-2-~1-Acetamido-2-(cis and traps)penten-1-yl)-3-lcis-propen-
1-
yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
i= ,
CH3
AcHN. N,.,~ xBu
H Boc
121A (t)-(2R 3S 5R 1'S)-1-f Butoxycarbonyi-2-(1-Acetamido -2-(cis and
traps)penten-1-yl)-3-(cis-propen-1-~l-pyrrolidine-5-carboxylic Acid f-Butyl
Ester
The title compound was prepared according to the method described in
Example substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
formyi)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
in
place of (t)-(2R,3R,5R,1'S)-i-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-
formyl-pyrrolidine-5-carboxylic acid t butyl ester and ~n-butyl-
triphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield:
21.0 mg, 66.2%).
MS: (M+H)+= 437.
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/_',
CH3
AcHN. N~,~OH
/ H H
O
TFA
121B (t)-(2R,3S,5R,1'Sl-2-(1-Acetamido-2-(cis and trans)penten-1- Iy )-3~cis-
propen-1-ylLp rr~ne-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-
2-(cis and traps)penten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t
butyl ester in place ofi (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester.
ester (yield: 16.0 mg, 98.1 %).
'H NMR (DMSO-d6): 8 0.93 (t, 3H), 1.62 (dd, 3H), 1.75 (m, 1H), 1.87 {s,
3H), 2.07 (m, 2H). 2.40 (m, 1 H), 3.17 (m, 1 H), 3.50 (m, 1 H), 4.34 (m, 1 H),
4.94
(m, 1 H), 5.23 (m, 1 H), 5.34 (m, 1 H}, 5.53 (m, 1 H), 5.58 (m, 1 H), 8.24 (d,
1 H),
9.25 (br s, 2H).
MS: (M+H)+= 281.
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Example 122
(t)-(2R.3S.5R.1'S)-2-(1-Acetamido-4-hydroxy-2-(cis and trans)buten-1-~)-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN_ N~., O~Bu
H Boc
TBSO
122A (t)-(2R,3S.5R.1'S)-1-t-Butoxycarbonyl-2-{1-Acetamido-4-(t-
butyldimeth~yloxY~2~cis and traps)buten-1-yl~cis-propen-1-~pyrrolidine-
5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
in
place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-
formyl-pyrrolidine-5-carboxylic acid t butyl ester and 4-(t-
butyldimethylsilyloxy)-
butyitriphenylphosphonium bromide for methyltriphenylphosphonium bromide
{yield: 23.1 mg, 66.9%).
MS: (M+H)+= 567.
CH3
AcHN_ N~_,~OH
/ H H
HO O
TFA
1228 (t)-f2R.3S.5R.1'S)-2-(1-Acetamido-4-hydroxv-2-(cis and trans)buten-1-vl)-
~cis-propen-1 yl~p~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-
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2-(cis and traps)-4-hydroxy-butenyl-2-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxyiic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-
butyl ester (yield: 16.9 mg, >100%).
'H NMR (DMSO-d6): 61.67 (dd, 3H), 1.78 (dt, 1H), 1.91 (s, 3H), 2.44 (m,
1 H), 2.50 (m, 1 H), 2.56 (m, 1 H), 2.65 {m, 1 H), 3.23 (m, 1 H), 3.54 (m, 1
H), 4.40
(m, 1 H), 4.47 (m, 2H), 5.01 (m, 1 H), 5.26 (m, 1 H), 5.54 (m, 2H), 5.63 (m, 1
H),
8.32 (d, 1 H), 9.27 (br s, 2H).
MS: (M+H)+= 297.
Example 123
ft)~2R.3S.5R,1'S)-2~1-Acetamidolbuyl-3-vinyl-pyrrolidine-5-carboxylic Acid
Hydrochloride
TBDPSO-,
iBu
IH~ o
Ph
123A (t)-(2R,3R,5R -1-Benzyl-2-vinyl-3-t-butyldiphenYlsilyioxymethYl-
hyrrolidine-5-carboxylic Acid t-But~rl Ester.
(t)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-hydroxymethyl-pyrrolidine-5-carboxylic
acid t-butyl ester (30.8 g, 97.1 mmol) was reacted with t-butyldiphenylsilyl
chloride (49.5 mL, 190.4 mmol) and imidazole in dichloromethane (650 mL) at 0
°C for 1 hour. The reaction was quenched methanol followed by
extraction with
dichloromethane (600 mL). The organic layer was dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was purified by column
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chromatography on silica gel using 2/1: chloroform/hexane to provide the title
compound (yield: 52.9 g, 98%).
'H NMR (CDC13) 7.62-7.67 (m, 4H), 7.32-7.44 (m, 6H), 7.25-7.30 (m, 5H),
5.58-5.72 (m, 1 H), 5.06-5.14 (m, 2H), 3.90 (d, 1 H), 3.72-3.78 (m, 1 H), 3.58-
3.68
(m, 2H), 3.44-3.52 (m, 2H), 2.26-2.40 (m, 1 H), 2.10-2.23 (m, 1 H), 1.68-1.78
(m,
1 H), 1.38 (s, 9H), 1.03 (s, 9H).
MS: (M+H)+=556
TBDPSO---
HO N~,~O~Bu
H
HO~ O
~Ph
1238 (t)-(2R,3R,y5R,1'RSl-1-Benzyl-2-(1.2-dihydroxy)eth
butyld~henYlsilylo~,rmethyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
{t)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-t butyldiphenylsilyloxymethyl-
pyrrolidine-5-carboxylic acid t-butyl ester (22.7 g, 41 mmol) was reacted with
Os04 (4%) (2.5 mL, 0.7 mol.%) and N-methyl morpholine N-oxide (18.5 g, 2.77
eq.) in acetone (500 mL) and water (60 mL) for 48h at room temperature. The
reaction was quenched with 10% aqueous NaZS203 (200 mL). The reaction was
concentrated in vacuo and the residue was partitioned between ethyl
acetate/water. The organic layer was dried over magnesium sulfate, filtered
and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel using 35% ethyl acetate/hexane to provide the title compound
(yield: 11
g, 55%).
'H NMR (DMSO-ds) s 7.58-7.63 (m, 5H), 7.40-7.48 (m, 7H), 7.20-7.35 (m,
3H), 4.41-4.45 (m, 2H), 3.98 (d, 1 H), 3.75-3.84 (m, 2H), 3.50-3.68 (m, 2H),
3.4-
3.46 (m, 1 H), 3.16-3.25 (m, 1 H), 2.97-3.0 (m, 1 H), 2.09-2.28 (rn, 1 H),
1.62-1.89
{m, 1 H), 1.34-1.39 (m, 1 H), 1.30 (s, 9H), .98,.96 (2s, 9H).
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MS: (M+H)+=590
TBDPSO~
HO N)-, ,OtBu
HH pO
HO
123C (t)-(2R,3R,5R,1'RS)-2-X1,2-dihydroxy)ethy!-3-t-
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3R,5R,1'RS)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-t-
butyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (11 g,
18.7
mmol) was reacted under 1 atmosphere of hydrogen with 20% Pd(OH)2/C (5 g )
and in ethanol (40 mL) vigorously stirred for 2.5 days at room temperature.
The
reaction was filtered, and the catalyst was washed with methanol (3x30 mL).
The
filtrate was evaporated in vacuo to give the title compound as an oil (yield:
8 g,
94%)
TBDPSO-,
HO_ N,., OtBu
H Boc
HO
123D (t)-(2R 3R 5R 1'R)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)eth
butt,rldiphenylsilyloxymethY-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 40D, substituting {t)-(2R,3R,5R,1'RS)-2-(1,2-dihydroxy)ethyl-3-t
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in
place of
(2R,3R,5R,1'RS)-2-(1,2-dihydroxy)ethyl-3-acetoxymethyl-pyrroiidine-5-
carboxylic
acid t butyl ester. The residue was purified by column chromatography on
silica
gel using 35% ethyl acetate/hexane to provide the title compound {yield: 20.5
g,
60%).
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'H NMR {DMSO-ds) 7.57-7.60 (m, 4H), 7.38-7.48 (m, 6H), 4.85,4.77 (2d,
1 H), 4.45-4.50 (m, 1 H), 4.02-4.10 (m, 1 H), 3.80-3.95 (m, 1 H), 3.73,3.68
(2s, 1 H),
3.45-3.67 (m, 2H),3.18-3.28 (m, 2H), 2.36-2.46 (m, 2H), 1:86,1.70 (2d, 1H),
1.40,1.35 (2s, 9H),1.32,1.26 (2s, 9H), 1.0,0.98 (2s, 9H).
MS: (M+H}+= 600
TBDPSO--
Ms0_ N)., OtBu
~ Boc
Ac0
123E (t)~2R 3R 5R 1'R)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-2-
acetoxy)ethyl 3 t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-
Butyl
Ester.
{t)-(2R,3R,5R,1'R)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)ethyl-3-t-
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (20.5
g,
34.2 mmole) was reacted with acetic anhydride (16.1 mL, 171 mmole) and
triethylamine (47.7 mL, 342 mmole) in dichloromethane (360 mL) at 0°C
for 16h.
The reaction was treated with methanol (35 mL) for 10 minutes and diluted
with dichloramethane (1300 mL). The organic layer was washed with water,and
brine, dried over MgS04, filtered and concentrated in vacuo. The residue was
reacted with methanesulfonyl chloride (4.0 mL, 51.3 mmole) and triethylamine
(14.3 mL, 103 mmole) in dichloromethane (350 mL) at 0°C for 1.5 hours.
The
reaction was quenched with water (300 mL) and diluted with dichioromethane
(1200 mL). The organic layer was washed with water,and brine, dried over
MgS04, filtered and concentrated in vacuo. The residue was purified by
chromatography on silica gel using 30% ethyl acetatelhexanes to provide the
title
compound (yield: 23.8 g, 97%).
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'H NMR (DMSO-d6) 87.58-7.62 (m, 4H), 7.38-7.50 {m, 6H), 5.12-5.26 (2m,
1 H), 4.06-4.25 (m, 3H), 4.00 (d, 1 H), 3.46-3.68 (m, 2H), 3.20,3.18 (2s, 3H),
2.40-
2.48 (m, 1 H), 2.02,1.99, (2s, 3H), 1.68-1.88 (m, 1 H), 1.42,1.36 (2s, 9H),
1.31,1.25
(2s, 9H), 1.00,0.98 (2s, 9H).
MS: (M+H)+= 720, (M+NH4)+=737
TBDPSO-
N ~ , ~O~Bu
O H Boc O
123F (~~2R 3R 5R.1'S)-1-t Butoxycarbonyl-2-oxiranyl-3-f-
butyldiphen rLlsilylox my ethyl pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3R,5R,1'S)-1-t Butoxycarbonyl-2-(1-methanesulfonyloxy-2-
acetoxy)ethyl-3-t-butyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-
butyl
ester (23.8 g, 33.1 mmole) was reacted with potassium carbonate (10.1 g,66.2
mmole) in methanol (160 mL) and THF (160 mL) at 25 °C for 18 hours. The
reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate
and washed with water,and brine, dried over MgS04, filtered and concentrated
in
vacuo. The residue was purified by chromatography on silica gel using 25%
ethyl
acetate/hexanes to provide the title compound, as an oil (yield: 16.7 g, 87%).
'H NMR (CDC13) 8 7.60-7.68 (m, 4H), 7.32-7.45 (m, 6H), 4.02-4.28 (m,
2H), 3.67-3.78 (m, 1 H), 3.52-3.62 {m, 1 H), 3.0-3.08 (m, 1 H), 2.68-2.75 (m,
1 H),
2.47-2.52 (m, 3H), 1.80-1.90 (m, 1 H), 1.48,1.42 (2s, 9H), 1.37,1.35 (2s, 9H),
1.07,1.03 (2s, 9H).
MS: (M+H)+= 582
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HO-
N>.,~O~Bu
N Boc O
1236 (t)-(2R,3R.5R,1'S?-1-t Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-
pyrrolidine-5-carbo Ix~Acid t-Butyl Ester.
(t)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-t-
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (4.17
g, 7.2
mmole) was reacted with tetrabutylamrnonium fluoride (1 M) (14 mL, 14.0 mmole)
in THF (7 mL) for 20 minutes at 0°C then for 1.5 hours at 25°C.
The reaction was
concentrated in vacuo the residue was dissolved in ethyl acetate and washed
with pH 7.0 buffer and brine, dried over MgS04, filtered and concentrated in
vacuo. The residue was purified by chromatography on silica gel using 50%
ethyl
acetate/hexanes to provide the title compound, as an oil (yield: 2.4 g, 97%).
' H NMR (DMSO-ds) 8 4.72-4.78 (m, 1 H), 3.94-4.05 (m, 2H), 3.35-3.47 (m,
1 H), 3.18-3.28 (m, 1 H), 3.03-3.08 (m, 1 H), 2.63-2.73 (m, 1 H), 2.37-2.44
(m, 1 H),
2.30-2.36 (m, 1 H), 2.08-2.20 (m, 1 H), 1.58-1.75 (m, 1 H), 1.40 (s, 9H),
1.37,1.34
(2s, 9H).
MS: (M+H)+= 344, (M+Na)+= 366
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H
O~
N'. , ~OtBu
O ~ Boc O
123H (t)-(2R.3R,5R,1'Sl-1-t-Butoxycarbonyl-2-oxiranyl-3-formyl-pyrrolidine-5-
carboxylic Acid t-But)rl Ester.
(t)-(2R,3R, 5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-
pyrrolidine-5-carboxylic acid t-butyl ester (2.4 g, 7.0 mmole) and
triethyiamine
(3.9 mL 28.0 mmole) in dichloromethane (70 mL) at 0°C was reacted with
sulfur
trioxide pyridine complex (3.35 g, 21.0 mmole) in dimethylsulfoxide (21 mL) by
dropwise addition followed by reaction for an additional 3 hours. The reaction
was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The
organic layer was washed with water,and brine, dried over MgSOa, filtered and
concentrated in vacuo to provide the title compound (yield: 2.2 g,).
' H NMR (DMSO-ds) (rotamers) 8 9.58 and 9.56 (2s, 1 H), 4.70 and 4.53
(2m, 1 H), 3.96 (dd, J=1.4, 9.2 Hz, 1 H), 3.25-3.20 {m, 1 H), 2.91 (m, 1 H),
2.71 (m,
1 H), 2.50-2.28 (m, 3H), 1.42, 1.37, 1.34, and 1.30 (4s, 18H)
MS: (M-H)~ = 340
N ). , ~O=Bu
O H Boc O
1231 (t~-(2R.3S.5R,1'S)-1-t-Butoxycarbonyl-2-oxiran I-y 3vinyl-pyrrolidine-5-
carboxylic Acid t-Butyi Ester.
Triphenylphosphoranylidenemethyl ylide (17.6 mmole) prepared by
reacting methyltriphenylphosphonium bromide (12.63 g, 35.4 mmole) and
potassium tert-butoxide (1 M) (17.6 mL, 17.6 mmoie) in THF (70 mL) for 1 hour
at
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25°C. (t)-(2R,3R,5R,1'S)-1-t Butoxycarbonyl-2-oxiranyi-3-formyl-
pyrrolidine-5-
carboxylic acid t-butyl ester (2.2 g, 6.5 mmole) in THF (10 mL) was added to
the
above solution at 0°C and stirred for 0.5 hours. The reaction was
quenched with
saturated ammonium chloride (50 mL) and diluted with ethyl acetate (200 mL).
The organic layer was washed with water,and brine, dried over MgS04, filtered
and concentrated in vacuo. The residue was purified by chromatography on
silica gel using 10% ethyl acetatelhexanes to provide the title compound
(yield: 2
g, 84%).
'H NMR (DMSO-ds) 8 5.80-5.95 (m, 1 H), 5.08 (d, 1 H), 4.94-5.04 (1 H),
4.00-4.07 (m, 1 H), 3.59,3.90 (2t, 1 H), 3.07-3.16 (m, 1 H), 2.73-2.81 (m, 1
H), 2.65-
2.72 (m, 1 H), 2.35-2.48 (m, 1 H), 1.59-1.76 (m, 1 H), 1.42 (s, 9H), 1.38,1.35
(2s,
9H).
MS: (M+H)+ = 340
Ms0 N,-, ~ tBu
H Boc ~
N3
123J (t)-(2R.3S 5R 1'R1-1-t Butoxycarbonyl-2-(1-methanesulfonyloxy-3-
azido eth I-~~rl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R, 3S,5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-vinyl-pyrrolidine-5-
carboxylic acid t-butyl ester (1.72 g, 5.1 mmole) and ammonium chloride (1.36
g,
25.4 mmole) in ethanol (45 mL) and water (5 mL) was reacted with lithium azide
(1.2 g, 24.5 mmoie) for 7 hours at 50°C. The reaction was concentrated
in vacuo
and diluted with ethyl acetate (200 mL). The organic layer was washed with
water,and brine, dried over MgS04, filtered and concentrated in vacuo. The
residue (2.15 g) was dissolved in dichloromethane (50 mL) and reacted with
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methanesulfonyl chloride (0.8 mL, '10.2 mmole) and triethylamine (2.8 mL, 20.4
mmole) for 0.5 hours at 0°C. The reaction was quenched with aqueous
sodium
bicarbonate (50 mL) and diluted with ethyl acetate (200 mL). The organic layer
was washed with water,and brine, dried over MgS04, filtered and concentrated
in
vacuo. The residue was purified by chromatography on silica gel using 10%
ethyl
acetatelhexanes to provide the title compound (yield: 1.87 g, 80%).
'H NMR (DMSO-ds) s 5.77-5.98 (m, 1H), 4.94-5.11 (m, 3H), 4.12-4.19 (m,
1 H), 3.99-4.06 (m, 1 H), 3.66,3.71 (2d, 1 H), 3.25,3.22 (2s, 3H), 2.92-3.02
(m, 1 H),
2.55-2.63 (m, 1 H), 1.68-1.82 (m. 1 H), 1.45,1.42 (2s, 9H), 1.38,1.36 (2s,
9H).
MS: (M+H)+= 461
N,. , ~OtBu
HN~ H goc
123K (t)-(2R,3S.5R.1'S1-1-t Butoxycarbonyl-2-aziridin I-vinyl-p r~lidine-5-
carboxylic Acid t-Bu I Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-methanesulfonyioxy-3-
azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.12 g, 4.6
mmole)
was reacted with triphenylphosphine (1.81 g, 6.9 mmole) in THF (30 mL) and
water (7.5 mL) at 65°C for 1 hour. The reaction was concentrated in
vacuo and
redissolved in ethyl acetate (200 mL). The organic layer was washed with
water,and brine, dried over MgS04, filtered and concentrated in vacuo. The
residue was purified by chromatography on silica gel using 4% methanol in
dichloromethane to provide 2 g of the crude title compound containing
approximately 60% product and 40% Ph3P0 which was used directly for
acylation.
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' H NMR (DMSO-ds) 8 5.78-5.5.98 (m, 1 H), 4.12 (d, 1 H), 3.42,3.19 {2d,
1 H), 2.53-2.73 (m, ZH), 2.00-2.15 {m, 1 H), 1.68-1.76 (m, 1 H), 1.62-1.68 (m,
1 H),
1.41 (s, 9H), 1.37,1.36 (2s, 9H).
MS: (M+H)+ = 339, {M+Na)+ = 361
N>. , ~O~gu
AcN~ H goc 0
123L (t~2R.3S 5R.1'S}-1-t-Butoxycarbonyl-~N-acetylaziridinyl -3-vinyl-
pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-
carboxylic acid t-butyl ester (1.03 g, 3.1 mmole) was reacted with acetic
anhydride (.42 mL, 4.7 mmoie) and triethylamine (1.3 mL, 9.3 mmole) in
dichloromethane (30 mL) at 25°C for 1 hours. The reaction was quenched
with
water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was
washed with water,and brine, dried over MgS04, filtered and concentrated in
vacuo. The residue was purified by chromatography on silica gel using 20%
ethyl
acetate/hexanes to provide the title compound (yield: .75 g, 64%).
' H NMR (DMSO-ds) 8 5.78-5.98 (m, 7 H}, 5.05 (d, 1 H), 4.98,4.94 (2d, 1 H),
4.12-4.20 (m, 1 H), 3.54,3.42 (2dd, 1 H), 2.54-2.98 (m, 3H), 2.40,2.49 (2d, 1
H),
2.15,2.19 (2d, 1 H), 2.02,2.04 (2s, 3H), 1.68-1.82 (m, 1 H), 1.42 (s, 9H),
1.48.1.45
(2s, 9H).
MS: (2M+Na)+= 783
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AcN. N,. O~Bu
H Boc
123M (tl-(2R 3S 5R 1'S)-1-t-Butoxycarbony~1-acetamido)butyl-3-vinyl-
pYrrolidine-5-carboxylic Acid t-Butyl Ester.
To a suspension of copper(I) bromide-dimethyl sulfide complex (0.0518,
0.248 mmol) in THF (1.0 ml) at 0°C was added ethylmagnesium bromide
(1M)
(1.0 ml, 1.0 mmol) in THF. After stirring for 10 minutes at 0 °C, a
portion of this
solution (0.60 ml) was added dropwise to a solution of (t)-(2R,3S,5R,1'S)-1-t
Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl
ester (0.020 g, 0.053 mmole) in THF (0.40 ml) at -78°C. After stirring
for 20
minutes at -78°C, the reaction was warmed to 0 °C and stirred
for 30 minutes.
The reaction was quenched with saturated ammonium chloride {1.0 mL) and
diluted with ethyl acetate (10 mL). The organic layer was washed with water
and
brine, dried over MgS04, filtered and concentrated in vacuo. The residue was
purified by chromatography on silica gel using a gradient of 0-75% ethyl
acetate/hexanes to provide the title compound (yield: 0.004 g, 19%).
' H NMR (DMSO-ds) (rotamers) 8 7.48 (d, J=9.5Hz, 1 H), 5.98-5.80 (m, 1 H),
5.00-4.90 (m, 2H), 4.45-4.25 (m, 1 H), 3.96-3.91 (m, 1 H), 3.60-3.57 and 3.53-
3.50
(2m, 1 H), 2.91-2.76 (m, 1 H), 2.59-2.42 (m, 1 H), 1.80 (s, 3H), 1.73-1.59 (m,
1 H),
1.42 and 1.41 (2s, 9H), 1.40-1.15 (m, 4H), 1.37 and 1.34 (2s, 9H), 0.89-0.82
{m,
3H)
MS: (M-H)-= 409, (M+H)+= 411
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AcHN_ N,.,~OH
H H
O
HCI
123N (t)-~2R.3S,5R,1'Sl-2-f 1-Acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic
Acid Hydrochloric Acid Salt
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-
acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic acid t butyl ester in place
of
(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-
carboxylic acid t-butyl ester (yield: 3.1 mg, 99%).
'H NMR (DMSO-d6) 8 8.11 (d, J=7.3Hz, 1 H), 5.76-5.69 (m, 1 H), 5.16 (d,
J=17.1 Hz, 1 H), 5.07 (dd, J=1.5, 10.3Hz, 1 H), 4.30 (dd, J=7.3, 9.8Hz, 1 H),
4.13
(m, 1 H), 3.50 (dd, J=5.9, 9.8Hz, 1 H), 2.90 (m, 1 H), 2.39 (m, 1 H), 1.92-
1.85 (m,
1 H), 1.87 (s, 3H), 1.52-1.18 (m, 4H), 0.85 (t, J=7.3, 3H)
MS: (M-H)-= 253, (M+H)+= 255
Examples 124-130
1. Organocuprate
Otg~ AcHN_ ).,~OH
AcN~ ' N~ 'j~ 2. 6N HCI H N
H Boc O R H O
HCI
The following title compounds were prepared in two steps according to the
methods described in Examples 123M and 123N, the denoted reagents and their
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respective methods of preparation are substituted in place of diethylcuprate
and
its preparation in Example 123M for step 1.
Example 124
AcHN. N~,~OH
H H
O
t~Ci
(t)-(2R,3S,5R.1'S~-2-(1-Acetamido)hexyl-3-vinyl-pyrrolidine-5-carboxv iii c
Acid
Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 123M, substituting 2M butylrnagnesium chloride
for 1 M ethylmagnesium bromide.
' H NMR (MeOD-ds) 8 5.82-5.70 (m, 1 H), 5.29 (d, J=17.OHz, 1 H), 5.17 (dd,
J=1.3, 10.2Hz, 1 H), 4.35 (dd, J=7.5, 10.2Hz, 1 H), 4.19 (m, 1 H), 3.65 (dd,
J=3.4,
9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s, 3H),
1.62-1.31
(m, 8H), 0.91 (t, J=6.4Hz, 3H)
MS: (M-H)- = 281, {M+H)+ = 283
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Example 125
AcHN. N~.,~OH
H H
O
HCI
(t~~2R.3S,5R.1'S -~-Acetamido-4-meth~pentyl-3-vinyl-pyrrolidine-5-
carboxylic Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 123M, substituting iso-butylmagnesium chloride
for ethylmagnesium bromide..
' H NMR (MeOD-d3) s 5.83-5.71 (m, 1 H), 5.29 (dd, J=0.7,17.OHz, 1 H), 5.17
(dd, J=0.7, 10.2Hz, 1 H), 4.34 (dd, J=7.5, 10.2Hz, 1 H), 4.15 (m, 1 H), 3.66
(dd,
J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s,
3H),
1.65-1.10 (m, 5H), 0.91 (d, J=6.4Hz, 3H), 0.91 (d, J=6.5Hz, 3H)
(M+H)+= 283
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Example 126
AcHN. N~.,~ H
H H
O
HCI
{t)-(2R 3S 5R 1'S)-2-(1-Acetamido-3.3dimethyl~bu I-3-vinyl-pyrrolidine-5-
carboxylic Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 123M, substituting 1 M tert-butylmagnesium
chloride for 1 M ethylmagnesium bromide.
' H NMR (MeOD-d3) 8 5.84-5.71 {m, 1 H), 5.31 (d, J=17.OHz, 1 H), 5.19 (d,
J=10.2Hz, 1 H), 4.39-4.33 (m, 2H), 3.66 (dd, J=3.4, 9.8Hz, 1 H), 3.02 (m, 1
H), 2.57
(m, 1 H), 2.08-1.97 (m, 1 H), 2.02 (s, 3H), 1.55 (dd, J=9.5, 14.6Hz, 1 H),
1.42 (dd,
J=1.4, 14.6Hz, 1 H), 0.95 (s, 9H)
(M+H)+ = 283
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Example 127
~OH
O
AcH N .
~ N
H
HCt
(t)-(2R 3S 5R 1'S~2-(1-Acetamido-2-phen~)ethyl-3-vinyl-pyrrolidine-5-
carboxylic
Acid Hydrochloric Acid Salt
Lithium diphenylcurpate was prepared according to the method described
by Lipshutz, B. H. in Org.,anometallics in Synthesis; Schlosser, M., Ed.;
Wiley and
Sons: New York, 1994; p.292. This cuprate was used according to the methods
described in Example 123M, substituting lithium diphenylcuprate for the
Grignard
derived diethylcuprate complex.
'H NMR (MeOD-d3) 8 7.35-7.21 (m, 5H), 5.87-5.75 (m, 1H), 5.37 (d,
J=16.6Hz, 1 H), 5.26 (dd, J=1.0, 10.2Hz, 1 H), 4.53 (m, 1 H), 4.37 (dd, J=7.5,
9.8Hz, 1 H), 3.70 (dd, J=3.7, 9.8Hz, 1 H), 3.11 (m, 1 H), 2.97 (dd, J=6.1,
14.2Hz,
1 H), 2.84 (dd, J=9.5, 14.2Hz, 1 H), 2.59 (m, 1 H), 2.08-1.99 (m, 1 H), 1.93
(s, 3H)
(M-H)-= 301. (M+H)+ = 303
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Example 128
~OH
O
(t)-(2R.3S.5R,1'S)-2-(1-Acetamido-4-phenyl~butyl-3-vinyl-pyrrolidine-5-
carboxylic
Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 123M, substituting 1 M phenethylmagnesium
chloride for 1 M ethylmagnesium bromide.
~~H NMR (MeOD-d3) s 7.29-7.13 (m, 5H), 5.77-5.65 (m, 1H), 5.24 (d,
J=16.6Hz, 1 H), 5.13 (dd, J=1.0, 9.8Hz, 1 H), 4.33 (dd, J=7.5, 10.2Hz, 1 H),
4.22
(m, 1 H}, 3.62 (dd, J=3.4, 9.8Hz, 1 H), 2.98 (m, 1 H}, 2.63 (m, 2H), 2.54 (m,
1 H),
2.06-1.95 (m, 1 H), 2.03 (s, 3H), 1.79-1.55 (m, 4H)
(M-H)-= 329, (M+H)+= 331
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Example 129
AcHN. N~.,~ H
H H
O
HCI
(t)-(2R 3S 5R 1'S)-2~1-Acetamido-3-phenyl)butyl-3-vinyl-ayrrolidine-5-
carboxylic
Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 123M, substituting 2M benzylmagnesium chloride
for 1 M ethylmagnesium bromide.
'H NMR (MeOD-d~) b 7.30-7.17 {m, 5H), 5.82-5.70 (m, 1H), 5.28 (d,
J=17.OHz, 1 H), 5.17 (d, J=11.2Hz, 1 H), 4.33 (dd, J=7.5, 10.2Hz, 1 H), 4.18
(m,
1 H), 3.64 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.78 (m, 1 H), 2.66-2.50
(m, 2H),
2.07 (s, 3H1, 2.07-1.85 (m, 3H)
(M-H)-= 315, (M+H)+ = 317
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Example 130
{t~2R,3S.5R,1'S)-2-(1-Acetamido-2-propen-2-yl)ethyl -3-vinyl-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
N>.., ~OtBu
BocN~ H Boc p
130A lt)-(2R.3S,5R.1'S)-1-t Butoxycarbonyl-2-(N-t Butoxycarbonylaziridin I~-3-
vinyl-pyrrofidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-
carboxylic acid t-butyl ester (0.058 g, 0.17 mmole) was reacted with di-t-
butyldicarbonate (95 mg, 0.44 mmole) and triethylamine (0.12 mL, 0.86 mmofe)
in
dichloromethane (2.0 mL) at room temperature for 1 hour. The reaction was
quenched with saturated sodium bicarbonate (1.0 mL) and diluted with ethyl
acetate (20 mL). The organic layer was washed with water,and brine, dried over
MgS04, filtered and concentrated in vacuo. The residue was purified by
chromatography on silica gel using a gradient of 0-15% ethyl
acetate/dichloromethane to provide the title compound (yield: 0.060 g, 80%).
'H NMR (DMSO-d6) (rotamers) 8 5.97-5.78 (m, 1H), 5.06-4.93 (m, 2H),
4.15 (dd, J=2.0, 9.8Hz, 1 H), 3.40-3.28 (m, 1 H), 2.94-2.49 {m, 3H), 2.39 and
2.33
(2d, J=6.1, 6.4Hz, 1 H), 2.17 and 2.11 (2d, J=3.7, 3.4, 1 H), 1.81-1.69 (m, 1
H),
1.42-1.36 (m, 27H)
MS: (M+Na)+= 461 (weak)
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BocHN. N>., O~Bu
H Boc
130B (t)-(2R,3S.5R.1'S~1-f-Butoxycarbony~1-N-f-butoxycarbonylamino-2-
propen-2- Iy )ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To a suspension of copper(I) bromide-dimethyl sulfide complex (0.0268,
0.127 mmol) in THF (1.0 ml) at 0 °C was added isopropenylmagnesium
bromide
(0.5M) (1.0 ml, 0.50 mmol) in THF. After stirring for 10 minutes at 0
°C, the
mixture was cooled to -78 °C and a solution of (t)-(2R,3S,5R,1'S)-1-f-
butoxycarbonyl-2-(N-t butoxycarbonylaziridinyi)-3-vinyl-pyrrolidine-5-
carboxylic
acid t-butyl ester (0.030 g, 0.068 mmole) in THF (1.0 ml) was added dropwise.
After stirring for 10 minutes at -78°C, the reaction was warmed to 0
°C and stirred
for 2 hours. The reaction was quenched with saturated ammonium chloride (1.0
mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with
water,and brine, dried over MgS04, filtered and concentrated in vacuo. The
residue was purified by chromatography on silica gel using a gradient of 0-10%
ethyl acetateldichloromethane to provide the title compound (yield: 0.026 g,
79%).
H NMR {DMSO-ds) (rotamers) 8 6.64 (m, 1 H), 5.96-5.76 (m, 1 H), 4.98-
4.89 (m, 2H), 4.76-4.68 (m, 2H), 4.40-4.25 (m, 1 H), 3.94 (m, 1 H), 3.60-3.53
(m,
1 H), 3.02-2.86 (m, 1 H), 2.62-2.42 (m, 1 H), 2.10-1.99 (m, 2H), 1.72 and 1.70
(2s,
3H), 1.72-1.55 (m, 1 H), 1.44-1.34 (m, 27H)
MS: (M-H)-= 479, (M+H)+= 481
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Ac
BocN. N>., O~Bu
H Boc
130C (t)-(2R,3S,5R.1'S)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-
2-propen-2-~ ethyl -3-vinyl-pyrrolidine-5-carboxylic Acid t-Butter.
{t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-
propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.024
g, 0.050
mmole) was reacted with lithium hexamethyldisilazide (1 M) (0.60 mL, 0.60
mmoie) in THF (2.0 mL) at -25°C for 1 hour. To the above reaction was
then
added acetyl chloride (0.085 mL, 1.20 mmole) at -25°C and the mixture
was
stirred for 30 minutes. The reaction was quenched with saturated sodium
bicarbonate (2.0 mL) and stirred for 30 minutes at room temperature. The
reaction was diluted with ethyl acetate (20 mL). The organic layer was washed
with water,and brine, dried over MgSO4, filtered and concentrated in vacuo.
The
residue was purified by chromatography on silica gel using a gradient of 0-15%
ethyl acetate/hexanes to provide the title compound {yield: 0.015 g, 58%)
along
with unreacted starting material.
'H NMR {DMSO-dfi) (rotamers) 8 6.01-5.84 (m, 1H), 4.99-4.89 (m, 2H),
4.76-4.58 (m, 3H), 4.33 and 4.23 (2d, J=7.8, 8.1 Hz, 1 H), 4.13-4.04 (m, 1 H),
2.69
(m, 1 H), 2.62-2.42 (m, 1 H), 2.29 (br s, 3H), 2.35-2.14 (m, 2H), 1.76-1.55
(m, 1 H),
1.60 (s, 3H), 1.50-1.35 (m, 27H)
MS: (M+H)+= 523
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AcHN. N~.,~OH
H H
O
TFA
130D (t)-(2R.3S,5R.1'S)-2-(1-Acetamido-2-propen-2-yl)ethyl -3-vinyl-
pyrrolidine-
5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-{2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-N-t-
butoxycarbonylacetamido-2-propen-2-yl)ethyl -3-vinyl-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester. (yield: 12 mg, 99%).
t H NMR (MeOD-d3) 8 5.83-5.70 (m, 1 H), 5.30 (dd, J=0.7, 17.OHz, 1 H),
5.19 (d, J=10.2Hz, 1 H), 4.79 (s, 1 H), 4.71 (s, 1 H), 4.46 (m, 1 H), 4.30
(dd, J=7.8,
9.8Hz, 1 H), 3.66 (dd, J=3.7, 9.8Hz, 1 H), 3.03 (m, 1 H), 2.56 (m, 1 H), 2.40-
2.19 (m,
2H), 2.08-1.96 (m, 1 H), 2.01 (s, 3H), 1.76 (s, 3H)
(M-H)-= 265, (M+H)+ = 267
Examples 131-135
t. Organocuprate
OtBu AcHN. ,.,~OH
2. I.iHMDS ' ~ N
BocHN~ H goc ~ 3. Acct H H
4. TFAICHzCIy R O
TFA
The following title compounds were prepared in 4 steps according to the
methods described in Example 130 the denoted reagents for step 1 and their
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respective methods of preparation are substituted in place of isopropenyl
cuprate
and its preparation in 1308
Example 131
_-,
AcHN_ N,.,~OH
H H
0
TFA
(t)-(2R 3S 5R 1'S)-2-(1-Acetamido-1-(cis and traps)-propen-1-yl)ethyl-3-vinyl-
p~rrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(/) bromide-dimethyl sulfide complex according to
the
methods described in Example 1308, substituting 0.5M 1-propenylmagnesium
bromide (mixture of cis and traps isomers) for 0.5M isopropenylmagnesium
bromide.
'H NMR (MeOD-d3) (2:1 trans:cis ratio) 8 5.81-5.54 (m, 2H), 5.43-5.30 (m,
1 H), 5.33-5.27 (m, 0.33H, cis isomer), 5.31-5.25 (m, 0.66H, frans isomer),
5.20-
5.15 (m, 1 H), 4.26-4.17 (m, 2H), 3.65 (dd, J=3.4, 9.8Hz, 1 H), 2.98 (m, 1 H),
2.58-
2.48 (m, 1 H), 2.45-2.19 (m, 2H), 2.08-1.94 (m, 1 H), 2.02 (s, 3H), 1.68 (m,
2H,
traps isomer), 1.63 (m, 1 H, cis isomer)
(M-H)-= 265, (M+H)' = 267
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Example 132
AcHN. N~.,~ H
H H
O
TFA
!t)-f2R.3SL5R,1'S~2-~1-Acetamido-2-allyllmeth I-3-vinyl-pyrrolidine-5-carbox~c
Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 1308, substituting 1 M vinylmagnesium bromide
for 0.5M isopropenylmagnesium bromide.
