Note: Descriptions are shown in the official language in which they were submitted.
2121898
~~ SYNTHESIS OF PROTOTYPES FOR RENIN INHIBITORS
This application relates generally to Canadian
Application No. ......... filed
This invention relates to the field of biological
activity relating to enzymatic and similar specific
chemical breakdown of angiotensinogen by scission to
angiotensin-I, then to angiotensin-II, which engages
receptors initiating biological activity as is well
known.
It is long known to use compounds of similar
chemical properties and general stereochemical
conformation either as substitutes for activators to
produce positive effects or to block specific receptors
to prevent negative effects. In practice despite massive
advances in knowledge of conformational structure of
chemical compounds, neither the exact conformation of a
particular compound, nor its chemical synthesis, nor its
biological properties are confidently predictable. In
the present invention the compounds envisaged are
important intermediates for the manufacture of prototype
Renin-inhibitors. Renin inhibitors prevent the
production of angiotensin-II, a potent vasoconstrictor
and therefore are potent antihypertensives.
The present invention contemplates novel
stereoselective chemical synthensis of compounds as of
the general formula shown below OH R3
RlA~,f ~ 4
A R2
Although the invention will be described and
referred to specifically as it relates to such compounds
and their processes of preparation, it will be understood
, 2121~g8
~- that the principles of this invention are equally
applicable to similar compounds and processes and
accordingly, it will be understood that the invention is
not limited to such compounds and processes.
BACKGROUND & PRIOR ART
The background is that of stereospecific synthetic
organic chemistry, a voluminous and ever expanding field,
in which it is a full time occupation to keep abreast of
general trends, especially in areas relating to human
medical applications.
Applicant is not aware of any prior art related to
the specific subject matter described herein.
A principal object of the invention is to develop
novel compounds suitable as prototypes for renin
inhibitors. It is a related principal object to
synthesize said novel compounds by novel chemical
processes. It is a subsidiary object to devise practical
synthetic schemes to prepare the novel compounds. It is
a further subsidiary object to prepare the novel
compounds as stereoisomerically pure as practicable. It
is a further object to characterize all the compounds so
prepared as fully as possible. Other objects would be
readily apparent to skilled practitioners in the art,
from the following specification, appended claims, and
accompanying schemes and figures.
DESCRIPTION OF lNv~llON
In one broad aspect the invention is directed to a
chemical compound having the structure
3~ 1 218~8
OH R3
RlA~
A
where n is 0-3 inclusive, A are either both hydrogen
atoms or together are a single carbon-nitrogen bond, R1 is
hydrogen, or hydrocarbylcarboxy wherein the hydrocarbyl
entity is selected from the group consisting of alkyl of
1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, Rz
is an alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to
6 carbon atoms, R3 is an alkyl of 1 to 4 carbon atoms, an
alkenyl of 2 to 4 carbon atoms, or phenylalkyl of 7 to 10
carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl
of 1 to 6 carbon atoms substituted by one or more oxygen
or nitrogen containing groups, R5 is selected from
aromatics, substituted aromatics and heteroaromatics,
substituted or unsubstituted cycloalkyls, cycloalkenes
having 3 to 8 carbon atoms, with substituents selected
from alkyl, alkoxy of 3 to 10 carbon atoms, primary and
secondary amides, alkyl derivatives. Preferably n is O.
Compounds of the formula 1, wherein n is O and both
A are hydrogen atoms, and their pharmaceutically accepted
salts exhibit Renin inhibitory activities which can be
shown, for example, by their inhibitory action in vitro
on Angiotensin-l formation in models substantially as
described in United States Patent No. 488986g. They can,
therefore, be used as agents for the treatment of
circulatory and related disorders responsive to Renin
inhibition, such as hypertension, congestive heart
failure, cardiac fibrosis, coronary artery diseases, high
eye pressure and glaucoma, etc.
Both A taken together may form a single carbon
nitrogen bond. In one variation R1 is preferably
alkylcarboxy and the alkyl group has l to 6 carbon atoms.-
A preferred compound is (l'S,2S,3R,3' ,5S)-5-[(3'-
Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-
= 421218 98
-- ~ pyrrolidine-l-carboxylic acid tert-butyl ester. Another
preferred compound is (l'S,2S,3_,3'B,5S)-5-[(3'-
Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-
pyrrolidine.
In a second variation Rl is preferably aralkylcarboxy
and the aralkyl group has 7 to lO carbon atoms. A
preferred compound is (l'S,2S,3B,3'_,5S)-5-[(3'-
Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-
pyrrolidine-l-carboxylic acid benzyl ester.
Both A may be hydrogen, when R1 is preferably
aralkylcarboxy and the aralkyl group has 7 to lO carbon
atoms. A preferred compound is (2_,4S,5S,7_)-5-[[(l,l-
Dimethylethoxy)carbonyl]amino]-4-hydroxy-2,7-dimethyl-8-
phenyl octanoic acid butyl amide. This compound can
- easily be converted into (2R,4R,5R,7R)-5-amino-4-hydroxy-
2,7-dimethyl-8-phenyl-octanoic acid which may serve as a
prototype for structurally related, more potent Renin
inhibitors as well as for HIV-protease inhibitors.
In another broad aspect the invention is directed to
processes of preparation of a first chemical compound of
structure OH R3
RlA~ ~ NH~R4
R
A R2
where n is 0-3 inclusive, A are either both hydrogen
atoms or form a single carbon-nitrogen bond, R1 is
hydrogen, or hydrocarbylcarboxy wherein said hydrocarbyl
is selected from the group consisting of alkyl of l to 6
carbon atoms or aralkyl of 7 to lO carbon atoms, R2 is an
alkyl of l to 4 carbon atoms or cycloalkyl of 3 to 6
carbon atoms, R3 is an alkyl of l to 4 carbon atoms, an
alkenyl of 2 to 4 carbon atoms, a phenylalkyl of 7 to lO
carbon atoms, R4 is alkyl of l to 6 carbon atoms or alkyl
of l to 6 carbon atoms substituted by one or more oxygen
- 5 2121898
or nitrogen containing groups, ~ is selected from
aromatics, substituted aromatics and heteroaromatics,
substituted or unsubstituted cycloalkyls, cycloalkenes
having 3 to 8 carbon atoms, with substituents selected
from alkyl, alkoxy of 3 to 10 carbon atoms, primary and
secondary amides, alkyl derivatives. The processes
include a step selected from the group consisting of (a)
hydrogenolysis of a second compound of the above formula
wherein both A together form a single carbon nitrogen
bond and R1 is alkylcarboxy wherein said alkyl has 1 to 6
carbon atoms, in the presence of Pd(OH) 2/C; (b)
hydrogenolysis of a third compound of the above formula
wherein both A together form a single carbon nitrogen
bond and R1 is aralkylcarboxy wherein said aralkyl has 7
to 10 carbon atoms, in the presence of Pd(OH)2/C, and
dialkyl dicarbonate wherein both said dicarbonate alkyl
groups are identical and have 1 to 6 carbon atoms; and
(c) treating a fourth compound having the structure
~ O
Rl 0
~ R3
n ~
R2
20 where n is 0-3 inclusive, R1 is hydrocarbylcarboxy wherein
said hydrocarbyl is selected from the group consisting of
alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon
atoms, R2 iS an alkyl of 1 to 4 carbon atoms or cycloalkyl
of 3 to 6 carbon atoms, R3 is an alkyl of l to 4 carbon
atoms, an alkenyl of 2 to 4 carbon atoms, a phenylalkyl
of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon
atoms or alkyl of 1 to 6 carbon atoms substituted by one
or more oxygen or nitrogen containing groups Preferably
n is zero, in both formulae. A preferred process of
claim 1, comprises the step of hydrogenolysis of said
second compound. Another preferred process, comprises
the step of hydrogenolysis of said third compound. A
further preferred process comprises the step of treating
said fourth compound, where in a preferred step R1 is
6 2121898
~~ alkylcarboxy, said alkyl group having l to 6 carbon
atoms. Alternatively R1 may be aralkylcarboxy, said
aralkyl having 7 to lO carbon atoms.
