Note: Descriptions are shown in the official language in which they were submitted.
CA 02634513 2008-06-09
NOVEL INTERMEDIATE COMPOUNDS AND PROCESSES FOR THEIR
PREPARATION
This invention relates, in one aspect, to a novel process for obtaining
compounds
useful as intermediates in the production of compounds having therapeutic
properties; in another aspect, this invention relates to novel intermediates
capable of being converted to therapeutically active compounds.
Background of the Invention
There are known therapeutically active compounds which are termed "Tekturna"
compounds, which in certain embodiments, have the formula A:
OMe OH H
H2N,,, NNHZ
I q
o o o O
MeO 15 The prior art contains several references relating directly or
indirectly to the
preparation of compounds of formula A, as well as their derivatives. Such
prior
art is disclosed in, for example, WO 2006/131304 and WO 2007/045420.
Of the prior art noted above, the process of preparing "Tekturna" compounds is
a
relatively complicated multi-stage process, and depending on the process
involved, the yields of the final therapeutic product are very low. This
results in
higher production costs as well as lengthy production procedures.
It would be desirable to find a more direct route to the preparation of the
final
"Tekturna" products and accordingly, this invention has, for its objects, to
disclose a route for producing "Tekturna" type compounds and a more efficient
1
CA 02634513 2008-06-09
process utilizing novel intermediates, which results in higher yields for the
"Tekturna" compounds.
Summary of the Invention
One embodiment of the present invention relates to a series of novel
compounds; these compounds are valuable for use in preparation of other
compounds, particularly as intermediates in the preparation of compounds which
can be used to prepare "Tekturna" compounds.
The compounds of the present invention which are considered novel are selected
from the group consisting of compounds of the following nature:
OMe OMe
R2 OH\ 15OHOHbbEE R1 p
R1
R1 R1
4a 4a
4b 4b
wherein R1 is CI-C7 alkyl, Cl-C7 alkoxyalkyloxy;halogen; or Cl-C7 alkoxy: R2
is
halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.
OM~ OMP,,,
~ ~
O O O
R2 O O O O O
R2
0;\ o
R1 R1 R1 R1
5a 5a 5b 5b
wherein R1 is Cl-C7 alkyl, CI-C7 alkoxyalkyloxy;halogen; or CI-C7 alkoxy: R2
is
halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.
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O\/ Me O
R2 O O
R1 R1
6a 6b
wherein R1 and R2 are members selected from the group consisting of
hydrogen, alkyl or alkoxy;
Me0
0 _ o =
R2 0 NSO3CH2CC13 NSO3CH2CCf3
R1 RI 7a 7b
wherein RI is Cl-C7 alkyl, Cl-C7 alkoxyalkyloxy;halogen; or Cl-C7 alkoxy: R2
is
halogen, C1_5 alkyl; Cti_5 alkoxyalkyloxy or combinations thereof.
Me0
C13C C13C
0 ~ O
~
R2 O;S'O O ~ p O:S O
N W.
R1 R1
8a 8b
wherein R1 is C1-C7 alkyl, Cl-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2
is
halogen, Cl_5 alkyl; Cl_5 alkoxyalkyloxy or combinations thereof.
in accordance with one preferred embodiment of the present invention, the
compounds of formula 4 have utility in the preparation of compounds of formula
5; and as well the compounds of formula 5 have utility in the preparation of
the
compounds of formula 6; the compounds of formula of 6 have utility in the
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CA 02634513 2008-06-09
preparation of compounds of formula 7; the compounds of formula 7 have utility
in the preparation of the compounds of formula 8; and thereafter, compounds of
formula 8 can be used as starting materials for ultimately preparing compounds
of formula 11 via intermediates of formulae 9 and 10. Thereafter, compounds of
formula 11 can be used to produce compounds of formula A (described above).
In another aspect of the present invention there is provided a process for
preparing a compound selected from compounds of formulae 4, 5, 6, 7 and 8.
In a first embodiment, the process of the present invention is directed to the
preparation of a compound of formula 4, which process involves the reaction of
a
compound of formula 3:
o
3
wherein the reaction involves reacting a compound of formula 3 with p-
MeOC6H4MgBr, Et20, -78 to 0 C, yield 65% (using a two step reaction) to yield
a
compound of formula 4.
In a second process embodiment, the process of the present invention is also
directed to the preparation of a compound of formula 5, which process involves
the reaction of one of the compounds of formula 4 identified above, e.g.:
R2 OH'~,-
R1
4a
wherein R1 and R2 are as defined above.
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wherein the reaction involves reacting compound 4 with an acid 1, CI3C6H2COCI,
Et3N, DMAP, PhCH3, 0 C to room temperature, 4 hours, yield 84%.
In a third process embodiment, the process of the present invention is also
directed to the preparation of a compound of formula (6), which process
involves
the reaction of one of the compounds of formula 5 identified above, e.g.:
~
R2 0 O ~
/ I
R1 \
5a
wherein the reaction involves reacting compound of formula 5 with Ti(i-PrO)4,
PhCH3 (10mM), O/N then 5 mol% 1st generation Grubb's catalyst, room
temperature 24 to 48 hours, yield 65%;
wherein R1 and R2 are as defined above.
In a fourth process embodiment, the process of the present invention is also
directed to the preparation of a compound of formula 7, which process involves
the reaction of one of the compounds of formula 6 identified above, e.g.:
O
R2 Ol
R1 ~
6a
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wherein the reaction involves reacting compound 6 with H2NSO3CH2CCI3, MgO,
Rh2(tfacam)4, PhI(Oac)2, PhCH3, 0 C to room temperature O/N, yield 80%;
wherein R1 and R2 are as defined above, to yield a compound of formula 7
defined above.
In a fifth process embodiment, the process of the present invention is also
directed to the preparation of a compound of formula 8:
MeO
C13C C13C
0 0
/_'00 O
R2 0 OS~O 0
`R1 R1 N,,.
8a 8b
which process involves the reaction of a compound of formula 7 with TFA:DCM
(1:5; v/v), -5 C, 15 minutes, yield 90%;
wherein R1 and R2 are as defined above to yield a compound of formula 8.
Preferred Embodiments
In the above-described process embodiments, compound 4 may be obtained by
a three-stage reaction using known processes and reactants. In particular,
compound 4 may be produced by the following reaction:
H02C a b I c
o y
88% HO 68%
2 3
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LiAIHa., Et20, 0 C then reflux O/N, yield 88% and Dess-Martin periodinane,
DCM,
room temperature, two hours.