'H NMR (Me~D-ds) 8 5.83-5.70 (m, 2H), 5.28 (d, J=17.OHz, 1 H), 5.19-5.'13
(m, 3H), 4.28 (m, 1 H), 4.19 (dd, J=8.5, 9.1 Hz, 1 H), 3.66 (dd, J=3.4, 9.5Hz,
1 H),
2.99 (m, 1 H), 2.57-2.48 (m, 1 H), 2.44-2.26 (m, 2H), 2.05-1.93 (m, 1 H), 2.01
(s,
3H)
(M+H)+ = 253
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Example 133
AcHN. N~.,~OH
H H
O
TFA
(t~2R,3S,5R,1'S)-2-(1-Acetamido)-2-(1-buten-2-yl)ethyl-3-vinyl-~ rroiidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 1308, substituting 0.5M 1-buten-2-ylmagnesium
bromide for 0.5M isopropenylmagnesium bromide.
'H NMR (MeOD-d3) 8 5.81-5.73 (m, 1 H), 5.30 (d, J=17.1 Hz, 1 H), 5.19 (d,
J=10.OHz, 1 H), 4.93 (s, 1 H), 4.83 (s, 1 H), 4.45 (m, 1 H), 4.31 (dd, J=7.6,
9.8Hz,
1 H), 3.69 (dd, J=3.2, 9.8Hz, 1 H), 3.03 (m, 1 H), 2.59-2.53 (m, 1 H), 2.38
(dd,
J=5.9, 14.9Hz, 1 H), 2.30 (dd, J=9.5, 14.9Hz, 1 H), 2.07 (q, J=7.6Hz, 2H),
2.05-
1.99 (m, 1 H), 2.01 (s, 3H), 1.05 (t, J=7.6Hz, 3H)
(M+H)+= 281
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Example 134
AcHN. >..,~ H
H3C H H
O
CH3 TFA
fit)-(2R.3S.5R 1'S)-2-(1-Acetamido-2-(trans-2-buten-2- rLl)ethyl-3-vinyl-
pyrrolidine-
5-carbolic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 1308, substituting 0.5M 1-methyl-1-
propenylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
'H NMR (MeOD-d3) 8 5.83-5.71 (m, 7 H), 5.41 (q, J=6.8Hz, 1 H), 5.31 (d,
J=17.3Hz, 1 H), 5.19 (d, J=10.2Hz, 1 H), 4.42 (m, 1 H), 4.31 (dd, J=7.5,
9.8Hz, 1 H),
3.61 (dd, J=4.0, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.62-2.52 (m, 1 H), 2.46 (dd,
J=9.5,
13.9Hz, 1 H), 2.26 (dd, J=5.8, 13.9Hz, 1 H), 2.09-1.99 (m, 1 H), 2.00 (s, 3H),
1.72
(s, 3H), 1.59 (d, J=6.8Hz, 3H)
(M+H)+ = 281
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Example 135
AcHN. N~.,~OH
H H
O
TFA
~t~-(2R 3S 5R.1'S.3'RS}-2-f 1-Acetamido-3-methyl)pentyl-3-vinyl-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a
catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to
the
methods described in Example 1308, substituting 2M sec-butylmagnesium
bromide for 0.5M isopropenylmagnesium bromide.
' H NMR (MeOD-d3) (1:1 mixture of methyl isomers) 8 5.82-5.69 (m, 1 H),
5.27 (d, J=17.OHz, 0.5H), 5.25 (d, J=17.OHz, 0.5H), 5.15 (d, J=10.2Hz, 1 H),
4.33
(m, 1 H), 4.18 (dd, J=2.7, 7.5Hz, 0.5H), 4.15 (dd, J=3.0, 7.8Hz, 0.5H), 3.62
(dd,
J=3.1, 9.8Hz, 0.5H), 3.57 (dd, J=4.07, 9.8Hz, 0.5H), 2.97 (m, 1 H), 2.57-2.47
(m,
1 H), 2.03-1.92 (m, 1 H), 2.03 (s, 1.5H), 2.02 (s, 1.5H), 1.72-1.06 (m, 5H),
0.95-
0.86 (m, 6H)
(M+H)+ = 283
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Example 136
(t)-(2R 3S 5R.1'RS)-2-(1-Acetamido-1-{N-methyl-N-benzylcarbamoyl)methyl-3-
vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
AcHN. N~.., OtBu
H Boc
HO O
136A (t)-(2R.3S 5R 1'R)-1-t-Buto~rcarbonyl-2-(1-acetamido-1-carboxyl)methyl-
3-vinyl-pyrrolidine-5-carboxylic Acid t Bu I Ester
The title compound was prepared according to the method of Example 2B
substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-1-
formyl)methyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-
(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-
carboxylic acid t-butyl ester.
AcHN ~. OtBu
N T~
Phi H Boc 'O
N O
CH3
1368 (t)-l2R 3S 5R.1'RS)-1-t-Butox~carbonyl-2-~1-acetamido-2-lN-methyl-N-
benzylcarbamoyl meth-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(t)-(2R, 3S,5R,1'R)-1-t-Butoxycarbonyl-2-( 1-acetamido-1-carboxyl)methyl-
3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (36 mg, 0.09 mrnole) was
reacted with N-methyl-N-benzylamine (32 mg, 0.26 mmole),
dimethylaminopyridine (1mg, 0.008 mmole) and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (30mg, 0.16mmole) in DMF (3 mL) at 25°C
for
16 hours. The reaction was quenched with water (3 mL) and diluted with ethyl
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acetate ( 20mL). The organic layer was washed with water, and brine, dried
over
MgS04, filtered and concentrated in vacuo. The residue was purified by
chromatography on silica gel using 50% ethyl acetatelhexanes to provide the
title
compound.
MS: (M+H)+=516, (M-H)- =514
AcH , ~OH
CH3 ~ O O
TFA
Ph
136C (t)-(2R.3S 5R.1'RS)-2-(1-Acetamido-1-(N-methyl-N-
benzylcarbamoyl)methyl-3-vi ~I-pyrrolidine-5-carboxylic Acid Trifluoroacetic
Acid
Salt
The title compound was prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'RS)-1-t-butoxycarbonyl-2-(1-
acetamido-2-(N-methyl-N-benzylcarbamoy!)methyl-3-vinyl-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-f-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl}-pyrrolidine-5-carboxylic
acid t-
butyl ester (yield: 7 mg, 95%).
' H NMR (DMSO-ds) 8 8.52( d, J=9.7HZ, 1 H), 7.30( m, 5H), 5.65( m, 1 H),
5.12(m, 4H), 4.62(m, 1 H), 4.40(m, 2H), 3.70(m, 1 H), 2.90(s, 3H), 2.20(m,
2H),
1.96(s, 3H),
MS: (M+H)+=360, (M+23)+ =382
N
H N
H
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Example 138
(t)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-(N phenyl-carbonylox)ethyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
AcH , ~OtBu
O O
Ph.N~O
H
138A lt)-(2R 3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-N-phenyl-
carbonyloxy)ethyl-3-vinyl:pyrrolidine-5-carboxylic Acid f Butyl Ester
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-
vinyl-pyrroiidine-5-carboxylic acid t-butyl ester (18 mg, 0.045 mmofe) was
reacted
with phenylisocyanate (16 mg, 0.14 mmole) and pyridine(0.1 ml) in THF (3 mL)
at
25°C for 16 hours. The reaction was quenched with water (2 mL) and
diluted with
ethyl acetate (10 mL). The organic layer was washed with water, and brine,
dried
over MgS04, filtered and concentrated in vacuo. The residue was purified by
chromatography on silica gel using 50% ethyl acetate/hexanes to provide the
title
compound (yield:7.5 rng, 33%).
MS: (M+H)+=518, (M-H)- =516
N.
N
H Boc
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--,
AcHN. N~.,~ H
H H
O O
O"N-Ph rFA
H
138B (t)-(2R,3S.5R,1'R)-2-(1-Acetamido-1-(N-phenylcarbonyloxy)ethyl-3-vinyl
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-N-phenyl-carbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester
(yield: 4 mg, 95%).
'H NMR (DMSO-ds) d 8.36( d, J=9.7HZ, 1 H), 7.30(m, 5H), 5.78(m, 1 H),
5.22(m, 1 H), 5.10(m, 1 H), 4.58(m, 1 H), 4.45(m, 1 H), 4.14(, 2H), 3.58(m, 1
H),
2.88( m, 1 H), 2.27(m, 1 H), 2.12(m, 1 H), 1.88(s, 3H)
MS: (M+H)+=362, (M+23)+ =384, (M-H)- =360, (M+35)- =396
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Example 139
(t)-(2 R, 3S, 5R,1 'R~-~-( 1-Acetamido-1-isobutyr)rloxy)ethyl-3-vinyl-
p~rrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
AcHN. N,., OtBu
~Boc
O
139A ~t)-(2R.3S,5R,1'R~-1-t-Butoxycarbonyl-2-(1-acetamido-2-
isobutyryloxy)eth~rl-3-vinyl-p~rrrolidine-5-carboxylic Acid t-Bu I Ester
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-
vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (15 mg, 0.04 mmole) was
reacted
with isobutyryl chloride (8 mg, 0.08 mmole) and triethylamine (8 mg, 0.08
mmole)
in dichloromethane (4 mL) at 0°C for 2 hours. The reaction was quenched
with
water (3 mL) and diluted with ethyl acetate (20 mL). The organic layer was
washed with water, and brine, dried over MgS04, filtered and concentrated in
vacuo. The residue was purified by chromatography on silica gel using 30%
ethyl
acetatelhexanes to provide the title compound (yield: 11 mg, 63%).
MS: (M+H)+=469, (M-H)- =467
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AcH , ~O H
O O
TFA
O
1398 (t)-(2R,3S.5R,1'R)-2-(1-Acetamido-1-isobutyrYloxY ethyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl
ester
in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
(yield:
6.0 mg, 96%).
'H NMR (DMSO-ds) 8 8.00( d, J=9.9HZ, 1 H), 5.63(m, 1 H), 5.08(m, 1 H),
4.98(m, 1 H), 4.35(m, 1 H), 4.25(m, 1 H), 4.08(m, 1 H), 3.55(m, 1 H), 3.45(m,
1 H),
3.38(m, 1 H), 2.83(m, 1 H), 2.33(m, 1 H), 1.78(s, 3H)
MS: (M+H)+ =243, (M+23)+ =265, (M-H)- =241
N.
H N
H
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Example 140
(t)-(2R,3S.5R.1'R}-2 ~1-Acetamido-2-N-ethyl-thiocarbonYloxy ethyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
-,
AcHN. N>., O~Bu
H Boc
O
N
S~ --~
H
140A (t)-(2R.3S,5R,1'R}-1-t Butoxycarbonyl-2-(1-Acetamido-2-N-ethyl-
thiocarbonyloxy)ethyl-3-vinyl pyrrolidine-5-carbox~ic Acid t-Butyl Ester
(t}-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-
vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (17 mg, 0.04 mmole) was
reacted
with ethylisothiocyanate ( 19 mg, 0.21 mmole) in pyridine (2 mL) at
70°C for 17
hours. The reaction was quenched with water (3 mL) and diluted with ethyl
acetate (20 mL). The organic layer was washed with water, and brine, dried
over
MgS04, filtered and concentrated in vacuo. The residue was purified by
chromatography on silica gel using 70% ethyl acetate/hexanes to provide the
title
compound (yield: 10 mg, 48%).
MS: (M+H)+=486, (M+23)' =508, (M-H)- = 485
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AcH , ~ H
O O
S~N~ TFA
H
140B (t)-12R.3S.5R,1'R)-2-(1-Acetamido-2-N-ethyl-thiocarbon~y)ethyl-3-
vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester
(yield: 7 mg, 94%).
' H NMR {DMSO-ds) 88.30(d, J=9.7HZ, 1 H), 5.78 (m, 1 H), 5.25(m, 1 H),
5.12(m, 1 H), 4.50(m, 1 H),4.33(m, 1 H), 4.18(m, 2H), 3.72(m, 1 H), 3.55(m,
2H),
2.30(m, 1 H), 2.10(m, 1 H), 1.82(s, 3H), 1.17(m, 3H)
MS: (M+H)+ =330, (M-H)- =328
N.
H N
H
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Example 141
~t~2R,3S.5R,1'S -2-) (1-Acetamido-2-amino)ethyl-3-vinyi-pyrrolidine-5-
carboxylic
Acid HydrochlorideSalt
-,
AcHN_ N~, O~Bu
H Boc
BocHN
141A (t)-(2R,3S.5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-t-
butoxycarbonylamino ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-azido)ethyl-3-vinyl-
pyrrolidine-5-carboxylic acid t-butyl ester (9.5 mg, 0.022 mmole} was reacted
with
triphenylphosphine (23.5 mg, 0.090 mmole) in ethanol (180 ~L) and water (45
~.L)
at 70°C for 30 minutes. The reaction mixture was concentrated in vacuo.
The
residue was dissolved in dichloromethane (220 pL) and to it was added di-tert
butyl Bicarbonate (7.3 mg, 0.034 mmol) and N,N-diisopropylethylamine (11.7 mL,
0.067 mmol) at 25°C. After 1 hour the reaction mixture was diluted with
water
and extracted with ethyl acetate. The organic layers were combined, washed
with brine, dried over MgS04, and concentrated in vacuo. The residue was
purified by chromatography on silica gel using 100% dichloromethane to 50%
dichloromethane/ethyl acetate to provide the title compound (yield: 7.5 mg,
67%).
' H NMR (DMSO-ds) (rotamers) 8 7.51 (d, J=10.5Hz, 1 H), 6.80-6.66(m, 1 H),
5.90-5.76(m, 1 H), 5.02-4.90(m, 2H), 4.38-4.19(m, 1 H), 3.98-3.94(m, 1 H),
3.68-
3.62(m, 1 H), 3.09-2.73(m, 2H), 2.60-2.42(m, 1 H), 1.80(s, 3H), 1.72-1.62(m, 1
H),
1.42-1.34(m, 27H).
MS: (M+H)+=498, (M+Na)+=520, (M-H)-=496, (M+CI)--532
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AcH , ~ H
H2N 2 Hci
141 B ~t)-(2R.3S.5R.1'S,)-2-(1-Acetamido-2-amino ethyl-3-vinyl-pyrrolidine-5-
carboxylic Acid DiHydrochloride
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-
2-f-butoxycarbonylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl
ester in
place of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyi-
pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.65 mg, 99%).
~H NMR (DMSO-ds) 8 8.24(d, J=7.9Hz, 1 H), 5.75-5.68(m, 1 H), 5.16(d,
J=17.1 Hz, 1 H), 5.06{d, J=10.4Hz, 1 H), 4.37-4.27(m, 2H), 3.60-3.16(m, 2H),
3.00-
2.88(m, 2H), 2.46-2.36(m, 1 H), 1.91-1.81 (m, 1 H), 1.86(s, 3H).
MS: (M+H)+=242, (M+Na)+=264, (M-H)-=240, (2M-H)-=481
N_
H N
H
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Example 142
jt)-(2R, 3S.5R,1 'Sl-2-~1-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5-
carboxylic Acid H~rdrochloride
AcHN. N)., O~Bu
H Boc
AcH N
142A (~~2R.3S.5R,1'S)-1-t Butoxycarbony!-2-(1-acetamido-2-acetamido)ethyl_
3-vin~pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-( 1-acetamido-2-amino)ethyl-3-
vinyl-pyrrolidine-5-carboxylic acid t butyl ester (9.4 mg, 0.024 mmole) was
reacted with acetic anhydride (11.2 uL) and triethylamine (33.1 ~L) in
dichloromethane (0.23 mL) at 0°C for 1 hour. The reaction was diluted
with
water (3 mL), extracted with ethyl acetate (12 mL), washed with brine, dried
over
MgS04, and concentrated in vacuo. The residue was purified by chromatography
on silica gel using 100% ethyl acetate to 90% ethyl acetatelmethanol to
provide
the title compound (yield: 6.8mg, 66%).
' H NMR (DMSO-ds) {rotamers) b 7.79-7.74(m, 1 H), 7.54(d, J=9.8Hz, 1 H),
5.97-5.81 (m, 1 H), 5.01-4.91 (m, 2H), 4.36-4.27(m, 1 H), 3.97-3.90(m, 1 H),
3.68-
3.63(m, 1 H), 3.21-3.15(m, 1 H), 3.10-2.76(m, 1 H), 2.88-2.78(m, 1 H), 2.58-
2.45(m,
1 H), 1.81 (s, 3H), 1.78(s, 3H), 1.76-1.64{m, 1 H), 1.42-1.36(m, 18H).
MS: (M+H)+=439, (M+Na)+=462, (M-H)-=438, (M+35)-=474
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AcHN , ~OH
AcHN O
HC!
142B (t)-(2R.3S,5811'S)-2-(1-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5-
carbox~fic Acid Hydrochloride
The title compound was prepared according to the method described in
Example 1 K, substituting (t)-(2R,3S,5R,1'S)-2-(1,2-di-acetamido)butyl-3-vinyl-
pyrrolidine-5-carboxylic acid Hydrochloridesalt in place of (t)(2R,3R,5R,1'S)-
2-(1-
acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t butyl
ester (yield: 3.30 mg, 80%).
MS: (M+H)+=284, (M-H)-=282, (M+CI)-=318
H N
H
Example 143
(t)-(2R.3S,5R,1'S)-2-(1-Acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-
carboxylic
Acid Hydrochloride
T
AcHN, N)., O~Bu
H Boc
N3
143A (t)-(2R.3S,5Ry1'S)-1-t-Butoxv cap rbonyl-2-(1-N-acetamido-2-azido)eth
vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S}-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-
pyrrolidine-5-
carboxylic acid t-butyl ester (21.6 mg, 0.064 mmole) was reacted with sodium
azide (41.6 mg, 0.64 mmole) and ammoniun chloride (34.2 mg, 0.64 mmol) in
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ethanol (270 ~L) and water (30 ~L) at 75°C for 1 hour. The ethanol was
then
removed in vacuo and the remaining aqueous was extracted with ethyl acetate.
The combined organics were washed with brine, dried over MgS04, and
concentrated in vaccro (crude yield: 20mg, 82%). To the crude mixture was
added acetic anhydride (31 ~L, 0.33 mmol) and triethylamine (92 uL, 0.66 mmol)
in dichloromethane (330 ~L) at 0°C for 30 minutes. The reaction mixture
was
then concentrated in vacuo. The residue was purified by chromatography on
silica gel using 100% dichloromethane to 50% dichloromethanelethyl acetate to
provide the title compound (yield: 10 mg, 60%).
'H NMR (DMSO-ds)(rotamers) 8 7.85 and 7.81 (d, J=9.5Hz and 9.8Hz,
1 H), 5.94-5.80(m, 1 H), 5.04-4.93(m, 2H), 4.58-4.38(m, 1 H), 4.04-3.96(m, 1
H),
3.72-3.66(m, 1 H), 3.41-3.21 (m, 2H), 3.09-2.79(m, 1 H), 2.59-2.46(m, 1 H),
1.84-
1.82(m, 3H), 1.79-1.53(m, 1 H), 1.43-1.35(m, 18H).
MS: (M+H)+=424, (M+Na)+=446, (2M+Na)+=869, (M-H)-=422, (M+CI)-=458
AcHN. N~,~OH
H H
N3 O
HCI
143B (t)-(2R.3S,5811'S)-2-(1-Acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-
carboxLrlic Acid Hydrochloric Salt.
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-
2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of
(t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-
carboxylic acid t-butyl ester (yield: 2.94 mg, 93%).
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' H NMR (DMSO-ds) 8 8.24(d, J=8.55Hz, 1 H), 5.74-5.67(m, 1 H), 5.14(d,
J=17.1 Hz, 1 H), 5.06(d, J=10.4Hz, 1 H), 4.41-4.35(m, 2H), 3.57-3.36(m, 3H),
2.93-
2.90(m" 1 H), 2.44-2.38(m, 1 H}, 1.96-1.84(m, 1 H), 1.84(s, 3H).
MS: (M+H)+=268, (M-H)-=266, (M+CI)-=302
Exa J~le 144
(2R.3S,5R,1'S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-
carboxyiic Acid Dihydrochloride
AcHN_ N~., OtBu
H Boc
HN
CH3
144A (t~(2R.3S.5R.1'S)-1-t-Butoxycarbony~1-N-acetamido-2-N-
meth IaminoLethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
Methylamine (.016 g, .53 mmole) was reacted with N,O-bis-
trimethylsilylacetamide (.079 g, .39 mmole) in DMSO (0.8 mL) at 0°C for
1 hour.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-
pyrrolidine-5-
carboxylic acid t-butyl ester (.040 g, .11 mmole) was then reacted with the
above
reagent N-trimethylsilylmethylamine at 75°C for 18 hours. The reaction
was
diluted with ethyl acetate (7 mL) washed with water and brine, dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue was
purified
by chromatography on silica gel using chloroform-methanol-ammonia to provide
the title compound (yield: .011 g, 25%).
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'H NMR (CDC13) b 5.78-5.98 (m,lH), 5.90-5.04 (2m, 2H), 4.40-4.55 (brm,
1 H), 3.90-4.02 {m, 1 H), 3.64-3.75 (2m, 1 H}, 2.25-2.40 (brm 3H), 2.83,2.85
(2d,
3H), 1.42,1.44 {2s, 9H), 1.34,1.37 (2s, 9H).
MS: (M+H)+= 412
AcHN ,~OH
HN O
2 HCI
CH3
1448 (t)-(~2R,3S.5R.1'S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vin~rl-
pyrrolidine-5-carboxylic Acid Dih rLdrochforide Salt
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-
2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in
place
of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-
5-carboxylic acid t butyl ester (yield: 7.2 mg, 99%).
H NMR (DMSO-ds) 8 8.25 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.50
(m,1 H), 4.40 (m,1 H), 2.55 (s, 3H), 1.85 (s, 3H).
MS: (M+H)+= 256
~ N
H
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Examples 145-164
t. RR'NH
OtBu 2. 6N HCI AcHN. ,.~ OH
~Ni_.~
AcN~ H goc ~ R'RN H H
O
2 HCI
The following title compounds were prepared according to the methods
described in Examples 141-144 where R' is equal to hydrogen. Where R or R'
are not equal to hydrogen the corresponding amine is used directly without the
intermediacy of trimethylsilylation.
Example 145
AcHN. N~..,~OH
H H
~'N O
/ H 2 HCt
,fit)-(2Ry3S.5R 1'S)-2-(1-Acetamido-2-N-isopropylaminolethLrl-3-vinyl-
pyrrolidine-
5-carboxylic Acid Dihydrochloride Salt
' H NMR (DMSO-d6) 8 8.30 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.40 (br,
2H), 3.52-3.68 (br, 1 H), 3.10-3.20 (br, 1 H), 2.82-2.97 (br, 1 H), 2.37-2.47
(br, 1 H),
1.88 (s, 3H), 1.25 (d, 6H).
MS: (M+H)+= 284
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Example 146
AcHN , ~OH
NN O
2HC1
(t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-butylamino)ethyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
' H NMR (DMSO-ds) 8 8.25 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H),4.50 (m,
1 H), 4.38 (m, 1 H), 3.60 (m, 1 H), 2.90 (m, 3H), 2.40 (m, 2H), 1.87 (s, 3H),
1.62 (m,
2H), 1.33 (m, 2H), 0.90 (t, 3H).
MS: (M+H)+= 298
AcH , ~OH
HN O
2HC1
Ph
(t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-benzylamino)ethyl-3-vinyl-pyrrolidine-5-
carbox\~lic Acid HydrochlorideSalt
'H NMR (DMSO-ds) b 7.56-7.43(m, 5H), 5.74-5.67(m, 1H), 5.15-4.99(m,
2H), 4.56(m, 1 H), 4.27-3.93(m, 3H), 3.66-3.15(m, 3H), 2.91-2.88(m, 1 H), 2.64-
2.34(m, 2H), 1.86(s, 3H).
MS: (M+H)+=332, (M+Na)+=354, (M-H)-=330, (2M-H)-=661
~ N
H
Example 147
-,
N.
H N
H
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Example 148
AcHN. N~.,~OH
H H O
HN
Ph~ 2HC~
(t)-~2R,3S.5R.1'S?-~1-Acetamido-2-N-phenethylamino)ethyl-3-vinyl-pyrrolidine-
5-carboxylic Acid Dihydrochloride Salt
H NMR (DMSO-ds) 8 8.25 (d, 1 H), 7.30 (m, 5H), 5.70 (m, 1 H), 5.10 (m,
2H), 4.50 (br, 1 H), 4.35 (br, 1 H), 3.61 (m, 1 H), 3.17 (m, 3H), 2.98 (m,
3H), 2.42
(m, 1 H), 1.88 (s, 3H).
MS: (M+H)+= 346
AcH , ~OH
-N O
I 2HCi
-(2R,3S.5R.1'S~-2-(1-Acetamido-2-N.N-dimethylamino)ethyl-3-vinyl-pyrrolidine-
5-carboxylic Acid Dihydrochloride Salt
' H NMR (DMSO-d6) 8 8.34(d, J=9.2Hz, 1 H), 5.74-5.67{m, 1 H), 5.12(d,
J=17.1 Hz, 1 H), 5.04(d, J=10.4Hz, 1 H), 4.67-4.62(m, 1 H), 4.40(dd, J=7.3,
10.4Hz,
1 H), 3.60-3.11 (m, 3H), 2.96-2.83(m, 1 H), 2.50(s, 6H), 2.44-2.38(m, 1 H),
1.92-
1.84(m, 1 H), 1.84(s, 3H).
Example 149
N.
~ N
H
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MS: (M+H)+=270, (M+Na)+=292, (M-H)-=268.
Example 150
AcHN , ~ H
~N O
2HC1
(t)-(2R.3S.,5R,1'S)-2-(1-Acetamido-2-N,N-diethylamino)ethyl-3-vinyl-
pyrrolidine-
5-carbolic Acid Di~drochloride Salt
'H NMR (DMSO-ds) 8 8.23 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.60 (br,
1 H), 4.40 (br, 1 H), 3.12 (m, 4H), 2.88 (m, 1 H), 2.42 (rn, 1 H), 1.85 (s,
3H), 1.22 (t,
3H).
MS: (M+H)+= 298
N
H H
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Example 151
AcHN. N~.,~ H
H H
~N O
2HC1
(t)-(2R, 3S, 5R.1'S)-2-( 1-Acetamido-2-N, N-dibutylamino)ethyl-3-vinyl-
pyrrolid ine-
5-carboxylic Acid Dihydrochloride Salt
' H NMR (DMSO-ds) 8 8.24 (d, 1 H), 5.70 (m, 1 H), 5.08 (m, 2H), 4.48-4.62
(br, 1 H}, 4.28-4.43 (1 H), 3.05 (m, 4H), 2.77-2.92 (br, 1 H), 2.34-2.46 (br,
2H),
1.84 (s, 3H), 7.64 (m, 4H), 1.30 (m, 4H), 0.93 (t, 6H).
MS: (M+H)+= 354
Example 152
AcHN. N~.,~OH
H H
HN O
~OH zHCI
~2R,3S.5R,1'S',i-2~1-Acetamido-2-~N-2-h~yethylamino )ethyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Dih~drochloride Salt
' H NMR (DMSO-ds) 8 8.20 (d, 1 H), 5.70 (m, 1 H), 5.15 (d, 1 H), 5.08 (d,
1 H), 4.50 (brm, 1 H), 4.38 (brm, 1 H), 3.68 (M, 1 H), 3.0 (brm, 2H), 2.90 (m,
1 H),
2.41 (m, 1 H), 1.85 (s, 3H).
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MS: (M+H)+= 286
AcH H
, ~
~N O
~OH
2HCi
(t)-(2R.3S, 5R.1'S)-2-( 1-Acetamido-2-(N-2-hydroxyethyl-N-ethylamino))ethyl-3-
vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
'H NMR (DMSO-dfi) s 5.81-5.74(m, 1 H), 5.38(d, J=17.1 Hz, 1 H), 5.22(d,
J=1 O.OHz, 1 H), 4.92-4.88(m, 1 H), 4.48(dd, J=7.6, 9.8Hz, 1 H), 3.91 (t,
J=4.9Hz,
2H), 3.85(dd, J=5.6, 1 O.OHz, 1 H), 3.63-3.53(m, 2H), 3.46-3.39(m, 4H), 3.16-
3.13(m, 1 H), 2.66-2.61 (m, 1 H), 2.08(s, 3H), 2.06-2.01 (m, 1 H), 1.38(t,
J=7.33,
3H).
MS: (M+H)+=314, (M+Na)+=336, (M-H)-=312, (M+CI)-=348, (2M-H)-=625
Example 153
N.
H N
H
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Example 154
AcHN. N~.,~OH
H H
~N O
~OH 2tiC~
(t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-2-h dY roxyethyl-N-propylamino))eth
vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
' H NMR (DMSO-d6) s 8.36(d, J=8.5Hz, 1 H), 5.75-5.68(m, 1 H), 5.13(d,
J=17.1 Hz, 1 H), 5.04{d, J=10.4Hz, 1 H), 4.62(m, 1 H), 4.36(m, 1 H), 3.77(t,
J=4.9Hz,
2H), 3.63-3.59(m, 1 H), 3.50-3.23(m, 3H), 3.22-3.19(m, 2H), 3.08(t, J=7.3Hz,
2H),
2.91-2.87(m, 1 H), 2.44-2.39(m, 1 H), 1.99-1.88(m, 1 H), 1.84(s, 3H), 1.75-
1.70(m,
2H), 0.90(t, J=6.7Hz, 3H).
MS: (M+H)+=328, (M+Na)+=350, (M-H)-=326, (M+CI)~=362, (2M-H)'=653
Example 155
AcHN. OH
~N O
N ~ 2HC~
(t)-~2R,3S,5R,1'S)-2-(1-Acetamido-2-(imidazol-1-vl))ethyl-3-vinyl-pyrrolidine-
5-
carboxylic Acid DiHydrochloride
' H NMR (MeOD-d3) 5.9.06(s, 1 H), 7.72(s, 1 H), 7.58(s, 1 H), 5.84-5.76(m,
1 H), 5.39(d, J=17.1 Hz, 1 H), 5.23{d, J=10.25Hz, 1 H), 4.70-4.66(m, 1 H),
4.52-
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4.43(m, 2H), 3.92-3.89(m, 1 H), 3.20-3.17(m, 1 H), 2.67-2.62(m, 1 H), 2.11-
2.04(m,
1 H), 1.95-1.89(m, 1 H), 1.91 (s, 3H).
MS: (M+H)+=293, (M-H)-=291, (M+35)+=327.
Example 156
AcHN. N~.,~ H
H H
~- N O
HO~ 2HCi
~OH
fit)-~2R, 3S.5R.1'S)-2-~1-Acetamido-2-(N, N-di-{2-hydrox~ylamino))ethyl-3-vine
pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
MS: (M+H)+=330, (M+Na)+=352, (M-H)-=328, (M+CI)-=364
Example 157
AcHN ,~ H
AcN O
I Hci
(tL{2R,3S,5R.1'S~~1-Acetarnid~N-acet~N-methylamino)eth I-3-vi~f-
pyrrolidine-5-carboxylic Acid Hydrochloride Sait
' H NMR {DMSO-ds) 8 8.01,7.95 (2d, 1 H), 5.68-5.80 (m,1 H), 5.02-5.22 (m,
2H), 4.30-4.45 (brm, 2H), 3.26,3.21 (2d, 1 H), 2.82-2.95 (brm, 1 H), 2.38-2.48
(m,
1 H), 1.98,2.02 (2s, 3H),1.79,1.82 (2s, 3H).
MS: (M+H)+= 298
N
H H
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Example 158
AcH , ~OH
CH3N O
~OH 2HCi
fit)-(2R.3S 5R,1'S)-2- 1-Acetamido-2-{N-2-hydroxyethyl-N-methylamino))ethyl-3-
yinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
'H NMR (DMSO-ds) 8 8.35(d, J=9.15Hz, 1 H), 5.74-5.67(m, 1 H), 5.12(d,
J=17.1 Hz, 1 H), 5.04(d, J=10.4Hz, 1 H), 4.70(m, 1 H), 4.39(dd, J=7.3, 10.4Hz,
1 H),
3.80-3.75(m, 3H), 3.61-3.43(m, 3H), 3.23-3.16(m, 2H), 2.91-2.82(m, 1 H),
2.82(s,
3H), 2.44-2.39(m, 1 H), 1.92-1.84{m, 1 H), 1.84(s, 3H).
MS: (M+H)+=300, (M+Na)+=322, (2M+H-HZO)+=581
Example 159
AcH , ~ H
CH3 ~ O
2iiCt
(t)-(2R,3S.5R.1'S~2-(1-Acetamido-2-(N-~propyl-N-methylamino eth I-~yl-
pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
'H NMR (DMSO-dfi) (broad) 8 8.3(1 H), 5.7(1 H), 5.12-5.04(2H), 4.6(1 H),
4.35(1 H), 2.61-2.35(11 H), 1.9(3H), 1.78-7 .63(2H), 1.9(3H).
MS: (M+H)+=298, (M+Na)+=320, (M-H)-=296, (M+Cl)'332, (2M-H)-=593
N_
H N
H
N _ ,.
H N
H
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Example 160
AcH , ~OH
CH3N O
2HCI
(t)-(2R,3S.5R,1'S)-2-(1-Acetamido-2-(N-c clue ohexyl-N-methylamino))ethyl-3-
vinyl-
pyrrolidine-5-carboxylic Acid Hydrochloride Salt
' H NMR (DMSO-dfi) b 8.26(m, 1 H), 5.75-5.65(m, 1 H), 5.08(d, J=17.1 Hz,
1 H), 5.02(d, J=10.3Hz, 1 H), 4.62(m, 1 H), 4.43-4.40(m, 1 H), 3.62-3.58(m, 1
H),
3.46-3.16(m, 2H), 2.89-2.84(m, 1 H), 2.72(s, 3H), 2.44-2.39(m, 1 H), 2.07-
1.80(m,
5H), 1.81 (s, 3H), 1.63(m, 1 H), 1.45-1.06(m, 6H).
MS: (M+H)+=338, (M+Na)+=360, (M-H)~=336, (M+CI)-=372
Example 161
AcH ~ ~ H
CH3N O
2HCI
~Ph
(~2R,3S,5R.1'S)-2-(1-Acetamido-2-(N-benzyl-N-meth~amino )eth I-3-vinyl-
pyrroiidine-5-carboxylic Acid Dih~chloride Salt
' H NMR (DMSO-ds) 8 8.36(m, 1 H), 7.61-7.46(m, 5H), 5.69-5.64(m, 1 H),
5.07(d, J=17.1 Hz, 1 H), 4.99(d, J=10.1 Hz, 1 H), 4.77(m, 1 H), 4.44-4.39(m,
2H),
N.
H N
H
N.
H N
H
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4.25(d, J=12.9, 1 H), 3.61 (m, 1 H), 3.43(m, 1 H), 3.22(m, 1 H), 2.93-2.85(m,
1 H),
2.73(s, 3H), 2.44-2.38(m, 1 H), 1.92-1.85(m, 1 H), 1.85(s, 3H).
MS: (M+H)+=346
AcH N
CH3N
2HCi
(t~-(2R.3S.5R.1'S~~-Acetamido-2-(N-phenethyl-N-methylamino))ethyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
'H NMR (DMSO-ds) 8 8.34(d, J=8.55Hz, 1H), 7.37-7.26(m, 5H), 5.76-
5.69(m, 1 H), 5.14(d, J=17.1 Hz, 1 H), 5_06(d, J=10.4Hz, 1 H), 4.72(m, 1 H),
4.46-
4.42(m, 1 H), 3.83-3.20(m, 6H), 3.13-2.99(m, 2H), 2.86(s, 3H), 2.95-2.83(m, 1
H),
2.46-2.40(m, 1 H), 1.95-1.81 (m, 1 H), 1.86(s, 3H).
MS: (M+H)+=360
Example 162
-,
H N
H
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Example 163
AcHN. N~.,~OH
H H
CH3N O 2HCi
(t)-(2R,3S.5R.1'S)-2-(1-Acetamido-2-(N-naphth IY methyl-N-methylamino))eth
vinyl pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
'H NMR (DMSO-ds) b 8.41(d, J=7.3Hz, 1H), 8.32-7.59(m, 7H), 5.60{m,
1 H), 5.04(d, J=17.1 Hz, 1 H), 4.91 (d, J=9.8Hz, 1 H), 4.97-4.73(m, 3H),
4.39(m, 1 H),
3.70-3.13(m, 3H), 2.90(m, 1 H), 2.72(s, 3H), 2.43-2.41 (m, 1 H), 2.01-1.74(m,
1 H),
1.87(s, 3H).
