Substituent effect on the enantioselectivity in lipase-catalyzed transesterification of trans-2,5-disubstituted pyrrolidines

Article abstract of DOI:10.1016/S0040-4020(01)00214-9

Kinetic resolutions of N-substituted benzyl-trans-2-acetoxymethyl-5-(hydroxymethyl)pyrrolidines using lipase-catalyzed transesterification have been systematically studied. The enantioselectivity depends significantly on the position of substituent at the aromatic ring and N-3,5-dimethylbenzyl group was found to transform trans-2,5-disubstituted pyrrolidine derivative into an efficiently-resolved substrate. Furthermore, the enantioselectivity could be improved up to E=108 using the immobilized lipase in alkyl silica gel.

Full text of DOI:10.1016/S0040-4020(01)00214-9

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 3349±3353
Substituent effect on the enantioselectivity in lipase-catalyzed
transesteri®cation of trans-2,5-disubstituted pyrrolidines
Yasuhiro Kawanami,a,p Noriko Iizuna,a,b Keiko Maekawa,a,b Kyoko Maekawa,a,b
Noriko Takahashia,b and Takeshi Kawadaa,b
aDepartment of Biochemistry and Food Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kagawa 761-0795, Japan
bDepartment of Chemistry, Faculty of Education, Kagawa University, Takamatsu, Kagawa 760-8522, Japan
Received 10 January 2001; accepted 13 February 2001
AbstractÐKinetic resolutions of N-substituted benzyl-trans-2-acetoxymethyl-5-*hydroxymethyl)pyrrolidines using lipase-catalyzed trans-
esteri®cation have been systematically studied. The enantioselectivity depends signi®cantly on the position of substituent at the aromatic ring
and N-3,5-dimethylbenzyl groupwas found to transform trans-2,5-disubstituted pyrrolidine derivative into an ef®ciently-resolved substrate.
Furthermore, the enantioselectivity could be improved up to Eˆ108 using the immobilized lipase in alkyl silica gel. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
the synthesis of pyrrolidine alkaloids possessing biological
activity.5 The several stereoselective syntheses via chiral
starting materials6 and double asymmetric dihydroxylation
of symmetric terminal dienes7 have been reported so far.
We previously reported that the lipase-catalyzed trans-
esteri®cations of N-substituted benzyl-trans-2-acetoxy-
methyl-5-*hydroxymethyl)-pyrrolidines possessing an
electron-withdrawing or electron-donating substituent and
tert-butyl groupin the para-position of the aromatic ring
showed moderate enantioselectivities and 3,5-dimethyl
benzyl derivative 1f afforded highest enantioselecitivity
for lipase PS *Eˆ52).8 These results suggested that the
substituent effect on the enantioselectivity is crucial in
orientation rather than polarity and bulkiness. In order to
con®rm these ®ndings, we have further investigated the
Recently, lipases have been widely used in organic
syntheses, in particular, kinetic resolutions of racemic
alcohols because of broad substrate speci®cities and
high enantioselectivities.1 Although lipases show high
enantioselectivity toward secondary alcohols, the enantio-
selectivity of primary alcohols is generally lower than that
of secondary alcohols and is the reversal of enantio-
preference when the stereocenter lacks an oxygen atom as
shown in Fig. 1. Because it is basically due to the ¯exibility
of the stereogenic center that is remote from the catalytic
site.2
In accompanying the preparation of optically pure chiral
C2-symmetric trans-2,5-disubstituted pyrrolidines,3 we
encountered the challenging question how the enantio-
selectivity in kinetic resolution of primary alcohols can be
increased. Chiral trans-2,5-disubstituted pyrrolidines have
been demonstrated as ef®cient chiral auxiliaries for a variety
of asymmetric syntheses4 beside chiral building blocks for
OH
N
OH
N
R1
R4
R1
R2
R3
R2
R3
vinyl acetate
lipase
OAc
OAc
R4
R1
OH
(-)-1
OAc
H
HO
M
H
( )-1
L
M
L
a R1=R2=R3=R4=H
R2
R3
b
c
d
e
f
R1=Me, R2=R3=R4=H
N
+
R2=Me, R1=R3=R4=H
R3=Me, R1=R2=R4=H
R3=R4=Me, R1=R2=H
R2=R4=Me, R1=R3=H
OAc
Figure 1. Empirical rules for the lipase-catalyzed kinetic resolution of
secondary and primary alcohols.