BRIEF DESCRIPTION OF THE APPENDED FIGURES AND SC~M~.
Figure l schematically indicates the cascade of
enzymatic steps that lead to biological activity;
Figure 2 indicates chemical formula of some
compounds of the invention;
Figure 3 indicates chemical formula and assigned
molecular stereochemical structure of a first compound of
the invention;
Figure 4 indicates chemical formula and assigned
molecular stereochemical structure of a second compound
of the invention;
Scheme l indicates a first synthetic route of the
invention;
Scheme 2 indicates a second synthetic route of the
invention;
Scheme 3 indicates a third synthetic route of the
invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The basic action of renin is as shown in Figure l,
wherein angiotensinogen is first cleaved to provide a
specific fragment (angiotensin I), then subcleaved to a
second specific fragment (angiotensin II), which engages
the appropriate receptor to initiate biological activity.
Scheme l shows detailed steps of a synthetic route
from ~S) methyl mandelate 4 to starting precursors
(2S,3R)-3-Methyl-5-oxo-2-phenyl-pyrrolidine-l-carboxylic
acid tert-butyl ester 12, and (2S,3R)-3-Methyl-2-phenyl-
3,4 dihydro-2H-pyrrole 14.
Scheme 2, shows detailed steps of a subsequent
7 2 1218g8
synthetic route starting from 12 to (2R,4S,SS,7R)-5-
t[(l,l-Dimethylethoxy)carbonyl~amino]-4-hydroxy-2,7-
dimethyl-8-phenyl octanoic acid butyl amide 3a.
Scheme 3, shows detailed steps of a subsequent
synthetic route starting from 14 to 3a.
Scheme 1, starts from methyl mandelate 4, wherein
the hydroxyl is protected by forming a Bom
(benzyloxymethyl) acetal 5 in 83% yield. The carbon
chain is then extended to give the phenyl trans-2-
butenoic acid 6 homolog by effective insertion of a trans
double bond, in 75% yield, with 6% of cis isomer. 6 was
then methylated to give 7 unpurified as a mixture of 94:6
of the diastereoisomers including 5% of the deconjugated
product crude yield approximately 96%. Crude 7 was
cyclized to lactone 8, phenyl methyl dihydrofuranone, in
72% yield (from 6). 8 was converted to the equivalent
hydroxymethyl ester 9 by hydrolysis and methylation in
98% yield. 9 was converted to the equivalent azido ester
10 in 89% yield as 96:4 diastereoisomeric mixture.
10 in one avenue is cyclized to lactam 11, methyl phenyl
pyrrolidinone in 86% yield, followed by protection of the
amino-hydrogen with carboxybutyl ester to give 12 in 99%
yield. In an alternate avenue 10 was converted to the
equivalent azido-aldehyde 13 in 77% yield, then cyclized
to imine 1~, methyl phenyl dihydro H pyrrole.
Scheme 2 starts with protected lactam 12, whose
amido-carbonyl is effectively reduced to hydroxyl to
hemiaminal 15a, as a mixture anomers and rotamers in 72%
yield. This was then methylated to give 16a, as a
mixture of four isomers, in 100% yield. ~his compound
was then treated effectively displacing/replacing methoxy
with the substituted furan, to form an unsaturated
lactone ring, to give 17a, in 98% yield of 6:1
threo:erythro isomeric ratio. Pure erythro 17a was
crystallized as a mixture of rotamers. 17a was
hydrogenated saturating the double furan/lactone bond to
8 2121898
~, give 93% yield of 18a as a mixture of two rotamers. The
saturated lactone ring of 18a was methylated, 67% of the
desired monomethyl 19a, and 15% of the dimethyl lactone
were obtained. Crystalline 19a was X-ray analyzed. The
lactone ring was opened by formation of the butyl amide
to give 2a in 76% yield. Then the pyrrolidine ring was
hydrogenolyzed to give 3a in 73% yield.
Scheme 3 is generally analogous to scheme 2,
starting with cyclized imine 14, and protecting the imino
nitrogen with a carboxybenzyl group rather than a
carboxybutyl group, to yield 67% (from 13) of 15b as a
mixture of anomers and rotamers. Thereafter the steps
are closely similar giving 89% of 16b, 78% of 17b, as 5:1
threo:erythro isomeric ratio. Pure erythro 17b was
crystallized as a mixture of rotamers. Crystalline 17b
was X-ray analyzed. Continuing gave 90% of 18b, 56% of
l9b, 52% of 2b, which was directly converted to 3a, in
46% yield.
ORTEP X-ray structures of l9a and 17b are shown
together with their chemical formulae in Figures 3 and 4.
2121898
~, . g
- f - EXPERIMENl'AL DATA
V
(S)-~Benzyloxy-methoxy)-phenyl ~cetic acid methyl ester ~:
To the solution of 6.5 g (39.5 mmol) of (S)-methyl m~ndel ~e in 90 mL of anhydrous THF
were added successively 12.0 mL (69 mmol) ot i-Pr2EtN, 8.2 mL (59.5 mmol) of benzyl
chloromethyl ether and 1.46 g (3.95 mmol) ot -Bu4N+I-. After the reaction was stirred at room
temperature overnight, 4.0 mL (23.0 mmol) of i-Pr~EtN and 2.7 mL (19.65 mmol) of benzyl
chlorome~hyl ether were added. The reaction was stirred at room temperature for 40 h and 2.0 mL
(1 l.5 mmol) of i-Pr2EtN and l.35 mL (9.8 mmol) of the alkylating agent were added and stirred :~t
room temperature for another 44 h. Methanol (1.5 mL) was added to collsllme the excess
alkylating agen~ After 30 min the reaction was parutioned bètween 150 mL of w~ter and 250 mL
of EtO~c. The organic layer was washed with 0.5 N HCl, pH 7 phosphate buffer, then with
brine, dried over MgSO4 and concenLlated. Pllrific l~ion of ~e residue by column chroma~raphy
~silica ~el, 15% E~)Ac/heY:-nes~, gave 9.~5 g (83%), of the ester ~ as a colorless syrup.
.
Ea]D+ll9 (c 1-24, CHCI3);IR(thinfilm) 1730, 1445,1260,1200,1160,1040 cm~l;
lH NhIR (CDC13, 300 MHz) ~ 7.50-7.27 (m, 10H, ArH), 5.25 ls, lH, PhCHO), 4.92 and 4.84
(AB quartet, 2E~, J= 7Hz, oCH2oj, 4.69 ~nd 4.59 ( AB quartet, 2H, J= 12Hz, OCH2Ph3, 3.7
(s,3H,OCH3~;l3C(CDCl3,75MHz~ol71.1, 137.3, 135.9, 128.7; 128.6, 128.3, 127.8,
1''7.7, 1~7.3, 93.2, 70.0, 52.~; exact mass calculated for C~1Ht904281.128334. found 287.130.