MS: (M+H)+=395, (M+Na)+=418, (M-H)-=394, (M+CI)-=430, (2M-H)-=789
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Example 764
,~OH
O
OJ 2HG1
AcH N
H N
H
N
(t)'(2R.3S,5R,1'S)-2~1-Acetamido-2-(N-morpholinyl~~eth I-3-vinyl-tayrrolidine-
5-
carboxylic Acid Dihydrochloride Salt
H NMR (DMSO-ds) 8 8.28 (d, 1 H), 5.75-5.78 (m, 1 H), 5.15 (d,1 H), 5.05 (d,
1 H), 4.65 (brm, 1 H), 4.42 (m, 1 H), 3.72-3.98 (brm, 3H), 3.62 (m, 1 H), 2.90
(m,
1 H), 2.38-2.48 (m, 1 H), 1.85 (s, 3H).
MS: (M+H)+= 312
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Example 165
(t)-(2R.3S,5R.1'S.3'R~-2-(1-Acetamido-2-(N-methyl-N-t butylamino-N-
oxide))eth~l-3-vinyl pyrrolidine-5-carbox,~lic Acid H~rdrochloride Salt
AcHN_ ,., OtB~ AcHN_
~ H Boc ~ ~ H Boc'
'N N
O ..CH3 O: .CHs
165A lt)-(2R.3S.5R,1'S,3'R~ and (t)-(2R,3S,5RL1'S,3'S)-1-t-Butoxycarbonyl-2-
(1-acetamido-2-(N-methyl-N-t-butylamino-N-oxide),leth r~yrrolidine-5-
carboxylic
Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-t-
butylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (37 mg,
.08
mmole) was reacted with the m-chloroperoxybenzoic acid (20 mg, .08 mmole) in
CH2C12 (0.9 mL) at 0°C for 1 hour. The reaction was chromatographed
directly
on silica gel eluting with a gradient of acetone to acetone/30% MeOH to
provide
the title compounds isomer (t)-(2R,3S,5R,1'S,3'R) {yield: .010 g, 27%) and
isomer {t)-(2R,3S,5R,1'S,3'S) (yield: .011 g, 29%).
,~OH
O
wCH3 Hci
1658 ~)-(2R.3S,5R,1'S,3'R,~-2-~1-Acetamido-2-lN-methyl-N-t-butylamino-N-
oxide))ethyl-3-vinyl pyrrolidine-5-carboxylic Acid Hydrochloride Salt
The title compound was prepared according to the method described in
Example 15C substituting (t)-(2R,3S,5R,1'S,3'R)-1-t-butoxycarbonyl-2-(1-
-,
AcHN
H N
H
N
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acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-pyrrolidine-5-carboxylic
acid t-butyl ester for (t)-(2R,3S,5R,1'S)-2-(1-acetarnido-3-ethyl)pentyl-3-
(imidazol-2-yl)-pyrroiidine-5-carboxylic acid t-butyl ester (yield: 6 mg,
80%).
' H NMR (CD30D) 8 5.72-5.87 (m, 1 H), 5.40 (d, 1 H), 5.20-5.28 (m, 2H),
4.44-4.53 (dd, 1 H), 3.73-3.95 (m, 3H), 3.57 (s, 3H), 3.08-3.19 {m, 1 H), 2.59-
2.72
(m, 1 H), 2.05-2.15 (m, 1 H), 2.04 (s, 3H), 1.54 (s, 9H).
MS: (M+H)+= 328
Exam~ies 166-178
1. MCPBA
2. chromatographic
ACHN_ ). OH separation AcHN_ ,_, OH
3. 6 N HCI O H H
R'RN ~ R'RN
HCi
The following title compounds were prepared according to the method
described in Example 165.
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Example 166
--,
AcHN. N~.,~OH
H H
O
O.N.CH HCi
3
(t)-(2R.3S,5R 1'S.3'R)-2-(1-Acetamido-2-(N-methyl-N-isopropylamino-N-
oxide))ethyl-3-vin~pyrroiidine-5-carboxylic Acid Hydrochloride Salt
1 H NMR (MeOD-dg) 8 5.87-5.74 (m, 1 H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m,
1 H), 5.21-5.18 (m, 1 H), 4.50 (dd, J=8.1, 9.8Hz, 1 H), 4.04-3.87 (m, 4H),
3.54 (s,
3H), 3.20-3.14 (m, 1 H), 2.69-2.60 (m, 1 H), 2.12-2.01 (m, 1 H), 2.05 (s, 3H),
1.50
(d, J=6.4Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+Na)+=336, (2M+1 )+= 627, (2M+Na)+=649.
Example 167
AcHN_ N~.,~ H
H H
O
N~-CH3 Hci
O
(t)-(2R.3S, 5R.1 'S, 3'S~-~ 1-Acetamido-2-(N-methyl-N-propylamino-N-oxideethyl-
3-vinyl-pyrroiidine-5-carboxyiic Acid HydrochlorideSalt
~ H NMR (MeOD-d3) 8 5.87-5.74 (m, 1 H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m,
1 H), 5.21-5.18 (m, 1 H), 4.50 (dd, J=8.1, 9.8Hz, 1 H), 4.04-3.87 (m, 4H),
3.54 (s,
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3H), 3.20-3.14 (m, 1 H), 2.69-2.60 (m, 1 H), 2.12-2.01 (m, 1 H), 2.05 (s, 3H),
1.50
(d, J=6.4Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+H-H20)-=295
AcH , ~OM
O
N
O ..CHs
{tLf2R.3S.5R.1'S.3'S -Z 2-(1-Acetamido-2-(N-meth-N-ethylamino-N-oxide) ethyl-
3-vinyl-pyrrolidine-5-carboxylic Acid HydrochlorideSalt
1 H NMR (MeOD-d3) 8 5.82-5.75 (m, 1 H), 5.44{d, J=17.1 Hz, 1 H), 5.26(d,
J=10.4Hz, 1 H), 5.14-5.11 (m, 1 H), 4.48-4.45(m, 1 H), 4.9(d, J=4.9Hz, 2H),
3.87(dd, J=4.9, 10.4Hz, 1 H), 3.76(q, J=6.7Hz, 2H), 3.54(s, 3H), 3.17-3.09(m,
1 H),
2.68-2.62 (m, 1 H), 2.06(s, 3H), 2.09-2.03 (m, 1 H), 1.45(t, J=7.3Hz, 3H).
MS: (M+H)+=300, (M+Na)+=322, (M+H-H20)+=282
Example 168
N.
H -N
H
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Example 169
AcHN. N~,~OH
H H
O
O'N~ CHg HCI
jt~-~2R 3S 5R.1'S)-2-~1-Acetamido-2-(N,N-dimethylamino-N-oxide)ethyl-3-vinyl-
pyrrolidine-5-carboxylic Acid Hydrochloride Salt
' H NMR (DMSO-ds) 8 8.58 (d, 1 H), 5.67-5.78 (m, 1 H), 5.20 (d, 1 H), 5.08
(d, 1 H), 4.62-4.78 (brm, 1 H), 4.25-4.42 (brm, 1 H), 4.06 (d, 1 H), 3.85-3.95
(brm,
1 H), 3.88-3.98 (brm, 1 H), 3.35-3.50 (brs, 6H), 2.36-2.48 (m, 1 H), 1.92 (m,
1 H),
1.85 (s, 3H).
MS: (M+H)+= 286
Example 170
AcHN. N~.,~ H
H H
O
Ph~N HCi
p ~CH3
(t)-(2R.3SL5R,1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N-
oxidelyethyl-3-vinyl-pyrrolidine-5-carboxylic Acid HydrochlorideSalt
' H NMR (MeOD-d3) 8 7.60-7.47(m, 5H), 5.75-5.65(m, 1 H), 5.39(d,
J=6.35Hz, 1 H), 5.21 (d, J=8.8Hz, 1 H), 5.18-5.11 (m, 1 H), 5.00-4.70(m, 2H),
4.35-
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4.27(m, 1 H), 4.00-3.94(m, 2H), 3.86-3.79(m, 1 H), 3.20(s, 3H), 3.14-3.05(m, 1
H),
2.77-2.50(m, 1 H), 2.08(s, 3H), 2.10-2.94(m, 1 H).
MS: (M+H)+=362, (M+Na)+=385, (M-H)~=360, (M+35)-=396
Example 171
AcHN. N~.,~ H
H H
O
O~N'CH3 HCi
(t)-(2R,3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N-oxide)ethyl-
3-vinyl-uyrrolidine-5-carboxLrlic Acid HydrochlorideSait
'H NMR (CD30D) b 5.80 (m, 1 H), 5.44 (d, 1 H), 5.27 (d, 1 H), 5.08 (m, 1 H),
4.34-4.44 (dd, 1 H), 3.83-3.94 (m, 3H), 3.38 (s, 3H), 3.02-3.18 (m, 1 H), 2.58-
2.72
(m, 1 H), 2.08 (s, 3H1, 1.97-2.08 (m, 1 H), 1.55 (s, 9H).
MS: (M+H)+= 328
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Example 172
AcHN_ N~.,~ H
H H
O
N
O~ 'CH3 ~ci
(t)-(2R.3S.5R,1'S,3'S)-2~1-Acetamido-2-(N-meth i-rL N-isoprowlamino-N-
oxide))ethyl-3-vinyl-p~rrolidine-5-carboxylic Acid Hydrochloride Salt
1 H NMR (MeOD-d3) 8 5.86-5.74 (m, 1 H), 5.53-5.47 (m, 1 H), 5.29-5.25 (m,
1 H), 5.22-5.19 (m, 1 H), 4.50 (dd, J=8.1, 9.5Hz, 1 H), 4.13-4.04 (m, 2H),
3.96 (dd,
J=4.1, 10.5Hz, 1 H), 3.87-3.82 (m, 1 H), 3.39 (s, 3H), 3.23-3.17 (m, 1 H),
2.70-2.61
(m, 1 H), 2.11 (s, 3H), 2.08-2.00 (m, 1 H), 1.50 (d, J=6.4Hz, 3H), 1.49(d,
J=6.4Hz,
3H).
MS: (M+H)+=314, (M+Na)+=336, (2M+1 )+=627, (2M~Na)+=649.
Example 173
AcHN. N~.,~OH
H H
O
O~N~CH3 Hci
t - 2R.3S.5R,1'S.3'R)-2-(1-Acetamido-2-(N-methyl-N-propylamino-N-
oxide))ethyl-3-vial-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
'H NMR (MeOD-d3) 8 5.82-5.75(m, 1 H), 5.45(d, J=17.1 Hz, 1 H), 5.26(d,
J=10.4Hz, 1 H), 5.07-5.13(m, 1 H), 4.48-4.42(m, 1 H), 3.98(d, J=5.5Hz, 2H),
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3.86(dd, J=4.3, 9.8Hz, 1 H), 3.67-3.64(m, 2H), 3.46(s, 3H), 3.16-3.01 (m, 1
H),
2.68-2.62(m, 1 H), 2.09-2.02(m, 1 H), 2.06(s, 3H), 1.92-1.86(m, 2H), 1.04(t,
J=7.3Hz, 3H).
MS: (M+H)+=314, (M+H-H20)-=295
AcH
O
ON'OH3 Hc~
(t;y(2R.3S,5R.1'S,3'R)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide) ethyl-
3-vin ELI-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1 H NMR (MeOD-d3) 8 5.82-5.75(m, 1 H), 5.45(d, J=17.1 Hz, 1 H), 5.26(d,
J=10.4Hz, 1 H), 5.13-5.10(m, 1 H), 4.48-4.44(m, 1 H), 4.02-3.94(m, 2H), 3.89
(dd,
J=4.3, 9.8Hz, 1 H), 3.82(q, J=7.3Hz, 2H), 3.46(s, 3H), 3.18-3.10(m, 1 H), 2.68-
2.62
(m, 1 H), 2.09(s, 3H), 2.07-2.02(m, 1 H), 1.46(t, J=7.3Hz, 3H).
MS: (M+H)+=300, (M+Na)+=322, (M+H-H20)+=282
Example 174
N.
H -N
H
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Example 175
AcHN. N~.,~OH
H H
O
Ph O~N~CH Hci
3
(t)-(2R,3S.5R,1'S.3'S)2-(1-Acetamido-2-(N-methyl-N-benzLrlamino-N-
oxideLhyl-3-vin rLi-p rr~ne-5-carboxylic Acid HydrochlorideSalt
'H NMR (MeOD-d3) S 7.60-7.47(m, 5H), 5.75-5.65(m, 1 H), 5.39(d,
J=6.35Hz, 1 H), 5.21 (d, J=8.8Hz, 1 H), 5.18-5.11 (m, 1 H), 5.00-4.70(m, 2H),
4.35-
4.27(m, 1 H), 4.00-3.94(m, 2H), 3.86-3.79(m, 1 H), 3.40(x, 3H), 3.14-3.05(m, 1
H),
2.77-2.50(m, 1 H), 2.08(s, 3H), 2.10-2.94(m, 1 H).
MS: (M+H)+=362, (M+Na)'=385, (M-H)'=360, (M+35)~=396
Example 176
AcHN. N,.,~OH
H H
O
~N
O
t - 2R.3S.5R,1'S)-2-(1-Acetamido-2-~N,N-diethylamino-N-oxide))eth I-~yl-
pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1 H NMR (MeOD-dg) 8 5.84-5.78(m, 1 H), 5.45(d, J=16.85Hz, 1 H), 5.26(d,
J=10.OHz, 1 H), 5.09-5.05(m, 1 H), 4.45-4.42(m, 1 H), 3.96-3.86(m, 3H),
3.76(q,
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J=6.6Hz, 2H), 3.70(q, J=7.3Hz, 2H), 3.15-3.11 (m, 1 H), 2.68-2.62(m, 1 H),
2.08-
2.02(m, 1 H), 2.08(s, 3H), 1.44-1.38(m, 6H}.
MS: (M+H)+=314, (M+Na)+=336, (M+2Na)+=358
Example 177
AcHN. N~.,~ H
H H
O
N
O
(t)-(2R.3S.5R,1'S.3'R)-2-(1-Acetamido-2-(N-pyrrolidinyl-N-oxide))ethyl-3-vinyl-
pyrrolidine-5-carbox I~Acid Hydrochloride Salt
~ H NMR (DMSO-ds) 8 8.74 (d, 1 H), 5.65-5.80 (m,1 H), 5.28 (d, 1 H), 5.10
{d,1 H), 4.82 (m, 1 H), 4.40-4.50 (dd, 1 H), 4.30 (d, 1 H), 3.60-4.12 (brm,
5H), 2.98-
3.15 (m, 1 H), 2.38-2.48 (m, 1 H), 2.05-2.20 (brm, 5H), 1.88-1.98 {m, 1 H),
1.87 (s,
3H).
MS: (M+H)+= 312
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Example 178
AcH , ~ H
O
Hc~
(t)-(2R.3S, 5R,1'S)-2-( 1-Acetamido-2-(N-morpholin~oxide~ethyl-3-vinyl-
~yrrolidine-5-carboxylic Acid Hydrochloride Salt
'H NMR (DMSO-ds) b 8.65 (d, 1 H), 5.66-5.80 (m, 1 H), 5.22 (d, 1 H), 5.09
(d, 1 H), 4.78 (brs, 1 H), 4.32-4.42 (dd, 1 H), 4.10-4.17 (brm, 2H), 3.50-4.02
(brm,
9H), 2.92-3.04 (brrn, 1 H), 2.37-2.48 (m, 1 H), 1.88-1.96 (m, 1 H), 1.87 (s,
3H).
MS: (M+H)+= 328
N. ,.
H N
H
Example 179
t - 2R 3S,5R,1'S,3'S)-2-(1-Acetamido-2-~,N-ethyl-N-methylamino-N-oxide))ethyl-
~cis-propen-1_yl)-pyrrofidine-5-carboxyiic Acid HydrochlorideSalt
N>.,~OtBu
O H Boc ~
179A (t)-i(2R.3S,5R.1'S)-1-t Butox~carbon~,rl-2-oxiranyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid t-Bu I Ester.
The title compound was prepared according to the method described in
Example 1231, substituting ethyltriphenylphosphonium bromide in place of
methyltriphenylphosphonium bromide (yield: 350 mg, 77%).
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'H NMR (CDC13) (rotamers) s 5.55-5.43 (m, 2H), 4.13-4.04 (m, 2H), 3.14-
3.11 (m, 2H), 2.76-2.50 (m, 3H), 1.75-1.70 (m, 1 H), 1.64(d, 3H), 1.48-1.43(m,
18H).
MS: (M+H)+=354, (M+Na) +=376, (2M+Na)+=729
Ms0 N,-, ~ tBu
H Boc 0
N3
179B (tl-(2R.3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-methanesulfonylox r-~3-
azido)ethyl-3-(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 1231, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-
(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl-pyrrolidine-5-
carboxylic acid t-butyl ester (yield: 1.08 g, 84%).
'H NMR (DMSO-ds) (rotamers) b 5.53-5.33 (m, 2H), 5.05-4.93 (m, 1H),
4.20-3.90 (m, 2H), 3.76-3.62 (m, 2H), 3.24 (s, 3H), 2.59-2.49(m, 1 H), 1.64-
1.55(m, 51-;), 1.43-1.36(m, 18H).
MS: (M+H)+=475, (M+Na)+=497, (2M+Na)+=971
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N>..,~ 1Bu
HN~ H goc 0
179C (t)-(2R,3S 5R 1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 123K, substituting (2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-
methanesulfonyloxy-3-azido)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid
t-butyl ester in place of (2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-
methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl
ester(crude yield: 564 mg, 71 %).
'H NMR(DMSO-ds) (rotamers) 8 5.45-5.30 (m, 2H), 4.15-3.99 {m, 1 H),
3.30-3.08 (m, 1 H), 3.07-2.84 (m, 1 H), 2.68-2.51 (m, 1 H), 2.13-1.85(m, 1 H),
1.80-
1.05(m, 3H), 1.57(d, J=5.4Hz, 3H), 1.41-1.35(m, 18H).
MS: (M+H)+=352, (M+23)+=375, (2M+H)+=705, (2M+23)+=727
N,.,~O~Bu
AcN~ H goc 0
179D yt)-(2R.3S,5R,1'S)-1-t-Butoxvcarbonyl-2-lN-acetylaziridin ly )-3-(cis-
propen-
1-YI)-pYrrolidine-5-carboxylic Acid t-Butvl Ester.
The title compound was prepared according to the method described in
Example 123L, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-
3-
(cis-propen-1-yl}-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-
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(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-
carboxylic
acid t-butyl ester(yield: 455 mg, 72%).
'H NMR(DMSO-ds} (rotamers) 8 5.74-5.34(m, 2H), 4.17(dd, J=2.4,
6.35Hz, 1 H), 3.41 (dd, J=1.95, 6.35Hz, 1 H), 3.14-2.99(m, 1 H), 2.73-2.58(m,
2H),
2.40(d, J=6.35Hz, 1 H), 2.17-2.12(m, 1 H), 2.05-2.00(m, 3H), 1.66-1.55(m, 1
H),
1.56(d, J=6.8Hz, 3H), 1.41-1.31 (m, 18H).
MS: (M+H)+=395, (M+Na)+=417, (M+H+Na)+=418,
~OtBu
O
I
179E fit)-f~2R,3S,5R.1'S)-1-t Butoxycarbon rLl-2~1-acetamido-2-N-ethyl-N-
met~lamino)ethyl-3~cis-propen-1-y~pyrroiidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 150, substituting N-ethyl-N-methyl-amine in place of diethylamine
(yield:
30 mg, 87%).
MS: (M+H)+=454, (M+Na)+=476, (M-H)-=452, (M+35)-=488
AcN. >.
N
H Boc
N
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AcN _ )_ , OiBu AcN. ).. , O~Bu
H Boc ~ ~ H Boc
O,N~-CH3 O'~N'CH3
179E (t)-~2R,3S,5R,1'S,3'R) and (t)-(2R,3S.5R,1'S.3'S)-1-t Butoxycarbonyl-2-
1-acetamido-2-(N-ethyl-N-methyiamino-N-oxide))ethyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 165A, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-(N-ethyl-N-methylamino))ethyl-3-{cis-propen-1-yl)-pyrrolidine-5-
carboxyiic acid t-butyl ester in place of (t)-(2R,3S,5R,1'S)-1-t
butoxycarbonyl-2-
(1-acetamido-2-N-methyl-N-t-butylamino)ethyl-3-{cis-propen-1-yl)-pyrrolidine-5-
carboxyiic acid t-butyl ester (yield: 15.2 mg, 51 %).
H3C
AcHN. N~, ~ H
H H
O
~ N ~'CH HCi
() 3
179F (t~-(2R,3S.5R,1'S,3'R)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-
oxide))et~l-3-(cis-~roaen-1-y~-pyrrolidine-5-carboxylic Acid Hydrochloride
Salt
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3S,5R,1'S,3'R)-1-t-butoxycarbonyl-2-{1-
acetamido-2-(N-methyl-N-ethyl-N-oxide))ethyl-pyrrolidine-5-carboxylic acid t-
butyl
ester for (t)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-
pyrrolidine-5-carboxylic acid t-butyl ester (yield: 8.7 mg, 29%).
~ H NMR (MeOD-d3) 8 5.75-5.69(m, 1 H), 5.37-5.30(m, 1 H), 5.07-5.04(m,
1 H), 4.49(dd, ,l=7.8, 10.2Hz, 1 H), 4.05-3.74(m, 4H), 3.61-3.32 (m, 1 H),
3.55(s,
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3H), 2.69-2.60(m, 1 H), 2.04(s, 3H), 1.95-1.84(m, 1 H), 1.75(dd, J=2.0, 7.1
Hz,
3H), 1.44 (t, J=7.1 Hz, 3H).
MS: (M+H)+=314, (M+35)+=348
Examples 179-184
1. MCPBA
2. chromatographic
AcHN_ ,., OH separation AcHN_ ,., OH
3. s N Hcc O H H
R'RN O R'RN O
HCI
The following title compounds were prepared according to the method described
in Example 179.
Example 180
/=,
H3C
AcHN_ N~.,~OH
H H
O
~N Hci
O~ ~CH3
(tl-(2R.3S 5R 1'S 3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))eth~
3-lcis=propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
' H NMR (MeOD-d3) 8 5.75-5.69(m, 1 H), 5.38-5.30(m, 1 H), 5.02-4.98(m,
1 H), 4.47(dd, J=7.8, 9.8Hz, 1 H), 4.02-3.77(m, 4H), 3.56-3.39(m, 1 H),
3.47(s, 3H),
2.69-2.59(m, 1 H), 2.07(s, 3H), 1.95-1.84(m, 1 H), 1.76(dd, J=1.7, 7.1 Hz,
3H),
1.46(t, J=7.1 Hz, 3H).
MS: (M+H)+=314, (M+35)+=348
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Example 181
,~ H
O
O~ ~~CH3
/= ,
H3C
AcH N .
H N
H
N HC~
~t)~2R 3S 5R 1'S 3'R)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-
oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxyiic Acid Hydrochloride
Salt
' H NMR (MeOD-d3) S 5.76-5.66(m, 1 H), 5.39-5.31 (m, 1 H), 5.17-5.11 (m,
1 H), 4.51 (dd, J=7.5, 10.2Hz, 1 H), 4.07-3.76(m, 4H), 3.55(S, 3H), 3.52-
3.39(m,
1 H), 2.69-2.60(m, 1 H), 2.02 (S, 3H), 2.08-1.84(m, 1 H), 1.75(dd, J=1.7, 7.1
Hz,
3H), 1.50(d, J=6.1 Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+35)'=348
Example 182
,~OH
O
O~ ~CH3
/~,
H3C
AcHN.
H N
H
N HCi
(t)-(2R.3S 5R 1'S 3'S)-2-(,1-Acetamido-2~N-isopropyl-N-methylamino-N-
oxide))ethyl-3-(cis-propen-1~rlLp~rrrolidine-5-carbox~c Acid Hydrochloride
Salt
' H NMR (MeOD-d3) b 5.76-5.68(m, 1 H), 5.39-5.31 (m, 1 H), 5.10-5.05(m,
1 H), 4.49(dd, J=7.8, 9.8Hz, 1 H), 4.12-3.84(m, 4H), 3.55-3.44(m, 1 H), 3.41
(S, 3H),
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2.69-2.60(m, 1 H), 2.08(S, 3H), 2.07-1.84(m, 1 H), 1.76{dd, J=1.7, 6.8Hz, 3H),
1.51{d, J=2.4Hz, 3H), 1.49(d, J=2.4Hz, 3H).
MS: (M+H)+=314, (M+35)+=348
Examele 183
',
H3C
AcHN. N,.,~OH
H H
O
NCH HCi
3
(t)-(2R 3S 5R 1'S 3'S~~1-Acetamido-2-(N-isobutyl-N-methylamino-N-
oxide))ethyl-3-(cis-eropen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride
Salt
' H NMR (MeOD-d3) 8 5.75-5.69(m, 1 H), 5.38-5.31 (m, 1 H), 5.18-5.12(m,
1 H), 4.53(dd, J=7.5, 9.8Hz, 1 H), 4.25-3.42(m, 6H), 3.65 (s, 3H), 2.68-
2.58(m,
1 H), 2.44-2.36(m, 1 H), 2.05(s, 3H), 1.94-1.87(m, 1 H), 1.76(d, J=2.7Hz, 3H),
1.14
(d, J=6.8Hz, 6H).
MS: (M+H)+=342, (M+Na)+=364, (M-H)-=340
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Example 184
/= ,
H3C
AcHN. N~., ~OH
H\ H
O
~N ~CH
3
(t)-(2R 3S 5R 1'S 3'R~-2-(1-Acetamido-2-(N-isobutyl-N-methvlamino-N-
oxide))eth_yl-~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride
Salt
~ H NMR (MeOD-d3) s 5.75-5.69(m, 1 H), 5.38-5.31 (m, 1 H), 5.06-5.02(m,
1 H), 4.48(dd, J=7.5, 9.8Hz, 1 H), 4.08-3.85(m, 3H), 3.70-3.57 (m, 2H),
3.52(s,
3H), 3.48-3.41 (m, 1 H), 2.70-2.60(m, 1 H), 2.40-2.36(M, 1 H), 2.08(s, 3H),
1.95-
1.84(m, 1 H), 1.75(dd, J=1.7, 7.1 Hz, 3H), 1.14 (d, J=6.8Hz, 6H).
MS: (M+H)+=342, (M+Na)+=364, (M-H)-=340
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Example 185
(t)-(2R,3S 5R 1'S)-2-(1-Acetamido-2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-
p~rrolidine-5-carboxylic Acid HydrochlorideSalt
AcHN. N>., O~Bu
H Boc
~N
i
OH
165A (t)-12R,3S,5R.1'S~1-t-Butoxycarbonyl-2-(1-acetamido-2-lN-isopropyl-N-
hydroxyamino eth rLl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-
isopropylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (21
mg,
0.048 mmole) was dissolved in 0.95 mL of acetone. It was then titrated with
0.14
mL of a solution of dimethyldioxirane (0.1 M) in acetone at -45°C for
0.5 hour.
The reaction was stopped by concentrating the mixture in vacuo. The residue
was purified by chromatography on silica gel using 100% dichloromethane to
90% dichloromethanelmethanol to provide the title compound (yield: 5.3 mg,
24%) and recovered starting material (yield 12 mg, 57%).
1 H NMR (MeOD-dg) 8 5.95-5.89(m, 1 H), 5.08-4.94(m, 2H), 4.75-4.68(m,
1 H), 4.13-3.83(m, 2H), 2.85-2.47(m, 4H), 1.96(s, 3H), 1.82-1.76(m, 1 H), 1.52-
1.44(m, 18H), 1.45-1.29(m, 1 H), 1.07-1.04(m, 6H).
MS: (M+H)+=456, (M+Na)+=478, (M-H)-=454, (M+35)-=490.
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,~ H
O
OH
1858 ~t)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-isopropyl-N-h~xyamino))ethyl-
3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-{1-acetamido-
2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl
ester in place of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-
methoxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (yield: 3.0 mg,
87%).
1 H NMR (MeOD-d3) b 5.83-5.71 (m, 1 H), 5.40(d, J=17.3Hz, 1 H), 5.24(d,
J=10.2Hz, 1 H), 4.48(dd, J=7.8, 10.2Hz, 1 H), 3.88-3.59(m, 4H), 3.17-3.10(m, 1
H),
2.67-2.58(m, 1 H), 2.10-1.99(m, 1 H), 2.09(s, 3H), 1.33-1.17(m, 1 H), 1.38(d,
J=6.4Hz, 6H).
MS: (M+H)+=300, (M-H)-=298, (2M-H)-=597
,
AcHN.
H N
H
N
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Example 186
CH3
AcHN. N~.,~ H
H H
0 O
/ TFA
(t)~2R 3S 5R 1'R~,-2-(1-Acetamido-2-oxo-2-phenyl)ethyl-3-(cis-aropen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting {t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid
t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f
butyl
ester (yield: 5.9 mg, 100%).
'H NMR (DMSO-ds) s 8.62 (d, J= 9.8Hz, 1H), 7.93 (m, 2H), 7.68 (m, 1H),
7.55 (t, J= 7.9Hz, 2H), 5.61 (m, 1 H), 5.48 (m, 1 H), 5.19 (m, 1 H), 4.50 (rn,
1 H),
3.98 {t, J= 9.8Hz, 1 H), 3.30 (m, 1 H), 2.38 (m, 1 H), 1.73 (m, 1 H), 1.71 (s,
3H),
1.59 (m, 3H).
MS: (M+H)+= 331, (M+Na)+= 353, (M-H)- = 329.
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Example 187
(t) ~2R 3S 5R 1'R 2'R)-2-(1-Acetamido-2-methoxy-4-vin rLl)butyl-3-(cis-propen-
1-
Lrl~-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
~OtBu
O
187A (tL{2R 3S.5Rs1'R.2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methox~
viny_I)but~rf-3-fcis-propen-1-~)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound is prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yi)-pyrrolidine-5-carboxylic
acid t butyl ester for (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester.
,~ H
O
OCH3
TFA
187B (t)-(2R 3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxv-4-vinyl)butvl-3-(cis-
propen-1-~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxy-4-vinyl)butyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester.
CH3
AcHN
N
H Boc
~OCH3
CH3
AcHN_ ~.
H N
H
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Example 188
{t) ~2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-
YI)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
,
CH3
AcHN. N~., OtBu
H Boc
OCH3
188A (t)-(2R 3S 5R 1'R 2'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-2-methoxv-4-
vinylbutyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f butoxycarbonyl-2-(1-
acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester for (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-
acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
(yield:
0.0044 g, 22%).
MS: (M+H)+=481, (M-H)-=479.
,~OH
O
OCH3
TFA
CH3
AcHN.
H N
\ H
188B (t)-~2R 3S 5R 1'R 2'Sl-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-
propen-1-yl)-p~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-hydroxy)butyl-3-(cis-propen-1-yf)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 0.0031 g, 100%).
' H NMR (DMSO-ds) b 7.93 (d, J=9.2Hz, 1 H), 5.81 (m, 1 H), 5.49 (m, 1 H),
5.26 (m, 1 H), 5.1-4.9 (m, 2H), 4.29 (m 1 H), 4.03 (m, 2H), 3.68 (m, 1 H),
3.26 (m,
1 H), 3.25 (s, 3H), 3.18 (quint., J=8.5Hz, 1 H), 2.40 (dt, J=12.7,7.3Hz, 1 H),
2.32
(M, 1 H), 2.20 (m, 1 H), 2.02 (m, 1 H), 1.85 (s, 3H), 1.68 (m, 1 H), 1.64 (m,
1 H), 1.61
(dd, J=6.7,1.8Hz, 3H), 1.55-1.40 (m, 2H).
MS: (M+H)+=325, (M+Na)+=347, (M-H)'=323.
Example 189
(t)-LR.3 R.5 R.1 ' R,2'S)-2-( 1-Aceta mid o-2.3-d ihyd roxy~~ropyl-3-(cis-
propen-1-yl)-
~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
TBDPSO-
Ms0 N~,~OtBu
H Boc O
N3
189A (t)-(2R.3R.5R.1'S)-1-t Butoxycarbony!-2-(1-methanesulfon~x~ 3-
azido)ethyl-3-t-but~diphenylsilyloxymethYl pyrrolidine-5-carboxylic Acid t-
ButLrl
Ester.
The title compound was prepared according to the method described in
Example 123J substituting (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-t
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in
place of
(2R,3S,5R,1'S)-2-oxiranyl-3-vinyl-pyrrolidine-5-carboxylic acid t butyl ester
(yield:
9.0 g, 90%).
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'H NMR (DMSO-ds) (rotamers) 8 7.62-7.58 (m, 4H), 7.49-7.38 (m 6H),
4.97-4.79 (m, 1 H), 4.19-4.02 (m, 2H), 3.79-3.48 (m, 2H), 3.15 and 3.13 (2s,
3H),
2.49-2.39 (m, 2H), 1.98-1.74 {m, 1 H), 1.43-1.25 (m, 18H), 1.02 and 1.00 (2s,
9H)
MS: (M+H)+= 703, (M+Na)+= 725
TBDPSO-,
N)., ~O~Bu
HN~ H goc O
1898 (t}-(2R.3R.5R.1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-t-
butyldiphenylsil~x~methyl_pyrrolidine-5-carboxylic acid t butyl ester
The title compound was prepared according to the method described in
Example 123K substituting(t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-(1-
methanesulfonyloxy-3-azido)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t}-(2R,3S,5R,1'S)-1-t
butoxycarbonyl-2-
(1-methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl
ester(yield: 5.9 g, 79%).
'H NMR (DMSO-ds) (rotamers) 8 7.60-7.56 (m, 4H), 7.49-7.39 (m 6H),
4.11-4.05 (m, 1 H), 3.67-3.48 (m, 2H}, 3.42-3.30 {m, 1 H), 2.49-2.39 (m, 1 H),
2.25-
1.61 (m, 5H), 1.40, 1.35, 1.33, and 1.27 (4s, 18H), 0.99 and 0.98 (2s, 9H)
MS: (M+H)+ = 581, (M+Na)+ = 603
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TBDPSO-
,
N ). , ~OtBu
AcN~ H Boc O
189C (~)-(2R.3R.5R,1'Sl-1-t-Butoxycarbonyl-2-N-acetylaziridinyl-3-t-
butyldiphenyisilylox~methyt-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 123L substituting (t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-
t-
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in
place of
(t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-
carboxylic
acid t-butyl ester (yield: 3.1 g, 96%).
'H NMR (DMSO-ds) (rotamers) 8 7.60-7.57 (m, 4H), 7.49-7.39 (m 6H),
4.18-4.11 (m, 1 H), 3.71-3.51 (m, 3H), 2.76-2.68 (m, 1 H), 2.58-2.45 (m, 1 H),
2.46
and 2.39 (2d, J=6.1, 6.1 Hz, 1 H), 2.40 and 2.47 (2m, 1 H), 2.08 and 2.05 (2d,
J=3.1, 3.1 Hz, 1 H), 2.02 and 1.99 (2s, 3H), 1.94-1.79 (m, 1 H), 1.41, 1.36,
1.35
and 1.29 {4s, 18H), 0.99 and 0.98 (2s, 9H)
MS: (M+H)+ = 623, (M+Na)+ = 645
TBDPSO-
AcHN- N~,~OtBu
Ac0 H Boc
189D {t~2R,3R.5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-acetox )Lthyl-3-t-
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-N-acetylaziridinyl-3-t-
butyldiphenylsilyloxyrnethyl-pyrrolidine-5-carboxylic acid f-butyl ester
(2.75g, 4.40
mmole) was reacted with potassium acetate (2.49 g, 25.37 mmole) and acetic
acid (1.45 mL, 25.37 mmole) in DMSO (45 mL) at 100°C for 16 hours. The
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reaction was quenched with 1 N NaHC03 (100 mL) and diluted with ethyl acetate
(300 mL). The organic layer was washed with water,and brine, dried over
MgS04, filtered and concentrated in vacuo. The residue was purified by
chramatography on silica gel using 100% dichloromethane to 50%
dichloromethane/ethyl acetate to provide the title compound (yield: 2.45g, 81
%).
MS: (M+H)+=683, (M+Na)+=705, (M-H)-=681, {M+CI)'=717
TBOPSO--
AcHN- N~.~ ~B~
HO H Boc
189E (t)-(2R,3R,5R,1'R)-1-t Butox~arbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-t
butyld~henylsilyloxvmethYl_pyrroiidine-5-carboxylic Acid t Butyl Ester
(t)-(2R, 3R,5R,1'R)-1-t-Butoxycarbonyl-2-( 1-acetamido-2-acetoxy)ethyl-3-t
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (2.45
g, 3.58
mmole) was reacted with potassium carbonate (1.48 g, 10.73 mmole) in methanol
(18 mL) and THF (l8mL) at 25°C for 45 minutes. The reaction was
quenched
with water (100 mL) and diluted with ethyl acetate (200 mL). The organic layer
was washed with water,and brine, dried over MgS04, filtered and concentrated
in
vacuo. The residue was purified by chromatography on silica gel using 85%
dichloromethanelethyl acetate to 100% ethyl acetate to provide the title
compound {yield: 2.05 g, 90%).