R4
(+)-2
Keywords: lipase; transesteri®cation; enantioselectivity; pyrrolidine.
Corresponding author. Tel.: 181-87-832-1601; fax: 181-87-832-1417;
e-mail: kawanami@ag.kagawa-u.ac.jp
p
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00214-9

3350
Y. Kawanami et al. / Tetrahedron 5702001) 3349±3353
Table 1. Substituent effect on the enantioselectivity in lipase-catalyzed
transesteri®cations of trans-2,5-disubstituted pyrrolidines
kinetic resolutions of a series of N-substituted benzyl-
pyrrolidines bearing the same size of methyl group but in
different positions. In this paper, we describe the study on
the substituent effect on the enantioselectivity of lipase-
catalyzed transesteri®cations of various N-substituted
benzyl-trans-2-acetoxymethyl-5-*hydroxymethyl)pyrrolidines
*Scheme 1).
Entry Substrate, R Lipase Time *h)
%eea
cb
Ec
*S,S)-1 *R,R)-2
1
2
3
4
5
6
7
8
1a H
PS
PS
PS
PS
3
3
3
3
3
3
1
1
1
1
1
1
45
58
81
87
99
56
50
36
45
82
96
71
84
78
76
70
67
94
61
82
80
48
71
85
0.35 18
0.42 14
0.52 18
0.55 16
0.60 25
0.38 52
1b 2-Me
1c 3-Me
1d 4-Me
1e 3,4-diMe PS
1f 3,5-diMe PS
2. Results and discussion
1a H
AK
AK
AK
AK
0.45
7
1b 2-Me
1c 3-Me
1d 4-Me
1e 3,4-diMe AK
1f 3,5-diMe AK
0.30 15
0.36 14
9
The substrates were prepared as shown in Scheme 2: trans-
2,5-diethoxycarbonyl pyrrolidine3 was acylated with
various substituted benzoyl chloride, followed by reduction
with LiAlH4 to give the corresponding diols. The subse-
quent acetylation with acetic anhydride in ether at 08C
afforded the corresponding monoacetate in 50±75% yield.
10
11
12
0.63
7
0.57 22
0.45 26
Reaction conditions: a mixture of substrate *0.2 mmol), vinyl acetate
*0.8 mmol), and lipase *60 mg) in hexane *2 ml) was stirred at 308C.
a
Determined by HPLC using a Dicel CHIRALCEL OJ.
Conversion calculated from cˆeeꢀS; S†=‰eeꢀS; S†1eeꢀR; R†Š:9
b
The enantioselective acylations of a series of the mono-
acetates 1a±f with lipase PS *Amano) from Pseudomonas
cepacia *PCL) and lipase AK *Amano) from P. ¯uorescens
*PFL) and vinyl acetate as an acylating agent were carried
out in hexane at 308C. In order to compare the reaction rate
conveniently, the reactions were carried out for the same
reaction time *3 h for PS and 1 h for AK). The enantiomeric
excess *ee) values of the monoacetates 1a±f and the di-
acetates 2a±f were determined by HPLC using a chiral
column. The absolute con®gurations of all the diacetates
were determined to be *2R,5R) by comparison with the
authentic diacetates by the similar procedure as described
in Ref. 3. These results are summarized in Table 1.
c
Calculated from Eˆln‰ꢀ12c†ꢀ12eeꢀS; S††Š=ln‰ꢀ12c†ꢀ11eeꢀS; S††Š:9
modi®ed trans-2,5-disubstituted pyrrolidine derivative into
an ef®ciently-resolved substrate.
