Lipase-catalyzed kinetic resolution of ethyl 3-aryl-3-hydroxypropionate: Preparation of the side chain of a novel carbapenem, J-114,870

Article abstract of DOI:10.1016/S0957-4166(00)00326-8

An optically active 3-aryl-3-hydroxypropionate 3a was prepared by lipase-catalyzed kinetic hydrolysis of a diastereomeric mixture of 3-aryl-3-(α-chloroacetoxy)propionate 6 in good conversion yield with adequate purity (>95% de). This enzymatic reaction proceeded with great efficiency as measured by reaction rate, chemical yield and stereoselectivity. The compound 3a was converted to J-114,870 1a, a novel ultra-broad spectrum carbapenem, without significant epimerization. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00326-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3609–3617
Lipase-catalyzed kinetic resolution of ethyl
3-aryl-3-hydroxypropionate: preparation of the side chain of
a novel carbapenem, J-114,870
Yuichi Sugimoto,* Hideaki Imamura, Aya Shimizu, Masato Nakano, Shigeru Nakajima,
Shinnosuke Abe, Koji Yamada and Hajime Morishima
Banyu Tsukuba Research Institute, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
Received 25 July 2000; accepted 17 August 2000
Abstract
An optically active 3-aryl-3-hydroxypropionate 3a was prepared by lipase-catalyzed kinetic hydrolysis
of a diastereomeric mixture of 3-aryl-3-(a-chloroacetoxy)propionate 6 in good conversion yield with
adequate purity (>95% de). This enzymatic reaction proceeded with great efficiency as measured by
reaction rate, chemical yield and stereoselectivity. The compound 3a was converted to J-114,870 1a, a
novel ultra-broad spectrum carbapenem, without significant epimerization. © 2000 Elsevier Science Ltd.
All rights reserved.
1. Introduction
In the course of investigating new carbapenems, we synthesized J-114,870 1a which possesses
a unique trans-3,5-disubstituted pyrrolidin-3-ylthio side-chain at the C-2 position of the 1b-
methylcarbapenem1 nucleus, and found that this novel carbapenem had an ultra-broad anti-
microbial spectrum covering clinically important strains such as methicillin-resistant Staphylo-
coccus aureus (MRSA) and Pseudomonas aeruginosa.2 Using (2R,4R)-4-hydroxy-2-phenylpyrro-
lidine derivative 4 as a precursor,3 the side chain of J-114,870 was synthesized using lipase as a
biocatalyst, or by chemical asymmetric synthesis.4
Biocatalysts have often played an important role in the preparation of homochiral compounds
that are not obtained easily by conventional chemical reactions. In particular, lipase5 has been
applied to many transformations such as kinetic resolution of racemic compounds6 and
asymmetric synthesis of chiral 1,3-propanediols7 because of its wide susceptibility of substrates,
stability under various conditions, and commercial availability. Enzymatic resolution of a
diastereomeric mixture of ethyl 3-aryl-3-hydroxy propionate 3 was considered to be a practical
method for preparing homochiral thiol 2a, a side chain of J-114,870 1a (Fig. 1). Herein, we
describe in detail the lipase-mediated resolution of a diastereomeric mixture of 3-aryl-3-hydroxy-
propionate 3 and the following transformation to a side chain of J-114,870.
* Corresponding author. Tel: +81-298-77-2220; fax: +81-298-77-2027; e-mail: sugmtoyt@banyu.co.jp
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00326-8

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Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
Figure 1. Synthesis of J-114,870 1a
2. Results and discussion
2.1. Synthesis and enzymatic resolution of the chloroacetates 6
Commercially available (R)-4-hydroxy-2-pyrrolidone was converted into 2,4-cis-disubstituted
pyrrolidine 4 with high enantiomeric purity (>99.5% de) according to our previous report.3 The
aldehyde 4 was subjected to aldol condensation with ethyl acetate by the action of lithium
hexamethyldisilazide (LHMDS) at −78°C to provide a diastereomeric mixture of 3-aryl-3-
hydroxypropionate 3 (ca. 10% de) (Scheme 1).