MS: (M+H)+=641, (M+Na)+=663, (2M+Na+H)+=1304, (M-H)'=639, (M+CI)'
=675
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TBDPSO-.
,
AcHN- N~,
O H'Boc O
189F (t)-(2R.3R 5R 1'R~-1-t-Butoxycarbonyl-2;~1-acetamido-2-formyl)ethyl-3-f
butyldiphen~silyloxymethy!-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 41A substituting (t)-{2R,3R,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-
2-hydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid
t-
butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl 2-(1-acetamido-2-
hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
'H NMR (DMSO-ds) (rotamers) 9.49(4, J=16.3, 1H), 8.33 and 8.29(24,
J=8.8 and 8.8Hz, 1 H), 7.58-7.38(m, 1 OH), 4.94 and 4.84(244, J=4.4, 8.8Hz and
4.4, 8.8Hz, 1 H), 4.26-3.37(m, 4H}, 2.47-2.30(m, 1 H), 1.97-1.83(m, 1 H),
1.92(s,
3H), 1.42-1.18(m, 18H), 1.42-1.18(m, 1 H), 1.00-0.97(m, 9H).
MS: (M+H)+=639, (M-H)'=637
TBDPSO-
AcHN- N~.
.~ H Boc O
189G {t?-(2R.3R.5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-vinyl)methyl-3-t
butyldiphen~IsilYlox~rmethyl-pyrrolidine-5-carboxylic Acid t Buty! Ester
The title compound was prepared according to the method described in
Example 118A substituting (t)-{2R,3R,5R,1'R)-1-t butoxycarbonyl-2-(1-
acetamido-2-formyl)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-
carboxylic
acid t butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl 2-(1-
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acetamido-2-forrnyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester.
'H NMR (DMSO-ds) (rotamers) 7.99-7.74(m, 1H), 7.59-7.39(m, 10H),
5.80-5.68(m, 1 H), 5.21-5.01 (m, 3H), 3.97-3.31 (m, 1 H), 3.78-3.74(m, 1 H),
3.60-
3.46(m, 2H), 2.53-2.37(m, 1 H), 2.09-1.72(m, 1 H), 1.87(s, 3H), 1.42-1.23(m,
19H),
1.00-0.99(m, 9H).
TBDPSO-~ TBDPSO-
AcHN- N~.~OtB~ AcHN- , N~,~O~Bu
H Boc [O H Boc O
~OH OH
OH OH
189H (t -(~ 2R,3R,5R 1'R.2'R) and (t)-(2R,3R.5R.1'R,2'S)-1-t-Butoxycarbon
(,1-acetamido-2.3-dih~drox~propyl-3-t-butyldiphenylsilyioxymethyl-pyrrolidine-
5-
carboxylic Acid t Bu I Ester
The title compounds were prepared according to the method described in
Example 20A substituting (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-
2-vinyl)ethyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t
butyl
ester in place of (t)-(2R,3S,5R)-1-benzyl-2-vinyl-3-t-
butyldimethylsilyloxymethyl-
pyrrolidine-5-carboxylic acid t-butyl ester (t}-(2R,3R,5R,1'R,2'S) isomer
(yield:
311mg, 24%) (t)-(2R,3R,5R,1'R,2'R) isomer (yield: 700 mg, 54%).
(t)-(2R,3R,5R,1'R,2'S) 'H NMR (DMSO-dfi) (rotamers) 7.62-7.39(m,
11 H), 4.56 and 4.51 (d, J=4.8, 1 H), 4.46-4.39(m, 2H), 3.97-3.82(m, 1 H),
3.74-
3.47(m, 3H), 3.28-3.21 (m, 2H), 2.89-2.64(m, 1 H), 2.51-2.45(m, 1 H), 2.05-
1.8(m,
1 H), 1.87-1.86(m, 3H), 1.43-1.23(m, 19H), 0.99-0.98(m, 9H).
(t)-(2R,3R,5R,1'R,2'R) 'H NMR (DMSO-d6) (rotamers) 7.63-7.40(m,
11 H), 4.56-4.54(d, J=4.8, 1 H), 4.47-4.33(m, 2H), 3.94-3.80(m, 1 H), 3.85-
3.80(m,
1 H), 3.76-3.68(m, 1 H), 3.60-3.51 (m, 1 H), 3.44-3.35(m, 1 H), 3.30-3.21 (m,
1 H),
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2.78-2.62(m, 1 H), 2.46-2.31 (m, 1 H), 2.07-1.98(m 1 H), 1.83(s, 3H), 1.39-
1.29(m,
19H), 1.00-0.99(m, 9H).
TBDPSO-
AcHN- N,-,~ tBu
H Boc O
~O
O
1891 ltl-(2R.3R.5R.1'R.2'S)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2,2-
dimethyl-1.3-dioxolan-4~yl), methyl-3-t butyldiphenylsilyloxymethyl-
pyrrolidine-5-
carbox~lic Acid t Butyl Ester
(t)-(2R,3R,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-( 1-acetamido-2,3-
dihydroxy)propyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid
t-
butyl ester was reacted with 2,2-dimethoxypropane (1.1 ml, 9.09 mmole) and p-
Toluenesulfonic acid (4.3 mg, 0.023 mmole) in tetrahydrofuran (4.5 mL) at
25°C
for 45 minutes. The reaction was quenched with triethylamine (3 mL). Stirring
was continued for an additional 10 minutes. The reaction was then diluted with
10% NaHC03(15 mL) and extracted with ethyl acetate (45 ml). The organic layer
was washed with water,and brine, dried over MgS04, filtered and concentrated
in
vacuo. The residue was carried over to the next step. purified by
chromatography on silica gel using 100% dichlormethane to 94%
dichloromethane/methanol to provide the title compound {yield: 194 mg, 91%).
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HO~
AcHN- N~,~OtBu
H Boc O
~O
O
189J (t~-(2R 3R 5R.1'R.2'S -1-) t-Butoxvcarbonyl-2-(1-acetamido-1-(2,2-
dimethyl-1 3-dioxolan-4-yl))methyl-3-hydroxymethyLpyrrolidine-5-carbox liy c
Acid
t Butyl Ester
The title compound was prepared according to the method described in
Example 1236 substituting (t)-(2R,3R,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester for
(t}-
(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-oxiranyl-3-t butyldiphenylsilyloxymethyl-
pyrrolidine-5-carboxylic acid t-butyl ester. The resulting residue was
purified by
chromatography on silica gel using 100% dichlormethane to 94%
dichloromethanelmethanol to provide the title compound (yield: 194 mg, 91%).
H
O
AcHN- N~.~OtBu
H Boc O
~O
O
189JJ (t)-(2R 3R 5R.1'R.2'Sl-1-t ButoxycarbonYi-2-(1-acetamido-1-(2.2-
dimethyl-1,3-dioxolan-4 yl))methyl-3-formyl-pyrrolidine-5-carboxylic Acid t
Butyl
Ester
The title compound was prepared according to the method described in
Example 123H substituting (t)-(2R,3R,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxymethyl-
pyrrolidine-
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5-carboxylic acid f-butyl ester for (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-
oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
H3C
AcHN- N~..~ tBu
H Boc O
~O
O
189K (t)-(2R.3S,5R,1'R,2'S)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-
1,3-dioxolan-4-~ I)~ )methyl-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid t-
Bud
Ester
The title compound was prepared according to the method described in
Example 35A substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t
butoxycarbonyl-2-
(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl
ester
(yield: 11.5 mg, 59%).
' H NMR (CDC13): b 6.62 (d, 1 H), 5.56 (m, 1 H), 5.40 (m, 1 H), 4.43 (m, 1 H),
4.25 (m, 1 H), 4.16 (m, 1 H}, 4.02 (m, 1 H), 3.88 (m, 1 H), 3.54 (m 1 H), 3.14
(m,
1 H), 2.54 (m 1 H), 2.04 (s, 3H), 1.71 (m 1 H), 1.60 (dd, 3H), 1.46 (s, 9H),
1.45 (s,
9H), 1.40 (s, 3H}, 1.32 (s, 3H).
MS: (M+H)+=483
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/= ,
CH3
AcHN. N~.,~OH
H H
O
~OH
OH TFA
189L (t)-(2R,3S,5R.1'R.2'S)-2-(1-Acetarnido-2,3-dih dy roxy)prop~-3-(cis-
proper-1-yl}-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-(cis-proper-1-yl)-
pyrrolidine-5-carboxylic acid t-butyl ester in place (t)-(2R,3S,5R,1'R,2'S)-1-
t
butoxycarbonyl-2-{ 1-acetam ido-2-hyd roxy)butyl-3-(cis-proper-1-y!)-
pyrrolidine-5-
carboxylic acid t butyl ester.
' H NMR (DMSO-ds): 8 7.84 (d, J=9Hz, 1 H), 5.49 (m, 1 H), 5.27 (m, 1 H),
4.47 (m, 1 H), 4.25 (m, 1 H), 4.17 (m, 1 H), 3.75 (rn, 1 H), 3.59 (m, 1 H},
3.35 (m,
1 H), 3.18 (m, 1 H), 2.43 (m, 1 H), 1.81 (s, 3H),1.55 (dd, 3H).
MS: (M+H)+=287
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Example 190
(t)-(2 R, 3R.5R,1' R, 2'R)-2-( 1-Acetamido-2.3-dihyd roxY)propYl-3-(cis-propen-
1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
TBDPSO-
AcHN- N~,~O~Bu
H Boc O
O
O
190A (t)-(2R.3R,5R,1'R,2'R)-1-t-Butoxycarbony~1-acetamido-1-(2.2-
dimetf~l-1,3-dioxolan-4-y~)methyl-3-t bu Idiphenylsilyloxyrnethyl-pyrrolidine-
5-
carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 1891 substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-
acetamido-2,3-dihydroxy)propyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'R,2'S)-1-t-
B utoxycarbonyl-2-( 1-acetamido-2, 3-d ihyd roxy)propyl-3-t
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
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HO-
AcHN- N,-. ~ tBu
H Boc ~
O
O
190B (t)-(2R,3R,5R,1'R,2'R)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2.2-
dimeth,/1-1.3-dioxolan-4-yIZ methyl-3-hydroxymethyl-gyrrolidine-5-carboxylic
Acid
t-Butyl Ester
The title compound was prepared according to the method described in
Example 1236 substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-
butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester for
(t)-
(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-
pyrrolidine-5-carboxylic acid t-butyl ester.
H
O
AcHN- N,.,~OtBu
H Boc O
O
O
190C (t)-(2R.3R,5R.1'RL2'R)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2,2-
dimethyl-1,3-dioxolan-4yl))methyl-3-formylpyrrofidine-5-carboxylicAcid t Butyl
Ester
The title compound was prepared according to the method described in
Example 123H substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxymethyi-
pyrrolidine-
5-carboxylic acid t-butyl ester for (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-
oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
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H3C
AcHN
N T~
H Boc 'O
-o
o~
190D (t)-~2R 3S 5R.1'R.2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2.2-
dimethyl-1.3-dioxolan-4.-yl))methyl-3-(cis-propen-1-yl)Lpyrrolidine-5-
carboxylic
Acid t Butyl Ester
The title compound was prepared according to the method described in
Example 35A substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t
butoxycarbonyl-2-
(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl
ester
(yield: 42 mg, 61 %).
' H NMR (CDC13): 8 7.88 (d, 1 H), 5.52 (m, 1 H), 5.34 (m, 1 H), 4.33 (m, 1 H),
4.21 (m, 1 H), 3.96 (m, 2H), 3.83 (m, 1 H), 3.60 (m, 1 H), 3.40 (m, 1 H), 2.53
(m,
1 H), 1.98 (s, 3H), 1.66 (dd, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.41 (s, 3H),
1.33 (s,
3H).
MS: (M+H)+=483
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/_',
CH3
AcHN_ N~,~OH
H H
O
OH
OH TFA
190E ~t~~2R 3S 5R 1'R 2'R)-2-(1-Acetamido-2.3-dihy_droxy)propyl-3-(cis-
pro en-1-yly-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-y!))methyl-3-(cis-propen-1-yl))-
pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-
1-t-
butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic acid t-butyl ester.
' H NMR (DMSO-ds): 8 7.98 (d, J=9Hz, 1 H), 5.48 (m, 1 H), 5.29 (m, 1 H),
4.60 (m, 1 H), 4.30 (m, 1 H), 4.12 (m, 1 H), 3.76 (m, 1 H), 3.52 (m, 1 H),
3.46 (m,
1 H), 3.32 (m, 1 H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.84 (s, 3H), 1.60 (dd,
3H).
MS: (M+H)+=287
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Example 193
(~2R.3S 5R 1'R 2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. N,.,~ ~Bu
H Boc O
O
193A (tL(2R,3S,5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-
ethoxy~pentyl-3-(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 88A, substituting ethyl iodide for methyl iodide (yield: 3.6 mg, 28%).
MS: (M+H)+= 483, (M+Na)+= 505, (M-H)- = 481.
/_.:.
H3C
AcHN, N~_.,,~~ H
H fO
'O
I TFA
1938 (t)-~2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethoxv)pentyl-3-(cis-propen-1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
ester
(yield: 3.2 mg, 100%).
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'H NMR (DMSO-ds) b 7.92 (d, J= 9.2Hz, 1 H), 5.47 (m, 1 H), 5.25 (m, 1 H),
4.25 (m, 2H), 3.70 (m, 1 H), 3.52 (m, 1 H), 3.33 (m, 2H), 3.18 (m, 1 H), 2.39
(m,
1 H), 1.85 (s, 3H), 1.66 (m, 1 H), 1.61 (dd, J= 6.7, 1.8Hz, 3H), 1.56 (m, 1
H), 1.37
(m, 1 H), 1.28 (m, 2H;1, 1.13 {m, 3H), 0.86 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 327, (M+Na)+= 349, (M-H)- = 325.
Example 194
(t)-(2R,3S,5R.1'R.2'R)-2-f 1-Acetamido-2-ethox)ilpentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
~O~Bu
O O
CH3
AcHN.
N
H Boc
194A (t)~2R.3S.5R 1'R.2'Ry-1-t Butox~rcarbonyl-2-(1-acetamido-2-
ethoxy pentyl-3-(,cis-propen-1 ~il~pyrrolidine-5-carboxylic Acid t Butyl Ester
The title compound is prepared according to the method described in
Example 88A, substituting ethyl iodide for methyl iodide.
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H3C
AcHN OH
N> ,~~~~
H H O
~~~'O
TFA
194B (t) ~2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-ethoxy~pentyl-3-(cis~r~oen-1-
yl)-pyrrolidine-5-carboxyic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester.
Examele 195
{2R.3S.5R.1'S)-2-(1-Acetamido-2-hydroxy)ethyl-3-vinyl-~yrroiidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
_ ~.
AcHN OH
N ~ .~'~~
HH O
HO
TFA
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-
2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place
of (t)-
(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester {yield: 19.9 mg,
100%).
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'H NMR (DMSO-ds) 8 7.80 (d, J= 8.8Hz, 1 H), 5.76 (m, 1 H), 5.23 (d, J=
17.1 Hz, 1 H), 5.15 (m, 1 H), 4.31 (m, 1 H), 4.03 {m, 1 H), 3.62 (m, 1 H),
3.53 (m,
2H), 2.79 (m, 1 H), 2.42 (m, 1 H), 1.90 (s, 3H), 1.85 (m, 1 H).
MS: (M+H)+= 243, (M+Na)+= 265, (M-H)- = 241.
Example 196
(t)-(2R,3S,5R,1'R.~2'S~-2-(1-Acetamido-2-hydroxv-3-dimethylphosphonyl)pro~,yl-
3-(cis-propen-1-yl~~ayrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
i= ,
CH3 CH3
AcHN_ )., O~Bo AcHN. ,., OtBu
H Boc ~ H Boc
OOH ~OH
O=P-OCH3 O=P-OCH3
OCH3 OCH3
196A (t)-(2R,3S.5R,1'R,2'S) and ~t~-(2R.3S.5R,1'R,2'R)-1-t-Butoxycarbonyl-2-
(1-acetamido-2-hydroxy-3-dimeth I~phosphonyl)~ropyl-3-(cis-propen-1-yl~
pyrrolidine-5-carboxylic Acid t-Butyi Ester.
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (78 mg, 0.19
mmoi) in
THF (5 mL) was added dropwise to a solution of dimethylphosphonylmethyl
lithium (3M) (0.32 mL, 0.95 mmoi) in THF (20 mL) at -78°C and reacted
for 40
minutes. The reaction was quenched with water (10 mL) and saturated aqueous
ammonium chloride (10 mL) followed by extraction using dichloromethane (2 x 50
mL). The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel using 5-7 0% methanol in dichloromethane to provide the title
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compounds (t)-{2R,3S,5R,1'R,2'R) isomer (yield: 27 mg, 27%) and (t)-
(2R,3S,5R,1'R,2'S) isomer (yield: 5.5 mg, 6%).
(t)-(2R,3S,5R,1'R,2'R) _ ' H NMR (CDC13) 8 5.98 (m, 1 H), 5.58(m, 1 H),
5.35(m, 1 H), 4.94(m, 1 H), 4.14(m, 2H), 3.74(m, 8H), 3.06(m, 1 H), 2.64{m, 1
H),
2.03(s, 3H), 1.95(m, 1 H), 1.83(m, 3H), 1.53(s, 9H), 1.46(s, 9H)
MS: (M+H)+=535, (M-H)- =533
(t)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=535, (M-H)-=533
CH3
AcHN_ N~.,~OH
H H
OH O
O=P-OCH3 TFA
OCH3
1968 ~t)-(2R.3S.5R.1'R,2'S)-2-{1-Acetamido-2-hydroxy-3-
dimethylphosphonyfZpropyl-3-(cis-propen-1-yl)-ayrrolidine-5-carboxylic Acid
Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f butoxycarbonyl-2-(1-
acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-
5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)- 1-t-
butoxycarbonyl-2-{1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic acid t-butyl ester (yield: 3 mg, 96%).
' H NMR {DMSO-d6) b 7.98(d, J=9.2 HZ, 1 H), 5.48(M, 1 H), 5.28(m, 1 H),
4.36(m, 1 H), 4.30(m, 1 H), 4.08(m, 2H), 3.70(m, 2H), 3.60(m, 6H), 3.18(m, 1
H),
2.40(m, 1 H), 2.05(m, 1 H), 1.85(s, 3H), 1.60(dd, J=6.2, 1.2 HZ, 3H)
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MS: (M+H)+=379, (M-H)' =377
Example 197
CH3
AcHN. N~.,~OH
HH O
~OH
O=P-OCH3 TFA
OCH3
-(2R.3S.5R.1'R.2'R}-~1-Acetamido-2-hydroxy-3-dimethylphosphon r~1 propyl-
~cis-propen-1-yl) pYrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-
5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t
butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolid
ine-5-
carboxylic acid t butyl ester (yield: 13 mg, 96%).
' H NMR (DMSO-d6) 8 7.72 (d, J=9.2 HZ, 1 H), 5.48(m, 1 H), 5.24(m, 1 H),
4.44(m, 1 H), 4.15(m, 2H), 3.62(m, 7H), 3.54(m, 1 H), 3.15(m, 1 H), 2.40(m, 1
H),
1.95(m, 1 H), 1.82(s, 3H), 1.72(m, 1 H), 1.54(dd, J=6.7, 1.2 HZ, 3H)
MS: (M+H)+= 379, (M-H)' = 377
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Example 198
{t)-{2R 3S 5R 1'S)-2-~1-Acetamido-3-hydroxY)propel-3-(cis-propen-1-~~
pyrrolidine-5-carboxyiic Acid Triffuoroacetic Acid Salt
CH3
AcHN. N,., O~Bu
H Boc
OCH3
198A (t)-(2R.3S 5R 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(cis and traps-2-
methoxyvinyl))methyl-3-(cispropen-1-YI)-pyrrolidine-5-carboxylic Acid t Butt
Ester
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-{1-acetamido-1-formyl)methyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (113 mg, 0.28
mmol)
was added to a solution of (methoxymethyl)triphenylphosphonium bromide (240
mg, 0.70 mmof) and potassium t-butoxide (0.56 mL, 0.56 mmol, 1 M in THF) in
toluene (3 mL) at 0°C for 15 minutes. The reaction was quenched with
saturated
aqueous ammonium chloride (3 mL) followed by extraction using
dichloromethane (2 X 3 mL). The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue was purified by
column
chromatography on silica get using 1 /4: ethyl acetatelhexane to provide the
title
compounds
' H NMR (CDC13) 8 8.65 (br d, 1 H) 6.01 (d, J=5.7Hz, 1 H), 5.40 (m, 3H),
5.11 (br t, 1 H), 4.15 (m, 2H), 3.72 (m, 1 H) 3.61 (s, 3H), 3.00 (m, 1 H),
2.42 (m,
1 H), 1.94 (s, 3H), 1.64 (dd, J=1.4, S.OHz, 3H), 1.45 (m, 9H), 1.25 (m, 9H)
MS: (M+H)+= 439.
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!-= ,
CH3
AcHN. N~.,~ ~Bu
p H Boc p
H
198B (t)-(2R.3S.5R.1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyt)ethLrl-3-
(cis-propen-1- r~pyrrolidine-5-carboxylic Acid t-Butyl Ester
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(cis and traps-2-
methoxyvinyi))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester
(21 mg, 0.048 mmol) was reacted with Liar (37 mg, 0.43 mmol) and AG50W-X2
ion exchange resin in CH3CN (2 mL) and water (0.1 mL) at room temperature for
45 minutes. The reaction was filtered and quenched with saturated aqueous
sodium bicarbonate (1 mL) followed by extraction using dichloromethane (2 X 1
mL). The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel using 1/4: ethyl acetate/hexane to provide the title compound.
' H NMR (CDC13) s 9.70 (dd, J=1.3, 2.4Hz, 1 H), 8.11 (d, J=7.8Hz, 1 H), 5.54
(m, 1 H), 5.41 (t, J=5.8Hz, 1 H), 4.52 (m, 1 H), 4.13 (dd, J=4.4, 4.8Hz, 1 H),
3.75
(dd, J=2.7, 3.1 Hz, 1 H), 2.86 (m, 1 H), 2.47 (m, 3H), 1.99 (s, 3H), 1.63 (dd,
J=1.6,
5.1 Hz, 3H), 1.46 (s, 9H), 1.45 (m, 1 H), 1.44 (s, 9H)
MS: (M+H)+= 425; (M-H)- = 423.
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/~,
CH3
AcHN. N~., OtBu
H Boc
OH
198C (t)-~2R.3S.5R.1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-hydroxy)propyl-3-
(cis-propen-1-~p~rrolidine-5-carboxylic Acid t-Bu I Ester
(t)-(2R, 3S, 5R,1'S)-1-t-Butoxycarbonyl-2-( 1-acetamido-2-formyl)ethyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (9 mg, 0.02
mmol) was
reacted with sodium borohydride (1 mg, 0.02 mmol) in methanol (0.1 mL) at room
temperature for 20 minutes. The reaction was quenched with saturated aqueous
ammonium chloride (1 mL) followed by extraction using dichloromethane (2 X 1
mL). The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel using 1/4: ethyl acetate/hexane to provide the title compound.
' H NMR {CDC13) b 8.45 (d, J=7.5Hz, 1 H), 5.55 (m, 1 H), 5.34 (t, J=7.8Hz,
1 H), 4.20 (dd, J=3.0, 5.4Hz, 2H), 3.71 (d, J=6.1 Hz, 1 H), 3.62 (m, 1 H),
3.50 (t,
J=9.1 Hz, 1 H), 2.92 (m, 1 H), 2.41 (m, 1 H), 2.04 (s, 3H), 1.66 (dd, J=2.0,
5.1 Hz,
3H), 1.62 (m, 1 H), 1.47 (s, 9H), 1.45 (m, 1 H), 1.43 (s, 9H), 1.22 (m, 2H)
MS: (M+H)+ = 427; (M-H)- = 425.
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/= ,
CH3
AcHN_ N~,~OH
H H
O
OH TFA
198D Ct)-f2R 3S 5R 1'S)-2-!1-Acetamido-3-h dY roxy_)propyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-
2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester in
place of (t)-(2R,3S,5R,1'R,2'S)- 1-f butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester.
ester
(yield: 4.6 mg, 100%).
~ H NMR (DMSO-ds) 8 9.25 (br s, 1 H), 8.13 (d, J=7.3Hz, 1 H), 5.52 (m, 1 H),
5.28 (br t, 1 H), 4.32 (br t, 1 H), 4.22 (m, 1 H), 3.49 (m, 4H), 3.18 (m, 1
H), 2.40 (m,
1 H), 1.90 (s, 3H), 1.73 (m, 1 H), 1.63 (dd, J=1.8, 5.5Hz, 3H), 1.57 (m, 1 H)
MS: (M-H)- = 269; (M+H)+ = 271.
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Example 199
!t)-(2R.3S,5R,1'S,3'S)-2-(1-Acetamido-3-h droxY)pentyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3 CH3
AcHN_ ,., OtB~ AcHN_ )., O~Bu
H Boc ~ H Boc
OH OH
199A (~2R.3S.5R,1'S.3'S) and (t)-(2R,3S,5R,1'R.3'R)-1-t-Butoxycarbonyl-2-
(1-acetamido-3-h~droxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid
(-
Butyl Ester
(t)-(2R,3S,5R,1'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (26 mg, 0.061
mmol)
was reacted with ethylmagnesium bromide (3.0 M) (0.122 mL, 0.367 mmol) in
THF (4 mL) at room temperature for 30 minutes. The reaction was quenched
with saturated aqueous ammonium chloride (10 mL) and water (10 mL) followed
by extraction using ethyl acetate (3 X 25 mL). The organic layer was dried
over
magnesium sulfate, filtered and concentrated in vacuo. The residue was
purified
by column chromatography on silica gel using 1/1 ethyl acetate/hexane followed
by 2/1 ethyl acetate/hexane to provide the title compounds (t)-
(2R,3S,5R,1'S,2'S)
(yield: 6.7 mg, 24%) and (t)-(2R,3S,5R,1'S,2'R) (yield: 6.8 mg, 24%).
(t)-(2R,3S,5R,1'S,2'S) MS: (M+H)+=455, (M+Na)+=477, (M-H)'=453.
(t)-(2R,3S,5R,1'S,2'R) MS: (M+H)+=455, (M+Na)+=477, (M-H)-=453.
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CH3
AcHN. N~,~OH
H H
O
OH TFA
199B ~t)-(2R,3S.5R.1'S.3'S)-2-(1-Acetamido-3-h~droxy)pentyl-3-(cis-propen-1-
~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S,3'S}-1-t butoxycarbonyl-2-(1-
acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester.
ester (yield: 6.2 mg, 100%).
' H NMR (DMSO-ds) 8 9.20 (bs, 1 H), 8.18 (d, J=7.3 Hz, 1 H), 5.51 (m, 1 H),
5.27 (m, 1 H), 4.30 (m, 1 H), 4.25 (m, 1 H), 3.58 (m, 1 H), 3.41 (m, 1 H),
3.18 (m,
1 H), 2.39 (m, 1 H), 1.90 (s, 3H), 1.75 (m, 1 H), 1.64 (dd, J=7.5,1.SHz, 3H),
1.51
(M, 1 H), 1.38 (m, 1 H), 1.32 (m, 1 H), 0.83 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 299, (M+Na)+ = 321, (M-H)' = 297, (2M-H)-=595.
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Example 200
f~2R,3S.5R.1'S,3'R~ 2-(1-Acetamido-3-hydroxy)pen I-3-(cis-propen-1=yl)-
pyrrolidine-5-carbolic Acid Trifluoroacetic Acid Salt
'=,
CH3
AcHN. N,.,~ H
H H
O
OH TFA
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'S,3'R)-1-t-butoxycarbonyl-2-(1-
acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester.
ester (yield: 6.5 mg, 100%).
' H NMR (DMSO-ds) 8 9.25 (bs, 1 H), 8.15 (d, J=7.3 Hz, 1 H), 5.52 (m, 1 H),
5.27 (m, 1 H), 4.31 (m, 2H), 3.52 (m, 1 H}, 3.36 (m, 1 H), 3.19 (quint.,
J=8.5Hz,
1 H), 2.38 (m, 1 H), 1.92 (s, 3H), 1.75 (m, 1 H), 1.64 (dd, J=7.3,1.SHz, 3H),
1.48
(m, 1 H), 1.33 (m, 2H), 0.85 (t, J=7.3Hz, 3H).
MS: (M+H)' = 299, (M+Na)+ = 321, (M-H)- = 297, (2M-H)-=595.
Example 201
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it~2R 3S 5R 1'R)-2-j1-Acetamido-2-oxo-3.3-difluoro-3-vinyl)propyl-3-(cis-
propen-1-y~-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
H
O
TFA
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-
Acetamid o-2-oxo-3, 3-d ifl uoro-3-vinyl)propyl-3-( cis-p rope n-1-yl)-pyrrol
id ine-5-
carboxylic Acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-2-( 1-acetamido-2-hyd roxy) butyl-3-(cis-propen-1-yl)-pyrrol id
ine-5-
carboxylic acid t butyl ester (yield: 0.0050 g, 100%).
' H NMR (DMSO-ds) 8 8.67 (d, J=8.5Hz, 1 H), 6.1-5.95 (m, 1 H), 5.78 (dd,
J=17.1, 2.4Hz, 1 H), 5.71 {d, 11.OHz, 1 H), 5.45 (m, 1 H), 5.12 (m, 1 H), 4.94
(t,
J=9.2Hz, 1 H), 4.51 (dd, J=12.2,6.1 Hz, 1 H), 3.98 (m, 1 H), 3.24 (m, 1 H),
2.32 (m,
1 H), 1.73 {s, 3H), 1.66 (q, J=11.9Hz, 1 H), 1.57 (dd, J=6.7,1.BHz, 3H).
MS: (M+H)+ = 331, (M+H20)+=349, (M+Na)+ = 353, (M-H)- = 329, (2M-H)-
=659.
CH3
AcH N
H N
H
~O
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Example 202
TBDPSO-, TBDPSO--
t t
AcHN- N~_~ Bu AcHN- N~,~ Bu
H Boc pO H Boc
~OH ~OH
202A (t)-(2R,3R.5Ry1'R,2'S) and (t)-(2R,3R,5R.1'R,2'R)-1-t Butoxycarbon
(1-acetamido-2-hydroxy~lbutyl-3-t but~ldiphenylsilyloxymethyl-pyrrolidine-5-
carboxylic Acid t-ButLrl Ester
The title compounds were prepared according to the method described in
Example 41 B substituting (t)-(2R,3R,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-
2-formyl)ethyl-3-t butyldiphenylsilyloxymethyi-pyrrolidine-5-carboxylic acid t
butyl
ester in place of (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-
formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
to
provide (t)-(2R,3R,5R,1'R,2'S) isomer (yield: 370 mg, 17%) and (t)-
(2R,3R,5R,1'R,2'R) isomer (yield: 1.2 g, 55%).
(t)-(2R,3R,5R,1'R,2'S) 1H NMR(d6-DMSO) 8 7.4-7.65 (m, 10H), 4.47
(d, 1 H), 4.32 (m, 1 H), 3.87 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 {m,
1 H), 2.7
(m, 1 H), 2.45 (m, 1 H), 2.0 (m, 1 H), 1.83 (d, 3H), 1.28-1.4 (m, 18H), 0.95
(d, 9H),
0.83 (dt, 3H)
MS: (M-H)- = 667, (M+35)+ = 703; (M+H) + = 669, (M+Na) + = 691
(t)-(2R,3R,5R,1'R,2'R) 1 H NMR(d6-DMSO) 8 7.4-7.65 (m, 10H), 4.40
(dd, 1 H), 4.12-4.32 (m, 1 H), 3.82-3.96 (m, 1 H), 3.66 (m, 2H), 3.52 (t, 1
H), 2.6-2.8
(m, 1 H), 2.45 (m, 1 H), 1.76-2.0 (m, 1 H), 1.87 (d, 3H), 1.25-1.4 (m, 18H),
0.95 (d,
9H), 0.83 (dt, 3H).
MS: (M-H)- = 667, (M+35)+ = 703; (M+H) + = 669, (M+Na) + = 691
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TBDPSO-
AcHN- N~,~O~Bu
H Boc O
OI
~O
I
202B (t)-(2R 3R 5R 1'R,2'S -) 1~t-Butoxycarbonyl-2-(1-acetamido-2-
metho~methYloxy}butyl-3-t butyldiphenYlsilyloxyrnethyl-pyrrolidine-5-
carboxylic
Acid t Butyl Ester
(t)-(2R,3R, 5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-
hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t
butyl
ester (0.58 g,0.87 mmole) was reacted with methoxymethyl chloride (1.15 mL,
10.07 mmole) and diisopropylethylamine (3.5 mL, 20.1 mmole) in
dichloromethane (1 mL) at room temperature for 5 hours. The reaction was
quenched with saturated NH4C1 (100 mL) and diluted with ethyl acetate (200
mL).
The organic layer was washed with water, and brine, dried over MgS04, filtered
and concentrated in vacuo. The residue was purified by chromatography on
silica gel using 5% methanoi/methylene chloride to provide the title compound
(yield: 0.64 g, 98%).
1 H NMR(d6-DMSO) 8 7.4-7.65 (m, 1 OH), 4.70 (s, 1 H), 4.62 (s, 1 H), 4.35-
4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 (m, 1 H),
3.24
(s, 3H), 2.55 (m, 1 H), 2.45 (m, 1 H), 2.0 (m, 1 H}, 1.85 (s, 3H), 1.28-1.4
(m, 18H),
0.99 (d, 9H), 0.8 (dt, 3H)
MS: (M-H)- = 755, (M+35)+ = 791; (M+H) + = 757, (M+Na) + = 779
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HO-
AcHN- N~,~OtSu
H Boc ~(O
O
~O
I
202C (tl~2R 3R 5R,1'R 2'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-
methoxymethyloxy)butt'l-3-hydrox~methyl-pyrrolidine-5-carboxylic Acid t-Butyl
Ester
The title compound was prepared according to the method described in
Example 1236 substituting (t)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-
5-carboxylic acid t butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t
butoxycarbonyl-
2-oxiranyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 0.416 g, 95%).
1 H NMR(d6-DMSO) 8 7.45 (t, 1 H), 4.62-4.74 (m, 3H), 4.48 (m, 1 H), 3.85
(m, 2H), 3.55-3.6 (m, 2H), 3.45 (t, 1 H), 3.2-3.4 (m, 2H), 3.25 (d, 3H), 2.4
(m, 2H),
1.82 (d, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.82 (dt, 3H).
MS: (M-H)- = 517, (M+35)+ = 553; (M+H) + = 519, (M+Na)+ = 541
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H
O~
AcHN- N~.~ ~B~
H Boc O
O
~O
I
202D (t)-(2R.3R 5R,1'R.2'S)-1-t-Butoxycarbon~r4-2-(1-acetamido-2-
methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester
The title compound was prepared according to the method described in
Example 123H substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-
oxiranyl-3-
hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.335 g,
80.8%).
1 H NMR(dg-DMSO) 8 9.55 (d, 1 H), 7.48 (m, 1 H), 4.55-4.72 (m, 4H) 3.9
(d, 1 H), 3.6 (m, 2H), 3.45 (m, 3H), 3.32 (s, 3H), 3.05 (t, 1 H), 2.25-2.45
(m, 4H),
1.83 (s, 3H), 1.58 (m, 3H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).
MS: (M-H)- = 515, (M+35)+= 551; (M+H)+ = 517
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OH
AcHN- N~.
H Boc ~O
O
~O
I
202E (t)-(2R.3R,5R.1'R,2'S.1"RS)-1-t Butoxycarbonyl-2-(1-acetamido-2-
methoxymethyloxy)buyl-3-(1-h dY roxy-2-propyn-1yl)-pyrrolidine-5-
carboxYlicAcid
t-Butyl Ester
The title compound was prepared according to the method described in
Example 38A substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxymethyioxy)butyl-3-formyl-pyrrolidine-5-carboxylic acid t
butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-
methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.27
g,
83%).
MS: (M-H)- = 541, (M+35)+ = 577; (M+H)+ = 543, (M+Na)+ = 565
0
AcHN- N~.,~O~Bu
H Boc O
O
~O
I
202F (t)-(2R.3R,5R.1'R.2'S)-1-t-Butox~carbony!-2-(1-acetamido-2-
methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic Acid t
Bu 1 Ester
The title compound was prepared according to the method described in
Example 38B substituting (t)-(2R,3R,5R,1'R,2'S,1"RS)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-methoxymethyloxy)butyl-3-( 1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S,1"RS)-1-t-
butoxycarbonyl-2-( 1-acetamido-3-methyl)butyl-3-( 1-hydroxy-2-propyn-1-yl)-
pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.2 g, 74%).