The novel compounds of the present invention of formula 8 can be utilized to
form a compound of formula A (see above) by reaction of the compound of
formula 8 under reaction conditions as follows: first, a compound of formula 8
is
converted to a compound of formula 9:
C13C\
R2 ~)S~o H0
NHn-Bu
o' N,,.
R1
~ o
9
wherein R1 and R2 are as defined above, under conditions using AIMe3, n-
BuNH2, DCM, room temperature, O/N, yield 91%.
The compound of formula 9 is then converted into a derivative thereof of
formula
10:
R~ BHo
oc NHn-Bu
R1 1- N
0
25
wherein R1 and R2 are as defined above, which compound 10 is then converted
into a compound of formula 11:
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OH
R2 H2N I NHn Bu
'Z~ O
R1
11
wherein R1 and R2 are as defined above, via a two step reaction of
hydrogenolysis as well as Boc deprotection (both steps being conventional
steps
known to those skilled in the art).
OH OH
BocHN,,, NHn-Bu H2N NHn-Bu
R t HCI, Dioxane, RT R2
RT
R1 quantitative
R1
10' 11
wherein R1 and R2 are as defined above.
The present invention also contemplates, with respect to the N-butyl
substituents
of the amide portion of each of compounds 9, 10 and 11, that other
substituents
may be employed, which are known in the art and more specifically, the N-butyl
compound can in fact be a lower alkyl substituent or any one of cycloalkyl,
Cl_
6hydroxyalkyl, C1_6alkoxy-C1-6alkyl, C1-6alkanoyfoxy-C1-6alkyl, Cl-
saminoalkyl, Cl-
6alkylamino-C1_6alkyl, C1_6dialkyfamino-C1_6alkyl, C,_6alkanoylamino-
C1_6alkyl,
HO(O)C-C1_6alkyl, C1-6alkyl-O-(O)C-C1-6alkyl, H2N-C(O)-C1_6alkyl, C1-6alkyl-HN-
C(O)-Cl-6alkyl or (C1_6alkyl)2N-C(O)-C1_6alkyl; or a pharmaceutically
acceptable
salt thereof.
The above compounds of formula 9 are known in the art (see for example WO
2006/131304 and WO 2007/045420).
Having thus generally described the invention, reference will now be made to
the
accompany examples described preferred embodiments of the invention.
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Example 1
(+)-(2S)-2-Isopropyl-pent-4-en-1-ol (2).
HO 2C LiAIH4, Et20
HO
0 C then
reflux O/N, 88%
1 2
C8H1402 C8H160
Mol. Wt.: 142.20 Mol. Wt.: 128.21
A first dry round-bottomed flask was charged with 570 mg of lithium aluminum
hydride (15.00 mmol, 3.0 eq.), a magnetic stirrer and equipped with a
condenser.
The condenser was topped with a rubber septum. The reaction vessel was
flushed with argon and 60 mL of dry diethylether ([lithium aluminum hydride] _
0.25 M) was introduced via a glass syringe. The resulting grey suspension was
stirred under an atmosphere of argon and allowed to cool to 0 C with an ice-
water bath. A second dry round-bottomed flask was charged with 711 mg of (+)-
(2S)-2-iso-propyl-pent-4-enoic acid 1 (5.00 mmol, 1.0 eq.) and 5 mL of dry
diethylether ([1] = 1.0 M). (+)-(2S)-2-Isopropyl-pent-4-enoic acid 1 was
dissolved
and transferred into the first flask in a dropwise manner via a glass syringe.
The
second flask was rinsed three times with minimum portions of dry diethyiether
and the reaction mixture was stirred at 0 C for ten minutes. The ice-water
bath
was removed, replaced by a siiicon oil bath and the reaction was heated to
reflux
over night. The silicon oil bath was then removed and the grey suspension was
allowed to cool to room temperature and then to 0 C with an ice-water bath.
The
reaction was then cautiously quenched at 0 C by slowly adding 20 mL of water,
the resulting biphasic solution was then allowed to warm to room temperature
by
removing the ice-water bath and 20 mL of a saturated solution of sodium
potassium tartrate and 20 mL of 1.0 M aqueous solution of sodium hydroxyde
were added. The resulting mixture was vigorously stirred for one hour at room
temperature and the aluminum salts were filtered off through a pad of Celite
under vacuum, the reaction flask and the pad of Celite were washed three times
with small amounts of diethylether. The aqueous layer was separated and
9
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extracted three times with portions of ether. The combined organic layers were
dried over magnesium sulfate and filtered. The solvent was removed under
pressure on a rotary evaporator to leave 564 mg of the titled compound 2 as a
colorless oil (4.40 mmol, 88%) which was used in the next step without any
further purification.
Example 2
(1 S,2S)-2-Isopropyl-l-(4-methoxy-phenyl)-pent-4-en-l-ol and (1 R,2S)-2-
Isopropyl-l-(4-methoxy-phenyl)-pent-4-en-1-ol (4a).
Dess-Martin 0 p-MeOC6H4MgBr OH'_'~ OH'__~
periodinane ~ CeC13 =
HO -- ~ + ~
DCM, 0 C THF, -78 C
to RT 68% (2 steps) MeO MeO
2 3 (S,S) 4a 1:4 (R,S) 4a
C8H160 C8H140 C15H2202 C15H2202
Mol. Wt.: 128.21 Mol. Wt.: 126.20 Mol. Wt.: 234.33 Mol. Wt.: 234.33
A dry round-bottomed flask 1 was charged with 1.28 g of anhydrous cerium (III)
chloride (5.20 mmol, 1.3 eq.), a magnetic stirrer and capped with a rubber
septum. The reaction vessel was flushed with argon and 10.4 mL of
tetrahydrofuran ([cerium (III) chloride] = 0.5 M) was introduced via a glass
syringe. The resulting slurry was stirred at room temperature overnight. The
reaction mixture was then allowed to cool to 0 C with an ice-water bath and
10.4
mL of a 0.5 M solution of para-methoxy benzyl magnesium bromine in
tetrahydrofuran (5.20 mmol, 1.3 eq.) was added dropwise via a glass syringe.