( ~E, 4R)-4-~Benzyloxy-methoxy)-4-phenyl-but-2-enoic acid methyl ester 6:
To a cooled (-78 C) solution of 8.5 g (29.7 mmol) of the ester ~ in 100 mL of anhydrous
toluene was added a cold (-78 C) solution of DIBAL-H (33 mL, lM in toluene, 33 mmol) in
anhydrous toluene (20 mL) via canula dropwise over a period of 30 min. The l~,a.;lion was stirred
at -78 C for another 3 h. Methanol (3.6 mL, 89 mmol~ was added dropwise and the resulting
solution was stinred at -78 C for 30 min. The coolLng bath was removed and the reaction was
allowed to warm to r~om tempe.~ . Methyl triphel~ylyhosphoranylidene acetate (15.0 g, 44.8
mmol) was added to the reaction mixture and stirred for 20 min. The ~II....il.l.... complex was
filtered and the soIvent evaporated. Ether was added and the insoluble PPh30 and excess reagent
fiitered. Solvent was e~,apol~ted and the residue purified by column chromatogr~phy (silica gel,
12% EtOAc/hPs~n~), to yieI'd 0.7 g (6~o i~or 2 steps), of the cis ester and 8.5 g (75% for 2 steps),
of the tr~ns ester 6 as a-colorless syrup, [OC~D+ 85 (c 1.55, CHC13); IR (thin film) 1710, 1645,
1440, 1290, 1260, 10l0 cm-l; IH NMR (CDC13, 300MHz) o 7.39-7.27 (m, 10H, ArH), 7.0 (dd,
lH, J= SHz, 16Hz, CHCH=), 6.13 (dd, lH, J= 2Hz, 16Hz, =CHCO2Me), 4.81 and 4.74 (AB
21218-98
'' ' 10
qualte~, 2H J= 7Hz, OCH2O). 4.64 and ~.56 (AB quartet, 2H, J= l~Hz, OC~,Ph). 3.i4 (s, 3H,
~H3): 13C (CDCl3, 75 ~Hz) ~ 166.6, 1~7.1, 138.4, 138.3, 128.6, 128.3, 128.2, 127.9,
127.7 127.3, 120.4, 91.9, 76.3, 69.7, 51.5; ex~ct mass calcul~ted for ClgH2lO4 313,14398 1.
found 3l~..1433.
( 3R, 4R)}4-(Benzyloxy-methoxy)-3-methyl-4-phenyl-butyric ~cid methyl
ester (7):
~ Iethyl lithium (116.6 mL, 1.4M in ether, 163.2 mmol) was added to the -78 C
suspensi~n of 15.54 g (81.6 mmol) of CuI in 400 mL of anhydrous-THF. The mixture was
warmed to 0C, held at that temp~aL~ for 10 min, and then recooled to -78 C. This mixture was
tre~ted with TMS-Cl (31 mL, 244.8 mmol) followed by a solution of the unsaturated ester 6 (8.49
g, 27.2 mmol) in anhydrous THF (40 mL). The reaction was stirred at -78 C for 2 h and then
quenched with 15 mL of 1:1 5% aqueous N~I40H and saturated aqueous NH4Cl solution. The
coolin~ bath w~s removed and the reaction allowed to warm to room temperature. Aqueous lO~o
NH40H ~50 mL) and ether (300 mL) were then added and the r~s~ ing mixture was stirred until a
homogenous org~nic phase and ~ d~r~ blue aqueous phase were ob~ined. The two layers were
separated. the organic phase was washed with water, brine, dried over MgS04 and conce~ d~d to
yield an insepar~ble mixture of 7 as a 94:6 di~stereomeric mixture and the deconjugated product
(5% by IH NMR). IH N~IR (CDCl3, 300MHz) ~ 7.39-7.23 (m, 10H, ArH), 4.68 and 4.46 (AB
quartet. ~H. J= 12Hz, OCH;~O), 4.67 and 4.58 (AB quartet, 2H, J= 7Hz, OCH2Ph), 4.42 (d,
lH, J= 8Hz, PhCHO), 3.67 (s, 3H, OCl'I3), 2.73 ~dd, lH, J= 5Hz, l5Hz, one of CH2CO2CH3),
2.42 (m~ lH, CHCH3), 2.24 (dd, lH, J= 9Hz, l5Hz, one of CH2CO2CH3), 0.83 (d, 3H, J=
7Hz, CHCH3); mass spectrum m/e 329 (M+ + H).
.
( 4R, 5R)-4-Methyl-5-phenyl-dihydro-furan-2-one 8:
To the cooled (-23 ocj solution of the unpurified ester 7 from the above reaction (8.55 g.
theore~ical yield 26.1 mmol) in 260 mL of anhydrous CH2Cl2 was added 10.3 mL ~78.3 mmol) ~f
TMS-Br ~nd the solution was ~radually allowed to warm to room temperature overnight. The
re~ction was diluted with more CH2CI2 (100 mL), w~shed with satur~ted aqueous NaHCO3 (2 x
50 mL), wa~er, brine, dned over MgSO4 and concentrated. The residue was purified by column
chrom~tooraphy ~silica oel, 24~b EtoAc/h~y~r~s)~ to yield 3.45 g (72% for 2 steps), of 8 as a
cryst~lline solid, mp 53-54 C; [a3365 -4 (C 0.88, CHC13); IR ~CHC13) 1780, 1280, 1150, 1005
crn~ H (CDC13, 300 MHz) ~ 7.44-7.27 (m, SH, ArH), 4.95 (d, lH, J= 8Hz, PhCHO), 2.81
ll 2121898
.. ~ ' - - , ,
~dd7 lH. J= 7Hz. 17Hz, one of CH2CO~ 2.49 (m, lH, CHCH3), 2.3 (dd. lH7 J= 10Hz, 17Hz,
on~ of CH2CO). 1.21 (d, 3H, J= 6Hz. CHCH3); ~3C (CDCl3, 75 MHz) ~ 176.V. 137.87 128.67
1. 5.~. 88.~. 39.7. 37.1, 16.3; e~act mass ~alculated for Cl IHI3O2 177.091555. tound 117.(~9()9.
(3R, 4~)-4-Hvdroxy-3-methyl-4-phenyl-butyric acid methvl ester 9:
To the cooled (0 C) solution of 2.43 g (13.8 mmol) of the l~ctone 8 in methanol (40 mL)
was added 41 mL of 0.5 N aqueous ~aOH. The 7l~action was warmed to room temperature and
sLilTed lor 2 h. Methanol was removed in vacuo and the residue diluted to 140 mL witll water.
The reaction mixture was cooled and the pH adjusted to 4 using lN aqueous HCI. Solid NaC1 was
added and the mixture allowed to warm to room lel-lpel.lture. It was extracted with EtOAc (200
mL x 3). The combined or~ganic layer was washed with brine, dried over MgSO, andconcerltrated. The residue was dissolved in EtOAc and methylated with diazomethane in ether.
Evaporation of the solvent afforded 2.82 g (98%), of the hydroxy ester 9 which was used in the
next step without further punfic~ion, IR (thin film) 3600-3260, 1740, 1725, 1460, 1170, 1020
H NMR (CDCl3, 300MHz) ~ 7.37-7.27 (m, 5H, ArH), 4.43 (d, lH, J= 7Hz, PhCHOH),
3.66 (s, 3H, OCH3), 2.63 (dd, lH, J= SHz, 15Hz, one of CH2CO2CH3), 2~.38 (br, s, lH, OH),
2.36 (m, lH, CHCH3), 2.26 (dd, lH, J- 8Hz, 15Hz, one of CH2CO2CH3), 0.85 (d, 3H, J=
7Hz, CHCH3); mass spectn~m m/e 209 (M~ + H).