Recently, in order to increase the activity and stability of
lipase, immobilizations of lipases have been studied and,
among them, the lipases immobilized in alkyl silica gel
have been shown to exhibit not only increased activity
and stability but also increased enantioselectivity.10 Next,
the supported lipases by lyophilizing a mixture of lipase and
celite in pH 7 phosphate buffer11 and the immobilized
lipases *PCL and PFL, Fluka) in alkyl silica gel were
examined in this kinetic resolution of 1f. These results
were summarized in Table 2.
The lipase PS-catalyzed acylations of the substrates *1b±d)
possessing a methyl substituent at the ortho-, meta-, and
para-position of the aromatic ring showed similar moderate
enantioselectivities as that of 1a *entries 2, 3, and 4 vs 1),
although the reaction rates were increased. On the other
hand, the lipase AK-catalyzed acylations of the substrates
*1b and c) bearing a methyl groupat its ortho- or meta-
position proceeded with a slightly higher enantioselectivity
than that of 1a *entries 8 and 9 vs 7). Furthermore, signi®-
cantly higher enantioselectivities were observed in the
acylations of the substrate 1e bearing 3,4-dimethyl groups
and, particularly, the substrate 1f with 3,5-dimethyl group
*entries 5, 6, 11 and 12). It is noted that symmetric 3,5-
dimethylbenzyl groupas the N-protecting one effectively
The supported lipase PS and AK provided slight increases of
reaction rates but similar enantioselectivities. Using the
immobilized lipases in alkyl silica gel resulted in increase
of the enantioselectivities. In particular, the immobilized
PFL afforded excellent high E-value *Eˆ108). Again
the substituent effect on the enantioselectivity was
examined in the transesteri®cations of 1a±f employing the
immobilized PFL. As predicted, the similar tendency as
Table 2. Lipase-catalyzed transesteri®cations of 1f
Lipase
Time *h)
%eea
cb
Ec
CO2Et
NH
EtO2C
O
R1
b
R2
R3
a
*S,S)-1
*R,R)-2
N
PS
AK
3
1
3
1
3
2
56
71
64
81
34
60
94
85
91
83
96
97
0.38
0.45
0.41
0.49
0.26
0.38
52
26
42
27
63
108
CO2Et
CO2Et
R4
PSd
3
4
AKd
PCLe
PFLe
OH
R1
R4
R2
R3
c
N
1a-f
Reaction conditions: a mixture of substrate *0.2 mmol), vinyl acetate
*0.8 mmol), and lipase *60 mg) in hexane *2 ml) was stirred at 308C.
OH
a
Determined by HPLC using a Dicel CHIRALCEL OJ.
Conversion calculated from cˆeeꢀS; S†=‰eeꢀS; S†1eeꢀR; R†Š:9
b
5
c
Calculated from Eˆln‰ꢀ12c†ꢀ12eeꢀS; S††Š=ln‰ꢀ12c†ꢀ11eeꢀS; S††Š:9
d
Scheme 2. *a) RnArCOCl, DMAP, Et3N, CH2Cl2, rt *83±90%); *b) LiAlH4,
THF, re¯ux; *c) Ac2O, ether, 08C *59±76%).
Lyophilized in celite and pH 7 phosphate buffer.
Immobilized in sol±gel-AK *Fluka).
e

Y. Kawanami et al. / Tetrahedron 5702001) 3349±3353
3351
repulsion with dimethyl substituent of *S,S)-enantiomer
and lead to high enantioselectivity.
3. Conclusions
In summary, we have demonstrated that the ef®cient modi-
®cation of substrate structure with 3,5-dimethylbenzyl
groupas the N-protecting one and using the immobilized
lipase PFL in alkylated silica gel enhanced the enantio-
selectivity of the lipase-catalyzed kinetic resolution of
trans-2,5-disubstituted pyrrolidines. These ®ndings should
provide an attractive strategy for lipase-catalyzed kinetic
resolution of primary alcohols.
Figure 2. Effect of substituent on the enantioselectivity.
4. Experimental
4.1. General
IR spectra were determined on a Shimadzu IR-435 spectro-
1
photometer. H NMR and 13C NMR spectra were recorded
at 90 and 23 MHz with a JOEL JNM-EX90 spectrometer.