The resulting slurry was stirred at 0 C for 3 hours and then cooled down to -
78 C.
Meanwhile, a dry round-bottomed flask 2 was charged with 513 mg of 2 (4.00
mmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The
reaction
vessel was flushed with argon and 16 mL of dichloromethane ([2] = 0.25 M) was
introduced via a glass syringe. The resulting colorless solution was stirred
under
an atmosphere of argon and allowed to cool to 0 C with an ice-water bath
before
adding 1.87 g of Dess-Martin periodinane (4.40 mmol, 1.1 eq.). A slurry formed
CA 02634513 2008-06-09
at once, the ice-water bath was removed and the reaction was monitored every
20 minutes by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC
analysis showed no more starting material, the reaction mixture was diluted
with
64 mL ether and poured into 40 mL of a saturated solution of sodium
bicarbonate
containing 6.95 g (28.00 mmol, 7.0 eq.) of sodium thiosulfate. The resulting
biphasic solution was stirred at room temperature until the organic layer
became
clear. The organic layer was separated and washed with 40 mL of saturated
solution of sodium bicarbonate, dried over sodium sulfate, filtered and
concentrated at low temperature on a rotary evaporator (cautious: the aidehyde
which is formed is volatile). The colorless oily residue corresponding to the
aldehyde 3 was dissolved in 4 mL of tetrahydrofuran ([3] = 1.0 M) and
transferred
in a dropwise manner into the round bottomed flask I via syringe at -78 C. The
reaction mixture was stirred at -78 C and monitored by TLC analysis (20:80
ethyl
acetate-hexanes, KMnO4). When TLC analysis showed no more starting
material, the reaction mixture was quenched with 20 mL of a saturated aqueous
solution of ammonium chloride, the dry ice-acetone bath was removed and the
reaction media was allowed to warm to room temperature. The aqueous layer
was separated and washed with three portion of diethylether. The combined
organic layers were dried over sodium sulfate, dried and filtered. The
solvents
were removed under reduced pressure on a rotary evaporator to leave 750 mg of
a oily residue which was purified by flash column chromatography (75 mL of
Si02) eluting with 10:90 ethyl acetate-hexanes to afford 638 mg of a colorless
oil
corresponding to the titled compounds (S,S) 4 and (R,S) 4 as a 1:4 inseparable
mixture (2.72 mmol, 68%).
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Example 3
(1 S,2S)-2-isopropyl-l-(4-methoxy-3-(3-methoxypropoxy)phenyl)pent-4-en-1-
ol and (1R,2S)-2-isopropyl-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)pent-
4-en-l-ol (4b).
^ /OMe i-PrMgCI OMe
Or Br n-BuLi IO M9Br
I \ THF I \
MeO ~ 0 C to RT Me0 ~
4-b ro mo -1-m eth o xy-2-
(3-methoxypropoxy)
benzene
C 11 H15B r03
Mol. Wt:275,14 OMe OMe
Dess-Martin O OH OH
periodinane
O O
HO +
DCM, 0 C THF, -78 C I I
to RT 50% (2 steps) Me0 Me0
2 3 (S,S) 4b 1:6 (R,S) 4b
C8H160 C8H140 C19H3004 C19H3004
Mol. Wt.: 128.21 Mol. Wt.: 126.20 Mol. Wt: 322,44 Mol. Wt: 322,44
A first dry round-bottomed flask 1 was charged with a magnetic stirrer and
capped with a rubber septum. The reaction vessel was flushed with argon and
2.0 mL of tetrahydrofuran was introduced via a glass syringe. The solution was
stirred and cooled down to 0 C with an ice-water bath and before adding via a
glass syringe 1.0 mL of a 2.0 M solution of iso-propyl magnesium chloride in
tetrahydrofuran (2.00 mmol, 1.0 eq.). The resulting mixture was stirred at 0 C
under an atmosphere of argon and 0.8 mL of a 2.5 M solution of n-butyllithium
in
hexanes (2.00 mmol, 1.0 eq.) was added dropwise at 0 C via a glass syringe.
The reaction was then allowed to warm up to room temperature and stirred for a
further 30 minutes before adding dropwise 2.0 mL of a 1.0 M solution of 4-
bromo-
1-methoxy-2-(3-methoxypropoxy)benzene tetrahydrofuran which was prepared in
a second dry round bottomed flask by dissolving 551 mg of 4-bromo-l-methoxy-
2-(3-methoxypropoxy)benzene (2.0 mmol, 1.0 eq.) in 2.0 mL of tetrahydrofuran.
The resuiting solution was then stirred for 3 hours at room temperature and
12
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allowed to cool to -78 C with dry ice-acetone bath. Meanwhile, a third dry
round-
bottomed flask was charged with 257 mg of 2 (2.00 mmol, 1.0 eq.), a magnetic
stirrer and capped with a rubber septum. The reaction vessel was flushed with
argon and 8 mL of dichloromethane ([2] = 0.25 M) was introduced via a glass
syringe. The resulting colorless solution was stirred under an atmosphere of
argon and allowed to cool to 0 C with an ice-water bath before adding 935 mg
of
Dess-Martin periodinane (2.20 mmol, 1.1 eq.). A slurry formed at once, the ice-
water bath was removed and the reaction was monitored every 20 minutes by
TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC analysis showed
no more starting material, the reaction mixture was diluted with 32 mL ether
and
poured into 20 mL of a saturated solution of sodium bicarbonate containing 3.5
g
(14.00 mmol, 7.0 eq.) of sodium thiosulfate. The resulting biphasic solution
was
stirred at room temperature until the organic layer became clear. The organic
layer was separated and washed with 20 mL of saturated solution of sodium
bicarbonate, dried over sodium sulfate, filtered and concentrated at low
temperature on a rotary evaporator (cautious: the aidehyde which is formed is
volatile). The colorless oily residue corresponding to the aidehyde 3 was
dissolved in 2 mL of tetrahydrofuran ([3] = 1.0 M) and transferred in a
dropwise
manner into the first round bottomed flask via syringe at -78 C. The reaction
mixture was stirred at -78 C and monitored by TLC analysis (20:80 ethyl
acetate-
hexanes, KMnO4). When TLC analysis showed no more starting material, the
reaction mixture was quenched with 20 mL of a saturated aqueous solution of
ammonium chloride, the dry ice-acetone bath was removed and the reaction
media was allowed to warm to room temperature. The aqueous layer was
separated and washed with three portion of diethylether. The combined organic
layers were dried over sodium sulfate, dried and filtered. The solvents were
removed under reduced pressure on a rotary evaporator to leave 560 mg of a
oily residue which was purified by flash column chromatography (60 mL of Si02)
eluting with 20:80 ethyl acetate-hexanes to afford 322 mg of a colorless oil
corresponding to the titied compounds (S,S) 4 and (R,S) 4 as a 1:6 inseparable
mixture (1.00 mmol, 50%).