Scheme 1. Synthesis of key intermediate 3a and conversion into J-114,870 1a

Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
3611
Enzyme-catalyzed acylation of alcohol 3 using vinyl acetate, isopropenyl acetate or acetic
anhydride as an acetylating agent did not proceed with acceptable yield or selectivity. Enzyme
hydrolysis of acetylated 3 afforded similar unsatisfactory results.
Next, diastereomers 3 were converted into the corresponding chloroacetates 6 by treatment
with chloroacetyl chloride and 4-dimethylaminopyridine (DMAP), and the resulting chloro-
acetates 6 were hydrolyzed by using several enzymes in phosphate buffer (Table 1). When lipase
LIP8 was used (entry 1), the reaction proceeded with the highest selectivity (E value9=747) and
ended within 2 hours. It should be noted that prolonged reaction time did not diminish the
diastereomeric excess of the hydrolyzed product. Sufficient diastereomeric excesses were also
obtained by lipase PS10 (entry 5), lipase MY (entry 10) and lipase Type VII (entry 13) with a
longer reaction time (14 h).
Lipase-catalyzed hydrolysis of chloroacetates 6 was carried out using buffer solutions between
pH 5 and 9 (Table 2). The results showed that the appropriate pH for this lipase-catalyzed
reaction was 7.0–8.5, which provided both diastereomers 3a and 6b with sufficient enantiomeric
purity (>95% de). Reactions conducted below pH 6.5 did not complete and the remaining 6b
showed moderate diastereomeric excess.
2.2. Application to the large scale synthesis
Thus, a diastereomeric mixture of benzyl alcohol 3 was successfully resolved by the lipase-
catalyzed hydrolysis of the corresponding chloroacetates 6 with good diastereoselectivity to
afford the hydrolyzed product 3a with (R)-configuration and intact 6b. Under optimized
conditions, hydrolysis of 1000 g of alcohol 3 took place smoothly to provide 3a (400 g) and 6b
(390 g), both of which showed excellent enantiomeric purity (>99% de). Chloroacetate 6b was
easily hydrolyzed by means of aqueous ammonia in ethanol to yield (S)-alcohol 3b. The
optically active alcohol 3a thus obtained could be converted into Alloc-protected amino
compound 7a by the conventional procedure, as described in Scheme 1, without any appreciable
epimerization of the resolved stereogenic center. Amino ester 7a was transformed into J-114,870
1a according to reported procedures,4 including coupling reaction of the side chain thiol 2a with
allyl-protected 1b-methylcarbapenem diphenylphosphate 5.
2.3. Determination of the stereochemistry of alcohols 3a and 3b
Absolute configuration of the stereogenic center (C7%) of 3a and 3b was determined by the
application of the advanced Mosher’s method11 to the MTPA esters 8a and 8b, which were
obtained from the secondary alcohols 3a and 3b, respectively, by acylation with (+)-MTPA-Cl
in the presence of DMAP and successive removal of the Boc group by TFA (Fig. 2).
Comparison of the 1H NMR spectrum of the MTPA esters 8a and 8b indicated that the resolved
stereogenic center of 3a was (R)- and hence 3b had (S)-configuration (Fig. 2, Table 3).
3. Conclusions
A diastereomeric mixture of the 3-aryl-3-(a-chloroacetoxy)propionate 6 was successfully
converted into the enantiopure 3-aryl-3-hydroxypropionates 3a and 3b in good conversion yield
via the lipase-catalyzed kinetic resolution process. Of all the enzymes tested, lipase LIP was the

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Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
Table 1
Effect of the enzymea
Entry Enzyme
Source
Time
(h)
3a
6b
E
% dej (% yield)
% dem (% yield) valuen
1
2
3
4
5
6
7
8
9
10
11
12
13
Lipase LIPb
Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas cepacia
Mucor ja6anicus
Aspergillus niger
Rhizopus ja6anicus
Rhizopus ni6eus
2
14
14
14
14
14
14
14
14
14
14
14
14
99 (44)
98 (42)
98 (32)
N.D.k
96 (47)
N.R.l
95 (38)
76 (48)
35 (62)
747
228
140
Lipase LIPb,c
Lipase LIPb,d
Lipase LIPb,e
Lipase PSf
96 (36)
194
Lipase M10f
Lipase A6f
N.R.l
Lipase F-AP15f
Newlase Ff
N.R.l
N.R.l
Lipase MYg
Lipaseh
Candida cylindracea
Steapsin
Porcine pancreas
94 (42)
97 (30)
93 (34)
136
340
N.R.l
Lipase Type IIi
Lipase Type VIIi
N.D.k
98 (42)
Candida cylindracea
a Standard conditions: 6 50 mg, enzyme 50 mg, acetone 0.5 ml, phosphate buffer (0.1 M, pH 7.0) 1.0 ml.