All NMR spectra were taken in CDCl3 solution with TMS as
the internal standard. Mass spectra were recorded on a JEOL
JMS-SX102A mass spectrometer. Optical rotations were
determined on a Yanagimoto OR-50 polarimeter. The
HPLC analysis was carried out using a Daicel CHIRALCEL
OJ column *0.46£25 cm) with a Shimadzu LC-6A. Tetra-
hydrofuran *THF) was distilled from sodium benzophenone
ketyl. TLC was carried out on Merck glass plates precoated
with silica gel 60F-254 *0.25 mm) and column chromato-
graphy was performed by using Merck 23±400 mesh silica
gel.
Lipase PS and AK were presented by courtesy of Amano
Pharmaceutical Co. PCL and PFL immobilized in sol±gel-
AK were obtained from Fluka Chemie AG.
4.1.1. N-4-Methylbenzoyl-trans-2,5-bis*ethoxycarbonyl)-
pyrrolidine *4d). 4-Methylbenzoyl chloride *0.33 ml,
2.52 mmol) was added to a solution of trans-2,5-bis*ethoxy-
carbonyl)pyrrolidine *3) *360 mg, 1.68 mmol) and triethyl-
amine *0.35 ml, 2.52 mmol) in CH2Cl2 *2 ml) at 08C, and
the mixture was stirred for 12 h at room temperature. The
reaction mixture was diluted with dichloromethane, washed
with saturated aqueous NaHCO3 and brine successively, and
dried over MgSO4. The residue was puri®ed by ¯ash column
chromatography *hexane/ethyl acetate 3:2) to give a white
solid 3 *498 mg, 89%); mp88±89 8C; UV *EtOH) 220 nm *e
74500); IR *KBr) 2990, 1740, 1640, 1395, 1185, 1025, 830,
Figure 3. Models of the *a) fast-reacting enantiomer; *b) slow-reacting
enantiomer, and energy minimized conformations of *R,R)- and *S,S)-
enantiomers.
lipase AK *PFL) was observed as shown in Fig. 2 and the
substrate 1f was found to be an excellent substrate.
Although the active site model of PCL by substrate
mapping12 and molecular modeling of transition state
analog bound to PCL13 or RDL *lipase from Rhizomucor
miehei)14 based on X-ray structure have been reported, the
simple box model proposed by Naemura et al.15 and other16
seems to be suf®cient to explain our results. Generally, it is
considered that two enantiomers have each conformation to
occupy the large moiety in large hydrophobic pocket as
shown in Fig. 3. This model and the minimized conforma-
tions by MM2 suggest that there might be severe interaction
between the 3,5-dimethyl groupat the aromatic ring of the
slow-reacting *S,S)-enantiomer and `wall' of active site and,
therefore, the reaction rate of *S,S)-enantiomer should be
decreased. Furthermore, it is considered that the immobili-
zation of PFL on the alkyl silica gel might cause larger
1
785, 755 cm21; H NMR d 1.08 *3H, t, Jˆ7.3 Hz), 1.28
*3H, t, Jˆ7.3 Hz), 1.70±2.50 *4H, m), 2.33 *3H, s), 3.97
*2H, q, Jˆ7.5 Hz), 4.29 *2H, q, Jˆ7.3 Hz), 4.49 *1H, d,
Jˆ6.8 Hz), 4.80 *1H, d, Jˆ6.2 Hz), 7.00±7.40 *4H, m);
13C NMR d 13.7, 13.9, 21.1, 27.3, 29.8, 59.5, 60.9, 61.2,
61.4, 126.4, 128.7, 133.2, 139.7, 170.4, 171.6, 171.8. Anal.
calcd for C18H23NO5: C, 64.85; H, 6.95; N, 4.20%. Found:
C, 64.70; H, 7.20; N, 4.04%.