(3R, 4R)-4-~zido-3-methyl-4-phenylbutyric acid methyl ester I0:
.
Triphenylphosphine (5.33 g, 20.3 mmol) was added to the solution of 2.82 g (13.56
mmol) of the hyd}oxyester 9 in 70 mL of anhydrous THF and cooled to 0 C. DEAD was added
dropwise foliowed by the dropwise addition of (PhO)2P(O)N3. The reaction was gradually
allowed to warm to room temperature overni~ht THF was removed and the residue purified by
column chromatography (silica gel, 12% EtOAclh~ ), to yield 2.8 g (89%), of the azido ester
10 as a 96:4 diastereomeric mixture, [a]D -164 (c 1.27, CHCI3); IR (thin filrn) 2100,1740,
1450, 1250, 1165 cm-l; IH NMR (CDCI3,300 MHz) ~ 7.42-7.26 (m, 5H, ArH)7 4.48 (d, lH,
J= 6Hz, PhCHN3),3.65 (s,3H, OCH3),2.37 (m, 2H, CHCH3, one of CH2CO2CH3), 2.09 (dd,
lH, J= lOHz,17Hz, one of CH2CO2CH3),0.99 (d, 3H, J= 6Hz, CHCH3); 13C (CDC13,75
MHz) ~ 172.6,137.9,128.5,128.1,127.1,70.2,51.4,37.9,36.0,15.6; exact mass calculated
for Cl 2HI 6N3O2 234.124252, found 234.125.
.
~ 12 2121898
- .
(4R, 55)-4-Methyl-~-phenyl-pyrrolidine-2~one 11:
To the solution ot 2.5 g (10.73 rnmol) of the azidoester 1 0 in meth~nol (55 mL) ;~t room
temper~ture, was added succesively 14 mL (80.48 mmol) of i-Pr2EtN ~nd 5.39 mL (53.65 mmol)
of 1,3-proap:~nedi~hiol and stirred for 48 h. M~thanol was removed in vacuo and the residue
diluted with EtOAc. It was washed wit~ 0.5 N aqueous NaOH (80 mL x 2), water, brine, dried
over MgS04 and concentrated. The n~sidue was purified by column chromatography (siLica gel,
25% EtOAcll.~ nes initi~lly and then 20% ~cetonelCHC13), to yield 1.62 g (86~o), of the lactam
11 as ;1 colorless solid, mp 105- 106 C; [a]D -27 (c 1.055, CHCI3); IR (CHCl3) 3460, 1710.
1450, 1340 cm-l; IH ~MR (CDCl3, 3()QMHz) o 7.4-7.17 (m, SH, ArH), 6.12 (br, s, lH, ~ihr),
4.79 (d, lH, J= 8Hz, PhC~N), 2. 86 (m, lH, CHCH3), 2.53 (dd, lH, J= 8Hz, 17Hz~ one of
CH2CO), 2.13 (dd, lH, J= 8Hz, 17Hz, one ot C~2CO), 0.66 (d, 3H, J= 7Hz, CHCH3); l~C
NMR (CDC13, 75 MHz) ~ 178.1, 138.6, 128.4, 127.7, 126.5, 61.5, 37.6, 34.2, 16.2; exact
mass calculated for Cl lH~3~O 175.09972, found 175.10029.
(2S, 3R~-3-Methyl-5-o~o-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl
ester 12:
To a solution of 1.37 g (7.83 mmol) of the lactam 11 in anhydrous CH2Cl2 (3~ m~ ~) was
added succesively the solution of 3.76 g (17.2 mmol) of di tert-~utyl dicarbonate in CH2CI2 (~
mL), 3.4 mL (19.58 mmol~ of i-Pr2EtN and 96 mg (0.78 mmol) of DMAP and stirred at room
temperature for 24 h The initially colorless reaction mL~t~ tumed darlc brown at the end of the
reaction. Solvent was ~emoved in vacuo and the residue purified by column chromatography
(silica gel, 30% E~tOAc/he~l~nes), to yield 2.12 g (99%) of the compound 1 2 as a colorless solid,
mp 74-75 C; [a3D-4.6 (c 0.835, CHCl3~; IR (CHCI3) 1780, 1740, 1720, 1460, 1340 1150
cm-l, lH NMR (CDCl3, 3~)0 MHz) ~ 7.38-7.10 (m, SH, A~H), 5.10 (d, lH, J= 8Hz, PhCH~),
2.75 (m, lH, CHCH3), 2.58 (dd, lH, J= XHz, 17Hz, one of CH2CO), 2.37 (dd, lH, J= 12Hz,
17Hz, one of CH2CO), 1.27 (s, 9H, C(CH3)3), 0.69 (d, 3H, J_ 7Hz, CHCH3); 13C (CDCl3, 75
MHz) ~ 174.3, 149.3, 137.0, 128.3, 127.6, 126.2, 82.5, 65.5, 38.8, 30.8, 27.5, 15.7; exac~
mass cqlr~ ed for Cl6H2lNO3 275.15213, found 275.15394.
(25, 3~, 5R, SS)-5-Hydroxy-3-méthyl-2-phenyl-pyrrolidine-1-carboxylic
acid tert-butyl ester 15a:
-
To a cooled (-78 C) solution of 1.1 ~ (4`mmol) of the compound 1 2 in 10 mL of
/
~1898
13
.. '~ ,
anhydrous toluene was added DIBAL-H (4.4 mL. IM in toluene, 4.4 mmol) dropwise and stirred
tor 4 h. Methanol (1.5 mL) was added and the reaction mixture stirred at -78 C for 30 min. The
re~ction mixture was warrned to room temperature and 50 mL of ether and a-drop of water were
~Id~d. The ~lumin~lm comple:c was filtered and solvent evaporated. The residu~ was purified by
column chromatography (silica oel, 20`'Yo EtOAc/hexanes), to yield 800 m~ (725~o), of 15a as a
mixture of anomers and rotamers, 240 mg of the starting m~ H NMR (CDCl3, 300MHz~
7.33-7.2 (m, 16H, 4 x ArH), 7.02 (m, 4H, ~ Y ArH), 5.94, 5.82 and 5.83-5.56 (m, 4H, 4 .c
CHOH), 4.89, 4.82, 4.74 (3 x d. 4H, ~= 8Hzt 4 x PhCHN), 4.47, 3.74, 3.52 ~nd 3.21 (4 :c br,
s, 4H. 4 x ofO~ 2.98-2.86 and 2.S~.~i0 (2 x m, 4H, 4 x CHCH3), 2.33-1.64 (m, 8H, 4 x
CH2CHOH), 1.2 and 1.18 (2 x s, 36H, 4 x C(GH3)3), 0.64 and 0.63 (2 x d, 12H, J= 7Hz, ~ ~c
CHCH3); mass S~)eCl~ m/e 260 ~M+ - OH).