b Purchased from TOYOBO.
c
Enzyme 25 mg.
d Enzyme 5 mg.
e
Enzyme 1 mg.
Purchased from AMANO.
f
g Purchased from MEITO.
h Purchased from TOKYO KASEI.
i
Purchased from SIGMA.
Determined by HPLC analysis using the chiral phase column (CHIRALCEL OD-H, DAICEL).
j
k Not determined.
l
No reaction.
mDetermined by HPLC (see footnote j) of the corresponding alcohol 3b.
n E=ln{1−c[1+3a(ee)]}/ln{1−c[1−3a(ee)]}, c=6b(ee)/[6b(ee)+3a(ee)] (Ref. 9).
most efficient catalyst as measured by stereoselectivity, reaction time and feasibility of large-
scale preparation. In addition, enantiopure alcohol 3a could be converted into J-114,870 1a, a
novel ultra-broad spectrum carbapenem, without appreciable epimerization.

Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
3613
Table 2
Effect of pHa
Lipase LIP
a
6 ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢁ 3a+6b
pH
5
5.5
6
6.5
7
7.5
8
8.5
9
% de of 3a
% de of 6b
E value
95.2
5.7
41
97.0
3.8
68
98.8
18.2
237
99.1
71.0
425
98.9
95.4
747
98.8
95.4
747
99.4
98.9
98.3
\99.8b
\869
\99.8b
\99.8b
\2293
\1171
a Conditions: 6 50 mg, lipase LIP 50 mg, acetone 0.5 ml, phosphate buffer (0.1 M) 1.0 ml.
b 3a was not detectable by HPLC analysis.
Figure 2. Conversion of 3a and 3b into MTPA ester 8a and 8b
4. Experimental
4.1. General methods
1
The H NMR spectra were recorded on a Varian VXR-300 (300 MHz) spectrometer and a
JEOL JNM-A500 (500 MHz) spectrometer with tetramethylsilane (TMS) as an internal stan-
dard. 13C NMR spectra were recorded on a JEOL JNM-A500 (500 MHz). IR absorption spectra
were recorded on a Horiba FT-200 spectrometer. Specific rotations were measured on a Jasco
DIP-370 polarimeter. Mass spectra (MS) were measured on a JEOL JMS-SX102A spectrometer.
The silica-gel TLC was performed with Merck Kieselgel F254 precoated plates. The silica gel
used for column chromatography was WAKO gel C-300. All reactions involving air-sensitive
reagents were performed under a nitrogen atmosphere using syringe-septum cap techniques.