1 H NMR(dg-DMSO) 87.49 (br d, 1 H), 5.0 (d, 1 H), 4.7 (br s, 1 H), 4.55-4.7
(m, 3H), 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H),
3.24 (s,
3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86
(dt,
3H)
MS: (M-H)' = 539, (M+35)+ = 575; (M+H)+ = 541, (M+Na)+ = 563
HN
N
AcHN- ~ O~Bu
N
H Boc'
-O
~O
I
2026 (t)-(2R 3R 5R 1'R 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-
methox)rmethyloxY~ut)rl-3-(pyrazol-3-YI~-pyrrolidine-5-carboxylic Acid t-Butyl
Ester
The title compound was prepared according to the method described in
Example 38C substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-
carboxylic acid t butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t
butoxycarbonyl-2-
(1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic
acid
t-butyl ester (yield: 180 mg, 87%).
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1 H NMR(dg-DMSO) ~ 7.57 (br t, 2H), 6.1 (d, 1 H), 4.50-4.7 (m, 4H) 3.95
(m, 1 H), 3.4-3.6 (m, 3H), 3.3-3.4(m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1 H),
2.2 (m,
1 H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (dt, 3H).
MS: {M-H)- = 553, (M+35)+ = 589; (M+H)+ = 553, (M+Na)+ = 577
HN
N
AcHN. N~.,~OH
H H
OH O
TFA
202H (t -(~ 2R,3R.5R.1'R,2'S~-~1-Acetamido-2-h r~droxY~but~pyrazol-3-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3R,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester in place (t)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-
methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester. Chromatography on
silica gel with 2-propanol:acetic acid:ethyl acetate:water 1:1:3:1 followed by
the
addition of 0.1 % trifluoroacetic acid gave the title compound (yield: 15 mg,
55%}.
1 H NMR(dg-DMSO) 8 7.95 (d, 1 H), 7.65 (br s, 1 H), 6,18 (d, 1 H), 4.37 (m,
1 H), 4.23 (m, 1 H), 4.38 (m, 1 H), 4.56 (m, 1 H), 2.63 (m, 1 H), 2.10 (m, 1
H), 1.78 (s,
3H}, 1.50 (m, 1 H), 1.25 (m, 1 H), 0.83 (t, J=7.46 Hz, 3H).
MS: (M-H)- = 309, (M+35)+ = 345; (M+H) + = 311, (M+Na) + = 333
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Example 203
(t)-(2R.3R,5R,1'R.2'R~2-~1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
TBDPSO-,
AcHN- ,- OtBu
~N
N Boc '~
~O
203B (t)-(2R,3R,5R.1'R.2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-
methoxymethyloxY)butyl-3-t butyidiphenylsilyloxymethyl-pyrrolidine-5-
carboxylic
Acid t-Butyl Ester
The title compounds were prepared according to the method described in
Example 202B substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'R,2'S)-1-t-
butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-t-butyld
iphenylsilyloxymethyl-
pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.217 g, 96%).
1 H NMR(dg-DMSO) 87.4-7.65 (m, 10H), 4.70 (s, 1 H), 4.62 (s, 1 H), 4.35-
4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H}, 3.25 (m, 1 H),
3.24
(s, 3H), 2.55 (m, 1 H), 2.45 (m, 1 H), 2.0 (m, 1 H), 1.85 (s, 3H), 1.28-1.4
(m, 18H),
0.99 (d, 9H), 0.8 (dt, 3H).
MS: (M-H)- = 755, (M+35)+ = 791; (M+H} + = 757, (M+Na) + = 779
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HO--
AcHN- N~,~OtBu
H Boc O
~O
'O
I
203C (t)-(2R,3R,5R,1'R,2'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-
methoxymeth~)butyl-3-hydroxymethyl pyrroiidine-5-carboxylic Acid t Butt
Ester
The title compound was prepared according to the method described in
Example 1236 substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-t-butyldiphenylsiiyloxymethyl-pyrrolidine-
5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t-
butoxycarbonyl-
2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 0.124' g, 83%).
1 H NMR(dg-DMSO) 8 7.42 (dd, 1 H), 4.62-4.8 (m, 3H), 4.48 (m, 1 H), 3.6-
3.85 (m, 3H), 3.35-3.6 (m, 4H), 3.25 (s, 3H), 2.25 (m, 1 H), 2.4 (m, 1 H),
2.28 (m,
1 H), 1.82 (s, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.9 (dt, 3H).
MS: (M-H)- = 517, (M+35)+ = 553; (M+H)+ = 519, (M+Na)+ = 541
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H
O~
,
AcHN- N,-, ~O~Bu
H Boc O
~O
'O
203D ~t~-(2R 3R 5R 1'R.2'R)-1-t-ButoxycarbonLrl-2-(1-acetamido-2-
methoxymethyloxY)butyl-3-formyl-pyrrolidine-5-carboxyiic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 123H substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxymethyfoxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-
oxiranyl-3-
hydroxymethyl-pyrroiidine-5-carboxylic acid t-butyl ester (yield: 0.106 g,
86%).
1 H NMR(d6-DMSO) 89.58 (d, 1 H), 7.58 (dd, 1 H), 4.6-4.72 (m, 3H),
4.48(d, 1 H), 3.88 (d, 1 H), 3.4-3.65 (m, 5H), 3.24 (s, 3H}, 3.15 (dd, 1 H),
2.20-2.48
(m, 4H), 1.86 (s, 3H), 1.58 (m, 3H), 1.30-1.40 (m, 18H), 0.86 (t, 3H).
MS: (M-H)- = 515, (M+35)+ = 551; (M+H)+ = 517
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OH
AcHN~ N~,~O~Bu
H Boc O
~O
~O
I
203E (t~~2R 3R 5R~1'R 2'R 1"RS)-1-f-Butoxycarbonyl-2-(1-acetamido-2-
methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic
Acid
f-Butyl Ester
The title compound was prepared according to the method described in
Example 38A substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3R,5R,1'S,1"RS)-1-f-butoxycarbonyl-2-(1-
acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl ester
(yield: 32 mg, 76%).
MS: (M-H)' = 541, (M+35)+ = 577; (M+H)+ = 543, (M+Na)' = 565
0
AcHN- N~,~OzBu
H Boc O
~O
'O
I
203F (t)-(2R 3R 5R 1'R 2'R~,-1-t-Butoxycarbonyl-2-(1-acetamido-2-
methoxymethyloxy)butyl-3-(1-oxo-2propyn-1-girl)-pyrrolidine-5-carboxylicAcid t
Butyl Ester
The title compound was prepared according to the method described in
Example 38B substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-methoxymethyloxy)butyl-3-( 1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-
carboxylic acid f-butyl ester in place of (t)-{2R,3R,5R,1'S,1 "RS)-1-t
butoxycarbonyl-2-( 1-acetamido-3-methyl)butyl-3-( 1-oxo-2-propyn-1-yl)-
pyrrolidine-5-carboxylic acid t butyl ester (yield: 25 mg, 78%).
1 H NMR(d6-DMSO) s 7.49 (br d, 1 H), 5.0 (d, 1 H), 4.7 (br s, 7 H), 4.55-4.7
(m, 3H) 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H), 3.24
(s,
3H), 2.4-2.7 (m, 2H), 1.84 {s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86
(dt,
3H).
MS: (M-H)~ = 539, (M+35)+ = 575; (M+H)+ = 541, (M+Na)+ = 563
HN
~(N
AcHN- ,- C~Bu
N
H Boc '
~O
'O
I
203~t)-(2R,3R,5R,1'R,2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-
methox~yloxylbutyl-3-(pyrazol-3-yl)-~rrrolidine-5-carboxylic Acid t-Butt'
Ester
The title compound was prepared according to the method described in
Example 38C substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-
carboxylic acid f butyl ester in place of (t)-(2R,3R,5R,1'S)-1-f-
butoxycarbonyl-2-
{1-acetamido-3-methyl)butyl-3-{1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic
acid
t butyl ester (yield: 18 mg, 72%).
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1 H NMR(d6-DMSO) 8 7.57 (m, 2H}, 6.1 (d, 1 H), 4.40-4.7 (m, 4H) 3.93 (m,
1 H), 3.4-3.6 (m, 3H), 3.3-3.4(m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1 H), 2.2
(m,
1 H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (m, 3H).
MS: (M-H)- = 553, (M+35)+ = 589; (M+H)+ = 553, (M+Na)+ = 577
H N
N
AcHN_ N~_,~OH
H H
~OH O
TFA
203H (t)-(2RL3R~5R,1'R,2'R)-2-(1-Acetamido-2-hydroxY~butyl-3-(p rLrazol-3-y_I}-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 15B, substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-
ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
Chromatography on silica gel with 2-propanol:acetic acid:ethyl acetate:water
1:1:3:1 followed by the addition of 0.1 % trifluoroacetic acid gave the title
compound (yield: 4 mg, 45%).
1 H NMR(d6-DMSO) b 7.65 (d, 1 H), 7.64 (d, 1 H), 6,16 (d, 1 H), 4.37 (m,
1 H), 4.23 (m, 1 H), 4.38 (m, 1 H), 4.56 (m, 1 H), 2.63 (m, 1 H), 2.10 (m, 1
H), 1.74 (s,
3H), 1.25-1.40 (m, 2H), 0.83 (t, J=7.46 Hz, 3H).
MS: (M-H)- = 309, (M+35)+ = 345; (M+H)+ = 311, (M+Na)+ = 333
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Example 204
(t)-~2R,3R,5R)-2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carbolic
Acid Hydrochloride.
TBDMSO~
H2N ~ , OtBu
O
Ph
204A {t)-(2R.3R,5R)-1-Benzyl-2-aminomethyl-3-t butyldimethylsilyloxymeth r~l-
pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound is prepared according to the method described in
Example 1 F, substituting (t)-(2R,3R,5R)-1-benzyl-2-formyl-3-t
butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in
place of
(t)-(2R, 3R, 5 R)-1-benzyl-2-( 1-oxo-3-ethyl)pentyl-3-t-butyld
imethylsilyloxymethyl-
pyrrolidine-5-carboxylic acid t-butyl ester.
MS: (M+H)+= 435
TBDMSO-
AcNH~., OtBu
O
Ph
2048 (t)-(2R.3R 5R)-1-Benzyl-2-acetamidomethyl-3-t-
butyldimeth isilylox~methYl-~~rolidine-5-carboxylic Acid t-Butyl Ester
The title compound is prepared according to the method described in
Example 1 G, substituting (t)-(2R,3R,5R)-1-benzyl-2-aminomethyl-3-t-
butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in
place of
(t)-(2R,3R,5R,1'R)- and (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-
3-
t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
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'H NMR (CDC13): 8 7.2-7.35 (m, 5H), 6.14 (br, 1H), 3.86 (dd, J=18Hz,
13.5Hz, 2H), 3.67 (m, 1 H), 3.60 (m, 1 H), 3.49 (m, 1 H), 3.28 (m, 1 H), 3.06
(m,
1 H), 2.19 (m, 2H), 1.95 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H).
MS: (M+H)+= 477
HO-
AcNH~., OtBu
HN
O
Ph
204C ft)-(2R 3R 5R)-1-BenzLrl-2-acetamidomethyl-3-hydroxymethyl-pyrrolidine-
5-carboxylic Acid t Butyl Ester
The title compound was prepared according to the method described in
Example 1 H, substituting (t)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-f-
butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in
place of
(t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-f-
butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
O
H "~
AcNH~~, OtBu
~ N
O
Ph
204D (t)-!2R 3R,,5R)-1-Benzvl-2-acetamidomethyl-3-formyl-pyrrolidine-5-
carboxylic Acid t But)rl Ester
The title compound was prepared according to the method described in
Example 2A, substituting (t)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-
hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (t)-
(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydrxoxymethyl-
pyrrolidine-5-carboxylic acid f butyl ester.
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' H NMR (CDC13): b 9.70 (s, 1 H), 7.22-7.36 (m 5H), 5.82 (br, 1 H), 3.83 (dd,
J= 3.3Hz, 13.5Hz, 2H), 3.74 (m, 1 H), 3.56 (d, J= 9Hz, 1 H), 3.15 (m, 1 H),
2.73 (m,
1 H), 2.36-2.10 (m, 2H), 1.98 (s, 3H), 1.45 (s, 9H).
MS: (M+H)+= 361
0
CH30"
AcNH~., OtBu
H N
O
Ph
204E fit)-(2R.3R.5R -1-Benz~l-2-acetamidomethyl-3-methoxycarbonyl-
pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 2B and 2C, substituting (t)-(2R,3R,5R)-1-benzyl -2-acetamidomethyl-3-
formyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (t)-
(2R,3R,5R,1'S)-1-
benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylic acid t
butyl
ester.
'H NMR (CDC13): 8 7.45-7.20 (m, 5H), 5.96 (br, 1 H), 3.90-3.73 (m, 4H),
3.71 (s, 3h-.), 3.52 (dd, J=9Hz, 2Hz, 1 H), 3.13 (m, 1 H), 2.84 (m, 1 H), 2.36
(m, 1 H),
2.18 (m, 1 H), 1.97 (s, 3H), 1.45 (s, 9H).
MS: (M+H)+= 391
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O
CH30
AcNH~~ OtBu
MN
H O
204F (t~-(2R.3R,5R~2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-
carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in
Example 2D, substituting (t)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-
methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-
(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-
pyrrolidine-5-carboxylic acid t-butyl ester.
'H NMR (CDC13): b 6.19 (br, 1H), 3.72 (m, 2H), 3.70 (s, 3H), 3.43 (m, 1H),
3.28 (m, 1 H), 2.74 (m, 1 H), 2.44 (m 1 H), 2.21 (m, 1 H), 2.00 (s, 3H), 1.48
(s, 9H).
MS: (M+H)+= 301
0
CH30"~
AcNH~~, OH
HN
H O
HCI
204G (t)-(2R,3R.5R)-2-Acetamidomethyl-3-methoxycarbon~yrrolidine-5-
carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in
Example 2E substituting (t)-(2R,3R,5R)-2-acetamidomethyl-3-methoxycarbonyl-
pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-2-
(1-
acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid t-
butyl
ester.
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' H NMR (D20): b 4.42 (t, J=8.25Hz, 1 H), 4.22 (m, 1 H), 3.83 (m, 1 H), 3.75
(s, 3H), 3.70-3.60 (m, 2H), 3.26 (m, 1 H), 2.78 (m, 1 H}, 2.43 (m, 1 H), 2.03
(s, 3H).
MS: (M+H)+= 245
Examples 205-213
HO-
AcHN~. OtBU AcHN~., OH
Boc
Example 204C
The following title compounds were prepared according to the methods
described in Examples 1-39 from the common intermediate prepared as
described in Example 204C.
Example 205
0
AcHN~.,,, OH
H N
H O
TFA
~t)-(2R,3R,5R)-2-Acetamidomethyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylic
Acid Trifluoroacetic Acid Salt.
'H NMR (D20) 8 4.30 (t, J=8.2Hz, 1 H), 4.21 (m, 3H), 3.62 (dd, J=2.4,
3.4Hz, 2H), 3.23 (m, 1 H), 2.74 (m, 1 H), 2.38 (m, 1 H), 2.02 (s, 3H), 1.2fi
(m, 3H)
MS: (M+H)' = 259; (M-H)- = 257.
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Example 206
~N
HN
AcHN ~.., OH
H H ,,
HCI
(t)-(2R,3R.5R~-2-Acetamidomethyl-3-(imidazol-2 yl)-pyrrolidine-5-carbox~iic
Acid
Hydrochloride
'H NMR (Dz0): 8 7.46 (s, 2H}, 4.53 (dd, J=9.5Hz, J=8.5 Hz, 1H), 4.28 (rn,
1 H), 3.96 (m, 1 H), 3.65 (m, 2H), 3.03 (dt, J=13.5Hz, J=7.6Hz, 1 H), 2.46 (m,
1 H),
1.94 (s, 3H).
MS: (M-~H)+=253, {M-H)'=251
Example 207
_ -.
AcHN ~.,, OH
H N ~~
H O
TFA
(t)-(2R,3S.5R~2-AcetamidomethLrl-3-vinyl-pyrrolidine-5-carboxylic Acid
Trifluoroacetic Acid Salt.
' H NMR (D20) 8 5.74 (m, 1 H), 5.24 (m, 2H), 4.20 {dd, J=1.7, 8.1 Hz, 1 H),
3.65 (m, 2H), 3.50 (m, 1 H), 2.84 (m, 1 H), 2.61 (m, 1 H), 2.03 (s, 3H), 1.95
(m, 1 H)
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MS: (M+H)+= 213.
Example 208
H3C
.;.
H3C
AcHN~.,,, OH
H N
H O
TFA
(t~~2R 3R 5R)-2-Acetamidomethyl-3-(2.2-dimethyl-vinyl)-pyrrolidine-5-carbox
Acid Trifluoroacetic Acid Salt.
' H NMR (D20) 8 5.01 (br d, 1 H), 4.18 (dd, J=2.1, 8.1 Hz, 1 H), 3.53 (m, 3H),
3.04 (m, 1 H), 2.55 (m, 1 H), 2.0 (s, 3H), 1.75 (m, 1 H), 1.72 (s, 3H), 1.67
(s, 3H)
MS: (M+H)+= 241, (M+Na)+ = 263; (M-H)- = 239.
Example 209
H3CN_!O
H3C
OH
N ~~~
AcHN H H O
HCI
(t)-(2R 3R 5R)-2-Acetamidomethyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt.
'H NMR (D20) s 4.60 (t, J=8.4Hz, 1H), 4.23 (m, 1H), 3.56 {d, J=5.8Hz, 2H)
3.50 (m, 1 H), 3.10 (s, 3H), 2.94 (s, 3H), 2.88 (m, 1 H), 2.19 (m, 1 H), 2.00
{s, 3H)
MS: (M+H)+= 258, (M-H)- = 256.
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Example 210
H3C, O
HN~~
N I
AcHN H ti O
TFA
~)-(2R 3R 5R~ 2-Acetamidomethyl-3-lN-methylcarbamoyl)-pyrrolidine-5-
carboxytic Acid Trifluoroacetic Acid Salt.
'H NMR (Dz0) 4.49 (t, J=8.5Hz, 1 H), 4.10 (m, 1 H), 3.57 (d, J=5.8Hz, 2H),
3.03 (m, 1 H), 2.76 (m, 1 H), 2.74 (s, 3H), 2.29 (m, 1 H), 2.00 (s, 3H)
MS: (M+H)+ = 244.
Example 211
Hs ~O
~.,,~~~OH
NN
AcHN H hi O
TFA
(t)-(2R 3R 5R)-2-Acetamidomethyl-3-propionyl-pyrrolidine-5-carboxyiic Acid
Trifluoroacetic Acid Salt.
' H NMR (D20) 8 4.24 (m, 2H), 3.55 (d, J=4.7Hz, 1 H), 3.40 (m, 1 H), 2.85
(m, 1 H), 2.64 (m, 3H), 2.16 (m, 1 H), 2.01 (s, 3H), 1.02 (t, J=7.1 Hz, 3H)
MS: (M+H)+ = 243; (M-H)- = 241.
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Example 212
H3C
O-
OH
AcHN H H O
HCI
(t)-(2R 3R 5R)-2-Acetamidomethyl-3-methoxymethyl-~pyrrolidine-5-carboxylic
Acid Hydrochloride
' H NMR (D20): b 4.44 (t, J=6Hz, 2H), 3.77 (m, 1 H), 3.65-3.48 (m, 3H),
3.35 (s, 3H), 2.64 (m, 1 H), 2.56 (m, 1 H), 2.03 (s, 3H), 2.00 (m, 1 H).
MS: (M+H)+= 231, (M-H)- = 229
Example 213
H3C;
OH
N I ~~~
AcHN H H O
TFA
(t)-(2R 3S 5R)-2-Acetamidomethyl-3-methyl-pyrrolidine-5-carboxylic Acid
Trifluoroacetic Acid Salt.
' H NMR (D20) 8 4.30 (m, 1 H), 3.fi4 (m, 1 H), 3.48 (m, 1 H), 3.20 (m, 1 H),
2.64 (m, 1 H), 2.03 (s, 3H), 1.7fi (m, 1 H), 1.32 (br t, 1 H), 1.12 (m, 4H)
MS: (M+H)+= 201, (M+Na)+ = 223.
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Example 214
(t)-(2R 3S 5R 1'R)-2-~1-Acetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-
carbox~rlic Acid Trifluoroacetic Acid Salt
BocHN, N,., OtBu
H Boc
S
214A (t)- 2R 3S 5R 1'R)-1-t-ButoxLrcarbonyl-2-(1-t butoxycarbonylamino-2-
ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To a solution of ethanethiol (0.047 mL, 0.63 mmol) in THF (2 mL) at
0°C
was added 2.5 M n-BuLi/hexane (0.248 mL, 0.62 mmol). The reaction mixture
was stirred for 45 minutes and a solution of (t)-(2R,3S,5R,1'S)-1-t-
butoxycarbonyl-2-(N-t-butoxycarbonylaziridinyl)-3-vinyl-pyrroiidine-5-
carboxylic
acid t-butyl ester (0.08 g, 0.182 mmole) in THF (0.5 mL) was added followed by
DMF (1.5 mL) and stirred at room temperature for 2 hours. The reaction was
quenched with 1 N NaHC03 (10 mL) and diluted with ethyl acetate (20 mL). The
organic laysr was washed with water,and brine, dried over MgS04, filtered and
concentrated in vacuo. The residue was purified by chromatography on silica
gel
using 10% ethyl acetate/hexanes to provide the title compound (yield: 61 mg,
fi7%).
1 H NMR(dg-DMSO) b 6.74 (br d, 1 H), 5.85 (m, 1 H), 4.9-5.0 (m, 2H), 4.20
(m, 1 H), 3.95 (m, 1 H), 3.75 (d, 1 H), 2.8-3.0 (dd, 1 H), 2.5 (m, 3H), 1.fi5
(m, 1 H),
1.32-1.45 (m, 27H), 1.17 (dt, 3H).
MS: (M-H)- = 499; (M+H)+ = 501, (M+Na)+ = 523
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Ac
BocN. N~, OtBu
H Boc
S
214B (t)-(2R 3S 5R 1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonvlacetamido-
2-et~lthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-
ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (58 mg,
0.116
mrnole) was reacted with lithium hexamethyfdisilazide (1 M) (1.16 mL, 1.16
mmoie) in THF (3 mL) at -78 °C. After 0.5 hour at -78 °C and 1
hour at -40 °C, the
above reaction mixture was reacted with acetyl chloride (0.166 mL, 2.33 mmole)
at -30 °C for 0.3 hours. The reaction was quenched with 1 N NaHCO3 (10
mL)
and extracted with ethyl acetate (20 mL). The organic layer was washed with
water,and brine, dried over MgS04, filtered and concentrated in vacuo. The
residue was purified by chromatography on silica gel using 10% ethyl
acetatelhexanes to provide the title compound (yield: 28 mg, 44%).
1 H NMR(dg-DMSO) 8 5.88 (m, 1 H), 4.9-5.0 (m, 2H), 4.52 (m, 1 H), 4.33
(m, 1 H), 4.1 (m, 1 H), 2.78 (dd, 1 H), 2.3-2.5 (m, 6H), 1.7 (m, 1 H), 1.32-
1.5 (m,
27H), 1.11 (t, 3H).
MS: (M+H) + = 543.
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AcHN OH
' N' .~~1~
HH O
S
TFA
214C (t)-(2R 3R 5R 1'R1-2-(1-Acetamido-2-ethylthio)eth I-3-vinyl-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-N-t
butoxycarbonylacetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl
ester
(yield: 7 mg, 95%).
1 H NMR(d6-DMSO) 8 8.15 (d, 1 H), 5.72 (m, 1 H), 5.05-5.2 (m, 2H), 4.2-
4.4 (m, 2H), 4.33 (m, 1 H), 2.93 (m, 1 H), 2.7-2.8 (2d, 1 H), 2.3-2.6(m, 3H),
1.85-
1.95 (m, 1 H), 1.93 (s, 3H), 1.17 (t, J=7.46 Hz, 3H)
MS: (M+H) + = 287.
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Example 215
(t)-(2R,3S.5R.1'R.3'S)-2-(1-Acetamido-2-ethylsulfin I~ethyl-3-vinyl-
pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
_~ Ac
BocN. ,/ OtBu Bo N, _ OtBu
N~,~ ~N~ ,~
H Boc O ~ H Boc O
S S
O O
215A (~-~2R 3S,5R,1'R.3'S) and (t)-(2R,3S,5R,1'R,3'R)-1-t-Butoxycarbon
~1-N-t-butox~rbonyiacetamido-2-ethylsulfinyl)ethyl-3-vin rLl-pyrrolidine-5-
carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-
2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (72 mg,
0.132
mmole) was reacted with 55% m-chloroperoxybenzoic acid (41 mg, 0.132 mmole)
in CHC13 (1.5 mL) at -40 °C for 30 minutes. The reaction was
concentrated in
vacuo. The residue was purified by chromatography on silica gel using ethyl
acetate to provide the title compounds (t)-(2R,3S,5R,1'R,3'S) isomer (yield:
14
mg, 18.9%) and (t)-(2R,3S,5R,1'R,3'R) (yield: 45 mg, 60.7%).
(2R,3S,5R,1'R,3'S) 1H NMR(dg-DMSO) s 5.88 (m, 1H), 4.9-5.0 (m, 2H),
4.50 (m, 1 H), 4.0-4.15 (m, 1 H), 2.7-2.9 (m, 3H), 2.55 (m, 1 H), 2.37 (s,
3H), 1.7
(m, 1 H), 1.32-1.5 (m, 27H), 1.12 (t, 3H)
MS: (M+H) + = 559, (M+Na) + = 581
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(2R,3S,5R,1'R,3'R) 1 H NMR(dg-DMSO) 8 5.88 (m, 1 H}, 4.9-5.0 (m, 2H),
4.50 (m, 1 H), 4.03-4.15 (m, 1 H), 3.2 (m, 1 H) 3.1 (dd, 1 H), 2.5-2.7(m, 2H),
2.38 (s,
3H), 1.75 (m, 1 H), 1.32-1.5 (m, 27H), 1.12 (t, 3H)
MS: (M+H) + = 559, (M+Na) + = 581
_ ~.
AcHN ' OH
H N ~ I
_H O
S
p TFA
2158 ~t~,~2R.3S,5R,1'R.3'S)-2-~1-Acetamido-2-ethylsulfinyl)eth !-y 3winyl-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,3'S)-1-t-butoxycarbonyl-2-(1-N-t
butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid
t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester. ester (yield: 9 mg, 86%).
1 H NMR(dg-DMSO) 8 8.39 (d, 1 H), 5.72 (m, 1 H), 5.15-5.2 (dd, 2H), 4.5
(m, 1 H), 4.37 (m, 1 H), 3.65 (m, 1 H), 2.85-3.04 (m, 3H), 2.6-2.85 (m, 2H),
2.4 (m,
1 H), 1.83-1.95 (m, 1 H), 1.86 (s, 3H), 1.20 (t, J=7.46 Hz, 3H).
MS: (M-H)- =301; (M+H)+ = 303, (M+Na)+ = 325
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Example 216
,fit)-(~2R 3S 5R.1'R 3'R)-2-(1-Acetamido-2-ethylsulfinyl)ethyl-3-vinyl-
pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
AcHN OH
N > ~~~~I~
H H O
S
p TFA
The title compound was prepared according to the method described in
ExampIe41C, substituting (t)-(2R,3S,5R,1'R,3'R}-1-t-butoxycarbonyl-2-(1-N-t-
butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid
t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl 2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 12 mg, 94%).
1 H NMR(d6-DMSO) 5 8.39 (d, 1 H}, 5.72 (m, 1 H), 5.15-5.2 (dd, 2H), 4.53
(m, 1 H), 4.41 (t, 1 H), 3.65 (m, 1 H), 3.2 (dd, 1 H), 2.9-3.0 (m, 2H), 2.65-
2.9(m,
2H), 2.4(m, 1 H), 1.83-1.95 (m, 1 H), 1.83 (s, 3H), 1.20 (t, J=7.46 Hz, 3H)
MS: (M-H)- =301; (M+H) + = 303, (M+Na) + = 325
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Example 217
~t)-(2R.3S.5R.1'Rl-2~1-N-t-butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-
vinyl pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
Ac
1
BocN. N~, O~Bu
H Boc
O S,
O
217A ft)~2R,3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-
2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1' R, 3'R)-1-t-Butoxycarbonyi-2-( 1-N-t-
butoxycarbonylacetamido-2-ethylsuffinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid
t-butyl ester (25 mg, 0.0448 mmole) was reacted with 55% m-
chloroperoxybenzoic acid (14 mg, 0.0448 mmofe) in CHC13 (1.5 mL) at 0
°C for
one hour. The reaction was concentrated in vacuo. The residue was purified by
chromatography on silica gel using 25% ethyl acetatelhexane to provide the
title
compound (yield: 23.7 mg, 92%).
~ H NMR(dg-DMSO) b 5.88 (m, 1 H), 4.85-5.0 (m, 2H), 4.38 (m, 1 H), 4.15
(m, 1 H), 3.7 (m, 1 H) 3.45 (dd, 1 H), 2.9-3.2 (m, 3H), 2.5-2.7 (m, 1 H), 2.3-
2.4 (m,
3H), 1.6-2.04 (m, 1 H), 1.35-1.55 (m, 27H), 1.15 (t, 3H)
MS: (M~H)+ = 575
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AcHN OH
~ O
~S~
O O TFA
29-7B (t)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-ethylsulfonyl)ethyl-3-vinyl-
pyrrolidine-
5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Exampie41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-N-t
butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester (yield: 12 mg, 94%).
1 H NMR(d6-DMSO) 8 8.34 (d, 1 H), 5.72 (m, 1 H), 5.05-5.25 (dd, 2H), 4.68
(m, 1 H), 4.39 (dd, 1 H), 3.7 (2d, 1 H), 3.48 (dd, 1 H), 3.3-3.4 (dd, 2H),
3.08 (q, 2H),
2.95 (m, 1 H), 2.42 (m, 1 H), 1.9 (m, 1 H), 1.84 (s, 3H), 1.23 (t, J=7.46 Hz,
3H).
MS: (M-H)- = 317, (M+35)+ = 353; (M+H)+ = 319, (M+Na)+ = 341
Examples 218. 220
1. RSH
gu - AcHN. ,.,~OH
N ~ ~ ~ 2. LiHMDSIAcCI ' ~ N
BocHN~ H goc O 3. TFAICHpCIz H H O
RS
TFA
The following title compounds were prepared in 3 steps according to the
methods described in Example 214.
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Example 218
(t)-(2R,3S.5R,1'R)-2-(1-Acetamido-2-isoprop l~ eth I-y 3-v_in.~pyrrolidine-5-
carbox~rlic Acid Trifluoroacetic Acid Salt
-,
BocHN, N~, O~Bu
H Boc
S
218A (t}-(2R.3S.5R,1'R)-1-t Butoxycarbanyl-2-(1-N-f-butoxycarbonylamino-2-
isopropylthio)ethyl-3-vinyl-eyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in
Example 214A, substituting isopropylthiol in place of ethanethiol (yield: 22
mg,
62%).
1 H NMR(dg-DMSO) 8 6.73 (d, 1 H), 5.85 (m, 1 H), 4.9-5.0 (m, 2H), 4.18 {m,
1 H), 3.95 (m, 1 H), 3.75 (br d, 1 H), 2.8-3.0 (m, 2H), 1.65 (m, 1 H), 1.32-
1.45 {m,
27H), 1.18 (dd, 6H)
MS: (M-H)- = 513; (M+H) + = 515, (M+Na) + = 537
Ac
BocN. N,., OtBu
~,~.,~ H Boc
~S
218B (t)-(2R.3S,5R,1'R}-1-f-Butoxycarbonyl-2-(1-(N-f-butoxycarbonyl-N-
acetamido)-2-isoprapylthio)ethyl-3-vinyl-p,~rrrolidine-5-carboxylic Acid t-
But~rl
Ester.
The title compound was prepared according to the method described in
Example 214B, substituting (t)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-t
butoxycarbonylamino-2-isoproylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid
t-
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butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-
butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 12 mg, 50%).
1 H NMR(dg-DMSO) 8 5.86 (m, 1 H), 4.88-5.0 (m, 2H), 4.54 (m, 1 H), 4.33
(m, 1 H), 4.13 (d, 1 H), 3.05 (m, 1 H), 2.73-2.84 (m, 2H), 2.38 (br s, 3H),
1.72 (m,
1 H), 1.32-1.5 (m, 27H), 1.14 (dd, 6H).
MS: (M+H) + = 557, (M+Na) + = 579
_ -.
AcH N OH
N > .~~'
O
S
TFA
218C (tL(2R.3S,5R,1'R)-2-(1-Acetamido-2-isopropylthio)ethyl-3-vinyl-
pyrrofidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 15B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-N-t
butoxycarbonylacetamido-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 8 mg, 97%).
1 H NMR(dg-DMSO) b 8.14 (d, 1 H), 5.72 (m, 1 H), 5.05-5.2 (dd, 2H), 4.2-
4.4 (m, 2H), 3.68 (dd, 1 H), 2.93 (m, 2H), 2.74 (dd, 1 H), 2.58 (dd, 1 H),
1.93 (m,
1 H), 1.87 (s, 3H), 1.2 (t, 6H)
MS: (M-H)- = 299; (M+H) + = 301, (M+Na) + = 323
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Example 219
St)-(2R 3S 5R 1'R~-2-(1-Acetamido-2-phenylthio~ethyl-3-vinyl-pyrrolidine-5-
carboxylic Acid Hydrochloride
H2N. ) ,, O~Bu
H Boc '
",- S
219A (t)-(2R 3S 5R 1'R)-1-t-Butoxycarbonyl-2-(1-amino-2-phenylthio)ethyl-3-
vinvl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-
carboxylic acid t-butyl ester (20.3 mg, 0.06 mmole) was reacted with the
phenylthiol (19.9 mg, 0.18 mmol) and triethylamine (0.047 mL, 0.34 mmol) in
MeOH (0.06 mL) at ambient temperature for 3.5 hours. The reaction solution
was concentrated in vacuo. The residue was purified by preparative thin layer
chromatography on silica gel using ethyl acetate/methanol/ammonium hydroxide,
99/0.05/0.05, to provide the title compound (yield: 20.7 mg, 77%).
1 H NMR (ds-DMSO) S 7.31 (m, 4H), 7.17 (m, 1 H), 5.87 (m, 1 H), 5.03 (d,
J=l7Hz, 0.4H), 5.01 (d, J=17Hz, 0.6H), 4.91 (d, J=11 H, 0.4H), 4.90 (d, J=11
Hz,
0.6H), 4.15 (m, 1 H), 3.82 (m, 0.6H), 3.76 (m, 0.4H), 3.39(m, 1 H), 2.92 (m,
2H),
2.55 (m, 1 H), 1.64 (m, 2H), 1.42 (s, 5.4H), 1.37 (s, 3.6H), 1.34 (s, 5.4H),
1.22 (s,
3.6H)
MS: (M+H)+ = 449, (M+Na)+ = 471
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AcH N
,.
H Boc
S
219B (t)-(2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-phenyithio)ethyl-
3-vinyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-amino -2-phenylthio)ethyl-3-
vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (17.2 mg, 0.04 mmole) was
reacted with the acetic anhydride (0.011 mL, 0.11 mmol) and triethylamine
(0.032
mL, 0.23 mmol) in CH2C12 (0.3 mL) at rt for 4.25 hours. The reaction solution
was concentrated in vacuo. The residue was purified by preparative thin layer
chromatography on silica get using 5% methanol/dichloromethane to provide the
title compound.
'H NMR (ds-DMSO) d 7.75 (d, J=9Hz, 0.6H), 7.73 (d, J=9Hz, 0.4H), 7.32
(m, 4H), 7.19 (m, 1 H), 5.87 (m, 1 H), 5.04 (d, J=17Hz, 0.4H), 5.00 (d,
J=17Hz,
0.6H), 4.95 (d, J=10Hz, 0.6H), 4.93 (d, J=10Hz, 0.4H), 4.59 (m, 0.4H), 4.45(m,
0.6H), 3.99 (dd, J=10Hz, 2Hz, 0.6H), 3.94 (dd, J=10Hz, 2.5Hz. 0.4H), 3.84 (m,
0.6H), 3.77 (m, 0.4H), 3.07 (dd, 13Hz, 5Hz, 0.6H), 2.95 (m, 1.8H), 2.83 (br t,
J=8Hz, 0.6H), 2.48 (m, 1 H), 1.84 (s, 1.2H), 1.81 (s, 1.8H), 1.68 (m, 1 H),
1.41 (s,
5.4H), 1.36 (s, 3.6H), 1.34 (s, 5.4H), 1.26 (s, 3.6H)
MS: (M-H)- = 489, (M+35)-; (M+H)+ = 490, (M+Na)+ = 513
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- -.
AcHN OH
w
O
HCI
219C (t)-l 2R.3S.5R.1'R)-2-l1-Acetamido-2-phenvlthio)et~-3-vinvl-pvrrolidine-5-
carboxylic Acid Hydrochloride
The title compound was prepared according to the method described in
Example 1K, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-
2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in
place of (t)-
(2R,3R,5R,1'S)-2-( 1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-
carboxylic acid t butyl ester (yield: 14.6 mg, 100%.)