(2S, 3R, 5R, 5S)-5-Methoxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic
acid tert-butyl ester 16a:
To the solution of 745 mg (2.69 mmol) of the h~o...;;l.~.in~l 15a, in 20 mL of methanol was
added 31 mg (0.133 mmol) of CSA and stirred at room temperature for 1 h. Et3N (10 drops) was
added and me~hanol removed under reduced pressure. The residue was purified by column
chromatography (silica ~ el, 209O EtOAc/hexanes), to yield 780 mg (lOO~o) of 16a as an anomeric
and rotameric mixture of four isomers, lH NMR (CDC13, 3QOMHz) ~ 7.33-7.2 1 (m, 12H, 4 x
ArH), 7.02 and 7.0 (2 x d, 8H, ~= 8Hz, 4 x ArH), 5.42 and 5.20 (2 x d, 2H, J= SHz, 2 x
CHOCH3), 5.26 (br, s, 2H, 2 x CHOCH3), 4. 92 ( br, s, 2H, 2 x PhCHN), 4.88 and 4.78 (2 x
d, 2H, J= ~E~z, 2 x PhCHN), 3.54, 3.48 and 3.43 (3 x s, 12H, 4 x OCH3), 2.93-1.63 (m, 12H,
4 x CHCH3 and 4 x CH2CHOHCH3), 1.44 and 1.08 (2 x s, 36H, 4 x C(CH3)3), 0.67, 0.59 and
0.57 (3 x d, 12H, J= 7Hz, 4 x CHCH3); mass spectrum m/e 290 (M ' - H).
(2S,2 'S, 3R, SS)-3-Methyl-5-o~o-(5' oxo-Z',5'-dihydro-furan-2-yl)-2-
phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 17a:
To a cooled ~-78 C) solution df 740 mg (2.54 mmol) of 1 6a in 26 mL of anhydrous
CH2Cl2 was added succèsively 0.64 mL (3.81 mmol) of 2-(trimethylsiloxy)-furan and 0.19 mL
(1.52 mmol3 of BF3.Et20 and the solu~ion was stirred for 1 h. The reaction mixture was quenched
with 10 mL of 2 N aqueous HCI and warmed to room temperature. The mixture was diluted with
EtOAc, washed with waoer, brine, dried over M~S04 and concentrated to yield 860 mg (98%), of
14 2121898 I
. ~
6~ H NMR) of threo:erythro isomers. The pure threo isomer 17a was obtained, as amiYture of rotamers, by fr~ctional crystal1iz~tion trom 30% EtOAc/he:~nes, mp 150-151 C;
[alD-l88o(c 1.155,CHCl3);IR(CHCI~) 1755, 1685, 1450, 1370, 1165, 1085cm~ HNMR
(CDCl~, 300 MHz) ~ 7.68 and 7.58 (2 x dd, 2H, J= 2Hz, 6Hz, 2 x OCHCH=), 7.31-7.17 (m,
6H, 2 ,~ Ar~), 7.0 and 6.97 (2 x d, 4H, J= 7Hz, ? x ArH), 6.~4 and 6.08 (2 x dd, 2H, J= 2Hz,
6Hz, 2 Y CH=CHCO), 5.55 (dt, 1H, ~= 2Hz, 4Hz, CHO), 5.40 (dt, lH, J= 2Hz, 3Hz, CHO),
4.8~ ~nd 4.71 ('~ x d, 2H, J= 8Hz. 2 x PhCHN), 4.66 (dt, lH, J= 3Hz, 4Hz, CHN), 4.62 (m,
lH, CH~), 2.77 and 2.35 (2 x m, 2H, CHCH3), 2.05-1.83 (m, 2H, CW2CHN), 1.76 (dd, lH,
J= 8Hz, 13Hz, one of CH2CHN), 1.60 (dd, lH, J= 7Hz, 13Hz, one of CH2C~IN), 1.44 and
1.02 (2 x s, 18H, 2 x C(CH3)3), 0.55 ~nd 0.53 (2 x d, 6H, J= 7Hz, 2 x CHCH3); l3C (CDC13,
7~ MHz3 ~ 173.1, 154.8, 154 ?~ 141.2, 127.8, 126.7, 126.3, 120.3, 84.7, 79.7, 66.7, 58.0,
36.1, 32.5, 27.5, 15.3; exact m~ss calculated for C2oH26NO4 344.18619, found 344.1867.
(2S,2'S,3R,55)-3-Methyl-5-~S'-oxo-tetrahydro~furan-2'-yl)-2-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester 18a:
To the solution of 250 mg (0.73 mmol) of 17a in 3 mL of EtOAc was added 30 mg of 10%
P(IIC ~nd the mixture w;~s stirred under ~ H~ atmosphere for 1 h. The catalyst wa~ filtered through
a pad of celite and the solvent evaporated to yield 230 mg (93%), of 18a as a mixture of two
ro~mers, mp 123-125 C, ~alD- 49.6 (1.015, CHC13); IR (CHCl3~ 1760, 1675, 1440~1350,
1150 cm~ H NMR (CDC13, 300 MHz) ~ 7.31-7.21 ~m, 6H, 2 x ArH), 7.0 (d, 4H, J= 8Hz, 2 x
ArH), 4.80 (dt, 2H, J= 3Hz, 7Hz, 2 x CHO), 4.91 and 4.76 (2 x d, 2H, J= 8Hz, 2 x PhCHN),
4.53 (dd, lH, J= 3Hz, 7Hz, CHN), 4.41 ~t, lH, J= 7Hz, CHN), 2.86 (m, lH, CHCH3), 2.68-
2.22 (m, 4H, ~2CH2CO), 1.96-190 (m, 2H, CH2CHN), 2.86-1.79 (m, 7H, CHCH3,
CH2CH2CO, CH2CHN), 1.42 and 1.05 (2 x s, 18H, 2 x C(CH3)3), 0.58 and 056 (2 x d, 6H,
J= 7Hz, 2 x CHCH3); 13C (CDC13, 75 MHz) ~ 177.0, 155.3, 141.5, 127.7, 126.5, 126.2, 82.4,
79.4, 6?.0, 58.7, 35.9, 33.4, 28.3, 27.5, 24.6, 15.4; exact mass calculated for C2oH28NO4
346.20184, found 346.20230.
~ 25,2 'S, 3R,4 'R, SS)-3-Methyl-5-(4'-methyl-5'-oxo-tetrahydro-furan-2'yl)-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 19a:
To ~ cool~d (-78 C) solu~ion of (TMS)2NLi (0.27 mL, lM in THF, 0.27 mmol) was added
.. 15 2121898
. ~
the solu~ion of 18a (85 mg, Q25 mmol) in 1 mL of anhydrous THF over a period of 3 min via
canula and the solution was stirred for 40 min. MeI (0.16 mL,2.5 mmol) was added and the
solution w~}s s~irred at -78 C for 90 min. a`ter which the reaction mixture was warmed to -50 C
and s~irred for another 1 h. The reac~ion mixture was quen~hed with a solution of AcOH (0.15
mL) in 0.4 mL anhydrous THF and allowed tO warm to room temperature, then diluted with
EtOAc, washed with water, brine, dried over MgSO4 and concentrated. p~lrifir~tion of the residue
by column chromatography (silica gel,25% ELOAc/hP,~:-n~s), afforded, 14 mg (15%) of the
dimelhylated lactone and j9 mg (67%), of the monomethylated product 19a as a mixture of
ro~mers,mpl43-144 C;[a]D-31.7(cO.85,CHCl3);IR(CHCI3) 1750, 1680, 1440, 1355,
1150 loao cm~ H NMR (CDC13, 300 MHz) o 7.3l-718 (m, 6H, 2 x ArH), 7.0 and 6.98 (2 x
d, 4H, J= 7Hz, 2 x ArH), 4.91 and 4.73 ~2 x d. 2H. J= 8Hz, 2 x PhCHN), 4.65 (dt, lH, J-
4Hz, 7Hz, CHO), 4.59 (dt, lH, J= 4Hz. 8Hz, CHO), 4.5 (dd, lH. J= 4Hz, 8Hz, CHN), 4.32 (t.