4.1.2. N-2-Methylbenzoyl-trans-2,5-bis*ethoxycarbonyl)-
pyrrolidine *4b). Yield 90%; UV *EtOH) 232 nm *e
27800); IR *neat) 2970, 1735, 1645, 1385, 1185, 1020,

3352
Y. Kawanami et al. / Tetrahedron 5702001) 3349±3353
1
770, 745 cm21; H NMR d 1.09 *3H, t, Jˆ7.1 Hz), 1.33
*3H, t, Jˆ7.3 Hz), 1.71±2.66 *4H, m), 2.39 *3H, s), 3.98
*2H, q, Jˆ7.2 Hz), 4.26 *2H, q, Jˆ7.1 Hz), 4.85 *1H, d,
Jˆ6.8 Hz), 6.92±7.48 *4H, m); 13C NMR d 14.0, 14.2,
18.8, 27.8, 29.8, 59.1, 61.1, 61.3, 125.5, 126.1, 129.2,
130.5, 134.9, 135.9, 170.3, 171.9. Anal. calcd for
C18H23NO5: C, 64.85; H, 6.95; N, 4.20%. Found: C,
65.09; H, 6.90; N, 4.18%.
1610, 1445, 1360, 1230, 1030, 805 cm21 1H NMR d
;
1.58±2.53 *4H, m), 2.04 *3H, s), 2.32 *3H, s), 3.10 *1H,
m), 3.22±3.70 *3H, m), 3.79 *2H, d, Jˆ1.8 Hz), 4.10 *2H,
d, Jˆ5.1 Hz), 7.05±7.40 *4H, m); 13C NMR d 21.1, 27.0,
27.5, 51.3, 58.8, 62.1, 62.4, 63.7, 128.1, 129.2, 136.3, 136.7,
171.0; EI HRMS C15H20NO2 *M12CH2OH) 246.1495.
Found 246.1498.
4.1.7. N-2-Methylbenzyl-trans-2-acetoxymethyl-5-*hydroxy-
methyl)pyrrolidine *1b). Yield 72%; IR *neat) 3430, 2940,
1735, 1605, 1455, 1375, 1365, 1230, 1030, 745, 630,
4.1.3. N-3-Methylbenzoyl-trans-2,5-bis*ethoxycarbonyl)-
pyrrolidine *4c). Yield 88%; UV *EtOH) 227 nm *e
41000); IR *neat) 2970, 1735, 1640, 1380, 1180, 1020,
1
600 cm21; H NMR d 1.55±2.55 *4H, m), 2.00 *3H, s),
1
780, 745 cm21; H NMR d 1.12 *3H, t, Jˆ7.3 Hz), 1.33
2.34 *3H, s), 3.10 *1H, m), 3.25±3.74 *3H, m), 3.87 *2H,
d, Jˆ2.7 Hz), 4.09 *2H, d, Jˆ5.1 Hz), 6.98±7.57 *4H, m);
13C NMR d 19.2, 20.9, 26.9, 27.5, 50.0, 59.5, 62.5, 62.9,
63.9, 125.9, 127.0, 128.4, 130.4, 136.3, 137.1, 170.9, EI
HRMS C15H20NO2 *M12CH2OH) 246.1495. Found
246.1497.
*3H, t, Jˆ7.3 Hz), 1.78±2.63 *4H, m), 2.35 *3H, s), 4.00
*2H, q, Jˆ7.2 Hz), 4.26 *2H, q, Jˆ7.0 Hz), 4.50 *1H, d,
Jˆ7.2 Hz), 4.85 *1H, d, Jˆ5.4 Hz), 6.91±7.45 *4H, m);
13C NMR d 14.0, 14.1, 21.2, 27.6, 30.0, 59.6, 61.2, 61.3,
61.6, 123.5, 127.1, 128.2, 130.5, 136.3, 138.1, 170.6, 171.8,
172.0. Anal. calcd for C18H23NO5: C, 64.85; H, 6.95; N,
4.20%. Found: C, 64.77; H, 7.37; N, 4.24%.