1 H NMR(d4-methanol) 8 7.43 (m, 2H), 7.31 {m, 3H), 5.75 (ddd, J=17Hz,
10Hz, 8Hz, 1 H), 5.32 (br d, J=17Hz, 1 H), 5.19 (dd, J=10Hz, 1.4Hz, 1 H),
4.58 (m, 2H), 3.89 (dd, J=10Hz, 3Hz, 1 H), 3.19 (dd, J=14Hz, 6Hz, 1 H),
3.09 (dd, J=14Hz, 9Hz, 1 H), 3.04 {m, 1 H), 2.57(dt, J=13Hz, 7Hz, 1 H), 2.04
(s, 3H), 2.03 (m, 1 H)
MS: (M-H}- = 333; (M+H)+ = 335, (M+Na)+ = 357
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Example 220
(t)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-Benz I~ ethyl-3-viny pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
-,
BocHN. N)., OtBu -
H Boc
~S
220A (t)-(2R,3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-f butoxycarbonylamino-2-
benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-But)rl Ester
The title compound was prepared according to the method described in
Example 214A, substituting benzylmercaptan in place of ethanethiol (yield: 28
mg, 72%).
1 H NMR(d6-DMSO) 8 7.2-7.35 (m, 5H), 6.80 (br d, 1 H), 5.84 (m, 1 H),
4.86-4.96 (m, 2H), 4.25(m, 1 H), 3.95 (m, 1 H), 3.7-3.8 (m, 3H), 2.76-2.94 (m,
1 H),
2.35-2.45 (m, 2H), 1.65 (m, 1 H), 1.32-1.45 (m, 27H)
MS: (M-H)- = 561; (M+H) + = 563, {M+Na) + = 585
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Ac
BocN. N,., OtBu
H Boc
S
220B (t)-(2R.3S,5R.1'R)-1-t-Butoxycarbonyl-2-(1-(N-t butoxycarbonyl-
acetamido)-2-benzylthio~ethyi-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl
Ester.
The title compound was prepared according to the method described in
Example 2148, substituting (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-
butoxycarbonylamino-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t
butoxycarbonylamino-2-ethylthin)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 3.3 mg, 61 %).
1 H NMR(d6-DMSO) ~ 7.2-7.35 (m, 5H), 5.84 (m, 1 H), 4.86-4.96 (m, 2H),
4.55(m, 1 H), 4.32 (d, 1 H), 4.05 (d, 1 H), 3.56-3.65 (m, 2H), 2.9 (m, 1 H),
2.3-2.65
(m, 3H), 2.42 (s, 3H), 1.76 (d, 1 H), 1.25-1.55 (m, 27H)
MS: (M+H) + = 605, (M+Na) + = 627
AcHN OH
' N~ ~~~1~
HH O
S
TFA
220C (t)-(2R,3S.5R.1'R)-2-(1-Acetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-
5-
carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-N-t
butoxycarbonylacetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic
acid
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t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-{1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 2.2 mg, 95%).
1 H NMR(d6-DMSO) 8 8.18 (d, 1 H), 7.2-7.32 (m, 5H), 5.68(m, 1 H), 5.02-
5.2 (m, 2H), 4.3-4.45 (m, 2H), 3.76 (s, 2H), 3.68 (dd, 1 H), 2.92 (m, 1 H),
2.62 (dd,
1 H), 2.32-2.55(m, 2H), 1.85-1.95 (m, 1 H), 1.89 (s, 3H).
MS: (M-H)' = 347; (M+H)+ = 349, (M+Na)+ = 371
Example 221
AcHN OH
w
N / ~ H H ~ .,~~I~
O
2HCI
(t)-f2R 3S 5R 1'R)-2-(1-Acetamido-2-(4-p~idinethio ethyl-3-vinyl-pyrrolidine-5-
carboxylic Acid DihYdrochloride.
The title compound was prepared according to the method of Example
219A-C substituting 4-thiopyridine for thiophenol as the reagent in Example
219A.
'H NMR(d4-methanol) d 8.57 (d, J=7Hz, 2H), 7.97 (d, J=7Hz, 2H), 5.85
(ddd, J=17Hz, 1 OHz, 9Hz, 1 H), 5.40 (br d, J=17Hz, 1 H), 5.25 (dd, J=17Hz,
10Hz,
1 H), 4.67 (dt, J=10Hz, 4Hz, 1 H), 4.47 (dd, J=10Hz, BHz, 1 H), 4.01 (dd, J=1
OHz,
4Hz, 1 H), 3.68 (dd, J=14Hz, 5Hz, 1 H), 3.45 (dd, J=14Hz, 10Hz, 1 H), 3.16 (m,
1 H), 2.65 (dt, J=14Hz, 7Hz, 1 H), 2.07 (m, 1 H), 2.04 (s, 3H)
MS: (M-H)- = 334; (M+H)+ = 336, (M+Na)+ = 358
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Example 222
/-.:.
H3C
AcHN~,, ~., OEt
H N ~~
H O
OH
(t)-(2R 3S 5R.1'R 2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-
~yrrolidine-5-carboxylic Acid Ethyl Ester.
Thionyl chloride (1.49 mL, 20.5 mmol) was reacted with ethanol (25 mL) at
0°C for 10 minutes. (t)-(2R,3S,5R,1'R,2'S)-2-{1-Acetamido-2-
hydroxy)butyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (815
mg,
2.05 mmol) in ethanol (50 mL) was added to the above solution and reacted at
room temperature for 17 hours. The reaction was concentrated in vacuo and the
residue was purified by chromatography on silica gel with 90/10/0.5
dichloromethane I methanol I ammonium hydroxide to provide the title compound
as a white solid (yield: 462 mg, 72%).
' H NMR (DMSO-ds) 8 7.49 (d, J = 9.8 Hz, 1 H), 5.31 (m, 2H) 4.11 (m, 2H),
3.72 (t, J = 7.7 Hz, 1 H), 3.69 (m, 1 H), 3.42 (m, 1 H), 3.07 (m, 1 H), 2.85
(m, 1 H),
2.22 (m, 1 H), 1.76 (s, 3H), 1.54 (d, J = 5.6 Hz, 3H), 1.45 (m, 1 H), 1.39 (m,
1 H),
1.21 (m, 1 H), 1.19 (t, J = 7.0 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H).
MS: (M+H)+= 313, (M+Na)+= 335, (M-H)~ = 311.
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Example 223
HN
../N
AcHN, OEt
N > .~~~I~
HH O
OH
~t)-(2R.3R.5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy)butyl-3- pyrazol-3-y1)-
pyrrofidine-5-carbox rLlic Acid Ethyl Ester
The title compound is prepared according to the method described in
Example 222, substituting (t)-(2R,3R,5R,1'R,2'S)-2-(1-acetamido-2-
hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic
acid salt
in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-
propen-
1-yl)-pyrrolidine-5-carboxylic trifluoroacetic acid salt (yield: 32 mg, 52%).
1 H NMR(d6-DMSO) 8 7.6 (br s, 1 H), 6.1 (br s, 1 H), 4.08 (q, J=7.12Hz,
2H), 3.78 (m, 1 H), 3.65 (m, 1 H), 3.55 (m, 1 H), 3.45 (m, 1 H), 3.25 (m, 1
H), 3.45
(m, 1 H), 1.72 (s, 3H), 1.45 (m, 1 H), 1.2 (m, 1 H), 1.16 (t, J=7.12 Hz, 3H),
0.82 (t,
J=7.46 Hz, 3H).
MS: (M-H)- = 337, (M+35)+ = 373; (M+H)+ = 339, (M+Na)+ = 361
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Example 224
H3C
AcHN. ~..,, OEt
~~ H H O
/ ~ N.CH3
O
(t)-(2R.3S 5R 1'S 3'S)-2-t1-Acetamido-2- N-isopropyl-N-methylamino-N-
oxidel)ether(cis-~~en-1-y~-pyrrofidine-5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in
Example 222, substituting (t)-(2R,3S,5R,1'S,3'S)-2-(1-acetamido-2-(N-
isopropyl)-
N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid
trifluoroacetic acid salt in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-
hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid
trifluoroacetic acid
salt (yield: 25 mg, 34%).
1 H NMR (MeOD-d3) S 5.51-5.43(m, 1 H), 5.34-5.27(m, 1 H), 4.36-4.30(m,
1 H), 4.18(q, J=7.1 Hz, 2H), 3.88(dd, J=6.8, 8.8Hz, 1 H), 3.82-3.67(m, 2H),
3.49-
3.42(m, 1 H), 3.34(s, 3H), 3.14-2.96(m, 1 H), 2.42-2.33(m, 1 H), 1.92(s, 3H),
1.64-
1.52(m, 1 H), 1.63(dd, J=1.7, 6.8Hz, 3H}, 1.41-1.24(m, 1 H}, 1.39(d, J=6.4Hz,
3H),
1.31 (d, J=6.4Hz, 3H), 1.26(t, J=7.1 Hz, 3H).
MS: (M+H)+=356, (M+Na)+=378, (M-H)-=354, (M+35)+=390.
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Example 225
H3C
AcHN. ~.,,, OEt
H ~IO~
~t)-(2R,3S.5R.1'S)-2-(1-Acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-
5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in
Example 222, substituting (t)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in
place of
(t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 838 mg, 94%).
1 H NMR (CDC13): 8 5.50 (m, 1 H), 5.41 (m, 1 H), 5.28 (m, 1 H), 4.21 (q,
J=7.5Hz, 2H), 4.06 (m, 1 H), 3.87 (t, J=7.5Hz, 1 H), 3.10 (m, 1 H), 2.97 (m, 1
H),
2.39 (m, 1 H), 1.97 (s, 3H), 1.66 (dd, 3H), 1.60 (m, 1 H), 1.40 (m, 2H), 0.94
(d,
J=7.5Hz, 3H), 0.93 (d, J=7.5 Hz, 3H).
MS: (M+H)+=311
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Example 226
c~
AcHN. N>..,,~I~ Et
H'H lO
(t)-(2R.3S.5R 1'S~-2~1-Acetamido-3-methyl)butyl-3-(cis-2-chioro-vin-1-Lrl
pvrrolidine-5-carboxylic Acid Eth I~Ester
The title compound is prepared according to the method described in
Example 222, substituting (t)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-
(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid
salt in place
of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 46%).
' H NMR (CDC13): 8 6.05 (d, J=7.5Hz, 1 H), 5.90 (dd, J1=9 Hz, J2=6Hz, 1 H),
5.31 (d, J=9Hz, 1 H), 4.19 (q, J=7.5Hz, 2H), 4.06 (m, 1 H), 3.82 (t, J=7.5Hz,
1 H),
3.17 (m, 2H), 2.45 (m, 1 H), 1.98 (s, 3H), 1.67 (m, 1 H), 1.60 (m, 1 H), 1.37
(m, 2H),
1.27 (t, J=7.5Hz, 3H), 0.91 (d, J=7.5Hz, 3H), 0.89 (d, J=7.5Hz, 3H).
MS: (M+H)+= 331
Example 227
Intentionally blank.
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Example 228
F~/'
F
AcHN. ~.,,, OEt
(tL~2R 3S 5R 1'S)-2-(1-Acetamido-3-methyl)butyl-3-(2.2-difluoro-vine
pyrrolidine-5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in
Example 222, substituting (t)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-
(2,2-difluoro-vinyl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt
in place of
(t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 57%).
' H NMR {CDC13): 8 4.22 (q, J=7.5 Hz, 2H), 4.14 (m, 1 H), 4.03 (m, 1 H),
3.29 (br, 1 H), 2.85 (m, 1 H), 2.52 (m, 1 H), 2.01 (s, 3H), 1.77 (m, 2H), 1.64
(m, 2H),
1.49 (m, 1 H), 1.38 (m, 1 H), 1.29 (t, J=7.5Hz, 3H), 0.93 (d, J=7.5Hz, 3H),
0.90 (d,
J=7.5Hz, 3H).
MS: (M+H)+= 333
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Example 229
HN
N
AcHN. N~ .,,I~OEt
H'H
O
(t)~2R,3R.5R,1'S)-2-C 1-Acetamido-3-methyl)butyl-3-tpyrazol-3-yl)-pyrrolidine-
5-
carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in
Example 222, substituting (t)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-
(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in
place of (t)-
(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 48 mg, 75.5%).
' H NMR (CDC13): 8 7.49 (d, 1 H), 7.26 (s, 1 H), 6.18 (d, 1 H), 4.18 (q,
J=7.5Hz, 2H), 4.12 (m, 1 H), 3.91 (t, J=7.5Hz, 1 H), 3.51 (t, J=7.5Hz, 1 H),
3.40 (q,
J=9Hz, 1 H), 2.64 (m, 1 H), 2.00 (m, 1 H), 1.82 (s, 3H), 1.75 (m, 1 H), 1.36
(m, 1 H),
1.26 (t, J=9Hz, 3H), 0.855 (d, 3H), 0.84 (d, 3H).
MS: (M+H)+= 337
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Example 230
(t)~2R,3S.5R 1'R~2-~1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
i- ,
CH3
AcHN. N~., O~Bu
OH cc
230A (t)-(2R.3S.5R,1'R~1-t-Butoxvcarbonyl-2-(1-acetamido-2-ethyl-2-
hydroxy)butyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
The title compound was prepared according to the method described in
Example 418, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-
2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
for (t)-
(2R, 3S, 5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-
propen-
1-yl)-pyrrolidine-5-carboxylic acid t butyl ester to provide the title
compound
{yield: 0.021 g, 51 %).
MS: (M+H)+= 469, (M+Na)+ = 491, (2M+Na)+=959, (M-H)- = 467.
CH3
AcHN. N~.,~OH
H' H O
~OH
TFA
2308 (t)-(2R,3S.5R,1'R)-2-(1-Acetamido-2-eth~ydroxy)bu~l-3-(cis-prohen-
1-yIZ pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 0.0039 g, 100%).
'H NMR (DMSO-ds) s7.52 (d, J=10.3Hz, 1 H), 5.45 (m, 1 H), 5.28 (m, 1 H),
4.32 (m, 2H), 3.68 (t, J=8.8Hz, 1 H), 3.16 (quint., J=8.5Hz, 1 H), 2.41 (dt,
J=13.2,8.3Hz, 1 H), 1.81 (s, 3H), 1.59 (m, 1 H), 1.53 (dd, J=6.8,1.SHz, 3H),
1.52-
1.42 (rn, 3H), 1.30 (m, 1 H), 0.86 (t, J=7.3Hz, 3H), 0.83 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 313, (M+Na)+ = 335, (M-H)' = 311, (2M-H)- = 623.
Example 231
(t)-(2R.3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydrox rL-2-methyl)pen I-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
~O~Bu
OH O
231A (t~-{,2R 3S.5R.1'R.2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-
methyl)pentyl-3-(cis-propen-1-~)-pyrroiidine-5-carboxylic Acid t Butyl Ester.
The title compound was prepared according to the method described in
Example 41B, substituting (t)-{2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-
2-oxo)pentyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t butyl ester
for (t)-
(2R,3S,5R,1'R)-1-t Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester and methyimagnesium
bromide for ethylmagnesium bromide to provide the title compound (yield:
0.0285
g, 45%).
MS: (M+H)+= 469, (M+Na)+ = 491.
CH3
AcHN. ).
N
H Boc
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,
CH3
AcHN. N~.,~OH
H\ H
OH O
- TFA
231 B (tL(2R.3S.5R,1'R,2'S)-2-(1-Acetamido-2-h~roxy-2-methyl)pentyl-3-(cis-
propen-1-yl)-pYrrolidine-5-carbox~ic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-2-methyl)pentyl-3-{cis-propen-1- yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester (yield: 0.0040 g, 100%).
' H NMR (DMSO-ds) 89.25 (bs, 1 H), 8.75 (bs, 1 H), 7.54 (d, J=10.3Hz, 1 H),
5.45 (m, 1 H), 5.29 (m, 1 H), 4.37 (bt, J=8.3Hz, 1 H), 4.22 (t, J=9.7Hz, 1 H),
3.62 (t,
J=8.8Hz, 1 H), 3.12 (quint., J=8.5Hz, 1 H), 2.41 (dt, J=12.7,7.8Hz, 1 H), 1.78
(s,
3H), 1.59 (m, 1 H), 1.53 (dd, J=6.8,2.OHz, 3H), 1.4-1.25 (m, 4H), 1.17 (s,
3H),
0.81 (t, J=6.5 Hz, 3H).
MS: (M+H)+= 313, (M+Na)+ = 335, (M-H)- = 311, (2M-H)~ = 623
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Example 232
(t)-(2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-ethyl-2-hydroxY)pentyl-3-(cis-propen-1-
yl~wrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
~O~Bu
OH O
232A (t~~2R 3S.5R.1'R,2'S)-1-t-Butoxycarbonvl-2-(1-acetamido-2-ethyl-2-
hydroxy)pentyl-3-(cis-propen-1-yl~-pyrrolidine-5-carboxylic Acid f-Butyl
Ester.
The title compound was prepared according to the method described in
Example 41B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-
2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
for (t)-
(2R,3S,5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic acid t butyl ester to provide the title
compound
(yield: 0.0222 g, 33%).
MS: (M+H)+= 483, (M+Na)+ = 505, (M-H)-=481.
CH3
AcHN _ >.
N
H Boc
CH3
AcHN. N~.,~ H
HH ~O
OH
/ TFA
232B (t)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-hydroxy)butyl-3-(cis-propen-1-yi)-pyrrolidine-5-carboxylic acid t-
butyl
ester (yield: 0.0035 g, 100%).
'H NMR (DMSO-dfi) ~ 9.1 (bs, 1 H), 8.75 (bs, 1 H), 7.53 (d, J=9.8Hz, 1 H),
5.44 (m, 1 H), 5.28 (m, 1 H), 4.35-4.25 (m, 2H), 3.67 (m, 1 H), 3.16 (quint.,
J=8.5Hz, 1 H), 2.41 (dt, J=12.8,7.9Hz, 1 H), 1.81 (s, 3H), 1.60 (m, 1 H), 1.53
{dd,
J=6.7,1.8Hz, 3H), 1.46 (m, 2H), 1.4-1.20 (m, 4H), 0.86 (t, J=7.3Hz, 3H), 0.82
(t,
J=6.7 Hz, 3H).
MS: (M+H)+= 327, (M-H)- = 325, (M+CF3COOH)-=439, (2M-H)' = 651
Example 233
i- ,
CH3
AcHN_ N~..,~OH
H
OHH O
TFA
~)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-progyl-2-hydroxy)pent-3-(cis_propen-1-vl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 232 substituting propyl magnesium bromide for ethyl magnesium
bromide.
'H NMR (DMSO-d6): 8 0.81 (t, 3H), 0.91 (t, 3H), 1.24-1.49 (m, 8H), 1.54
(dd, 3H), 1.60 (m, 1 H), 1.81 (s, 3H), 2.41 (m, 1 H), 3.15 (m, 1 H), 3.69 (t,
1 H), 4.28
(t, 1 H), 4.35 (t, 1 H), 5.17 (br s, 1 H), 5.28 (td, 1 H), 5.45 (dq, 1 H),
7.54 (d, '! H), 8.80
(br s, 1 H), 9.12 {br s, 1 H).
MS: (M+H)+= 341.
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Example 234
(t)-(2 R.3S, 5 R.1 ' R)-2-( 1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-
1~1)-
pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN_ N~., OtBu
H Boc
J _o~
S-
234A (t)-~2R.3S.5R.1'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2-
(methylthio)methyloxy)butyl-3-(cis-propen-1-yl) pyrrolidine-5-carboxylic Acid
t-
Bu I Ester
(t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-
methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
was
reacted with dimethylsufoxide and acetic anhydride according to the method of
Marshall, J. A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title
compound.
i- ,
CH3
AcHN_ N~_, OtBu
H Boc
J -ocH3
234A (t)-(2R,3S.5R.1'R.2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2-
methoxy)butyl-3-(cis-propen-1-yl~~ayrrolidine-5-carboxylic Acid t-Butyl Ester
(t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-
(methylthio)methyloxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid
t-
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butyl ester is reacted with Raney Nickel according to the procedure of
Marshall, J.
A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title compound.
/=.:.
H C
Ac~~-IN _ OH
~N~ ~~~I~
HH O
'OCH3
TFA
(~2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1=
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-ethyl-2-rnethoxy)butyl-3-(cis-propen-1-yl)-pyrrolid ine-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester.
Example 235
...
HsC~
AcH N O H
CH3
TFA
~t)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-methoxy)pen /I-3-(cis-propen-1-
yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in
Example 234 substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
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acid t-butyl ester for (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-
ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl ester
in 234A.
Example 236
(t)-(2R.3S.5R,1'R.2'S)-2-(,1-Acetamido-2-hydroxymethyl-2-hydroxy~pen I-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
H3C
AcHN. N~.,, OtBu
OHBoc/ ~~
~o o~
236A (t)-(2R.3S.5R.1'R.2'S -1-t-Butoxycarbonyl-2-(1-Acetamido-2-((1-
ethoxy)ethyloxymethyl)-2-h_ydrox~pentyl-3-(cis-propen-1- rLpyrrolidine-5-
carboxylic Acid t-Butyl Ester
(t)-(2R, 3 S, 5R,1 ' R, 2'S)-1-t-Butoxycarbonyl-2-( 1-acetamid o-2-oxo)pentyl-
3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (50 mg, 0.11
mmole)
was reacted with (ethoxyethyloxymethyl)tributylstannane (260 mg, 0.66 mmole)
according to the method of Stifl, W. C. (J. Am. Chem. Soc., 100, 1481(1978))
to
provide the title compound (yield: 26.8 mg, 43.8%).
'H NMR (CDC13): s 0.89 (t, 3H), 1.19 (m, 3H), 1.29 (dd, 3H), 1.45 (s, 9H),
1.46 (s, 9H), 1.52-1.73 (m, 8H), 1.99 (s, 3H), 2.44 (m, 1 H), 3.24-3.74 (m,
5H),
3.91-4.22 (m, 3H), 4.49 (m, 1 H), 4.62 (m, 1 H), 5.37 (m, 1 H), 5.64 (m, 1 H),
5.97-
6.41 (m, 1 H).
MS: (M+H)+= 557.
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~.
H3C
AcHN, N~.,, OH
H H
OH O
OH TFA
2368 (t)-(2R 3S 5R,1'R 2'Sl-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-
3-(cis-prJ~en-1-Y)-pyrrolidine-5-carbox~ic Acid Trifluoroacetic Acid Salt
(t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-(1-ethoxy-2-
ethoxymethyl)-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
Acid
t-Butyl Ester (13.5 mg, 0.024 mmol) was dissolved in THF (1 mL) and treated
with
0.5 N HCI ( 1 mL) at room temperature for 1 hr. The solvents were removed and
the resulting white solid was reacted with trifluoroacetic acid (0.8 mL) in
dichloromethane (0.2 mL) at room temperature for 6 hours. The reaction was
concentrated in vacuo overnight to provide the title compound (yield: 10.7 mg)
as
a off white solid.
'H NMR (DMSO-ds): 8 0.81 (t, 3H), 1.24-1.38 (m, 4H), 1.52 (dd, 3H), 1.62
(rn, 1 H), 1.78 (s, 3H), 2.41 (m, 1 H), 3.11 (m, 1 H), 3.51 (qAB, 2H), 3.77
(t, 1 H),
4.23 (t, 1 H), 4.40 (m, 1 H), 5.27 (t, 1 H), 5.45 (m, 1 H), 7.55 (d, 1 H),
8.87 (br s, 1 H),
9.26 (br s, 1 H).
MS: (M+H)+= 329
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Example 237
(t~(2R,3S 5R 1'R 2'S)-2-(1-Acetamido-2-allyloxy-2-vin I~)ethyl-3-(cis-propen-1-
yl} pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/_ =:
H3C~
AcHN OtBa
N~..,,
O Boc 0
237A (t)-(2R,3S.5R 1'R.2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allylox~2-
vinyl)ethyl-3-(cis-propen-1-ylLpyrrolidine-5-carboxylic Acid t-Butyl Ester
(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-
vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
was
reacted according to the method described in Example 84A substituting allyl
iodide for methyl iodide (yield: 28 mg, 80%).
MS: (M+H)+= 479, (M-H)- = 477
/_ :.
H3C~
AcHN OH
H N / II~
H O
TFA
2378 (t)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-alylox -y 2-vinyl)ethyl-3-(cis-
propen-1 yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic acid
f butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t
butyl
ester. (yield: 4 mg, 100%).
'H NMR (DMSO-d6) 8 7.98 (d, J=7.8 Hz, 1 H), 5.90 (m, 1 H), 5.55 (m, 1 H),
5.48 (m, 1 H), 5.32 (m, 2H), 5.26 (m, 2H), 5.16 (m, 1 H), 4.28 (m, 2H), 3.96
(m,
1 H), 3.79 (m, 1 H), 3.73 (m, 1 H), 3.66 (m, 1 H), 3.26 (m, 1 H), 2.40 (m, 1
H), 1.81 (s,
3H), 1.70 (m, 1 H), 1.64 (dd, J=6.9, 1.5 Hz, 3H).
MS: (M+H)+= 323, (M-H)' = 321.
Example 238
{t)-,~2R.3S.5R.1'R 2'S -) 2i(1-Acetamido-1-(2,5-dihydrofuran-2- rLl) methy~cis-
propen-1- ly )ip~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/_ :.
H3C
AcHN, N~.,, OtBu
o Soc '~~
238A ~t)-(2R.3S35R.1'R,2'S)-2-(1-Acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-
Scis-propen-1-yl)-pyrroiidine-5-carboxylic Acid t-Butyl Ester
(t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-{1-acetamido-2-allyloxy-2-
vinyl)ethyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester
(21 mg,
0.044 mmole) prepared according to the procedure of Example 237A was reacted
with bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride [Grubb's
catalyst] (7.5 mg, 0.009 mmole) in methylene chloride (5 mL) at 25°C
for 2 hours
under a nitrogen atmosphere. The reaction was concentrated in vacuo and the
resulting residue purified by chromatography on silica gel using 75% ethyl
acetatelhexanes to provide the title compound (yield: 18 mg, 90%).
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MS: {M+H)+= 451, (M-H)~ = 449.
/_ ,,.
H C
Ac~N OH
N / I,'~
H H O
TFA
2388 (t)-f,2R,3S,5R.1'Rj,2'S)-2-(1-Acetamido-1-(2.5-dihydrofuran-2-yl))methyl-
3-
(cis-~ropen-1-yl~wrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f-Butoxycarbonyl-2-(1-
acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t-
butyl ester. (yield: 7 mg, 100%).
' H NMR (DMSO-d6) b 8.09 (d, J=8.8 Hz, 1 H), 6.10 (m, 1 H), 5.87 (m, 1 H),
5.50 (m, 1 H), 5.27 (m, 1 H), 4.68 (m, 2H), 4.58 (m, 1 H), 4.33 (m, 1 H), 4.06
(m,
1 H), 3.68 (m, 1 H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.85 (s, 3H), 1.68 (m, 1
H), 1.60
(dd, J=6.8, 1.5 Hz, 3H),
MS: (M+H)+= 295, (M-H)- = 293.
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Example 239
(t)-~ R, 3S, 5R,1'R.2'S)-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(cis-propen-
1_yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/_.:.
HC
Ac~HN OtSu
'~Ni..~.
B~C O
239A (t)-(2Ry3S.5R,1'R.2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-
all~rl~thyl-3-(cispro~en-1 yl~pyrrolidine-5-carboxylic Acid t-Buyl Ester
(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-
allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester
was
reacted according to the method described in Example 84A substituting allyl
iodide for methyl iodide iodide (yield: 19 mg, 36%).
MS: (M+H)+= 493, (M-H)- = 491.
/_ =.
H C
Ac~HN OH
H N / I~
_ H O
TFA
239B (t)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-allylox -y tall r~l ethyl-3-(cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
Acetamido-2-allyloxy-2-allyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
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acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl
ester. (yield: 5.7 mg, 100%).
' H NMR (DMSO-d6) b 8.06 (dd, J= 8.8 Hz, 1 H), 6.92 (m, 1 H), 6.77 (m,
1 H), 5.50 (m, 1 H), 5.29 (m, 2H), 5.17 (m, 1 H), 5.05 (m, 2H), 4.27 (m, 2H),
4.10
(dd, J= 12.2, 5.4 Hz, 1 H), 3.83 (m, 1 H), 3.78 (m, 1 H), 3.40 (m, 1 H), 3.20
(m, 1 H),
2.46 (m, 1 H), 2.38 (m, 1 H), 2.20 (m, 1 H), 1.88 (s, 3H), 1.69 (m, 1 H), 1.63
{dd, J=
6.8, 1.5 Hz, 3H).
MS: (M+H)+= 337, (M+Na)+= 359, (M-H)- = 335.
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Example 240
t~j2R.3S,5R.1'R,2'S)-2-{1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-
jcis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/_.:.
H3C
AcHN N~ ,,, OtBu
O Boc ~~
240A (t)-(2R,3S,5R.1'R.2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-p ry an-2-
yl))methyl-3-(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid t-But I Ester
(t)-{2R,3S,5R,1'R,2'S)-1-t Butoxycarbonyl-2-(1-Acetamido-2-allyloxy-2-
allyl)ethyl-
3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (11.5 mg,
0.023
mmole) prepared according to the procedure of Example 239A was reacted with
bis(tricyclohexylphosphine)benzylidine ruthenium(I~ dichloride [Grubb's
catalyst]
(3.8 mg, 0.005 mmole) in methylene chloride (3 mL) at 25°C for 3 hours
under a
nitrogen atmosphere. The reaction was concentrated in vacuo and the resulting
residue purified by chromatography on silica gel using 75% ethyl
acetate/hexanes
to provide the title compound (yield: 5.7 mg, 53%).
MS: (M+H)+= 465, (M+Na)+= 487, (M-H)- = 463
/_.:.
H C
Ac~-IN OH
H N/ ,/~~I~
_ H O
TFA
240B (t)-(2R.3S.5R,1'R.2'S)-2!1-Acetamido-1-X3,6-dih d~-H-pyran-2-
yl) methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic
Acid
Salt
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The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-
pyrroiidine-5-
carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-
butoxycarbonyl-
2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic
acid t
butyl ester. (yield: 5.9 mg, 100%).
'H NMR (DMSO-d6) 8 8.04 (d, J= 8.8Hz, 1 H), 5.77 (m, 2H), 5.50 (m, 1 H),
5.25 (m, 1 H), 4.21 (m, 2H), 4.14 (m, 1 H), 4.04 (m, 1 H), 3.81 (m, 1 H), 3.40
(m,
1 H), 3.23 (m, 1 H), 2.41 (m, 1 H), 2.09 (m, 1 H), 1.88 (s, 3H), 1.83 (m, 1
H), 1.70 (m,
1 H), 1.63 (d, J= 6.8Hz, 3H).
MS: (M+H)+ = 309, (M+Na)+ = 331, (M-H)- = 307
The following compounds were synthesized according to the methods
previously described in Examples 1-240
Exam~ole 241
...
H C
Ac~iN OH
H N/ ,/~
H O
~ TFA
it)~2R.3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3.6-dihydro-2-H-pLrran-2- I)~p~-3-
(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Satt
1 H NMR (DMSO-d6) 8 7.90 (d, 9.1 Hz, 1 H), 5.79 (m, 2H), 5.48 (m, 1 H),
5.23 (m, 1 H), 4.43 (m, 1 H), 4.24 (m, 2H), 4.17 (m, 2H), 3.73 (m, 1 H), 3.64
(m,
1 H), 3.19 (m, 1 H), 2.42 (m, 1 H), 2.02 (m, 1 H), 1.85 (s, 3H), 1.78 (m, 1
H), 1.75 (m,
1 H), 1.56 (dd, J= 7.5, 1.5 Hz, 3H).
MS: (M+H)+ = 309, (M+Na)+ = 331, (M-H)- = 307.
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Example 242
/= ~.
H~C~
AcllN OH
N~ .~~'
HH O
'OH
TFA
{t)-(2R,3S 5R 1'S 2'RS)-2-(1-Acetamido-2-hvdroxy)pentvl-3-(cis-propen-1-vl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
'H NMR (DMSO) 8 7.7 (d, J= 9.8 Hz, 1 H), 5.61 (m, 1 H), 5.19 (dt, J= 1.8,
11.0 Hz, 1 H), 4.33 (dd, J= 6.7, 10.3 Hz, 1 H), 3.81 (m, 1 H), 3.70 (dd, 1.8,
10.3 Hz,
1 H), 3.54 (q, J= 6.1 Hz, 1 H), 3.10 (m, 1 H), 2.35 (dt, J= 12.8, 6.8 Hz, 1
H), 1.90 (s,
3H), 1.7 (m, 1 H), 1.59 (dd, J= 0.7, 7.3 Hz, 3H), 1.4 (m, 3H), 1.2 (m, 2H),
0.90 (t,
J= 6.7 Hz, 3H).
MS: (M+H)+= 299
Example 243
H C
Ac~-IN OH
E., N~ ~~~'I~
H O
'OH
O OEt TFA
(t)-(2R 3S 5R 1'S 2'RS)-2~1-Acetamido-2-hydroxy-3-ethoxycarbon~prop
cis-proaen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO) b 7.75 (m, 1 H), 5.60 (m, 1 H), 5.29 (m, 1 H), 4.55-4.25 (m,
3H),4.15-4.0 (m, 3H), 3.9-3.6 (m, 3H), 3.15 (m, 1 H), 2.45-2.3 {m 2H), 1.9 (s,
3H),
1.8-1.5 (m, 5H), 1.2 (m, 3H).
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MS: (M+H)+= 343
Examele 244
/_ :.
H3C
AcHN , .,, OH
H ~IO~
'OCH3
TFA
(t)-(2R,3S,5R.1'R,2'S)-2 ~1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-proeen-1-
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
'H NMR (DMSO-ds) d 7.91 (d, J=8.05Hz, 1 H), 5.50(m, 2H), 5.30(m, 3H),
4.27(m, 1 H), 4.23(m, 1 H), 3.75(m, 1 H), 3.48(m, 1 H), 3.23(m, 1 H), 3.15(s,
3H),
2.40(rn, 1 H), 1.80(s, 3H), 1.68(m, 1 H), 1.64(dd, J=1.83, 7.32Hz, 3H)
MS: (M+H)+= 297, (M-H)-= 295
Example 245
/_ ...
H3C
AcHN N~.,,, OH
H H ~I
O O
TFA
(t)-(2R,3S.5R.1'R.2'S~-2-(1-Acetamido-2-ethoxy-2-vinyl)eth I-y 3-(cis-preen-
1_yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR(DMSO-ds) d 7.90(d, J=7.85Hz, 1 H), 5.57(m, 2H), 5.48(m, 3H),
4.27(m, 1 H), 4.22(m, 1 H), 3.77(m, 1 H), 3.60(m, 1 H), 3.46(m, 1 H), 3.23(rn,
2H),
2.39(m, 1 H), 1.80(s, 3H), 1.70(m, 1 H), 1.64(dd, J=1.47, 6.73Hz, 3H), 1.12(t,
J=6.83 Hz, 3H)
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MS: (M+H)+= 311, (M-H)- = 309
Example 246
H3C
AcHN N,.,,, OH
~ H ~I~
OH O
TFA
fit)-(2R~3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydroxy~propeny-2-yl))ethyl-3-(cis-
propen-1-yl)-pyrrofidine-5-carboxylic Acid Trifluoroacetic Acid Salt
'H NMR(DMSO-ds) 8 7.69(d, J=9.75Hz, 1H), 5.47(m, 1H), 5.28(m, 1H),
5.03(m, 1 H), 4.86(m, 1 H), 4.40(m, 1 H), 4.30(m,1 H), 4.18(m, 1 H), 3.97(m, 1
H),
3.68(m, 1 H), 3.21 (m, 1 H), 2.43(m, 1 H), 1.82(m, 1 H), 1.73(s, 3H), 1.64(s,
3H),
1.59(m, 3H)
MS: (M+H)+= 297, (M-H)-= 295
Example 247
H C
Acl1 N OH
H N/ r~~I~
H O
~OH
TFA
(t)-(,2R.3S,5R,1'R,2'R)-2-f 1-Acetamido-2-hydroxy~propen~yl)ethyl-3-(cis-
propen-1-yl)pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 7.65(d, J=9.80 HZ, 1 H), 5.48(m, 1 H), 5.23(m, 1 H),
4.99(s, 1 H), 4.88(s, 1 H), 4.46(m, 1 H), 4.30(m, 1 H), 4.19(m, 1 H), 3.55(m,
1 H),
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3.22(m, 1 H), 2.44(m, 1 H), 1.78(s, 3H), 1.75(m, 1 H), 1.65(s, 3H), 1.58(dd,
J=1.23,
6.70HZ, 3H)
MS: (M+H)+= 297, (M-H)-=295
Example 248
H3C
AcHN, OH
OCH3 O
TFA
(t)-(2R,3S,5R.1'R,2'S)-2-(1-Acetamido-2-methoxy-2-(propeny-2-yl))ethyl-3- cis-
propen-1-yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1 H NMR (DMSO-d6) d 7.77(d, J=9.8 Hz, 1 H), 5.49 (m, 1 H), 5.25(m ,1 H),
5.07(m, 1 H), 4.94(m, 1 H}, 4.32(m, 1 H), 4.25(m, 1 H), 3.75(m, 1 ), 3.48(m, 1
H),
3.25(m, 1 H), 3.08(s, 3H), 2.40(m, 1 H), 1.77(s, 3H), 1.68(m, 1 H), 1.fi4(dd,
J=1.22,
6.71 Hz, 3H), 1.56(s, 3H)
MS: (M+H)+=311, (M-H)~=309
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Example 249
/_ :.