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Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
Table 3
1H NMR of MTPA esters 8a and 8b
Proton
2
3
4
5
2%
3%
7%
8%
10%
11%
8a
2.932
3.051
2.923
3.041
−9
2.735
3.014
2.740
4.034
4.061
4.117
4.152
+83
+91
4.112
4.462
7.439
7.352
6.404
1.177
2.412
2.412
90
8b
4.080
4.457
7.370
7.197
6.344
1.227
Dl×10−3 ppm
+5
−32
−5
−69
−155
−60
+50
−10
+10
4.2. Synthesis of the substrates 6
4.2.1. (2R,4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[4-(1-hydroxy-2-(ethoxy-
carbonyl)ethyl)phenyl]pyrrolidine 3
To a solution of LHMDS (1 M in THF, 308 ml, 308 mmol) in THF (300 ml), EtOAc (31.5
ml, 323 mmol) was added dropwise at −78°C. After stirring for 1 h at −78°C, a solution of 4
(50.0 g, 123 mmol) in THF (200 ml) was added dropwise to the mixture over 1 h at −78°C. The
reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and evaporated under reduced pressure. The residue was purified
by silica gel column chromatography (n-hexane/EtOAc=7:1–3:1) to give 3 (55.5 g, 91%) as a
1
yellow oil. IR (KBr) wmax 2931, 1736, 1697, 1398, 1367, 1254, 1159, 1093, 839, 777 cm−1; H
NMR (300 MHz, CDCl3) l 0.03 (6H, s), 0.79 (9H, s), 1.15 (6H, s), 1.27 (3H, t, J=7.4 Hz), 1.44
(3H, s), 1.87 (1H, m), 2.48 (1H, m), 2.70 (2H, m), 3.41 (1H, m), 3.84 (1H, m), 4.18 (2H, q,
J=7.4 Hz), 4.37 (1H, m), 4.72 (0.7H, m), 4.88 (0.3H, m), 5.11 (1H, m), 7.23 (2H, d, J=8.2 Hz),
7.28 (2H, d, J=9.6 Hz); FAB-HRMS calcd for C26H43NO6SiNa (M+Na)+: 516.2757. Found
516.2783.
4.2.2. (2R,4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[4-(1-chloroacetoxy-2-
(ethoxycarbonyl)ethyl)phenyl]pyrrolidine 6
To a solution of 3 (1032 g, 2.09 mol) and DMAP (1268 g, 10.4 mol) in CH2Cl2 (2000 ml),
chloroacetyl chloride (1056 g, 9.35 mol) was added under a nitrogen atmosphere at 0°C. After
the completion of the reaction, 6N hydrochloric acid was added to the reaction mixture to
quench excess DMAP. The organic phase was washed with a saturated solution of NaHCO3 and
brine, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane/EtOAc=5:1) to give 6 (922 g, 77%) as
1
a yellow oil. IR (KBr) wmax 2956, 1743, 1697, 1396, 1365, 1257, 1172, 1093, 837, 777 cm−1; H
NMR (300 MHz, CDCl3) l 0.02 (6H, s), 0.78 (9H, s), 1.14 (6H, s), 1.24 (3H, t, J=7.1 Hz), 1.45
(3H, s), 1.87 (1H, m), 2.47 (1H, m), 2.76 (1H, m), 3.01 (1H, m), 3.42 (1H, m), 3.80 (1H, m), 4.02
(2H, dd, J=17.4, 14.7 Hz), 4.14 (2H, q, J=7.1 Hz), 4.37 (1H, m), 4.72 (0.7H, m), 4.93 (0.3H,

Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
3615
m), 6.23 (1H, dd, J=9.3, 4.7 Hz), 7.26 (4H, m); FAB-HRMS calcd for C28H44ClNO7SiNa
(M+Na)+: 592.2473. Found 592.2477.
4.3. Enzymatic resolution of the substrates 6
4.3.1. (2R,4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[4-((R)-1-hydroxy-2-
(ethoxycarbonyl)ethyl)phenyl]pyrrolidine 3a and (2R,4R)-1-tert-butoxycarbonyl-4-tertbutyl-
dimethylsiloxy-2-[4-((S)-1-chloroacetoxy-2-(ethoxycarbonyl)ethyl)phenyl]pyrrolidine 6b