13
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Synthesis of 4-bromo-1 -methoxy-2-(3-methoxypropoxy)benzene: this compound
was synthesized according to known procedure in the literature (WO 2001-19785
and WO 2007-048620).
Example 4
(S,S,S)-2-Isopropyl-pent-4-enoic acid 2-isopropyl-l-(4-methoxy-phenyl)-
pent-4-enyl ester and (S,R,S)-2-Isopropyl-pent-4-enoic acid 2-isopropyl-l-
(4-methoxy-phenyl)-pent-4-enyl ester (5a).
H02C
OH OH O O~ O O
= 1 =
~/ DMAP, Et3N, ~ ~
MeO MeO C13C6H2COC1 MeO MeO
0 CtoRT
(S,S) 4a 1:4 (R,S) 4a 84% (S,S,S) 5a 1:4 (S,R,S) 5a
C15H2202 C15H2202 C23H3403 C23H3403
Mol. Wt.: 234.33 Mol. Wt.: 234.33 Mol. Wt.: 358.51 Mol. Wt.: 358.51
A first dry round-bottomed flask was charged with 299 mg of (+)-(2S)-2-iso-
propyl-pent-4-enoic acid 1 (2.10 mmol, 1.05 eq.), a magnetic stirrer and
capped
with a rubber septum. The reaction media was flushed with argon and 21 mL of
dry toluene ([1] = 0.1 M) were introduced via a glass syringe. The resulting
solution was stirred under an atmosphere of argon and allowed to cool to 0 C
before adding first 335 pL of triethylamine (2.40 mmol, 1.2 eq.), then 375 pL
of
2,4,6-trichlorobenzoyl chloride (2.40 mmol, 1.2 eq.) via a glass syringe in a
dropwise manner and last 293 mg of 4-dimethylaminopyridine (2.40 mmol, 1.2
eq.) in one portion. The resulting white slurry which formed as 4-
dimethylaminopyridine dissolved in the reaction media was stirred at 0 C for
ten
minutes during which the white slurry turned yellow and then in a second dry
round-bottomed flask a solution of 469 mg of 4a (2.00 mmol, 1.0 eq.) in the
minimum amount of dry toluene via syringe was transferred into the first round-
bottomed flask in a dropwise manner at 0 C. The second dry round-bottomed
flask that contained 4a was rinsed three times with the minimum portion of dry
14
CA 02634513 2008-06-09
toluene and the reaction media was allowed to warm at room temperature by
removing the water-ice bath. The reaction was stirred at room temperature and
monitored by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC
analysis showed no more starting material, the solvent was removed under
reduced pressure on a rotary evaporator. The resulting yellow solid was taken
up
in 10 mL ethyl acetate and 10 mL of water. The aqueous layer was separated
and extracted with three portions of ethyl acetate. The combined organic layer
were successively washed with one portion of a 10 % aqueous solution of acid
citric and one portion of a saturated solution of sodium bicarbonate, dried
over
magnesium sulfate and filtered. The solvent was removed under reduced
pressure on a rotary evaporator to afford 670 mg of a yellow oil which was
purified by flash column chromatography (67 mL of Si02) eluting with 5:95
ethyl
acetate-hexanes to give 602 mg of a colorless oil corresponding to the titled
compounds (S,S,S) 5a and (S,R,S) 5a as a 1:4 inseparable mixture (1.68 mmol,
84%).
Example 5
(S,S,S)-2-Isopropyl-pent-4-enoic acid 2-isopropyl-l-(4-methoxy-3-(3-
methoxypropoxy)-phenyl)-pent-4-enyl ester and (S,R,S)- 2-tsopropyl-pent-4-
enoic acid 2-isopropyl-1 -(4-methoxy-3-(3-methoxypropoxy)-phenyl)-pent-4-
enyl ester (5a).
OMe OMe OM J,,,. Me~
H02C % .~
OH OH O O O O_
O I\ + I\ DMAP, Et3N,~ O/ I +O / I
Me0 Me0 C13C6H2COCI Me0 Me0
0 C to RT
(S,S) 4b 1:6 (R,S) 4b 84% (S,S,S) 5b 1:6 (S,R,S) 5b
C19H3004 C19H3004 C27H4205 C27H4205
Mol. Wt.: 322.24 Mol. Wt.: 322.24 Mol. Wt.: 446.62 Mol. Wt.: 446.62
A first dry round-bottomed flask was charged with 96 mg of (+)-(2S)-2-iso-
propyl-
pent-4-enoic acid 1 (0.75 mmol, 1.05 eq.), a magnetic stirrer and capped with
a
rubber septum. The reaction media was flushed with argon and 7.5 mL of dry
CA 02634513 2008-06-09
toluene ([1] = 0.1 M) were introduced via a glass syringe. The resulting
solution
was stirred under an atmosphere of argon and allowed to cool to 0 C before
adding first 120 pL of triethylamine (0.86 mmol, 1.2 eq.), then 135 pL of
2,4,6-
trichlorobenzoyl chloride (0.86 mmol, 1.2 eq.) via a glass syringe in a
dropwise
manner and last 105 mg of 4-dimethylaminopyridine (0.86 mmol, 1.2 eq.) in one
portion. The resulting white slurry which formed as 4-dimethyiaminopyridine
dissolved in the reaction media was stirred at 0 C for ten minutes during
which
the white slurry turned yellow and then in a second dry round-bottomed flask a
solution of 230 mg of 4b (0.75 mmol, 1.0 eq.) in the minimum amount of dry
toluene via syringe was transferred into the first round-bottomed flask in a
dropwise manner at 0 C. The second dry round-bottomed flask that contained 4b
was rinsed three times with the minimum portion of dry toluene and the
reaction
media was allowed to warm at room temperature by removing the water-ice bath.
The reaction was stirred at room temperature and monitored by TLC analysis
(30:70 ethyl acetate-hexanes, KMnO4). When TLC analysis showed no more
starting material, the solvent was removed under reduced pressure on a rotary
evaporator. The resulting yellow solid was taken up in 10 mL ethyl acetate and
10 mL of water. The aqueous layer was separated and extracted with three
portions of ethyl acetate. The combined organic layer were successively washed
with one portion of a 10% aqueous solution of acid citric and one portion of a
saturated solution of sodium bicarbonate, dried over magnesium sulfate and
filtered. The solvent was removed under reduced pressure on a rotary
evaporator
to afford 305 mg of a yellow oil which was purified by flash column
chromatography (30 mL of Si02) eluting with 10:90 ethyl acetate-hexanes to
give
268 mg of a coloriess oil corresponding to the titled compounds (S,S,S ) 5b
and
(S,R,S) 5b as a 1:6 inseparable mixture (0.60 mmol, 80%).