H C
Ac~-IN OH
H O
TFA
(tl~2R.3S,5R.1'R -~1-Acetamido-2-ethyl)buty~cis-propen-1-yl)-pyrrolidine-5-
carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) 8 7.62(d, J=9.21 Hz, 1 H), 5.58(m, 1 H), 5.28(m, 1 H),
4.37(m, 1 H), 3.98(m, 1 H), 3.57(m, 1 H), 3.10(m, 1 H), 2.45(m, 1 H), 1.92(s,
3H),
1.76(m, 1 H), 1.62(dd, J=1.83, 6.72Hz, 3H), 1.24(m, 5H), 0.84(t, J=7.61 Hz,
3H),
0.77(t, J=7.61 Hz, 3H)
MS: (M+H)+=297, (M-H)-=295
Example 250
/_ ...
H3C
AcHN. OH
H ~>~~~~I~
O
TFA
St)~2 R.3S.5R,1'S,)-2-( 1-Acetamido-2-ethyl) butyl-3-(cis-propen-1-yl)-
pyrrolid i ne-5-
carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) b 7.76(d, J=9.2 Hz, 1 H), 5.46(m, 1 H), 5.29(m, 1 H),
4.23(m, 1 H), 3.63(m, 1 H), 3.15(m, 1 H), 3.01 (m, 1 H), 2.38(m, 1 H), 1.87(s,
3H),
1.71 (m, 1 H), 1.60(m, 3H), 1.36(m, 1 H), 1.20(m, 4H), 0.83 (t, J=7.3Hz, 6H)
MS: (M+H)+=297, (M-H)-=295
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Example 251
/= ,
H C H C
Ac~HN H N).,~ Et Ac~iN H N~OEt
OH O ~OH
~-)-(2R.3S.5R 1'Sl-2~1-Acetamido-2-eth~rlLut~l-3-(cis-propen-1-yl)-pyrrolidine-
5-
carboxylic Acid Ethyl Ester and (+)-(2S,3S.5S.1'R)-2-(1-Acetamido-2-ethyl)but
rLl-
3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester
(t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid ethyl ester (100 mg) was chromatographed in one
injection on a chiral HPLC column of dimensions 5 x 30 cm. The column was
packed with Chiralpak AD chiral stationary phase packing from Chiral
Technologies. The mobile phase consisted of 1:9 ethanol:hexanes at a flow rate
of 117 mUmin. Two peaks were observed at (24-36) minutes (-)-(2R,3S,5R,1'S)
(yield: 45 mg) and at (66-96) min (+)-(2S,3S,5S,1'R) (yield: 45 mg).
(-)-(2R,3S,5R,1'S) [ajo = -26° (c=0.78, dichloromethane)
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Example 252
~(2R, 3S.5R.1'S)-2-( 1-Acetamido-2-ethyl)butyl-3-f cis-propen-1-yl)-
pyrrolidine-5-
carboxylate Ammonium Salt
...
AcHN O NN4
O
OH
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic acid ethyl ester (4.9 mg, 0.0157 mmoie) prepared
according to the procedure of Example 251 was reacted with lithium hydroxide
(0.75 mg, 0.0314 mmole) in a mixture of methanol (0.75 mL) and water (0.25
mL) at 0°C for 7 hours. Then 0.1 N aqueous Hydrochloric acid (1 mL) was
added, the reaction was concentrated in vacuo and the resulting residue
purified
by ion exchange chromatography on Aldrich Dowex 50WX8-400 strongly acidic
resin. The residue was placed on the column and washed with water (5 mL)
followed by elution using 0.5 N aqueous Ammonium hydroxide to provide the
title
compound as a colorless solid (yield: 3.9 mg, 83%). [a)o = - 40° ,
c=0.08 (water).
1 H NMR (DMSO-d6) s 7.71 (d, J= 9.2 Hz, '! H), 5.38 (m, 1 H), 5.29 (m, 1 H),
3.92 (m, 1 H), 3.65 (t, J= 8.5 Hz, 1 H), 3.43 (m, 1 H), 3.33 (m, 1 H), 2.98
(m, 1 H),
2.23 (m, 1 H), 1.76 (s, 3H), 1.54 (dd, J= 6.7, 1.8 Hz, 3H), 1.46 (m, 2H), 1.23
(m,
1 H), 0.84 (t, J= 7.3 Hz, 3H).
MS: (M+H)= 285, (M+Na)+= 307, (M-H)- = 283.
[a]o = - 40° , (c=0.08, water).
Example 253
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H3C
AcHN N~.,,~ H
H H I IO
~OCH3
OCH3
TFA
~tL,2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2.3-dimethoxy)propel-3-(cis-propen-1-yl~
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (MeOD-d3) s.7.8(d, J=9.3Hz, 1 H), 5.49-5.43(m, 1 H), 5.25(dd,
J=1.95, 9.3Hz, 1 H), 4.38-4.31 (m, 2H), 3.57-3.50(m, 1 H), 3.46(dd, J=4.9,
10.3Hz,
1 H), 3.42(s, 3H), 3.35-3.32(m, 2H), 3.27(s, 3H), 3.16-3.09 (m, 1 H), 2.46-
2.40(m,
1 H), 1.80(s, 3H), 1.72-1.65(m, 1 H), 1.55(d, J=6.8Hz, 3H).
MS: (M+H)+=315, (M+Na)+=337, (M-H)-=313, (M+CI}-=349, (2M-H)-=627.
Example 254
H3C
AcHN N~.,~ H
H H
OCH3 O
OCH3
TFA
(t~(2R.3S 5R31'R 2'R)-2-(1-Acetamido-2,3-dimethox~prop~3-(cis-propen-1-~rl)-
pyrrolidine-5-carbox~ Acid Trifluoroacetic Acid Salt
'H NMR (MeOD-d3) 8.8.04(d, J=8.5Hz, 1 H), 5.52-5.48(m, 1 H), 5.27-
5.22(m, 1 H), 4.32-4..25(m, 2H), 3.74-3.71 (m, 1 H), 3.53(dd, J=2.4, 10.1 Hz,
1 H),
3.33-3.25(m, 2H), 3.31 (s, 3H), 3.25(s, 3H), 3.21-3.17(m, 1 H), 2.42-2.36(m, 1
H),
1.86(s, 3H), 1.71-1.63(m, 1 H), 1.62(d, J=7.3Hz, 3H).
MS: (M+H)+=315, (M+Na)+=337, (M-H)-=313, (M+CI)-=349, (2M-H)-=627
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Example 255
H3C
AcHN. N~.,~OH
H H
OH O
OH TFA
(t~ ~2 R.3S, 5R.1' R,2' Rl-2-( 1-Acetamido-2-)~droxyethyl-2-hyd roxy~ pentyl-3-
(cis-
propen-1- I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds): 8 7.60 (m, 1 H), 5.46 (m, 1 H), 5.30 (m, 1 H), 4.54 (m,
1 H), 4.35 (m, 1 H), 4.03 (m, 1 H), 3.96 (m, 1 H), 3.69 (m, 1 H), 3.15 (m, 1
H), 2.40
(m, 1 H), 1.98 (m, 2H), 1.80 (s, 3H), 1.70-1.50 (m, 5H), 1.38 (m, 3H), 0.83
(m, 3H).
MS: (M+H)+=343, (M-H)-=341
Example 256
/_',
H3C
AcHN, N~.,~OH
H H
O
TFA
(t)-(2R.3S,5R,1'R~-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-propen-1_yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (MeOD-d3) 8 5.69-5.59 (m, 1 H), 5.33-5.25 (m, 1 H), 4.39 (m, 1 H),
4.34 (dd, J=7.8, 10.2Hz, 1 H), 3.73 (dd, J=4.8, 10.2Hz, 1 H), 3.58-3.47 (m,
2H),
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3.38-3.24 (m, 1 H), 3.27-3.20 (m, 1 H), 2.61-2.52 (m, 1 H), 2.02 (s, 3H), 1.90-
1.78
(m, 1 H), 1.70 (dd, J=1.7, 6.8Hz, 3H), 1.60-1.50 (m, 4H), 0.92 (t, J=7.5Hz,
6H)
(M+H)+= 327, (M+Na)+= 349
Example 257
/= ,
H3C
AcH N N ~. , ~ H
H H
O
TFA
(t)-(2R.3S,5R.1'S)-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-propen-1-yl)-
pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
'H NMR (MeOD-d3) S 5.73-5.66 (m, 1 H), 5.32-5.25 (m, 1 H), 4.36 (dd,
J=7.8, 10.2Hz, 1 H), 4.09 (m, 1 H), 3.68 (dd, J=6.1, 10.2Hz, 1 H), 3.61 (d,
J=4.4Hz,
2H), 3.35-3.23 (m, 1 H), 3.24-3.16 (m, 1 H), 2.65-2.55 (m, 1 H), 2.03 (s, 3H),
1.92-
1.80 (m, 1 H), 1.70 (dd, J=2.0, 7.1 Hz, 3H), 1.59-1.47 (m, 4H), 0.94-0.88 (m,
6H)
(M+H)+ = 327, (M+Na)+ = 349
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Exami~le 258
/=.:.
H C
Ac~iN OH
~ N / .,'~~
HH O
'O
~~ TFA
(~~~2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-
yl~pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds) s 8.01 (d, J= 8.6Hz, 1 H), 5.76 (m, 1 H), 5.49 (m, 1 H),
5.25 (m, 1 H), 5.05 (m, 2H), 4.28 (m, 1 H), 4.02 (m, 1 H), 3.77 (m, 1 H), 3.62
(m,
1 H), 3.36 (m, 1 H), 3.29 (m, 1 H), 3.18 (m, 1 H), 2.43 (m, 1 H), 2.38 (m, 1
H), 2.16
(m, 1 H), 1.87 (s, 3H), 1.69 (m, 1 H), 1.63 (dd, J=6.7, 1.2 Hz, 3H), 1.12 (t,
J=6.7
Hz, 3H).
MS: {M+H)= 325, (M-H)- = 323
Example 259
...
H C
Ac~i N OH
N~ .°I~
H H
O O
TFA
ft)-(2R,3S.5R.1'R)-2-{1-Acetamido-2-allyloxy)ethLrl,-3-(cis-propen-1-yl)-
evrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
H NMR {DMSO-ds) 8 9.16 (m,2H), 8.13(d,J=7.5Hz,1 H), 5.88(m,1 H), 5.50
(m,1 H), 5.15-5.32(m, 3H), 4.35(m,2H), 3.95(m,2H), 3.61 (m,1 H), 3.40(m,2H),
3.20(m, 1 H), 2.40(m,1 H), 1.87(s,3H), 1.72(m,1 H), 1.62(d, J=6.2,3H)
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MS: (M+1 )=297, (M+23)=319, (2M+23)=615
Example 260
/_',
H3C
AcHN N~., ~ H
H H
OH O
~O
OEt TFA
(t)-(2R 3S 5R 1'R 2'RS)-2-(1-Acetamido-2-hydroxy-2-(2-ethoxycarbonyl))pentrl-
3-(cis-propen-1-yl)-pyrrolidine-5-carbox Iy IC Acid Trifluoroacetic Acid Salt
' H NMR (DMSO-ds): 8 7.57 (d, J=1 OHz, 1 H), 5.45 {m, 1 H), 5.29 (m, 1 H),
4.35 (rn, 1 H), 4.09 (m, 1 H), 3.68 (m, 1 H), 3.44 (m, 1 H), 3.17 (m, 1 H),
2.87 (m,
1 H), 2.64 (m, 1 H), 2.39 (m, 1 H), 1.80 (s, 3H), 1.65-1.56 (m, 2H), 1.53 (m,
3H),
1.50-1.30 (m, 3H), 1.21 (t, J=7.5Hz, 3H), 0.80 (t, J=7.5Hz, 3H).
MS: (M+H)+=385, (M-H)-=383
Example 261
!_',
H3C
AcHN N~.,~ H
HO, H H
O
TFA
HO
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,~t~-~2R 3S 5R 1'S 3'R)-2-(1-Acetamido-3,4-dihydrox~butyl-3-(cis-propen-1-yl~
pyrrolidine-5-carboxylic Acid Trifluoraacetic Acid Salt
H NMR (CD30D) 8 5.58-5.70 (m, 1 H), 5.24-5.38 (m, 1 H), 4.34-4.50 (m,
2H), 3.58-3.72 (m, 2H), 3.42-3.48 {d, 2H), 2.50-2.63 (m, 1 H), 2.04 (s, 3H),
1.77-
1.95 (m, 1 H), 1.65-1.76 (m, 4H), 1.50-1.63 (m, 1 H).
MS: (M+H)+= 301
Example 262
/_',
H3C
AcHN. N~,~ H
HO H H O
TFA
HO
(t)-(2R 3S 5R.1'S 3'S)-2 ~1-Acetamido-3,4-dihydroxy)butyl-3-(cis-proc~en-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
'H NMR (CD~OD) 8 5.58-5.72 (m, 1 H), 5.25-5.37 (m, 1 H), 4.30-4.45 (m,
2H), 3.63-3.77 (m, 2H), 3.44-3.49 (d, 2H), 2.50-2.63 (m, 1 H), 2.03 (s, 3H),
1.76-
1.95 (m, 2H), 1.65-1.75 (m, 4H).
MS: (M+H)+= 301
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Example 263
(t)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-methox )ythyl-3-(cis-propen-1-yl)-
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
CH3
AcHN_ N)., OiBu
H Boc
H3C0
263A (t)-(2R 3S 5R.1'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-methoxy)ethyl-3-
(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid f-Bu I Ester.
The title compound was prepared according to the method described in
Example 84A, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-
2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester for
(t)-(2 R, 3S, 5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-
(cis-
propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.2 mg, 20%).
MS: (M+H)+=427, (M+Na)+=449, (M-H)-=425.
CH3
AcHN_ N~.,~ H
HH O
H3C0
TFA
2638 (t)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-methoxy)ethyl-3-(cis-propen-1-yIL
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-
acetamido-2-methoxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-
butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-
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2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl
ester
(yield: 0.0031 g, 100%).
'H NMR (DMSO-ds) b 8.12 (d, J=7.9Hz, 1 H), 5.50 (m, 1 H), 5.23 (m, 1 H),
4.33 (m 1 H), 3.56 (dd, J=9.7,8.OHz, 1 H), 3.4-3.3 (m, 2H), 3.26 (s, 3H), 3.19
{m,
1 H), 2.39 (dt, J=12.8,7.3Hz, 1 H), 1.86 {s, 3H), 1.71 (m, 1 H), 1.61 (dd,
J=6.7,1.8Hz, 3H).
MS: (M+H)+=271, (M+Na)+=293.
Example 264
fit)-{2R.3S.5R 1'R 2'S)-2-(1-Acetamido-2-h day-3-dimethyl)butyl-3-(cis-propen-
1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
CH3
AcHN_ N,., OtBu
H Boc
-OH
264A ~t)-(2R,3S,5R,1'R,2'Sl-1-t-Butoxvcarbonyl-2-(1-acetamido-2-hydrox~3-
dimethyl)butyl-3-(cis-t~ropen-1-yl)-pyrroiidine-5-carboxylic Acid t-Butyl
Ester.
The title compounds were prepared according to the method described in
Example 41 B, substituting t butyl lithium for ethyl magnesium bromide to
provide
(t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbony!-2-(1-acetamido-2-hydroxy-3-
dimethyl)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester
(yield:
2.5 mg, 11 %)
(t)-(2R,3S,5R,1'R,2'S) MS: (M+H)+ = 469; (M-H)- = 467.
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/_',
CH3
AcHN. N~.,~OH
H'H
O
OH
TFA
264B (t)-(2R 3S 5R.1'R.2'S)-2~1-Acetamido-2-hy"droxy-4-vinyl)butyl-3~cis-
propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in
Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-
acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-
carboxylic
acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-
butyl
ester (yield: 2.3 mg, 100%).
'H NMR (DZO) 8 5.40 (m, 1 H), 5.10 (t, J=5.5Hz, 1 H), 4.13 (t, J=9.2Hz,
1 H), 3.46 (m, 1 H), 3.22 (d, J=7.3Hz, 1 H), 3.00 (m, 1 H), 2.41 (m, 1 H),
1.70 (s, 3H),
1.45 (m, 1 H), 1.39 (d, J=4.9Hz, 3H), 1.07 (t, J=5.5Hz, 1 H), 0.70 (s, 9H)
MS: (M+H)'' = 313.
Using the methods described above and the general knowledge of one
skilled in the art, compounds of the invention can be prepared which are
represented by taking one core from Table 1 (wherein Ac is acetyl), one Y
substituent from Table 2, one R substituent from Table 3 and one R3
substituent
from Table 4a, 4b, 4c, 4d, 4e, 4f or 4g.
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Table 1
Y, Y,
AcHN, 3 H N~ ~OR AcHN 3 H Nil ~OR
R H IOI R ~ H IIO
1 2
Y~ Y,
CH3S02tiN, >. OR CH3S02i-IN ~. OR
N ~ N
R3H H O RsN H O
3 4
O Y, O Y,
II II
CF3C-HN, 3 H N~.. ~OR CF3C-HN 3 H N~ ~OR
R H IOI R ~ H IIO
6
Table 2
H3 ~ ~ HN
H3C ~~~~- H ~~~~ CI
1 2 3 4
H3 ~ H3C
"- ""~". H3C ,~~~ ~ "",~
5 6 7 8
F~
H ,~~~~ , F ~~-
9 10 11 12
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HN~N ~N ~O F3C F
HN~ N~ CI~
13 14 15 16
Ha ~ Hs ~ ~ F3
F ~~- CI ~~ F3C ~~~~ H
17 18 19 20
H3 ~ HN =~ N~ N=
N
H 3C ...,.", , ,
21 22 23 24
F3 ~ F~ F3 ~ N~S
F ~~~- F3C ~~~, CI ,~~~-
25 26 27 28
--I H F
Et Et Et
29 30 31 32
F3 ~ I F~CI Et, H3C ,,O
,N
H
C
F r,~~~, F3C ~~~~ H ."...... .,.",.
33 34 35 3
36
H\ CH3 F\ HN~ CI,
Hj~.,~..".C i ~ ~~..~~H
37 38 39 40
HO O
=~ N-N
N
41 42 43 44
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HN~~ > N\N~ ~NO
~
N -N N-N
45 46 47 48
N.N HN~N' HN~N" N HN~N~ N
N N=( ~ ' N
~(
N , , ,
49 50 51 52
/ ~N
N
HN ,
, N-N
53 54 55 56
S ~ , S'.=( SN=( g=
57 58 59 60
~ O, N, S~ N
S
61 62 63 64
F~ H
H F F
65 66 67 68
F\ F F' .F ~ H3 H3 ~ H3
H/~(\ F~ H
C
69 70 3 72
71
H3 ~ H ~ I CI, CI CI' CI
H ~~~~~~ H~)--.(~ CI/~~(\~~~~
C
3 74 75 76
73
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CI~ ~ I ~ F3 F3 ~ F3
CI/ \ CI
77 78 79 80
H C F3C CI CI CH3
F3C ..:,.... F3C~ H3C~ CI~
81 82 83 84
1 ~ H3 F3 ~ F3 H3 ~ i
H3C .~.~. CI F3C H3C
85 86 87 88
CI CH3 H3C CI H3C CH3 CI CH3
CI~ H3C
89 90 91 92
F~ F~ ~ H3 H3 ~ I
F ~ H3C F ~ CI
93 94 95 96
CI CI CH3 F F CH3
H3C .,.:.... F~ H3C ' H3C
97 98 99 100
H3 ~ F\ ,CH3 H3 ~ F~F
""."", ~(\ F .,.,.,.". H3C~~-."",r,
101 102 103 104
H3 ~ F3 ~ H3 ~ F3 H3 ~ H3
F3C ~ H3C ~ H3C F3C
105 106 107 108
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H3C CF3 F3C CH3 CF3 F3C CH3
C/ \ F
C
109 110 H3 3
111 112
H3 H3 ~ F3 F3 ~ F3 CI'-\
F F H F
. C C
C
~..."", 3 3 116
3 114 115
113
F\ .CI F' ,CI CI~ ~ I
F~~--(~ F
117 118 119 120
CI, .F CI, C1 F' _F
CI CI~)--.(~~ F~~--(~ C ~~---(~I
121 122 123 124
CI"F CI, CI CI~ CI, CF3
F~)---(~ C~~.-(~~ C/
F F
125 ~ 3 128
126 127
F3 ~ 1 F3 ~ I F3 ~ i F3 ~ F3
F CI ~~-w ...""~, CI
C
3 130 131 132
129
CF3 CI CI CF3 CI CF3
C1~' F CI~ F3C
C~
133 3 135 136
134
F' ,CF3 F\ ,CF3 F' .CF3 F' ,F
~ C~~.(~ ~~--(~C
F F
137 F 3 3
138 139 140
-507-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/47945
Fs ~ Fs ~ ~ Fs F3
F .,."..", ~""..., F .,...",~. F3C .",.""
141 142 143 144
F3t ~ F3 H3 ~ H3 ~ I
F3C .""..., F .~...r". CI ~~~~~~ F
145 146 147 148
CI"F F~CI F' ,CH3 CI' CH3
C~~.~(~~ C~~--~(~~~~~ CI/~\ /u\F
H H
3 3 151 152
149 150
H3 ~ F3 H3 ~ I CI~ F3 F3 ~ I
C ~ HsC ~' H3C .~.
F
CI .~,~."~ 3 155 156
153 154
F3 ~ H3 Cli \ H3 H3 ~ F3 H3
CI ~~~ F F F
C C
157 3 i59 3
158 160
F\ .CF3 F~CF3 F3 ~ F3 ~ H3
C/~\ C~~--(~ H F
H H C
3 3 3 164
161 162 163
F~CH3 CI, CF3 CI"F F~CF3
C~~-(~ F~~-(~ C~---~ C ~~-(~I
F F
3 166 3 168
165 167
NH H2N~ H2N
N
HZN-~/ N ~ ,
H ~ ~
3
169 170 171 172
-508-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
H2N, NH
~'" H2N-l/
~NH
173 174
Table 3
-H
CH3 ~ CH3
~~CH3 / CH3 ~~CH3
l~./ 4 6
CH3
CH3 CH3 ~,,~' _
~~CH3 ~ . \
CH3 ~ CH3
H3C / CH3 CH3
,r,,.~~CH3 \.-~-CH3
10 CH3 11 CH3 12
,CH3 ~~ CH3 ~~ ~--CH3
~ N N
'-CH3 13 CH3 14 ~CH3 15
-509-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
Table 4a
CH3 ~ CH3
H C~ ~ HsC~OH
OH 3 OH OH
CH3
1 2 3 4
3 ~'
HsC OH HsC l -OH ~OH
OH H C
CH CHs s CH3
3 H3C
6 7 8
CHs
/\ OH OH OH OH
H3C CHs CHs
9 10 11 12
HsC CH3,~"' ~ \
H3C
OH -OH OH OH
H3C CHs HsC CHs
13 14 15 16
CHs CHs
\ \
~OCH H3C~OCH ~ H3C~OCH
CHs 3 3 OCHs 3
17 18 19 20
CHs
HsC~OCH OCHs H3C~OCH3 OCHs
CH CHs HsC CHs
3 H3C
21 22 23 24
-5 7 0-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
CH3
~OCH3 OCH3 OCH3 OCH3
H3C CH3 CH3
25 26 27 28
H3C CH3~ ~ \
H3C
OCH3
OCH3 H3C CHOCH3 OCH3
H3C CH3
29 30 31 32
OH ~~~~ OH
~ H C H C
OCH 3 ~ H 3 ~OCH3
i\ 'OH ~ s H C O HsC H
H3C CH3 H3C CH3 3 CH3 C
33 34 35 36
H3C _
H3C\~ ~~
H3C~OH - 'OH H3C - -OH
OH
37 38 39 40
OH ~ OH
OH -OH
H3C CH3
41 42 43 44
H3C
H3C\~ ~, ~
HsC~OCH3 - 'OCH3 H3C~OCH3
OCH3
45 46 47 48
OCH3 ~OCH3 OCH3 ~OCH3
H3C CH3
49 50 51 52
-511-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
Table 4b
i 'OH ~OCH3 ~O~CH3 ~O~
OH OH OH OH CH3
1 2 3 4
"OH ~ "OCH3 ~ "O~CH3 ~ "O~
OH OH OH OH CH3
6 7 8
HO~~OH HO~OCH3 HO'~O CH3 HO~'O
OH OH off OH CH3
9 10 11 12
HO~OH HO~OCH3 Ho' Y 'o CH3 HO~O
OH OH OH CH3
13 14 15 16
HO~~ "OH HO~ "OCH3 HO~ ~O~CH3 HO~ "O~
OH OH ~H OH CH3
17 18 19 20
HO~ "OH HO~ "OCH3 HO~ O cH3 HO~ "O~
OH OH OH CH3
21 22 23 24
~O~ ~~ "O HO~O HO~O
OH II OH ~ OH ~ OH
25 26 27 28
-512-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
HO~~'O HO~'O ~OCH3 ~~OCH3
OH ~ OH ~ OCH3 OCH3
29 30 31 32
CH30~~OCH3 CH30~OCH3 CH30~'OCH3 CH30~'OCH3
OCH3 OCH3 OCH3 OCH3
33 34 35 36
HC
H3C~OH H3C~OCH3 H3C~0~CH3 H3C~0
OH 3 OH OH OH CH3
37 38 39 40
CH~",~".
HsC OH HsC~OCH3 H3C~0~CH3 H3C~~
IOH O OH
H C OH H3C Hs OH CH3
3
41 42 43 44
H3C
H3C~OH H3C~OCH3 H3C~O~CH3
OH OH OH OH CH3
45 46 47 48
H3C~OH HsC'~OCH3 H3C'~O~OH3 H3C~0
OH OH OH OH CH3
49 50 51 52
~~ ~ ~~ HC~~
H3C "r 'OH H3CY 'OCH3 H3C Y 'O~CH3 3 ~O~
OH OH OH OH CH3
53 54 55 56
I ~ l
H3C~;~OH H~C~~OCH3 H3C''~O~CH3 H3C~0
OH OH OH OH CH3
57 58 59 60
-513-

CA 02329422 2000-10-19
WO 99/54299 PCT1US99/07945
HC ~,
H3C~ ~OH H3C~'OCH3 H3C~ ~O~CH3 H3
OH 3 OH OH OH CH3
61 62 63 64
CHI.."",.
H3C~ ~OH H iC~'OCH3 H3C~ 'O~~H3 H3C
OH H C OH H3C OH
H3C s OH CH3
65 66 67 68
H3C~OH H3C~OH H3C~OCH3 H3C~OCH3
OOH CH3 OOH ~~CH3 OH CH3 jOH ~'CH3
69 70 71 72
H3C~OH H3C~~/~'OH H3C~OCH3 H3C--~OCH3
OH CH3 OH ~CH3 OH CH3 OH ~CH3
73 74 75 76
H3C ~OH H3C~OH H3C~OCH3 H3C~OCH3
H3C O CH3 H3C~OH '-CH3 H3C~OH CH3 H3C~OH ''-CH3
77 78 79 80
CH~~- CH3~~~~~ H3C
H C~,~ OH OH ~OCH3 H3C~OCHg
~f"i3 '-CH H3C~ ,CH '-CH
OH 3 OH 3 OH
H3C CHOH
3
81 82 83 84
Table 4c
CH3 H3C
H3C''-CH3 HsC~-CH3 ~-CH3 ~CH
OH OH pH s
CH3
I 2 3 4
-514-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
\. ' I
-CHs ~CH3 CHs ~'~'CH3
CHs CHs CH3 ICHs
6 7 8
CHs ~ CHs ~~~-
.CH H3C \ ~CH3 \ ~CH H3C~ ~CH3
3 ~ 3
CHs CHs
9 10 11 12
CHs ,~~~- CHs .~~~- \
CHs H3C~ ~CH HsC \ ~CH
3 ~ 3 ~CH3
HsC CHs H3C CHs
13 14 15 16
H3C~.CH3 H3C~.CH3 _CH3 .CHs
CHs HsC CHs
17 18 19 20
CHs '~"" CHs ""~' CHs
'CHs ~CH3 ~ ~CH3 ~CH3
H3C CHs CHs CHs H3C CHs
21 22 23 24
CHs '~"' HsC \
HsC~.CHs ~~.CH3 .,..",.CHs .CHs
OH OH OH OH
25 26 27 28
CH CH HsC
1' 'CHs ~ ~CH3 CH
~CH3 ~ 3
OH OH ~H OH
29 30 31 32
-515-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
OH OH OH
:CHs ,~,.GH3 .~.GH3
CH3
OH OH H3C CH3
33 34 35 36
CH3 H3G
H3C
HsC CH3 CH3 CH3
CH3
37 38 39 40
"CH3 \~ _ 'CH3 ~'CH3
CH3 CH3
41 42 43 44
CH3 ~ CH3
~CH HsC \ CHs \ CH HsC~CHa
3 ~ 3
CH3 CH3
45 46 47 48
' CH3 GH3 ,~.~- \
CH3 H3C CH3 H3C~CH3 ~CH3
HsC CHs HsC CHs
49 50 51 52
H3C~CH3 H3C CH3 CH3 CH3
GH3 I-I3C GH3
53 54 55 56
CH3 ~ CH3 """' CH3
GH3 [ CH3 Y 'CH3 ~GH3
H3C CH3 CH3 CH3 H3C CH3
57 58 59 60
-516-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
CH3 ','." H3C \,
H3C~CH3 ~~CH3 ~CH3 CH3
OH OH OH OH
61 62 63 64
CH CH HsC
Y 'CH3 Y 'CH3 CH
~CH3 ~ 3
OH OH ~H OH
65 66 67 68
OH '~"' OH
Y 'CH3 CH3 ~CH3
CH3
OH OH H3C CH3
69 70 71 72
CH3 H3C\
H3C~.~C1"lg HsC~CH3 ~.~CH3 l~~I.~CH3
73 74 75 76
~~~CH3 ~.~CH3 ~~'~CH3 ~~~iCH3
CH3
77 78 79 80
CH3 CH3 ~~~-
~~./CH3 HgC~'.~CH3 ~ ..~CH3 H3C~'.~CH3
CH3
CH3
81 82 83 84
CIH3 I CH3 ~ \
~. ~CH3 H3C~. ~CH3 H C ~ . ~CH3 CH
3 ~ ~~ 3
H C CH3 H3C CHa
3
85 86 87 88
-517-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
H3C ~. ~CH3 H3C ~. ~CH3 ~. ~CH3 ~. ~CH3
CH3 H3C CH3
89 90 91 92
CH3 .",."' CH3 '""" CH3
. ~CH3 ~ . CHs ~. ~CH3 ~. ~CH3
H3C CH3 CH3 CH3 H3C CH3
93 94 95 96
I CH3 ....'.' H3C \
H3C~.~CH3 ~~,~CH3 , CH ,~CH3
iOH OH OH OH
97 98 99 100
CH CH Hs0 \
~../CH3 ~\~'../CH3 ~~./~H3 ~../CH3
OH OH OH OH
101 I02 103 104
OH i OIH OIH
\ .NCH ~'1~~L~..iCH3 ~'.iCH3 ~'.iCH3
OH 1OH H3C/ICH3
105 106 107 108
CH H3~
H3C~CH3 HsC~CH3 ~CH3 ~~H3
109 110 111 112
C
113 114 115 116
-518-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
,...,... .~,~., C~ ~"". HsC~CHs
' \C~H ~3
C ~3
117 118 119 120
CH3 CH3 ~ \
CH3 H3C;~CH3 H C \ CH3 CH
3 ~ 3
HsC CHs HsC CHs
121 122 123 124
H3C ~CH3 H3C CH3 CH3 CH3
CH3 H3(., CH3
125 126 127 128
CH3 "."" CH3 '~"' CHs CH
CH3 CH ~ 3 CH3
' 3
H3C CH3 CH3 CH3 H3C CH3
129 130 i31 132
I CIH3 .""" H3C \
H3C~CH3 ~CH3 \~CH3 CH3
i j O
' _ ~'
OH OH OH OH
133 134 135 136
CH3 H3C, ~ \~ I
H3C~'~CH3 ~CH3 ~CH3 ~CH3
OH OH OOH ~' ~~O'' ~~''H
137 138 139 140
i OH OH OH
\ ~ ~ CH3 ~CH3 CH3 CH3
OH H3C CH3
141 142 143 144
-519-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
CHs CHs CH3 ; CHs
H3C~ ~ J H3C~. . J . ~ H3
145 146 147 148
CHs w CH CHs CHs
J. J ~. J 3 J.J .....~. J
J
CHs
149 150 150A ISOB
CHs CHs CHs CHs ~ CHs ~ Hs
J.. J ~3C-~J. ~-~ ~ . J H3~-~ J..
CHs
CH3
i51 152 153 1~4
CHs CHs CHs CHs ~.~~,~ Hs ~ .""..~ Hs
~ . J H C-~-J . J J~
H3C 1
CHs HsC CH
HsC 3
I55 156 157 158
H3C .,.",.~ Hs HsC ."..".~ Hs .,..",.~ Hs .~.", J Hs
CHs HsC CHs
159 160 161 162
CHs ""~'~ CHs ',.."'~ CH. 3 j 'J ~ ".~'~
Hs Hs Hs Hs
H3C CHs CHs CH3 H3C CHs
163 164 165 166
"..",.J CHs ...."'~ H30 ~~ Hs ~ '~"'~
Hs Hs Hs
H3C
OH OH OH OH
167 168 169 170
-520-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
CH, 3 j 'J Hs CH3 j 'J Hs H3C~'~ H3 ~ '~ Hs
OH OH OH OH
171 l72 173 174
.~.... J H pH ; ' CHs OH '"""'~ Hs OH """'~ Hs
/I\
OH OH HsC CHs
175 176 177 178
HsC i CHs ; CHs CH~CH3 HsC
J HsC 1 j ,CHs
179 180 181 I8 '\~2
CHs \ CHs I CHs \ i 'CHs
\~C'H ~3
183 184 185 186
CH~CH3 CHs CHs ~ CHs CHs
[\\ Ej3C~\-~J \ HgC
CH3
CHs
187 188 189 190
CHs CHs CHs CH3 CHs \ CHs
H3C' v v H3C
CH3
HsC HsC CHs
191 192 193 194
CHs CHs CHs CHs
H3C 1 H3C' I
CHs HsC CHs
195 196 197 198
-521-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
CHs .'~' CHs CHs ""~' CH3 j ,CHs ~ CHs
CHs
H3C CHs CHs CHs H3C CHs
199 200 201 202
I CIHs CHs """' HsC CHs \ CHs
H3C CHs
i
'
O OH OH OH
H
203 204 205 206
CH3 j ,CHs CH3 j ,CHs f"13C~~CH3 \ CH3
J '~.~~~J
OH OH OH OH
207 208 209 210
~CH OH j ,CHs OH CHs OH CHs
J ~
H
OH OH 3 CHs
211 212 213 214
H3C~'~ H3C~'~ CH. 3 ; 'J HsC
~.J
215 216 217 218
. J ~.~: . J ~. . J
CHs
219 220 221 222
C~i . J H3C-,-~ . C~ ~ J H3C \ ~J
J
CHs CHs
223 224 225 226
-522-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
CH CH
~.J H~C-~.J H3C ; .~~ ~.J
CH3 HsC CH
H3C s
227 228 229 230
H3C .~J H3C ~.J .~J ~.J
CH3 H3C CH3
231 232 233 234
CH3 ~ '~ CH3 '~"'~ CH3 j ' J y. J
H3C CH3 CH3 CH3 HOC CH3
235 236 237 238
H C ~: . .J ~ 3 ~: J H3c ~: ~ ~ ~: J
3
OH OH OH OH
239 240 241 242
°H~, J ~~,~ "3° ~:J ~~J
OH OH ~H OH
243 244 245 246
~"~. J °" ~ J °H ~:J
H C' '
OH OH 3 CHg
247 248 249 250
CH3 H3C
H3C~ H3C
251 252 253 254
-523-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
\
CHs
255 256 257 258
CH3 ; " /~ CH3
HsC \ \w~I H3C/
I
CHs CHs
259 260 261 262
CHs ~ CHs ~~~-
H3C~ HsC w
HsC CHs HsC ~CH3
263 264 265 266
HsC ~ HsC
i
CHs HsG CHs
267 268 269 270
CH3 """' I CHs """" I CH
H3C CHs CHs CHs H3C CHs
271 272 273 274
CHs ~ ~ HsC \
H3C
OH OH OH OH
275 276 277 278
CH~ ~~ HsC
OH OH ~H OH
279 280 281 282
-524-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
i I I O~ OH I OH
~'Y~~
OH OH H3C CH3
283 284 285 286
H CH3 ~ H3C J
H3C
287 288 289 290
H3C J
H3C
CH3
H3C
291 292
Table 4d
1 2 3 4
H3C CH3 H.~C CH3 H3C CH3
6 7 8
H3C
H3C' O H3C O
O HOC O
9 10 11 12
-525-

CA 02329422 2000-10-19
WO 99/54299 PCTNS99/07945
H3C ~ H3C ~ H3C
H;3C O ~ O O
13 14 15 16
H3C
H3C- ~O H3C ~O
~O H3C ~O
17 18 19 20
H3C ~ H3C ~ H3C
H3C ~O ~ ~O ~O
21 22 23 24
~O ~O ~O 'O
\ \
25 26 27 28
H3C H3C
~O ~ 'O H3C ~O H3C 'O
29 30 31 32
H3C H3C H3C
H3C H3C H3C
33 34 35
-526-

CA 02329422 2000-10-19
WO 99154299 PCT/US99/07945
Table 4e
CH3 H3C _
H3C~.~OH HsC~OH ~,~OH ~.