To a solution of 6 (922 g, 1.62 mol) in acetone (9.2 l) and 0.1 M phosphate buffer (18.4 l, pH
8.0), lipase LIP (TOYOBO, 1.0 kg) was added and the mixture was stirred for 22 h at room
temperature. After lipase was removed by filtration through a pad of Celite®, the filtrate was
diluted with H2O (10 l) and extracted three times with EtOAc (40 l). The organic layer was
washed with brine (10 l), dried over MgSO4, and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (n-hexane/EtOAc=7:1–3:1) to give 6b
(389 g, 42%) as a yellow oil and 3a (407 g, 52%, >99% de by HPLC) as a yellow oil. 6b: [h]D20
−13.2 (c 1.0, CHCl3); IR (KBr) wmax 2956, 1741, 1697, 1396, 1365, 1255, 1162, 1092, 837, 777
1
cm-1; H NMR (300 MHz, CDCl3) l 0.03 (6H, s), 0.79 (9H, s), 1.16 (6H, s), 1.24 (3H, t, J=7.3
Hz), 1.46 (3H, s), 1.87 (1H, m), 2.47 (1H, m), 2.75 (1H, m), 3.01 (1H, m), 3.40 (1H, m), 3.81
(1H, m), 4.02 (2H, dd, J=17.3, 14.6 Hz), 4.14 (2H, q, J=7.3 Hz), 4.37 (1H, m), 4.72 (0.7H, m),
4.93 (0.3H, m), 6.24 (1H, dd, J=9.1, 4.8 Hz), 7.26 (4H, m); FAB-HRMS calcd for
C28H44ClNO7SiNa (M+Na)+: 592.2473. Found 592.2476. 3a: [h]D20 +54.2 (c 1.0, CHCl3); IR
1
(KBr) wmax 2933, 1734, 1697, 1398, 1367, 1254, 1159, 1093, 837, 777 cm−1; H NMR (300 MHz,
CDCl3) l 0.03 (6H, s), 0.79 (9H, s), 1.16 (6H, s), 1.27 (3H, t, J=7.4 Hz), 1.44 (3H, s), 1.86 (1H,
m), 2.50 (1H, m), 2.70 (2H, m), 3.39 (1H, m), 3.84 (1H, m), 4.18 (2H, q, J=7.4 Hz), 4.37 (1H,
m), 4.72 (0.7H, m), 4.89 (0.3H, m), 5.11 (1H, m), 7.23 (2H, d, J=8.7 Hz), 7.28 (2H, d, J=10.0
Hz); FAB-HRMS calcd for C26H43NO6SiNa (M+Na)+: 516.2757. Found 516.2756. The enan-
tiomeric purity of 3a was determined by HPLC analysis: column, Chiralcel OD-H (Daicel,
4.6f×250 mm); eluent, n-hexane:i-PrOH=95:5; flow rate, 1.0 ml/min; detection, UV 250 nm; rt,
9.3 min (3b) and 11.3 min (3a).
4.3.2. (2R,4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[4-((S)-1-hydroxy-2-(ethoxy-
carbonyl)ethyl)phenyl]pyrrolidine 3b
To a solution of 6b (389 g, 683 mmol) in EtOH (2 l), 25% aqueous ammonia (800 ml) was
added and the mixture was stirred for 0.5 h at 15°C. The reaction mixture was poured into H2O
(5 l) and the whole was extracted with EtOAc (6 l). The organic layer was washed successively
with 1N HCl (5 l), a saturated solution of NaHCO3 (5 l) and brine (5 l), and then dried over
MgSO4. After evaporation under reduced pressure, the residue was purified by silica gel column
chromatography (n-hexane/EtOAc=5:1–3:1) to give 3b (310 g, 92%, >99% de by HPLC) as a
yellow oil; [h]2D0 +12.8 (c 1.0, CHCl3); IR (KBr) wmax 2931, 1734, 1697, 1398, 1367, 1254, 1159,
1
1092, 837, 777 cm−1; H NMR (300 MHz, CDCl3) l 0.03 (6H, s), 0.79 (9H, s), 1.16 (6H, s), 1.25
(3H, t, J=7.4 Hz), 1.44 (3H, s), 1.87 (1H, m), 2.50 (1H, m), 2.70 (2H, m), 3.41 (1H, m), 3.84
(1H, m), 4.18 (2H, q, J=7.4 Hz), 4.37 (1H, m), 4.72 (0.7H, m), 4.88 (0.3H, m), 5.11 (1H, m),
7.23 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.9 Hz); FAB-HRMS calcd for C26H43NO6SiNa
(M+Na)+: 516.2757. Found 516.2739.