4.1.8. N-3-Methylbenzyl-trans-2-acetoxymethyl-5-*hydroxy-
methyl)pyrrolidine *1c). Yield 59%; IR *neat) 3430, 2940,
1735, 1605, 1450, 1365, 1380, 1230, 1030, 885, 780, 695,
600 cm21; 1H NMR d 1.45±2.53 *4H, m), 2.00 *3H, s), 2.32
*3H, s), 3.09 *1H, m), 3.24±3.72 *3H, m), 3.81 *2H, d,
Jˆ2.6 Hz), 4.11 *2H, d, Jˆ4.8 Hz), 6.82±7.44 *4H, m);
13C NMR d 21.0, 21.4, 26.9, 27.4, 51.5, 58.8, 62.0, 62.4,
63.7, 125.1, 127.8, 128.3, 128.8, 138.0, 139.2, 170.9; EI
HRMS C15H20NO2 *M12CH2OH) 246.1495. Found
246.1499.
4.1.4. N-3,4-Dimethylbenzoyl-trans-2,5-bis*ethoxycar-
bonyl)pyrrolidine *4e). Yield 83%; mp51±52 8C; UV
*EtOH) 210 nm *e 41900); IR *KBr) 2970, 1740, 1650,
1
1410, 1170, 1030, 920, 730 cm21; H NMR d 1.05 *3H, t,
Jˆ7.0 Hz), 1.25 *3H, t, Jˆ7.0 Hz), 1.77±2.45 *4H, m), 2.14
*6H, s), 3.98 *2H, q, Jˆ6.8 Hz), 4.18 *2H, q, Jˆ7.1 Hz),
4.45 *1H, d, Jˆ6.8 Hz), 4.76 *1H, d, Jˆ6.2 Hz), 6.83±
7.34 *4H, m); 13C NMR d 13.9, 14.1, 19.5, 19.6, 27.5,
30.0, 59.6, 61.1, 61.2, 61.7, 123.9, 127.7, 129.4, 133.7,
136.6, 138.5, 170.6, 172.1. Anal. calcd for C19H25NO5: C,
65.69; H, 7.25; N, 4.03%. Found: C, 65.71; H, 7.37; N,
3.89%.
4.1.9. N-3,4-Dimethylbenzyl-trans-2-acetoxymethyl-5-
*hydroxymethyl)pyrrolidine *1e). Yield 74%; IR *neat)
3450, 2940, 1730, 1610, 1450, 1380, 1240, 1030,
1
820 cm21; H NMR d 1.74±2.49 *4H, m), 2.04 *3H, s),
4.1.5. N-3,5-Dimethylbenzoyl-trans-2,5-bis*ethoxycar-
bonyl)pyrrolidine *4f). Yield 77%; mp53±54 8C; UV
*EtOH) 228 nm *e 72600); IR *KBr) 2970, 1730, 1650,
2.23 *6H, s), 3.10 *1H, m), 3.21±3.70 *3H, m), 3.75 *2H,
brs), 4.11 *2H, d, Jˆ5.1 Hz), 6.92±7.32 *3H, m); 13C NMR
d 19.4, 19.8, 21.1, 27.0, 27.5, 51.3, 58.8, 62.0, 62.4, 63.7,
125.6, 129.5, 129.7, 135.3, 136.6, 171.0; EI HRMS
C16H22NO2 *M12CH2OH) 260.1652. Found 246.1661.
1
1390, 1180, 1020, 860, 760 cm21; H NMR d 1.13 *3H, t,
Jˆ7.3 Hz), 1.32 *3H, t, Jˆ7.3 Hz), 1.70±2.50 *4H, m), 2.29
*6H, s), 4.02 *2H, q, Jˆ7.6 Hz), 4.25 *2H, q, Jˆ7.0 Hz),
4.47 *1H, d, Jˆ7.0 Hz), 4.81 *1H, d, Jˆ6.2 Hz), 6.94±
7.28 *4H, m); 13C NMR d 14.0, 14.1, 21.1, 27.6, 30.0,
59.5, 61.2, 61.3, 61.6, 124.1, 131.4, 136.2, 138.0, 170.8,
171.9, 172.1. Anal. calcd for C19H25NO5: C, 65.69; H,
7.25; N, 4.03%. Found: C, 65.50; H, 7.37; N, 3.89%.