OOH
1 2 3 4
~.'~OH ~'~OH ~.~OH ~.~OH
CH3
6 7 8
CH3 CH3
~,~OH H3C~.~OH \ ,OOH H3C~.~OH
CH3 CH3
9 10 11 12
CH3 CH3 ,~~~- \
~.~OH H3C~~~OH H3C \ ~~OH ~~OH
HsC CHs HsC CH3
13 14 15 16
H3C ~ . OOH H3C ~~OH ~. OOH ~~OH
CH3 H3C CH3
17 18 19 20
CH3 "'~' CH3 """' CH3
. OOH , OOH ~ , OOH ~ ~~OH
H3C CH3 CH3 CH3 H3C CH3
21 22 23 24
-527-

CA 02329422 2000-10-19
WO 99154299 PCT/tlS99/07945
'""" CHs "."" HsC \
H3C~.~OH ~.~.~OH ~~OH .~pH
[OH TOH OH OH
25 26 27 28
CH CH HsC
~.~OH ~.~OH ~~OH .OOH
OH OH pH OH
29 30 31 32
i OH OH OH
\ I J- OH ~~..iOH ~. OOH ~. OOH
OH OH HsC CHs
33 34 35 36
CHs H3C
H3C~OH HsC.,.~OH ~OH OH
37 38 39 40
~OH OH ~OH ~OH
lCH ~3
41 42 43 44
CHs CHs ~~~,
H3C~OH \ OH H3C~OH
CH3 __ RICH ''''3
45 46 47 48
CHs CH3 -~~~- \
OH H~C~OH HsC \ OH OH
H C CHs HsC CHs
3
49 50 51 52
-528-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
H3C~OH H3C~OH OH OH
'~C'H3 ~ H3C~CH '3
53 54 55 56
CH3 ~ OH ~ 3 ~ OH CH~OH ~ OH
H3C CH3 CH3 CH3 H3C CH3
57 58 59 60
CH3 .,.",. H3C \
H3C ~OH ~ OH OH OH
OH OH OH OH
61 62 63 64
CH3 HsC \
H3C~OH ~~OH OH \~OH
OH OH ~H OH
s5 ss s7 s8
OH OH OH
\ I OH ~~OH OH OH
OH H3C CH3
69 70 71 72
OH OH
HO~OH ~~ H3CO~OCH3
69 70 71 72
-529-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
Table 4f
CH3 H3C
H3C' '-CH3 H3C~-CH3 ~-CH3
OH OH OH ~CH3
CH3
1 2 3 4
CH3
-CH3 ~CH3 /~-~CH3
GH3 CHH3 GH3 H3C CH3
3
6 7 8
CH3 CH3 ~~~.
,,CH H3G~, H3 ~ -CH3 H3CyCH3
3 C~3 ~GH3 GH3
CH3 CH3 CH3
9 10 11 12
CH3 CH3 .,.",...
CHs H3C_ V 1-CH3 H3C ~ -CH3 ~GH3
CH3 CH ~GH3 CH
H3C 3 CH3 H3C CH3 3
13 14 IS I6
H3C~-CH3 H3G~-CH3 CH3 CH3
'~' ~CH3 H C~ -CH3 CH3 CH3
CH;j 3 GH3
17 18 I9 20
CH3 '."" CH3 '~""' CH3
-CH3 -CH3 ~ CH3 ~ -CH3
~CH3 ~CH3 , CH3 ~CH3
H3C CH3 CH3 CH3 H3C CH3
21 22 23 24
-530-

CA 02329422 2000-10-19
WO 99/54299 PCT/US99/07945
CHs "."" H3C
HsC -~ CH3 ~~./~ 'CH3 ~-CH3 'CHs
CH I CH
OH s OH s OH CHs OH CHs
25 26 27 28
CH CH ''~"' HsC
~CH 3 ~~'CH3 ~CH3 CHs
3 CHs , CHs
OH OH ' CHs OH
OH
29 30 31 32
OH OH OH '~"'
~'CH ~~~CH3 'CHs CH s
CH ~CH
CHs OH s OH s HsC CHs
33 34 35 36
CHs H C CHs CHs ~~~- CHs HsC CH
H3C 3 ~ 3
CHs H3C CHs CHs
37 38 39 40
CHs ~ ~ CHs ~~CH3
CHs ~ 11 11,,~~ CH
CHs CHs CHs s
CHs
41 42 43 44
3 ~ J H3 .......,./ 3
Cw ~~CH3 H3C~.~CH C~ HsC ~ CH
~~--CH
s CH ~ CHs CHs
CHs s CH3
45 46 47 48
CHs ~~~ CHs CHs .~..,- CHs
~CH3 H3C~J HsC~~ ~ ~CH3
H C ~CH3 ~CH3 ' 'C~H3 \CHs H3C CHs CHs
3
49 50 51 ~2
-531-

CA 02329422 2000-10-19
WO 99!54299 PCT/US99/07945
H C CHs H C CHs CHs CHs
3 3
H3C
CHs CHs CHsCHs CHs CHs
53 54 SS 56
CHs i CHs 'Hs "..."'~ Hs CH~CH3 I ~~ Hs
~~.~J CHs ~-CH3 ~'' ~~~~./CHs ~ i'~CH3
H3C CHs CHs CHs H3C CHs
S7 58 59 60
H C
HsC _ CHs ~H3 ".""'~ Hs s ~ ~~CH3 ~ ~~CH3
~CH 1 '-CHs 1 '--CH CHs
OH s OH OH s OH
61 62 63 64
CHs ',.""~ Hs ~H~~CHs HsC~ CHs ~Cf"r3
~Y~,~ ~ ~J
CHs , CHs ~CH3 ~ CHs
OH OH OH OH
65 66 67 68
OH OH OH CHs
~~CH3 '~~CH3 ~~CH3 ~J
, CH ~CH ~~CHs
CHs OH s OH s HsC CHs
69 70 71 72
H3C ~V HsC H3C
H3C
73 74 7S 76
HsC .~
HsC
77 78 79 80
-532-

CA 02329422 2000-10-19
WO 99154299 PCT/US99/07945
HsC .~"" HsC H3C
H;jC
81 82 83 84
HsC HsC HsC H3C
85 86 87 88
HsC H3C HsC HsC
i
89 90 91 92
CHs ~~ H3C
H C ~ ~CH3 HsC CHs CH3 CH
3 3
CHs CHs CHs CHs
93 94 95 96
CHs W CH CHs CHs
3
CHs
CHs CH CH3 CHs
3
97 98 99 100
CH3 -~ H3C
HsC \ \
H3C ~ w
1
101 102 103 104
.,..,.,.
CHs il
105 106 107 108
-533-

CA 02329422 2000-10-19
WO 99154299 PCT/US99/07945
CHs
HO~-CHs HO CHs HO HO
'~ NCH
3 CH3
CHs
109 110 IlI 112
CHs
HO -CHs HO%~CHs HO HO
CH3 ~-CHs
CHs
l13 114 115 I16
OH OH CHs '~~' OH HsC
H3C~ HsC OH
OH HO
OH OH
117 118 119 120
OH CHs ~ OH HsC OH
HsC H3C ~OH
-OH OH OH OH
121 122 123 124
Table 4g
~~~, C H 3 ~~~.
H3C/' CHs H sC ~-CH s ~..~-CH s ~'CH3
OH OH pH OH
1 2 3 4
CHs CHs CHs CHs I CHs
H3C~- _ / H3~~_ J ~_ J ~_ J
OH OH OH OH
6 7 8
-534-

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H3C~-_ / CHs H C~_~CH3 CH~CH3 ~-~CH3
OH s OH 1~IOH O../H
9 10 11 12
H3C~' ._ ~ H3C~_ ~ CH~_
OH '~ 'OH V 'OH OH
13 14 15 16
CHs
H3C~~CH3 H3C~-CH3 ~-CHs yCH3
OCHs OCHs OCHs OCHs
17 18 19 20
CHs ' CHs CHs CHs ~ CHs
H3C~_ _ l H3C~_ J ~_ _I _ .J
OCH3 '''''' ~'OCHs OCHs OCHs
21 22 23 24
H3C~-_ ~CH3 H C~_~CH3 CH~CH3 ~-~CH3
/ ~ J3
OCHs OCHs OCHs OCHs
25 26 27 28
H3C~~ _ ~ H3C~_ ~ CH~_
OCH3 Y 'OCH3 v 'OCHs OCHs
29 30 31 32
CHs
H3C' ' OH HsC~-OH ~-OH ~-OH
CHs CHs CHs CHs
33 34 35 36
H3C~H HsC~H f~3 ~-OH ~H
NCH _ NCH ~ CHs
3 3 C H3
37 38 39 40
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CHs ,."",.
i
HsC -OH HsC -OH -OH -OH
CHs CHs CHs CHs
41 42 43 44
CHs
HsC -OH HsC -OH -OH -OH
45 46 47 48
CHs
H3C~-OCHs HsC~-OCH3 ~-OCHs ~-OCHs
CHs CHs CHs CHs
49 50 51 52
~ ~ CHs
H3C~CH3 H3C~CH3 -OCHs ~CH3
~CH3 CHs ~CH3 CHs
53 54 55 56
CHs ~~~.
HsC -OCHs HsC -OCHs -OCHs -OCHs
CHs CHs CHs CHs
57 58 59 60
CHs
HsC -OCHs HsC -OCHs -OCHs -OCHs
61 62 63 64
CHs
-CHs ~-CHs -CHs -CHs
OH ~' \ OH OH
OH
65 66 67 68
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_ CH3 ~_ JCH3 CH3 ~~~ CH3 \ ~~~yCH3
_J
OH ~ OH OH OH
69 70 71 72
_ I CH3 ~~CH3 CH3 ~~~,~CH3
OH ~ OH ~ OH OH
73 74 75 76
_ ~ ~' CH3 ~~ \
OH OH OH OH
77 78 79 80
CH3 ~ \
CHs ~ CHs ~ CH3 ~-CH3
OCH %' \ OCH3 / \ OCH
OCH3
81 82 83 84
_ CH3 ~""~ H3 CH3 ~~ H3 ~-~ Hs
OCH3 OCH3 ~ OCH3 OCH3
85 86 87 88
_ ~CH3 ~~CH3 CH3 ~~CH3 \ ~ ~CH3
.l __
OCH3 OCH3 ~ OCH3 OCH3
89 90 91 92
_ ~ _ ~ CH3 ~ ~_ \ ."",
OCH3 ~ OCH3 OCH3 OCH3
93 94 95 96
CH3 ~"" \
-OH -OH -OH -OH
CH3 CH3 CH3 CH3
97 98 99 100
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CH3 ""~. \
-OH ~ -OH -OH ~-ON
CH3 CH3 ~-CH3 CH3
101 102 103 104
CH3 """,. \
-OH ~ -OH -OH -OH
CH3 CH3
CH3 CH3
105 106 107 108
CH3 "."", \
-OH ~ -OH -OH I-OH
,I
109 110 111 112
CH3 """ \
-OCH3 -OCH3 -OCH3 -OCH3
CH3 CH3 CH3 CH3
113 114 115 116
CH3 .,~", \
-OCH3 ~ -OCH3 -OCH3 -OCH3
CH3 CH3
CH3 CH3
117 118 119 120
CH3 ,...". \
-OCH3 ~ -OCH3
-OCH3 -OCH3
CH3 CH3
CH3 CH3
121 122 123 124
CH3 ,~"" \
-OCH3 -OCH3
-OCH3 -OCH3
125 126 127 128
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CH3 -~~~ I \
HsC -OH ~ -OH -OH ~-OH
OH OH OH OH
129 130 131 132
CH3 ~~~, I \
HsC -OCH3 ~ -OCH3 -OCH3 ~-OCH3
OH OH OH OH
133 134 135 136
CH3 ~ I \
HsC -OCH3 -OCH3 -OCH3 ~-OCH3
OCH OCH3 OCH3 OCH
137 138 139 140
~ CH3 ~ I \
HsC~H ~..~ -OH ~H ~-OH
OOH '-OH OH
OH
141 142 143 144
~ - CH3 ~~~ I \
H3C~~CH3 ~.~ -OCH3 ~CH3 ~-OCH3
~~..----OH ~OH OH
OH
145 146 147 148
CH3 ~ I \
HsC~CH3 ~-OCH3 ~CH3 ~-OCH
OCH3 ~OCH3 OCH3 3
OCH3
149 150 151 152
-OH /~~H -OH -OH
'-OH ~ OOH OH OOH
153 154 155 156
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-OCH3 ~~CH3 -OCH3 -OCH3
' ~
~
'-OH ~ OH '-OH
-OH
~
157 158 159 160
HsC~~CH3 W~-OCH3 ~-OCH3 ~-OCH3
L ~
OCH ~ OCH3
CH3 s OCH OCH3
s
161 162 163 164
CH3 ~I ~ \
HsC~~OH ~~OH ~OH ~
OH
O
OH H OH OH
165 166 167 168
CH3 ~ ~
H3C~OCH ~~ ~OCH
g OCH3 3 OCH
3
OH OH OH OH
169 170 171 172
CH3 ~ ~
H3C~OCH ~OCH ~OCH
3 3 3 OCH
3
OCH OCH OCH3 O
3 CH
3
173 174 175 176
CH3
H3C~OH ~..OH ~OH
OH
'-OH ~,--OH '--OH ~'-OH
177 178 179 180
CH3 II ! \
HsC~OCH3 ~OCH ~OCH3 ~
3 OCH3
OH ~-OH OH
~-OH
181 182 183 184
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CH3 I \
HsC~OCH3 ~OCH3 ~OCH3
'_ ~ ~OCH3
OCH3 'OCN3 OCH3 '-OCH
3
185 186 187 188
\
OH OH OH
'~-OH ~'-OH '~OH ' OH
~OH
189 190 191 192
".."' ...,." \
OCH3 OCH3 OCH3
',r '~ ',- ~OCH3
OH ~ OH OH
'-OH
193 194 195 196
HsC~OCH3 OCH3 ~OCH3 ~OCH3
OCH ~ OCH3 '-OCH3
CH3 3 'OCH3
197 198 199 200
-OH -OCH3 -OH -OCH3
201 202 203 204
-OH OH -OCH3 OCH3
205 206 207 208
-OH OH -OCH3 OCH3
209 210 211 212
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OH OCH3 O -O~
~-CH3 CH3
213 214 215 216
.~.,.. CHs .~.".. ~ , CHs ~---~
CH
O O CHs O ( ,O s
217 218 219 ~/ 220
-CHa -1 , CHs ,
O O CH3 O O CH3
221 222 223 224
The ability of the compounds of the invention to inhibit neuraminidase in
vitro can be determined according to the method described below.
Neuraminidase Inhibition Assay:
Influenza virus A/N1/PR/8/34 was grown in the allantoic cavity of fertilized
eggs and purified by sucrose density gradient centrifugation (Layer, W. G.
(1969)
in "Fundamental Techniques in Virology" (K. Habel and N. P. Salzman, eds.) pp.
92-86, Academic Press, New York). Influenza virus A/N2lTokyo/3/67 was
obtained from the tissue culture supernatents of virus grown on MDCK cells.
Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus
with TPCK-trypsin followed by centrifugation and then purification of the
neuraminidase catalytic fragment using sucrose density gradient centrifugation
and dialysis as described previously (Air, G. M., Layer, W. G., Luo, M.,
Stray,
S. J., Legrone, G., and Webster, R. G. (1990) Virolo4v 177, 578-587).
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The neuraminidase inhibition assays used the neuraminidase enzymatic
activity associated with the A/N1/PRIB/34 or A/N2/Tokyol3/67 whole virus, or
the
B/Memphis/3/89 catalytic head fragment. The whole virus or catalytic fragment
was diluted appropriately with 20 rnM N-ethylmorpholine, 10 mM calcium
choride,
pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays
were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5
buffer with 5% DMSO. Reaction mixtures included neuramfnidase, inhibitor (test
compound) and 20-30,uM 4-methylumbelliferyl sialic acid substrate in a total
volume of 200,uL and were contained in white 96-well U-shaped plates.
Typically,
five to eight concentrations of inhibitor were used for each Ki value
measurement.
The reactions were initiated by the addition of enzyme and allowed to proceed
for
30-60 minutes at room temperature. The fluorescence for each well of the plate
was measured once each minute during the reaction period by a Fluoroskan Il
plate reader (1CN Biomedical) equipped with excitation and emission filters of
355
+/- 35 nm and 460 +/- 25 nm, respectively. The plate reader was under the
control of DeItaSoft II software (Biometallics) and a Macintosh computer. If
the
compound exhibited linear reaction velocities during the reaction period, then
the
reaction velocities for the dose-response study were fit to equation 1 using a
nonlinear regression program (Kaleidagraph) to determine the overall Ki value
(Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-Interscience, New
York).
(1 - ViNo) _ [l]l {[I] + Ki(1 + [S]/Km)} eqn 1
In equation 1, Vi and Vo represent inhibited and uninhibited reaction
velocities,
respectively, and Km = 16 - 40 ~M depending on the neuraminidase strain
tested. For those compounds exhibiting slow-binding inhibition (Morrison, J.
F.
(1982) Trends Biochem. Sci. 7, 102-105), a second experiment was performed
in a manner identical to the first except that neuraminidase and inhibitor
were
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preincubated in the absence of substrate for 2 hours at room temperature prior
to
initiating the reactions with substrate. Data analysis for the resulting
linear
velocities was conducted as described above.
Equation 2 was used to measure Ki values in the sub-nanomolar range
(Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2, 347-
368).
V = A{sqrt{(Ki' + It -Et)~2 + 4Ki'Et} - (Ki' + It - Et)] eqn. 2
In equation 2, V = velocity; A = akcat[S]/2(Km + [S]); a is a factor to
convert
fluorescence units to molar concentrations; Ki' = Ki(1 + [S]/Km); It = total
inhibitor concentration and Et = total active concentration of neuraminidase.
The compounds of the invention inhibit influenza A neuraminidase and
influenza B neuraminidase with Ki values between about 0.1 nanomolar and
about 500 micromolar. Preferred compounds of the invention invention inhibit
influenza A neuraminidase and influenza B neuraminidase with Ki values
between about 0.1 nanomolar and about 3.5 micromolar.
The ability of the compounds of the invention to inhibit plaque formation in
cell culture can be determined by the method described below.
Cell Culture Plague Formation Inhibition Assav
Cell Cultures: MDCK cells obtained from the American Type Culture Collection
were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose
(GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mM
HEPES buffer (GibcoBRL) and antibiotics (GibcoBRL). Cells were routinely
cultured in flasks or roller bottles at 37°C and 5% C02. At confluence
cells were
reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL)
treatment of the monolayer followed by cell centrifugation, resuspension, and
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dilution into growth media. Cells were planted at a volume to surface area
ratio of
1 ml over 1 cm2 of growth surface.
Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media
was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with
1 % fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed
virus (influenza AlTokyo/3/67 [H2N2]) (40 -100 plaque forming units) and 2x
concentration test compound. The plates were placed on a rocker and incubated
for 2 hours at room temperature. During the virus adsorption period agar
overlay
media was prepared. In a microwave oven 2X agarose (final concentration of
0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted
and then placed in a 48°C water bath for temperature equilibration.
After the
virus adsorption period was completed 1.5 ml agar over media was added and
mixed with the 1.5 ml virus and test compound containing media per well.
Cultures were incubated at 35°C for the period required for plaque
development, usually several days. Plaques were fixed with 3.7% formalin in
PBS for 20 minutes followed by removal of the agar overlay and staining with
0.1 % crystal violet in distilled water for 15 minutes. Plaques were counted
and
EC 50 concentration determined from multiple concentrations of the tested
compound using regression analysis.
Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated
at 37°C in DMEM supplemented with 1 % FCS, 40mM HEPES buffer, and
antibiotics. Bottles were inoculated with a multiplicity of infection of
approximately
0.1 plaque forming unit for each cell. Roller bottles were harvested after the
cytopathic effect of the virus was observed to be complete. Stocks were
prepared from the supernatant resulting from the low speed centrifugation of
the
media and cell lysate. Stocks were titered and stored at -80°C.
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Compounds of the invention provided plaque formation inhibition for
influenza virus A/N2lTokyo in MDCK cells with EC50 values between about 100
micromolar and about 1 nanomolar. Preferred compounds of the invention
provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK
cells
with EC50 values between about 1 micromolar and about 1 nanomolar.
The compounds of the invention can be tested for in vivo antiviral activity
using the method described below.
In Vivo Antiviral Efficacy Method
Female BALB/c mice were placed under anesthesia (sevoflurane) and
inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8-
34) at 10-2 (diluted from frozen stock). This viral concentration consistently
produced disease in mice within 5 days of inoculation. Animals were treated
4h.
pre-infection and 4h. post-infection, andperiodically thereafter, with one of
the
following therapies: no treatment; test compound (100, 25, 6.25, 1.39
mg/kglday
BID, PO); or vehicle (sterile water BID, PO). A group of ten animals
(designated
as control) was inoculated with 0.9% saline. Percent survival was determined.
On day five, lungs were harvested, weighed and assigned scores of 0,1, 2, 3 or
4
based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%,
respectively). In addition, each lung pair was image analyzed to determine
objective lung consolidation percentages.
The compounds of the present invention can be used in the form of salts
derived from inorganic or organic acids. These salts include but are not
limited to
the following: acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,
digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,
fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate
(isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-
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naphthalenesuifonate, oxalate, pamoate, pectinate, persulfate, 3-
phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
thiocyanate, p-
toluenesuifonate and undecanoate. Also, basic nitrogen-containing groups can
be quaternized with such agents as lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like
dimethyl,
diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,
lauryl,
myristyl and stearyl chlorides, bromides and iodides, aralkyi halides like
benzyl
and phenethyl bromides, and others. Water or oil-soluble or dispersible
products
are thereby obtained.
Examples of acids which may be employed to form pharmaceutically
acceptable acid addition salts include such inorganic acids as hydrochloric
acid,
hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as
oxalic acid, malefic acid, succinic acid and citric acid. Other salts include
salts
with alkali metals or alkaline earth metals, such as sodium, potassium,
lithium,
calcium or magnesium or with ammonium or N(R**)4+ salts (where R** is
loweralkyl).
In addition, salts of the compounds of this invention with one of the
naturally occurring amino acids are also contemplated.
Preferred salts of the compounds of the invention include hydrochloride,
methanesulfonate, sulfonate, phosphonate and isethionate.
The compounds of the formula I, II and III of this invention can have a
substituent which is an acid group (for example, -C02H, -S03H, -S02H, -P03H2,
-P02H). Compounds of the formula I, II and 111 of this invention having a
substituent which is an ester of such an acidic group are also encompassed by
this invention. Such esters may serve as prodrugs. The prodrugs of this
invention are metabolized in vivo to provide the above-mentioned acidic
substituent of the parental compound of formula I, ll or III. Prodrugs may
also
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serve to increase the solubility of these substances and/or absorption from
the
gastrointestinal tract. These prodrugs may also serve to increase solubility
for
intravenous administration of the compounds. Prodrugs may also serve to
increase the hydrophobicity of the compounds. Prodrugs may also serve to
increase the oral bioavailability of the compounds by increasing absorption
and/or
decreasing first-pass metabolism. Prodrugs may also serve to increase tissue
penetration of the compounds, thereby leading to increased activity in
infected
tissues and/or reduced rate of clearance.
Such esters contemplated by this invention include:
alkyl esters, especially loweralkyl esters, including, but not limited to,
ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters
and the
like;
alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but
not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl,
isopropoxymethyl,
t-butoxymethyl esters and the like;
alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyl
esters, including, but not limited to, 2-methoxyethoxymethyl esters and the
like;
aryloxyaikyl esters, especially, aryloxy-substituted loweralkyl esters,
including, but not limited to, phenoxymethyl esters and the like, wherein the
aryl
group is unsubstituted or substituted as previously defined herein;
haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyl esters,
including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the
like;
alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyi-substituted
loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters
and
the like;
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cyanoafkyl esters, especially, cyano-substituted loweralkyl esters,
including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;
thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methyl
esters, including, but not limited to, methylthiomethyl, ethylthiomethyl
esters and
the like;
alkylsulfonyialkyl esters, especially, loweralkylsulfonyl-substituted
loweralkyl esters, including, but not limited to, 2-methanesulfonylethyl
esters and
the like;
arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyl
esters, including, but not limited to, 2-benzenesulfonylethyl and 2-
toiuenesulfonylethyl esters and the like;
acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyl
esters, including, but not limited to, formyloxymethyl, acetoxymethyl,
pivaloyloxymethyl, acetoxyethyi, pivaioyloxyethyl esters and the like;
cycloalkylcarbonyloxyalkyi esters including, but not limited to,
cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl,
cyclopentanecarbonyloxyethyl, cyclohexanecarbonyioxyethyl esters and the like;
arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyi
esters and the like;
(alkoxycarbonyloxy)alkyl esters, especially, (loweralkoxycarbonyloxy)-
substituted loweralkyl esters, including, but not limited to,
methoxycarbonyloxymethyi, ethoxycarbonyioxymethyl, 1-
(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl esters and the like;
(cycloalkyloxycarbonyioxy)alkyl esters, especially,
(cycloalkyioxycarbonyloxy)-substituted loweralkyl esters, including, but not
limited
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to, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl,
cyclohexyloxycarbonyloxypropyl esters and the like;
oxodioxolenytmethyl esters including, but not limited to, (5-phenyl-2-oxo-
1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxoien-4-ylJmethyl,
[5-
(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-
1,3-
dioxolen-4-yl]methyl, [5-(4-chlorophenyt)-2-oxo-1,3-dioxolen-4-yl)methyl, (2-
oxo-
1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-
oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-
isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-1,3-dioxolen-4-
yl)methyl
esters and the like;
phthatidyl esters wherein the phenyl ring of the phthalidyl group is
unsubstituted or substituted as defined previously herein, including, but not
limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl esters and the
like;
aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters
and the like;
arylalkyl esters, especially, aryl-substitued loweralky! esters, including,
but
not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and
the
like, wherein the aryl part of the arylalkyf group is unsubstituted or
substituted as
previously defined herein;
dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyl
esters, including, but not limited to, 2-(N,N-dimethylamino)ethyl, 2-(N,N-
diethylamino)ethyl ester and the like
(heterocyclic)alkyl esters, especially, heterocyctic-substituted loweralkyl
esters wherein the heterocycle is a nitrogen-containing heterocycle,
including, but
not limited to, (heterocyclic)methyl esters and the like, wherein the
heterocyclic
part of the (heterocyclic)alkyl group is unsubstituted or substituted as
previously
defined herein; and
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carboxyalkyl esters, especially, carboxy-substituted loweralkyl esters,
including, but not limited to carboxymethy! esters and the like;
and the like.
Preferred prodrug esters of acid-containing compounds of the Formula t, II
or III are loweralkyl esters, including, but not limited to, ethyl, n-propyl,
isopropyl,
n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and benzyl esters
wherein the
phenyl ring is unsubstituted or substituted as previously defined herein.
Methods for the preparation of prodrug esters of compounds of the
Formula I, II or III are well-known in the art and include:
reacting the acid with the corresponding halide (for example, chloride or
acyl chloride) and a base (for example, triethylamine, DBU, N,N-
dimethyiaminopyridine and the like) in an inert solvent (for example, DMF,
acetonitrile, N-methyipyrrolidone and the tike);
reacting an activated derivative of the acid (for example, an acid chloride,
sulfonyl chloride, monochlorophosphonate and the like) with the corresponding
alcohol or aikoxide salt; and the like.
Other examples of prodrugs of the present invention include esters of
hydroxyl-substituted compounds of formula I, tl or III which have been
acylated
with a blocked or unblocked amino acid residue, a phosphate function, a
hemisuccinate residue, an acyl residue of the formula R'°°C(O)-
or R'°°C(S)-
wherein R'°° is hydrogen, lower alkyl, haloalkyl, alkoxy,
thioalkoxy, alkoxyalkyl,
thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula
Ra-C(Rb)(Rd)-C(O)- or Ra-C(Rb)(Rd)-C(S)- wherein Rb and Rd are independently
selected from hydrogen or lower alkyl and Ra is -N{Re)(R~, -ORe or -SRe
wherein
Re and Rf are independently selected from hydrogen, lower alkyl and haloalkyl,
or
an amino-acyl residue having the formula R'°' NH(CH2)ZNHCHZC(O)- or
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R'°'NH(CH2)20CHZC(O)- wherein R'°' is hydrogen, lower
alkyl, (aryl)alkyl,
(cycloalkyl)aikyl, acyl, benzoyl or an a-amino acyl group. The amino acid
esters
of particular interest are of glycine and lysine; however, other amino acid
residues
can also be used, including any of the naturally occuring amino acids and also
including those wherein the amino acyi group is -
C(O)CH2NR'°ZR'°3 wherein R'°2
and R'°3 are independently selected from hydrogen and lower alkyl, or
the group
-NR'°2 R'°3, where R'°2 and R'°3, taken together,
forms a nitrogen containing
heterocyclic ring.
Other prodrugs include a hydroxyl-substituted compound of formula I, II or
III wherein the hydroxyl group is functionalized with a substituent of the
formula
-CH(R'°4)OC(O)R'°$ or -CH(R'°4)OC(S)R'°5 wherein
R'°5 is lower alkyl, haloalkyl,
alkoxy, thioalkoxy or haloalkoxy and R'°4 is hydrogen, lower alkyl,
haloalkyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.
Such prodrugs can be prepared according to the procedure of Schreiber
{Tetrahedron Left. 1983, 24, 2363) by ozonolysis of the corresponding
methallyl
ether in methanol followed by treatment with acetic anhydride.
The preparation of esters of hydroxyl-substituted compounds of formula
formula I, II or III is carried out by reacting a hydroxyl-substituted
compound of
formula formula I, II or III, with an activated amino acyl, phosphoryl,
hemisuccinyl
or acyl derivative.
Prodrugs of hydroxyl-substituted-compounds of the invention can also be
prepared by alkylation of the hydroxyl substituted compound of formula formula
I,
II or III, with (halo)alkyl esters, transacetalization with bis-
(alkanoyl)acetals or
condensation of the hydroxyl group with an activated aldehyde followed by
acylation of the intermediate hemiacetal.
In preparing prodrugs it often is necessary to protect other reactive
functional groups, in order to prevent unwanted side reactions. After
protection of
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the reactive groups the desired group can be functionalized. The resulting
functionalized product is then deprotected, to remove the protecting groups
that
were added to prevent unwanted side reactions. This will provide the desired
prodrug. Suitable reaction conditions for preparing protecting groups are well
known in the art. One source for reaction conditions is found in T.H. Greene
and
P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley &
Sons, New York (1991 ).
This invention also encompasses compounds of the Formula I, II or III
which are esters or prodrugs and which are also salts. For example, a compound
of the invention can be an ester of a carboxylic acid and also an acid
addition salt
of an amine or nitrogen-containing substituent in the same compound.
The compounds of the present invention are useful for inhibiting
neuraminidase from disease-causing microorganisms which comprise a
neuraminidase. The compounds of the invention are useful (in humans, other
mammals and fowl) for treating or preventing diseases caused by
microorganisms which comprise a neuraminidase
The compounds of the present invention are useful for inhibiting influenza
A virus neuraminidase and influenza B virus neuraminidase, in vitro or in vivo
(especially in mammals and, in particular, in humans). The compounds of the
present invention are also useful for the inhibition of influenza viruses,
orthomyxoviruses, and paramyxoviruses in vivo, especially the inhibition of
influenza A viruses and influenza B viruses in humans and other mammals. The
compounds of the present invention are also useful for the treatment of
infections
caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo,
especially the human diseases caused by influenza A and influenza B viruses.
The compounds of the present invention are also useful for the prophylaxis of
infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses
in vivo in humans and other mammals, especially the prophylaxis of influenza A
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and influenza B viral infections; and, in particular, the prophylaxis of
influenza A
and influenza B viral infections in human subjects who are at high risk of
developing other respiratory diseases concurrent with or as a consequence of
influenza virus infections, or who suffer from chronic respiratory illness,
such as
asthma, emphysema, or cystic fibrosis.
Total daily dose administered to a human or other mammal host in single
or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body
weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit
compositions may contain such amounts of submultiples thereof to make up the
daily dose.
The amount of active ingredient that may be combined with the carrier
materials to produce a single dosage form will vary depending upon the host
treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors including the
activity of the
specifc compound employed, the age, body weight, general health, sex, diet,
time of administration, route of administration, rate of excretion, drug
combination, and the severity of the particular disease undergoing therapy.
Administration of a compound of this invention will begin before or at the
time of infection or after the appearance of established symptoms andlor the
confirmation of infection.
The compounds of the present invention may be administered orally,
parenterally, sublingually, intranasally, by intrapulmonary administration, by
inhalation or insufflation as a solution, suspension or dry powder {for
example, in
a spray), or rectally, in dosage unit formulations containing conventional
nontoxic
pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The
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term parenteral as used herein includes subcutaneous injections, intravenous,
intramuscular, intrastemal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or
oleagenous suspensions may be formulated according to the known art using
suitable dispersing or wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable solution or suspension
in a
nontoxic parenterally acceptable diluent or solvent, for example, as a
solution in
1,3-propanediol. Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution, and isotonic sodium chloride solution.
In
addition, sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be employed
including synthetic mono- or diglycerides. In addition, fatty acids such as
oleic
acid fnd use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by
mixing the drug with a suitable nonirritating excipient such as cocoa butter
and
polyethylene glycols which are solid at ordinary temperatures but liquid at
the
rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets,
pills, powders, and granules. In such solid dosage forms, the active compound
may be admixed with at least one inert diluent such as sucrose lactose or
starch.
Such dosage forms may also comprise, as is normal practice, additional
substances other than inert diluents, e.g., lubricating agents such as
magnesium
stearate. In the case of capsules, tablets, and pills, the dosage forms may
also
comprise buffering agents. Tablets and pills can additionally be prepared with
enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups, and elixirs containing
inert
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diluents commonly used in the art, such as water. Such compositions may also
comprise adjuvants, such as wetting agents, emulsifying and suspending agents,
and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the
form of liposomes. As is known in the art, liposomes are generally derived
from
phospholipids or other lipid substances. Liposomes are formed by mono- or
multi-lamellar hydrated liquid crystals that are dispersed in an aqueous
medium.
Any non-toxic, physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome form can
contain, in addition to a compound of the present invention, stabilizers,
preservatives, excipients, and the like. The preferred lipids are the
phospholipids
and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example,
Prescott, Ed., Methods in Cell Biologv, Volume XIV, Academic Press, New York,
N.Y. (1976), p. 33 et seq.
While the compounds of the invention can be administered as the sole
active pharmaceutical agent, they can also be used in combination with one or
more anti-infective agents andlor other agents used to treat other acute or
chronic respiratory ailments. Other agents to be administered in combination
with
a compound of the present invention include: an influenza vaccine; other
influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin,
and
the like; another influenza neuraminidase inhibitor, such as, for example,
zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial
infections and bronchitis, such as, for example, erythromycin, ciarithromycin,
azithromycin and the like; and agents used to treat asthma, such as, for
example,
zileuton, albuterol (salbutamol), salmeterol, formoterol, ipratropium bromide,
inhaled steroids and the like, or anti-inflammatory agents for treating asthma
such
as, for example, beclomethasone dipropionate, fluticasone propionate,
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budesonide, triamcinolone acetonide, flunisolide, crornolyn, zafirlukast,
montelukast used in combination with a compound of the present invention.
When administered as a combination, the therapeutic agents can be
formulated as separate compositions which are given at the same time or
different times, or the therapeutic agents can be given as a single
composition.
The foregoing is merely illustrative of the invention and is not intended to
limit the invention to the disclosed compounds. Variations and changes which
are obvious to one skilled in the art are intended to be within the scope and
nature of the invention which are defined in the appended claims.
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