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Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
4.4. Synthesis of the MTPA esters 8a and 8b for determination of absolute configuration
4.4.1. (2R,4R)-4-tert-Butyldimethylsiloxy-2-[4-((R)-1-[(R)-(h-methoxy-h-(trifluoromethyl)-
phenylacetoxy]-2-(ethoxycarbonyl)ethyl)phenyl]pyrrolidine 8a
To a solution of 3a (327 mg, 0.662 mmol) in CH2Cl2 (10 ml), DMAP (324 mg, 2.65 mmol)
and (S)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride ((S)-(+)-MTPA-Cl, 247 ml,
1.32 mmol) were added at room temperature. After being stirred for 1 h at the same
temperature, H2O was added to the reaction mixture. The organic phase was separated and
the aqueous phase was extracted with CHCl3. The combined organic layer was washed with
brine, dried over MgSO4, and evaporated under reduced pressure. The residue was purified
by silica gel column chromatography (n-hexane/EtOAc=5:1) to give a colorless oil (405 mg,
86%).
To a solution of the material obtained above (100 mg, 0.141 mmol) in CH2Cl2 (2 ml), TFA
(100 ml) was added at 0°C and the mixture was stirred for 1 h at same temperature and then
for 1.5 h at room temperature. The mixture was poured into H2O and the whole mixture was
extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3
and brine, dried over MgSO4, and evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (CHCl3/MeOH=10:1) to give 8a (39 mg, 45%)
as a yellow oil. [h]2D0 +52.8 (c 1.0, CHCl3); IR (KBr) wmax 2954, 1749, 1257, 1173, 1122, 1020,
1
837, 777, 721 cm−1; H NMR (300 MHz, CDCl3) l 0.08 (6H, s), 0.90 (9H, s), 1.17 (3H, t,
J=7.1 Hz), 1.73 (1H, m), 2.42 (1H, m), 2.73 (1H, dd, J=16.2, 4.5 Hz), 2.93 (1H, dd,
J=11.7, 4.4 Hz), 3.02 (2H, m), 3.41 (3H, s), 4.07 (3H, m), 4.45 (1H, m), 6.40 (1H, dd,
J=9.7, 4.4 Hz), 7.35 (5H, m); 13C NMR (125 MHz, CDCl3) l 13.9, 18.0, 25.8, 40.7, 44.1,
55.3, 56.9, 60.8, 61.9, 73.6, 74.3, 84.2, 122.0, 124.3, 127.1, 127.38, 127.42, 128.1, 129.4, 132.1,
136.4, 145.1, 165.4, 169.1; FAB-HRMS calcd for C31H43F3NO6Si (M+H)+: 610.2812. Found
610.2803.
4.4.2. (2R,4R)-4-tert-Butyldimethylsiloxy-2-[4-((S)-1-[(R)-(h-methoxy-h-(trifluoromethyl)-
phenylacetoxy]-2-ethoxycarbonyl)ethyl)phenyl]pyrrolidine 8b
By using the same procedure for preparing 8a described above, 3b (391 mg, 0.792 mmol)
was condensed with (S)-(+)-MTPA-Cl to give a colorless oil (505 mg, 90%). The obtained
material (100 mg, 0.141 mmol) was then treated with TFA to afford 8b (44 mg, 51%) as a
yellow oil. [h]2D0 +22.8 (c 1.0, CHCl3); IR (KBr) wmax 2956, 1749, 1257, 1171, 1122, 1022, 837,
1
777, 721 cm−1; H NMR (300 MHz, CDCl3) l 0.08 (6H, s), 0.90 (9H, s), 1.23 (3H, t, J=7.1
Hz), 1.73 (1H, m), 2.41 (1H, m), 2.74 (1H, dd, J=16.5, 4.0 Hz), 2.92 (1H, dd, J=11.7, 4.6
Hz), 3.03 (2H, m), 3.51 (3H, s), 4.12 (3H, m), 4.46 (1H, m), 6.35 (1H, dd, J=10.0, 3.9 Hz),
7.29 (5H, m); 13C NMR (125 MHz, CDCl3) l 14.0, 18.0, 25.8, 41.0, 44.1, 55.5, 56.9, 60.9,
62.0, 73.7, 74.5, 84.4, 122.0, 124.3, 126.7, 127.23, 127.24, 128.1, 129.4, 132.0, 136.4, 144.9,
165.2, 169.5; FAB-HRMS calcd for C31H43F3NO6Si (M+H)+: 610.2812. Found 610.2806.