16
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Example 6
(3S,8S,9R)-3,8-Diisopropyl-9-(4-methoxy-phenyl)-4,7,8,9-tetrahydro-3H-
oxonin-2-one (6a).
/ O
O O~ O O~ Ti(i-PrO)4 O '
5mol % 1st generation / I
~ ~ \ ~ Grubb's catalyst, ~
Me0 Me0 PhCH3 (10 mM ), RT Me0
65%
(S,S,S) 5a 1:4 (S,R,S) 5a 6a
C23H 3403 C23H 3403 C21H3003
Mol. Wt.: 358.51 Mol. Wt.: 358.51 Mol. Wt.: 330.46
A dry round-bottomed flask was charged with 359 mg of 5a (1.00 mmol, 1.0 eq.),
a magnetic stirrer and capped with a rubber septum. The reaction media was
flushed with argon and 100 mL of dry toluene ([5] = 0.01 M) were introduced
via
a glass syringe. The resulting solution was stirred at room temperature under
an
atmosphere of argon and 586 pL of titanium (IV) isopropoxide (2.00 mmol, 2.0
eq.) was added via a syringe. The reaction was stirred overnight at room
temperature and then 41 mg of the first generation Grubb's catalyst (0.05
mmol,
0.05 eq.) was added in one portion. The resulting purple solution was stirred
at
room temperature and monitored by TLC analysis (20:80 ethyl acetate-hexanes,
KMnO4). After 24-48 hours of stirring at room temperature when TLC analysis
showed no more evolution the catalyst was slowly filtered off through a short
pad
of silica (20 mL) topped with a thin layer of florysil (0.5 cm). The pad of
silica and
florysil were washed two times with 50 mL of a 1:9 solution of ether-hexanes.
The solvents were removed under reduced pressure on a rotary evaporator to
afford 350 mg of a colorless oil which was purified by flash column
chromatography (35 mL of Si02) eluting slowly with 3:97 ether-hexanes first
until
the first spot on TLC analysis came out and then 10:90 ether-hexanes to yield
215 mg of a colorless oil corresponding to the titled compound 6a as a single
diastereoisomer (0.65 mmol, 65%). The starting material (S,S,S) 5a did not
undergo ring closing metathesis and was not recovered after purification. The
nature of the first spot on TLC analysis remained unknown.
17
CA 02634513 2008-06-09
Example 7
(3S,8S,9R)-3,8-Diisopropyl-9-(4-methoxy-3-(3-methoxypropoxy)-phenyl)-
4,7,8,9-tetrahydro-3H-oxonin-2-one (6b).
OMe OM J,, OMe O =
O O~ O O~ Ti(i-PrO)4 O '
O ~ = 5mol % 1st generation
/ + / ~ ~ \ ~ Grubb's catalyst, ~ ~
MeO Me0 PhCH3 (10 mM ), RT Meo
72%
(S,S,S) 5b 1:6 (S,R,S) 5b 6b
C27H4205 C27H4205 C25H3805
Mol. Wt.: 446.62 Mol. Wt.: 446.62 Mol. Wt.: 418.57
A dry round-bottomed flask was charged with 250 mg of 5 (0.56 mmol, 1.0 eq.),
a
magnetic stirrer and capped with a rubber septum. The reaction media was
flushed with argon and 56 mL of dry toluene ([5b] = 0.01 M) were introduced
via
a glass syringe. The resulting solution was stirred at room temperature under
an
atmosphere of argon and 328 pL of titanium (IV) isopropoxide (1.12 mmol, 2.0
eq.) was added via a syringe. The reaction was stirred overnight at room
temperature and then 23 mg of the first generation Grubb's catalyst (0.03
mmol,
0.05 eq.) was added in one portion. The resulting purple solution was stirred
at
room temperature and monitored by TLC analysis (20:80 ethyl acetate-hexanes,
KMnO4). After 48-72 hours of stirring at room temperature when TLC analysis
showed no more evolution the catalyst was slowly filtered off through a short
pad
of silica (12 mL) topped with a thin layer of florysil (0.5 cm). The pad of
silica and
florysil were washed two times with 25 mL of a 20:80 solution of ether-
hexanes.
The solvents were removed under reduced pressure on a rotary evaporator to
afford 240 mg of a colorless oil which was purified by flash column
chromatography (50 mL of Si02) eluting slowly with 15:85 ether-hexanes first
until the first spot on TLC analysis came out and then 20:80 ether-hexanes to
yield 169 mg of a colorless oil corresponding to the titled compound 6b as a
single diastereoisomer (0.40 mmol, 72%). The starting material (S,S,S) 5b did
not undergo ring closing metathesis and was not recovered after purification.
The
nature of the first spot on TLC analysis remained unknown.
18
CA 02634513 2008-06-09
Example 8
(1S,3S,4R, 7S, 9R)-3,7-Diisopropyl-4-(4-methoxy-phenyl)-6-oxo-5-oxa-10-aza-
bicyclo[7.1.0]decane-10-sulfonic acid 2,2,2-trichloro-ethyl ester (7a).
o = O =
O H2NSO3CH2CC13, MgO O
' [Rh(tfacam2)]2, Phl(OAc)2 NSO 3CH2CCI3
/ Me0 \( PhCH3, 0 C to RT Me0
O/N, 80%
6a 7a
C21H3003 C23H32CI3NO6S
Mol. Wt.: 330.46 Mol. Wt.: 556.93
A dry round-bottomed flask was charged with 56 mg of 6a (168 pmol, 1.0 eq.), a
magnetic stirrer and capped with a rubber septum. The reaction media was
flushed with argon and 840 pL of dry toluene ([6a] = 0.2 M) were introduced
via a
glass syringe. The resulting solution was stirred under an atmosphere of argon
and cooled down to 0 C with an ice-water bath before adding successively in
one
portion 43 mg of 2,2,2-trichloroethylsulfamate (185 pmol, 1.1 eq.), 16 mg of
magnesium oxide (403 Nmol, 2.4 eq.), 76 mg (diacetoxy)iodobenzene (235 pmol,
1.4 eq.) and last 2.2 mg of rhodium acetamide dimer (3.4 pmol, 0.02 eq.). The
resulting paie blue slurry was then allowed to warm slowly to room temperature
and turned progressively orange. The reaction was stirred overnight leaving
the
ice-water bath in place before adding a second time 2.2 mg of Rh2(tfacam)4
(3.4
pmol, 0.02 eq.) if TLC analysis (10:90 ethyl acetate-hexanes, CAM) still
showed
starting material. The ice-water bath was removed, the reaction was stirred at
room temperature and monitored by TLC analysis (10:90 ethyl acetate-hexanes,
CAM). When TLC analysis showed no more starting material the reaction media
was diluted with 3.2 mL of dichloromethane and filtered through a pad of
Celite.