lH, J= 8Hz, CHN), 2.94-2.62 (m, 5H, 2 x CHCH3, 2 x CHCH3CO, one of OCHCH,CHCH3),2.62-2.29 (m, lH, one of OCHCH2), 2.03-1.81 (m, 5H, 3 x one of CH2CHN, 2 x one of the
HCH2), 1.70 (dd, lH, J= 6HZ 13Hz. one of CH2N), 1.31 and 1.27 (2 x d, 6H, J= 7Hz,
CHCH3CO), 1.39 and 1.03 (2 x s, 18H, 2 x C(CH3)3), 0.54 and 0.57 (2 x d,6H, J= 7Hz, 2 x
CHCH3); l3C (CDCl3,75 MHz) ~i 180.2, 155.6, 141.7, 128.0, 127.8, 126.6, 126.4, 80.8, 79.6,
67.2, 59.3, 35.9, 35.1,34.2,33.7,33.3, 32.7, 28.0, 27.6, 16Ø 15.5; exact mass calculated ~r
C2lH30NO4360.2175, found 360.2159.
(1 'S,25, 3R,3 'R, 3S )-5-(3'-Butylcarbamoyl)- 1 '-hvdroxy-butyl)-3-methyl-2-
phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 2a:
To the solution of 56 mg (0.156 mmol) of 19a in 0.9 mL of anhydrous CH2Cl2 w~s added
BuNHALMe2 (0.28 m~, 0.67M in CH2C12, 0.23 mmol) and stirred at room tempe.~lu.c for 7 h.
~he re~ction ~ Lu~ was cooled to 0 C ~nd quenched with 2 mL of 1 N aqueous HCl, then
diluted with EtOAc, washed with brine, dried over Na2SO4 and conce~ ed. Punfic~io~ of the
residue by column ch~omatography (silica gel, 10% ~eton~lCHCI3), afforded 51 mg (765~o), of
tl~e amide 2a ~s a syrup, ~a~D -79.9 (c 1.015 CHCl3); IR (CHCl3) 3480, 3500-3300, 1665,
1465~ 1415, 1155 cm-l; lH ~MR (CDCl3, 300 MHz) ~ 7.30-7.19 (m, 3H, ArH), 6.98 (d,2H, J=
7Hz, ArH3, 6.0 (br, t, lH, J= SHz, NH), 4.78 (d, lH, J= 6Hz, OH), 4.71 ~d, lH, J= 8Hz,
PhCHN), 4.12 (t, lH, J= 8Hz, CHN), 3.50 (m, lH, CHOH), 3.35-3.15 (m, 2H, C~2NH),2.74-2.49 (m, 2H, CHCH3, CHCH3CO), 1.94-1.70 (m, 3H), 1.54-1.21 (m, 5H), 1.17 (d, 3H,
J= 7Hi, CHCH3CO), 1.06 (s, 9H, C(CH3)3), 0.93 (t, 3H, J= 7Hz, CH2CH}), 0.55 (d. 3H, J=
7Hz, CHCH3); l3C NMR (CDCl3, 75 MHz) ~; 176.1, 158.0, 141.0, 127.8, 126.6, 80.3,74.5,
.
- 16 2121898
63 4~ 4().9. 38.9, 37.1, 35.7, 32.9, 31.7. 27 7, 20.0, 18.5. 15.0, 13.7; mass sp~citrum m/e 433
(M+ ~ H).
(2R, 4S, SS, 7R)-5-[[1,1-Dimethylethoxy)c~rbonyl]amino]-4-hydroxy-~,7-
dimèthyl-8-phenyl-octanoic acid butyl amide 3a:
To the solution of 40 m8 (0.93 mmol) of the amide 2a in 1 mL of ~0% EtOWEtOAc was
added 40 mg of Pearlman's catalyst (20% Pd(OH)2/C) and the suspension w~s stirred under 56 psi
H2 pressure for 2 days. The catalyst was filtered and the solvent evapor~ted. Purifi~ion of the
residue using PTLC (lO~Yo ~eton~o~CH~13), afforded 4 mg of the starting m;lt~ l and 29 mg
(73%) of 3, mp 83-84 C; [a3D -17.1 (c 1.47 CHCl3); ~ (CHCl3) 3460, 3400-3300, 1710, `J
1660, 1500, 1370, 1170 cm~ H NMR (CDCl3, 300MHz) ~ 7.29-7.15 (m, 5H, ArH), 5.82 ~br,
sj CH2NH), 4.75 (d, lH, J= 8Hz, NHBoc), 3.72-3.61 (m, 2H, CHOH, CHNHBoc), 3.33-3.17
(m, 2H, CH2N), 2.86 (dd, lH, J= SHz. 13Hz, one of PhCH2), 2.55 (m, lH, CHCH3CO), 2.26
(dd, lH, J= 9Hz, 13Hz, one of PhCH2), 1.80 (m, lH, CHCH3), 1.68 (t, 2H, J= 6Hz), 1.55-
1.23 (m, 6H), 1.47 (s, 9H, C(CH3)3), 1.20 (d, 3H? J= 7Hz, CHCH3CO), 0.93 (t, 3H, J= 7Hz,
CH2CH3), 0.87 (d, 3H, J= 7Hz, CHCH3); 13C (CDCl3, 75 MHz) ~ 176.8, 156.4, 141.1, 129.1,
127.9, 125.6, 79.1, 70.1, 52.1, 42.6, 40.0, 39.1, 38.4, 37.6, 31.9, 31.6, ~8.3, 19.9, 19.8,
17.0, 13.6; mass spectrum m/e 435 (M+ + H~.
(3R, 4S)-4-Azido-3-methyl-4-phenyl-ibutyraldehyde 13:
To a cooled (-78 C) solution of 820 mg (3.52 mmol) of the compound 1 0 in 35 mL of
- anhydrous toluene was added DIBAL-H (3.9 mL, lM in toluene, 3.9 mmol) dlu~ ise via canula
over a period of lS min and was stirred for another 45 min. Meth~nol (0.43 mL, 10.6 mmol) was
added and the reaction mixture stirred at -78 C for 20 min. The re~ction mixture was allowed to
warm to room temperature and ether and a drop of water were added. The ~lumimlm complex was
filtered and solvent evaporated. The residue was purified by column chroamatography (silica gel,
1% Et3N, 14~o EtOAc, 85%h~ nes), to yield 550 mg (77~o) of 1 3, ~O~]D -205 (C 1.33, CHCI3);
IR (thin film) 2100, 173~, 1450, 1245 cm~ H NMR (CDCI3, 300MHz) o 9.66 (s, lH, CHO),
7.~7.26 (m, SH, ArH), 4.46 (d, lH, J= 7Hz, PhCHN3), 2.48 (m, 2H, CHCH3, one of
CH2CHO), 2.22 (dd, lH, J= 9Hz, 18Hz, one of CH2CHO), 1.02 (d, 3H, J= 7Hz, CHCH3);
7 21~1B98
~J , - ,
~ . . .