Acknowledgements
We are grateful to Ms. A. Dobbins, Merck & Co. Inc., for her critical reading of this
manuscript.

Y. Sugimoto et al. / Tetrahedron: Asymmetry 11 (2000) 3609–3617
3617
References
1. Ito, Y.; Terashima, S. J. Syn. Org. Chem. Jpn. 1989, 47, 606–618.
2. (a) Imamura, H.; Ohtake, N.; Shimizu, A.; Jona, H.; Sato, H.; Nagano, R.; Ushijima, R.; Yamada, K.;
Hashizume, T.; Morishima, H. Bioorg. Med. Chem. Lett. 2000, 10, 109–113. (b) Imamura, H.; Ohtake, N.;
Shimizu, A.; Sato, H.; Sugimoto, Y.; Sakuraba, S.; Kiyonaga, H.; Suzuki-Sato, C.; Nagano, M.; Nagano, R.;
Yamada, K.; Hashizume, T.; Morishima, H. Bioorg. Med. Chem. Lett. 2000, 10, 115–118.
3. Imamura, H.; Shimizu, A.; Sato, H.; Sugimoto, Y.; Sakuraba, S.; Nakano, R.; Yamada, K.; Hashizume, T.;
Morishima, H. J. Antibiot. 2000, 53, 314–316.
4. Imamura, H. et al. Tetrahedron 2000, 56, 7705–7713.
5. (a) Iwai, M. Lipases: Their Foundation and Application; Saiwai Shobou: Tokyo, 1991. (b) Schmid, R. D.; Verger,
R. Angew. Chem., Int. Ed. 1998, 37, 1609–1633. (c) Chen, C.-S.; Liu, Y.-C. J. Jpn. Oil Chem. Soc. 1992, 41,
724–733. (d) Robert, S. M., Ed.; Preparative Biotransformations: Whole Cell and Isolated Enzymes in Organic
Synthesis; John Wiley & Sons Ltd: Chichester, England, 1992.
6. (a) Otera, J. Chem. Rev. 1993, 93, 1449–1470. (b) Ogasawara, K. J. Syn. Org. Chem. Jpn. 1996, 54, 15–26.
7. (a) Yokomatsu, T.; Minowa, T.; Murano, T.; Shibuya, S. Tetrahedron 1998, 54, 9341–9356. (b) Guanti, G.;
Narisano, E.; Riva, R. Tetrahedron: Asymmetry 1998, 9, 1859–1862. (c) Itoh, T.; Takagi, Y.; Tsukube, H. J. Mol.
Catal. B: Enzym. 1997, 3, 259–270. (d) Achiwa, K. Yakugaku Zasshi 1995, 115, 681–699. (e) Banfi, L.; Guanti,
G.; Mugnoli, A.; Riva, R. Tetrahedron: Asymmetry 1998, 9, 2481–2492.
8. (a) Mizuguchi, E.; Suzuki, T.; Achiwa, K. Synlett 1996, 743–744. (b) Kita, Y.; Naka, T.; Imanishi, M.; Akai, S.;
Takebe, Y.; Matsugi, M. Chem. Commun. 1998, 1183–1184. (c) Sugahara, T.; Ogasawara, K. Synlett 1996,
319–320. (d) Sakai, T.; Miki, Y.; Nakatani, M.; Ema, T.; Uneyama, K.; Utaka, M. Tetrahedron Lett. 1998, 39,
5233–5236. (e) Yoshida, N.; Kamikubo, T.; Ogasawara, K. Tetrahedron: Asymmetry 1998, 9, 3325–3329.
9. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299.
10. (a) Amano Pharmaceutical Co., Ltd; Amano Enzyme USA Co., Ltd; Amano Enzyme Europe Ltd Lipases for
Resolution and Asymmetric Synthesis; 1995. (b) Nakamura, K.; Hirose, Y. J. Syn. Org. Chem. Jpn. 1995, 53,
668–677. (c) Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 205–208. (d) Bianchi, D.; Battistel, E.;
Bosetti, A.; Cesti, P.; Fekete, Z. Tetrahedron: Asymmetry 1993, 4, 777–782.
11. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
.