The pad of Celite was washed three times with minimum portions of
dichloromethane. The solvent were removed under reduced pressure to leave
100 mg of a brown oil which was purified by flash column chromatography (10
mL of Si02) eluting with 5:95 ethyl acetate-hexaries to afford 75 mg of the
titled
compound 7a (135 pmol, 80%) as a colorless gel.
19
CA 02634513 2008-06-09
Preparation of 2,2,2-trichloroethylsulfamate
1) Formic acid, 0 C
2) CH3CN, 0 C, 1 h
~ then RT, 8 h ~~ NH2
CI-S-N=C=O "'~ '
0 3) C13CCH2OH, DMA CI3C 0 0
3 h, 0 C toRT, 85%
Chlorosulfonyl isocyanate 2,2,2-Trichloroethylsulfamate
CCINO3S C2H4CI3NO3S
Mol. Wt.: 141.53 Mol. Wt.: 228.48
A round-bottomed flask was charged 5.7 mL of chlorosulfonyl isocyanate (65.6
mmol, 1.5 eq.), a magnetic stirrer and equipped with a dropping funnel capped
with a rubber septum. The reaction vessel was flushed with argon, placed in a
water-ice bath and 2.5 mL of formic acid (65.6 mmol, 1.5 eq.) was introduced
into
the dropping funnel via a glass syringe under an atmosphere of argon. Formic
acid was added dropwise to the neat chlorosulfonyl isocyanate under vigorous
stirring. Gas evolution was observed during the addition process and within a
few
minutes the mixture solidified. To the solid mass was added 44 mL of
acetonitrile
and the resulting solution was stirred for one hour at 0 C. The water-ice bath
was
removed and the reaction was stirred eight hours at room temperature. The
reaction was then cooled down to 0 C with an ice-water bath and 4.2 mL of
trichloroethanol (43.8 mmol, 1.0 eq.) and 44 mL of dimethylacetamide
([trichioroethanol] = 1 M) were introduced into the dropping funnel. The
solution
of trichloroethanol in dimethylacetamide was then added dropwise to the
reaction
mixture at 0 C. The reaction media was allowed to warm to room temperature by
removing the water-ice bath and after three hours of stirring at room
temperature
the solution was diluted with 50 mL of water and 50 ml of diethylether. The
organic layer was separated was washed successively with one portion of water,
two portions of brine, dried over magnesium sulfate and filtere. The solvents
were removed under reduced pressure on a rotary evaporator to leave 10 g of an
oily residue which was purified by flash chromatography (600 mL of Si02)
eluting
with 25:75 to 50:50 gradient ethyl acetate-hexanes to afford 8.5 g of the
desired
product as a white solid (37.3 mmol, 85%).
CA 02634513 2008-06-09
Prepartion of rhodium trifluoroacetamide dimer
[Rh(OAc)2]2 CF3CONH2 [Rh(CF3CONH)2]2
Chlorobenzene
rhodium acetate 155 C rhodium trifluoroacetamide
dimer quantitative dimer
CgH12o8Rh2 CgH4F12Nq.O4Rh2
Mol. Wt.: 441.99 Mol. Wt.: 653.93
A round-bottomed flask was charged with 140 mg of rhodium acetate dimer (0.32
mmol, 1.0 eq.) and 18 mL of chlorobenzene, and to this suspension was added
512 mg of trifluoroacetamide (4.50 mmol, 14 eq.). The reaction flask was
equipped with a short-path distillation head fitted with a receiving flask.
The
apparatus was placed in an oil bath preheated to 155 C. At this temperature,
solvent distilled at a rate of about 1 mL per hour for 36 h. Approximately
every 8
h, an appropriate amount of chlorobenzene was added in order to restore the
solvent volume of the reaction to about 18 mL. The solution color slowly
changed
to a deep green and a white crystalline precipitate (trifluoroacetamide)
slowly
formed in the receiving flask. After 36 h, additional 512 mg of
trifluoroacetamide
(4.50 mmol, 14 eq.) was added to this reaction mixture and heating at 155 C
was
continued. Within 48 h, a dark blue-green solid slowly collected on the sides
of
the reaction vessel. Following this time, the reaction was cooled to 25 C and
the
mixture was filtered. The blue-green solid was washed thoroughly with
dichloromethane, and the filtrate discarded. To ensure quantitative recovery
of
the desired product, acetone was used to dissolve the powder. The purple
filtrate
was concentrated under reduced pressure and the isolated material was dried by
heating at 50 C in vacuo (1 mm Hg) for 1 h. For all applications, the rhodium
trifluoroacetamide dimer complex was used without further purification.
21
CA 02634513 2008-06-09
Example 9
(1 S,3S,4R, 7S, 9R)-3,7-Di isopropyl-4-(4-methoxy-3-(3-methoxypropoxy)-
phenyl)-6-oxo-5-oxa-10-aza-bicyclo[7.1.0]decane-10-sulfonic acid 2,2,2-
trichloro-ethyl ester (7b).
Me0 0 MeC) 0
0 H2NSO3CH2CC13, Mg0 O
[Rh(tfacam2)]2, Phl(OAc)2 0 / NS03CH2CCI3
~ I PhCH3, 0 C to RT ~ I
Me0 O/N, 75% Me0
6b 7a
C25H3805 C27H40CIgNO8S
Mol. Wt: 418,57 Mol. Wt: 645,03
A dry round-bottomed flask was charged with 134 mg of 6b (320 pmol, 1.0 eq.),
a
magnetic stirrer and capped with a rubber septum. The reaction media was
flushed with argon and 1.6 L of dry toluene ([6b] = 0.2 M) were introduced via
a
glass syringe. The resulting solution was stirred under an atmosphere of argon
and cooled down to 00 with an ice-water bath before adding successively in one
portion 88 mg of 2,2,2-trichloroethylsulfamate (384 pmol, 1.1 eq.), 183 mg of
magnesium oxide (800 pmol, 2.5 eq.), 155 mg (diacetoxy)iodobenzene (480
pmol, 1.5 eq.) and last 4.5 mg of rhodium acetamide dimer (6.4 pmol, 0.02
eq.).