13C(CDCI3, 75 MHz) ~200.9, 137.7 128.7, 128.3, 127.2, 70.4, 47.4, 33.9, 16.1; m~ss
spectrum m/e 203 (M+)
(2S, 3R ?-3-Methyl-2-pheny!-3,4 dihydro-2H pyrrole 14:
Triphenylphosphine (750 mg, 2.86 mmol) was added to the solution of 527 mg (2.6
mmol) of the azidoald~hyde 1 3 in 26 mL of .mhydrous toluene and stirred for 16 h when the
re~c~ion was judged complete by tlc ~Y:lmin:l~ion The above was used in the next step.
- - (2S, 3R, SR, 5S)-5-Hydroxy-3 methyl 2 phenyl~pyrrolidine~
c~rboxylic acid benzyl ester 15b:
.
To the above solution of the imine in toluene at -78 C was added benzyl chloroformate
(0.37 mL, 2.6 mmol) and stirred for 1 h. The reaction was qu~-nched by adding 2 N aqueous HCl
and allowed to warm to room t~ pel~ture. The lea~l.on mixture was diluted with EtOAc, washed
with unsaturated brine. and bnne, dried over MgS04 and concentrated. The residue was purified
by column ch~omato~Mphy (silica gel, 1% Et3~, 29% EtOAc, 70% hexanes), to yield 541 mg
(67% for 2 steps) of the hemi:lmin~l l Sb as an anomeric and rotameric Illi~lUI~;, lH N~IR (CDCI3,
300 MHz) ~ 7.~7.16 (m, 18H, 2 x ArH), 7.37-7.02 (m, 18H, 2 x ArH), 6.9-6.87 (m, 2H, 2 x
ArH), 6.80 (d, 2H, J= 7Hz, 2 x Arhr), 5.86 and 5.77 (2 x d, 2H, J= 6Hz, SHz, 2 x CHOH),
5.68 (t, 2H, J= 7Hz, 2 x CHOH), 5.21 and 5.12; 5.08 and 4.98 (2 x AB quartet, 4H, J= 13H~, 2
x CO2CH2Ph), 5.22 and 5.11; 5.07 and 4.93 (2 x AB quartet, 4H, J= 13Hz, 2 x CO2CH2Ph),
4.98 and 4.96 (2 x d7 2H, J= 9Hz, 2 x PhCHN), 4.95 and 4.88 (2 x d, 2H, J= 8Hz, PhCHN),
4.38,4.0,3.52and3.26(4xbr,s,4H,4xOH~, 2.g6and2.51 (2xm,4H,CHCH3), 2.30,
1.73 and 1.99-1.75 (3 x m, 8H, 4 x CH2CHOH), 0.65, 0.64 and 0.63 (3 x d, 12H, J= 7Hz, 4 x
CHCH3); mass S~llulll (m/e) 310 (M+ - H).
(2S,3R,5R,SS~S-Methoxy-3-methyl~2-phenyl-pyrrolidine-1-carbo~ylic
acid benzyl ester 16b:
To the solution of 540 mg (1.74 mmol) of the hemi:-min:ll. 15b, in 9 mL of methanol was
added 18 mg (0.078 mmol) of CSA and s~irred at room tem~alule for 1 h. Et3N (10 drops) was
added and methanol remov~d under reduced plCSSUlC. The residue was purified by column
.. 18 2121898
.
chromatography (silica gel. 20% EtOAc/hex~nes~, to yield 502 mg (89%) of 1 6 b as amLlcture of
anomers and rotamers, lH NMR (CDCl3, 300MHz) ~ 7.37-6.98 ( m, 36H, 4 x Ar~l), 6.82 and
6.6 (2 ~c d, 4H? ~= 7Hz, 4 x Ar~I), 5.16 and 5.30 (2 x d, 2H. J= SHz, CHOCH3), 5.34 (br, s,
2H, 2 x C~OCH3), 5.18 ~nd 5.08; 5.02 and 4.82 (2 x AB quartet, 8H, J= 13Hz, 4 %
CO2CH2Ph), 4.96 and 4.9l (2 x d, 4H, J= 7Hz, 4 x PhCHN), 3.56 (br, s, 3H, OCH3), 3.52,
3 5() ~nd 3.35 (3 x s, 9H, 3 x OCH3), ~.99-1.66 (m, 12H, 4 x CHCH3, 4 x CH2CHOCH3), 0.68
~nd ~).61 ( x d, 12H, J= 7Hz. 4 x CHCH3); rnass s~,e~trulll m/e 324 (M+ - H).
(2S',2 'S, 3R, SS)-3-Methyl-5-oxo-(~'-oxo-2',5'-dihydro-furan-~-yl)-2-
phenyl-pyrrolidine-1-carboxylic ac~d benzyl ester 17b:
To acooled (-78 C) solution of 500 mg (1.54 mmol) of 16b in 15 mL of anhydrous
CH2Cl2 was- added ~uccesb~rely Q38 mL (2.31 mmol) of 2-(trimethylsiloxy)-furan and 0.11 mL
(0.92 mmol) of BF3.Et20 and the solution was stirred for 2 h. The reaction mixture was q~le~-ched
with 5 mL of 2 N aqueous HCl and warmed to room temperature. The l~liAIul~ was diluted with
EtOAc, washed with water, b~ine, dned over MgSO4 and concentrated to yield 452 mg (78%) of a
5:1 (by }H N~) of threo:erythro isomers. The pure threo isomer 17b was obtained, as a
mixture of rotamers, by fractional cryst~lliz ~ion from EtOAc/h~ ~ ~nf5, mp 157- 158 C; [a~D - 168
(c 1.02, CHC13); IR (thin film) 1750, 1690, 1390, 1330, 1010 cm-l; IH NMR (CDCl3, 300
MHz), ~ 7.67 (dd, 2H, J= 2Hz, 6Hz, 2 x OCHCH=), 7.41-6.94 (m, 16H, 2 x ArH), 6.6 (d, 4H,
J= 7Hz, 2 x ArW), 6.08 (dd, 2H, J= 2Hz, 6Hz, 2 x CH=CHCO), 5.48 (dt, 2H, J= 2Hz, 5Hz, 2
7c CHO), 5.16 and 5.07; 4.89 and 4.75 (2 x P~B quartet, 4H, J= 13EIz, 2 x CO2CH2Ph), 4.93 and
4.84 (2 x d, 2H, J= 8Hz, 2 x PhCHN), 4.71 (dd, 2H, J= 2Hz, SHz, 2 x CH~), 2.74 and 2.45
~2 x m, 2H, 2 x CH~H3), 1-.92-1.61 (m, 4H, 2 x CH2CHN), 0.55 and 0.S3 (2 x d, 6H, J= 7Hz,
2 x CHCH3); 13C (CDCI3, 75 MHz) ~ 173.0, 154.4, 140.3, 135.7, 128.6, 128.3, 128.2, 128.0,
127.5, 127.2, 127.1, 127.0, 126.1, 120.8, 66.9, 66.4, 58.6, 36.3, 32.2, 15.2; exact mass
c~lc~ ed for C23H231~O4 378.170534, found 3~8.1681.
(25,2 'S, 3R, SS)-3-Methyl-5-(5'-oxo--tetrahydro-furan-2'-yl)-2-phenyl-
pyrrolidine-1-carboxylic acid benzyl ester 18b:
To the solu~ion of 210 mg (0.56 mmol) of 17b in 4 mL of ~n7~.~ was added 20 mg of
5% Pt/C and the mixture was stirred under a H2 atrnosphere for 1 h. The catalyst was filtered
through a pad of celite and the solvent evaporated to yield 190 mg (90%), of a ro~mpn~ mix~re o
2121898
, .