4.1.10. N-3,5-Dimethylbenzyl-trans-2-acetoxymethyl-5-
*hydroxymethyl)pyrrolidine *1f). Yield 77%; IR *neat)
3430, 2940, 1730, 1610, 1455, 1360, 1240, 1030,
1
842 cm21; H NMR d 1.56±2.42 *4H, m), 2.04 *3H, s),
2.30 *6H, s), 3.10 *1H, m), 3.23±3.74 *3H, m), 3.77 *2H,
d, Jˆ2.9 Hz), 4.11 *2H, d, Jˆ4.8 Hz), 6.84±7.26 *3H, m);
13C NMR d 21.1, 21.3, 26.9, 27.5, 51.5, 58.8, 62.0, 62.5,
63.8, 125.9, 128.7, 138.0, 139.2, 171.0; EI HRMS
C16H22NO2 *M12CH2OH) 260.1652. Found 246.1666.
4.1.6. N-4-Methylbenzyl-trans-2-acetoxymethyl-5-*hydroxy-
methyl)pyrrolidine *1d). The ester 4d *498 mg,
1.48 mmol) in THF *3 ml) was added to LiAlH4 *197 mg,
4.92 mmol) in THF *13 ml) at 08C and the mixture was
stirred for 1 h at room temperature. Water *0.5 ml) and
aqueous 10% NaOH *0.4 ml) were added to the reaction
mixture and stirring was continued over night. The mixture
was ®ltered through celite and washed with dichloro-
methane. The ®ltrate was evaporated under reduced pres-
sure to give the colorless viscous oil 5d. Acetic anhydride
*0.20 ml, 2.2 mmol) was added to the diol 5d in Et2O *8 ml)
at 08C and the mixture was stirred for 5 h. The reaction
mixture was diluted with dichloromethane, washed with
saturated aqueous NaHCO3 and brine successively, and
dried over MgSO4. The residue was puri®ed by ¯ash column
chromatography *hexane/ethyl acetate 1:2) to give a color-
less oil 1d *292 mg, 71%); IR *neat) 3420, 2910, 1720,
4.1.11. Typical procedure for lipase-catalyzed acetyl-
ation of monoacetate *1f). Vinyl acetate *74 ml,
0.8 mmol) was added to a suspension of the monoacetate
1f *58.3 mg, 0.2 mmol) and lipase *60 mg) in water-
saturated hexane *2 ml) and the mixture was stirred at
308C. The reaction was monitored by TLC. The reaction
mixture was ®ltered off on celite and washed with dichloro-
methane. The extract was dried over MgSO4 and evaporated
under reduced pressure. Puri®cation of the residue by ¯ash
column chromatography *hexane/ethyl acetate 1:1) afforded
the diacetate 2f *HPLC, CHIRALCEL OJ, hexane/i-PrOH
10:1, 0.5 ml min21, typical retention times; 20 and 27 min
for the *S,S)- and *R,R)-enantiomer, respectively) and the

Y. Kawanami et al. / Tetrahedron 5702001) 3349±3353
3353
5. For example, Impellizzeri, G.; Mangia®co, S.; Oriente, G.;
Piateli, M.; Sciuto, S. Phytochemistry 1975, 14, 1549.
6. Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7,
927 *and references cited therein).
monoacetate 1f *HPLC, CHIRALCEL OJ, hexane/i-PrOH
10:1, 0.5 ml min21, typical retention times; 17 and 23 min
for the *S,S)- and *R,R)-enantiomer, respectively).
7. Takahata, H.; Takahashi, S.; Kouno, S.; Momose, T. J. Org.
Chem. 1998, 63, 2224.
Acknowledgements
8. Kawanami, Y.; Iizuna, N.; Okano, K. Chem. Lett. 1998, 1231.
9. *a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 102, 7294. *b) Guo, Z.-W.; Wu, S.-H.; Chen,
C.-S.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1990, 112,
4942. *c) Caron, G.; Kazlauskas, R. J. Org. Chem. 1991, 56,
7251.
We are grateful to Professor T. Katsuki for helpful dis-
cussion and to Amano Pharmaceutical Co. for providing
lipase Amano PS and AK.
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