The resulting pale blue slurry was then allowed to warm slowly to room
temperature and turned progressively orange. The reaction was stirred
overnight
leaving the ice-water bath in place before adding a second time 2.2 mg of
Rh2(tfacam)4 (6.4 pmol, 0.02 eq.) if TLC analysis (30:70 ethyl acetate-
hexanes,
CAM) still showed starting material. The ice-water bath was removed, the
reaction was stirred at room temperature and monitored by TLC analysis (30:70
ethyl acetate-hexanes, CAM). When TLC analysis showed no more starting
material the reaction media was diluted with 4 mL of dichloromethane and
filtered
through a pad of Celite. The pad of Celite was washed three times with minimum
portions of dichloromethane. The solvent were removed under reduced pressure
to leave 250 mg of a brown oil which was purified by flash column
22
CA 02634513 2008-06-09
chromatography (25 mL of Si02) eluting with 15:85 ethyl acetate-hexanes to
afford 155 mg of the titled compound 7b (240 pmol, 75%) as a colorless gel.
Example 10
(2R,2'S,3S,4'S,5S)-3-isopropyi-5-(4-isopropyl-5-oxo-tetrahydro-furan-2-yi)-2-
(4-methoxy-phenyl)-pyrrolidine-1-sulfonic acid 2,2,2-trichloro-ethyl ester
(8a).
C13C
\/ > 0
0 = O
S=0 0
O',
9Nso3cH2ccI3 TFA:DCM (1:5; v/v) Me0 ~~1 N
/
Me0 \ ( -5 C, 15 min.
90%
7a 8a
C23H32C I3N O6S C23H 32C I3N 06S
Mol. Wt.: 556.93 Mol. Wt.: 556.93
A dry round-bottomed flask was charged with 74 mg of 7a (131 Nmol, 1.0 eq.), a
magnetic stirrer and capped with a rubber septum. The reaction media was
flushed with argon and 1.3 mL of dry dichloromethane ([7] = 0.1 M) were
introduced via a glass syringe. The resulting solution was stirred under an
atmosphere of argon and cooled down to -5 with an ice-water-salt bath before
adding dropwise 260 pL of trifluoroacetic acid (one fifth of the volume of
dichloromethane). The reaction was stirred at -5 and monitored by TLC
analysis
(20:80 ethyl acetate-hexanes, CAM). When TLC analysis showed no more
starting material the reaction media was diluted with 2 mL of toluene, the
trifluoroacetic acid and dichloromethane were first removed under reduced
pressure at room temperature and then the toiuene at higher temperature to
leave 70 mg of yellow foam which was purified by flash column chromatography
(7 mL of Si02) eluting first with 10:90 ethyl acetate-hexanes and then with
10:90
ethyl acetate-hexanes to afford 66 mg of the titled compound 8a (119 pmol,
90%)
as a white foam.
23
CA 02634513 2008-06-09
Example 11
(2R,2'S,3S,4'S,5S)-3-Isopropyl-5-(4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-2-
(4-methoxy-3-(3-methoxypropoxy)-phenyl)-pyrrolidine-1-sulfonic acid 2,2,2-
trichloro-ethyl ester (8b).
M e0
C13C
0
MeO O O
O 0
O O,S~
O
O N
NS03CH2CC13 TFA:DCM (1:5; vlv) MeO
Me0 \ I 0 C to RT, 30 min.
85%
7b 8b
C27H40C13N08S C27H40C13N08S
Mol. Wt: 645,03 Mol. Wt: 645,03
A dry round-bottomed flask was charged with 150 mg of 7b (232 pmol, 1.0 eq.),
a
magnetic stirrer and capped with a rubber septum. The reaction media was
flushed with argon and 2.3 mL of dry dichloromethane ([7b] = 0.1 M) were
introduced via a glass syringe. The resulting solution was stirred under an
atmosphere of argon and cooled down to 01 with an ice-water bath before adding
dropwise 460 pL of trifluoroacetic acid (one fifth of the volume of
dichioromethane). The reaction was stirred at 0 for 10 minutes and then
allowed
to warm to room temperature. The reaction was monitored by TLC analysis
(20:80 ethyl acetate-hexanes, CAM). When TLC analysis showed no more
starting material (about 30 minutes) the reaction media was diluted with 2 mL
of
toluene, the trifluoroacetic acid and dichloromethane were first removed under
reduced pressure at room temperature and then the toluene at higher
temperature to leave 152 mg of yellow foam which was purified by flash column
chromatography (15 mL of Si02) eluting first with 10:90 ethyl acetate-hexanes
and then with 20:80 ethyl acetate-hexanes to afford 127 mg of the titled
compound 8b (198 pmol, 85%) as a white foam.
24
CA 02634513 2008-06-09
Example 12
(1'S,2R,3S,3'S,5S)-5-(3-Butylcarbamoyl-1-hydroxy-4-methyl-pentyl)-3-
isopropyl-2-(4-methoxy-phenyl)-pyrrolidine-l-sulfonic acid 2,2,2-trichloro-
ethyl ester (9).