19
e ~ .
18b as a syrup, ra]D- 52 (0.86, CHCI3); ~R (thin film) 1780, 1700, 1400,1340, 1160 cm-l;
I H NMR (CDCI3, 300 MHz) ~ 7.33-6.96 (m, 16H, 2 ~ ArH), 6.66 (d, 4H, J= 7Hz, 2 x ArH),
5.1 ~AB quartet, 2H, ~= 12Hz, CO2CH2Ph), 4 97 (d, lH, J= 8Hz, PhCHN), 4.90-4.68 (m. SH,
2 ~c OCH, PhCHN, CO2CH2Ph), 4.58 ~m, lH, CHN), 4.48 (t, lH, J= 7Hz, CHN), 2.88-1.83
(m, 14H), 0.58 and 0.57 (2 x d, 6H, J= 7Hz, CHCH3); 13C NMR (CDCI3, 75MHz) ~ 176.9,
156.0, 140.6, 135.8, 128.2, 128.0, 127.4, 12?.3, 126.9, 126.2, 81.8, 66.9, 66.6, 59.3, 36.3,
32.9, 28.5, 24.7, 15.5; ex~ct mass calculated for-C23H26NO4 380.186184, found 380.1822.
(2S j2 'S , 3R, 4 'R, SS)-3-Methyl-5-(4'-methyl-5'-oxo-tetrahydro-furan-~ 'yl)-
2-phenyl-pyrrolidine-1-c~rboxylic acid benz~rl ester l9b:
To a cooled (-78 C) solution of (TMS)2NLi ~0.24 mL, IM in h~Y~n~s, 0.24 mmol) in 0.24
mL of anhydrous THF, was added-MeI (0.14 mL, 2.19 mmol) followed by the solution of 18b
(79 mg, 0.21 mmol) in I mL of anhydrous THF and the solution was stirred for 40 min. The
reaction mixture was yu~ ched with a saturated aqueous NaHCO3 solution and allowed to w~n to
room temperature, then diluted with EtOAc, w~shed with water, brine, dried over MgS04 and
concentrated. pllnfic~ion of the residue by column chromatography (silica gel, 35%
EtOAc/h.oY~n~c), af~orded 46 mg (56%), of the mono.~ làted produc`t l9b as a l~ e of
rotamers, [a~D-32(c 1.43, CHCl3); ~ (thin film) 1155, 1675, 1440, 1390, 1225 cm~ H NMR
(CDCI3, 300 MHz) o 7.39-6.95 (m, 16H, 2 x ~rH), 6.65 ( d, 4H, J= 7Hz, 2 x ArH~, 5.07 and
4.82 (2 x AB quartet, 4H, J= 12Hz, 2 x CO2CH2Ph), 4.97 and 4.87 (2 x d, 2H, J= 8Hz, 2 x
PhCHN), 4.71 and 4.62 ~2 x m, 2H, 2 x CHO~, 4.53 (dd, lH, J= 5Hz, 8Hz, CHN), 4.4 (t, lH,
J= 7Hz, CHN), 2.9-1.7 (m, 12H), 1.27 and 1.18 (2 x d, 6H, J= 7Hz, 2 x CHCH3CO), 0.57 and
0.55 (2 x d, 6H, J= 7Hz, 2 x CHCH3); 13C NMR (CDC13, 75MH~) ~ 179.9, 156.1, 140.6,
135.8, 128.2, 128.0, 127.4, 126.8,~12ff.1, 80.0, 66.9, 66.6, 59.8, 36.1, 33.6, 33.5, 33.1, 15.9,
15.4; exact mass r!~lcu~ted for C24H28NO4 394.201834, found 394.20260.
(1'S,2S,3R,3'R,5S)-5~(3'-Butylcarbamoyl)-1'-hydroxy-butyl)-3-methyl-2-
phenyl-pyrrolidine-l-carboxylic acidben~!l ester 2b:
To tne solution of 45 mg (0.11 mmol) of 19b in 0.5 mL of anhydrous CH2Cl2 was added
BuNHAlMe2 (0.33 mL, 0.67M in CH2C12, 0.22 mmol) and stirred at room temperature for 2 h.
The reaction mixture was cooled to 0 C- and quenched with 2 mL of 1 N aqueous HCl, then
diluted with EtOAc, washed with brine, dr;ed over Na2SO4 and concentrated. Purification of the
20 21218~8
.
residue by PTLC ( 10% ~oetom ~CHCl3), afforded 22 mg (52%), of the amide 2 b as a syrup, []D
-80.0 (c 0.99 CHCl~); IR (thin film) 3500-3300, 1710. 1670, 1550, 1410, 1340 cm~ H NMR
(CDCl3, 300 MHz) o 7.4-6.96 (m, 8H, Ar~l), 6.63 (~d. 2H, J= 7Hz, ArH), 5.9 (br. s, lH, ~H),
4.85 (d, IH, J= 7Hz, PhCHN), 4.89 (AB quartet, 2H, J= 13Hz, CO2CH2Ph), 4.63 (br, s, lH,
OH), 4.17 (dt, lH, J= 2Hz, 9Hz, CHN), 3.56 (dt, lH~ J= 2Hz, 9Hz, CHOH), 3.36-3.17 (m,
2H, CH2NH), 2.75-2.51 (m, 2H, CHCH3, CHCH3CO), 1.96-1.72 (m, 3H), 1.55-1.23 (m,
SH), 1. ~9 (d, 3H, J= 7Hz, CHCH3CO), 0.93 (t, 3H, J= 7Hz, CH2C~3), 0.57 (d, 3H, J= 7Hz,
C~CH3); 13C (CDC13, 75MHz) ~ 176.0, 158.3, 140.2, 135.8, 128.1, 128.0, 127.4, 127.0,
126 9, 126.3, 74.3, 67.2, 66.2, 64Ø 40.6, 38.9, 37.1, 20.0, 18.4, 14.9, 13.6; exact mass
calculated for C28H3gN204 467.290983, found 467.29'~5.
(2R, 45, 55, 7R)-S-[~ DimethyIethoxy~c~rbonyl]amino]-4-hydroxy-2,7-
dimethyl-8-phenyl-octanoic acid butyl amide 3a:
To the mixture of 15 mg (0~032 mmol) of the amide 2b and 28 mg (0.129 mmol) of di
tert-butyldicàrbonate in 0.5 mL of 40~; MeOH/EtOAc w~s added lS mg of Pe:~rlm~n~s catalyst
(20% Pd(OH)2/C) and the susp~ncion was stirred under 60 psi H2 ~I~UI~, for 3 days. The
catalyst was filtered and the solvent evaporated. Purification of the residue using PTLC (10%
acetone/CHC13), 6.4 mg (46%), of 3a identical to the sa~Tiple obtained from the hydrogenolysis of
the amide 2a.
2121898
21
As those skilled in the art would realize-these
preferred described details and processes can be
subjected to substantial variation, modification, change,
alteration, and substitution without affecting or
modifying the function of the described embodiments.
Although embodiments of the invention have been described
above, it is not limited thereto, and it will be apparent
to persons skilled in the art that numerous modifications
lo and variations form part of the present invention insofar
as they do not depart from the spirit, nature and scope
of the claimed and described invention.