C13C C13C
/) O /)
O O
O O ~ %O OH
g= õ O~S
N AIMe3, n-BuNH2 N, NHn-Bu
Me0 DCM Me0 õ
O
RT, O/N
91%
8 9
C23H32C13NO6S C27H43C13N2O6S
Mol. Wt.: 556.93 Mol. Wt.: 630.06
A first dry round-bottomed flask was charged with 64 mg of 8 (114 pmol, 1.0
eq.),
a magnetic stirrer and capped with a rubber septum. The reaction media was
flushed with argon and 1.1 mL of dry dichloromethane ([8] = 0.1 M) were
introduced via a glass syringe. The resulting solution was stirred under an
atmosphere of argon at room temperature. A second dry round-bottomed flask
was charged with 62 pL of n-butylamine (456 pmol, 4.0 eq.), a magnetic stirrer
and capped with a rubber septum. The reaction media was flushed with argon
and 456 pL of dry dichloromethane ([n-butylamine] = 1.0 M) was introduced via
a
glass syringe. The resulting solution was stirred under an atmosphere of argon
at
room temperature and 228 pL of a 2.0 M solution of trimethylaluminum in
toluene
(456 pmol, 4.0 eq.) was added drop wise. The reaction mixture was stirred for
10
minutes at room temperature and transferred via cannula into the first round-
bottomed fiask in a dropwise manner. The resulting solution was stirred at
room
temperature overnight and then monitored by TLC analysis (50:50 ethyl acetate-
hexanes, CAM). When TLC analysis showed no more starting material the
reaction media was quenched by adding 2 mL of a saturated aqueous solution of
ammonium chloride at room temperature. The resulting biphasic solution was
stirred at room temperature for 30 minutes and the aqueous layer was separated
CA 02634513 2008-06-09
and extracted with three portions of dichloromethane. The combined organic
layers were washed with one portion of brine, dried over magnesium sulfate and
filtered. The solvents were removed under reduced pressure to leave 70 mg of a
yellow oil which was purified by flash column chromatography (7 mL of Si02)
eluting with 30:70 ethyl acetate-hexanes to afford 65 mg of the titled
compound 9
(103 pmol, 91 %) as a white solid.
Example 13
(1'S,2R,3S,3'S,5S)-5-(3-Butylcarbamoyl-1-hydroxy-4-methyl-pentyl)-3-
isopropyl-2-(4-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl
ester (10a).
C13C
~ 1) Zn(Cu)
0%0 HO AcOH:MeOH (1:1; v/v), O/N Ho
O S NHn-Bu then HCI in MeOH Boc NHn-Bu
Me0 ~ N 6 hours, 45 C Me0 ~~ N/
O O
2) Boc20, sat. K2CO3
DCM,O CtoRTO/N,52%.
9 10
C27H43C13N206S C30H50N205
Mol. Wt.: 630.06 Mol. Wt.: 518.73
A first dry round-bottomed flask was charged with 91 mg of zinc (copper)
couple
(470 pmol, 5.0 eq.), a magnetic stirrer and capped with a rubber septum. The
reaction media was flushed with argon and a second round-bottomed flask was
charged with 60 mg of 9a (94 pmol, 1.0 eq.) which was dissolved in 940 pL of a
1:1 (v/v) mixture of methanol and acid acetic ([9a] = 0.1 M). The latter
solution
was transferred via a glass syringe into the first round-bottomed flask.
Transfer
was made quantitative with two minimum additional portion of a 1:1 (v/v)
mixture
of methanol and acid acetic and the resulting suspension was stirred
vigorously
stirred under an atmosphere of argon for 16 hours. After this time, the
reaction
contents were filtered through a pad of Celite and the filter cake was rinsed
three
times with a minimum amount of methanol. The filtrate was concentrated to
dryness under reduced pressure to afford a white solid. The round-bottomed
flask containing the white solid was then charged with a magnetic stirrer and
26
CA 02634513 2008-06-09
capped with a rubber septum. The reaction vessel was flushed with argon and
940 pL of a 2.0 M solution of anhydrous hydrochloric acid in methanol (140 pL
of
acetyl chloride in 2 mL of anhydrous methanol gave 2 mL of a 2.0 M solution of
anhydrous hydrochloric acid in methanol) was added to the round-bottomed flask
containing the white solid which was dissolved by stirring under an atmosphere
of argon. The resulting solution was allowed to warm at 45 C and stirred at
this
temperature for six hours. After this time, the reaction media was diluted
with 4
mL of toluene, the anhydrous hydrochloric acid in methanol was removed under
reduced pressure on a rotary evaporator at room temperature and then the
toluene at higher temperature to leave a yeliow oil. The round-bottomed flask
containing the yellow oil was charged with a magnetic stirrer and capped with
a
rubber septum. The reaction media was flushed with argon and 520 pL of
dichloromethane was introduced in the reaction vessel via a syringe. The
reaction media was stirred and cooled down to 0 C with a water-ice bath before
adding via a syringe 520 pL of a saturated solution of potassium bicarbonate
and
41 mg of di-tert-butyl carbamate (188 pmol, 2.0 eq.) in a portion wise manner.
The biphasic solution was stirred vigorously at 0 C for ten minutes and then
allowed to warm to room temperature by removing the ice-water bath. The
reaction was stirred at room temperature overnight and then diluted with I mL
of
dichloromethane and 1 mL of an aqueous solution of sodium carbonate. The
aqueous layer was separated and extracted with three portions of
dichloromethane. The combined organic layers were dried over magnesium
sulfate and filtered. The dichloromethane was removed under reduced pressure
to leave 40 mg of yellow residue which was purified by flash column
chromatography (4 mL of Si02) eluting with 25:75 ethyl acetate-hexanes to
afford
25 mg of the titled compound 10a (49 pmol, 52%) as a colorless oil.
27
CA 02634513 2008-06-09
Example 14
(1S,2S,2'S,4S)-{4-Butylcarbamoyl-2-hydroxy-l-[2-(4-methoxy-benzyl)-3-
methyl-butyl]-5-methyl-hexyl}-carbamic acid tert-butyl ester (10').
Hydrogenolysis
OH OH
Boc NHn-Bu NHn-Bu
N, BocHN,.
Me0 H2, 10% Pd/C
MeOH, RT, 3 days
60% MeO 10 10'
C30H50N2O5 C30H52N205
Mol. Wt.: 518.73 Mol. Wt.: 520.74
Birch reduction
OH OH
;Boc NHn-Bu BocHN,,, NHn-Bu
,
Me0 O Li
THF, -78 C
90% MeO xx xx
C30H50N205 C30H52N205
Mol. Wt.: 518.73 Mol. Wt.: 520.74
Example 15
(2S,4S,5S, 7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-methoxy-benzyl)-8-
methyl-nonanoic acid butylamide (XX).
OH OH
BocHN,,. NHn-Bu H2N NHn-Bu
HCI, Dioxane, RT
O -- O
I RT quantitative
MeO MeO
10' 11
C30H52N2O5 C25H44N203
Mol. Wt.: 520.74 Mol. Wt.: 420.63
28
CA 02634513 2008-06-09
In the above-described Examples, it will be appreciated by those skilled in
the art
that various other reagents may be employed which are equivalent to those
specifically used. Thus, for the aromatic organometallic reagents having the
substituents R1 and R2, various arolithium, as well as other metals copy 300
can
be employed,
It will be understood that various modifications can be made without departing
from the spirit and scope of the invention disclosed herein.
29
