Kinetic resolution of racemic 2-substituted 3-cyclopenten-1-ols by lipase-catalyzed transesterifications: A rational strategy to improve enantioselectivity

Article abstract of DOI:10.1021/jo961144s

The effect of the acyl group of acylating agents on the enantioselectivity in the Pseudomonas cepacia lipase-catalyzed acylations of racemic alcohols has been studied. 2-[(N,N-Dimethylcarbamoyl)-methyl]-3-cyclopenten-1-ol (1) and 2-[2-(tert-butyldimethylsilyloxy)ethyl]-3-cyclopenten-1-ol (4) were resolved with a variety of enantioselectivities. In the case of alcohol 1, the enantiomeric ratio (the E value) was increased by changing the acylating agent from vinyl acetate (E = 30) to vinyl butyrate (E = 156) and dropped substantially with longer acyl donors. With vinyl chloroacetate, the reaction rate was fast and the enantioselectivity was high (E = 89), whereas the resolution with vinyl trifluoroacetate resulted in a very poor enantioselectivity (E = 4). The bulky acylating agent, vinyl pivalate, gave a moderate enantioselectivity (E = 15). In the case of alcohol 4, the enantioselectivities were excellent (E > 142) except vinyl pivalate (E = 12). It is indicated that the acyl group transiently attached at the active site of the lipase acts as a stereochemical controller. The solvent effect is also described briefly. A clear correlation was observed between the E values and the log P values of the organic solvents; the smaller the log P value of the solvent, the higher the E value.

Full text of DOI:10.1021/jo961144s

8610
J . Org. Chem. 1996, 61, 8610-8616
Kin etic Resolu tion of Ra cem ic 2-Su bstitu ted 3-Cyclop en ten -1-ols
by Lip a se-Ca ta lyzed Tr a n sester ifica tion s: A Ra tion a l Str a tegy To
Im p r ove En a n tioselectivity
Tadashi Ema,* Soichi Maeno, Yusuke Takaya, Takashi Sakai, and Masanori Utaka*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima,
Okayama 700, J apan
Received J une 17, 1996X
The effect of the acyl group of acylating agents on the enantioselectivity in the Pseudomonas cepacia
lipase-catalyzed acylations of racemic alcohols has been studied. 2-[(N,N-Dimethylcarbamoyl)-
methyl]-3-cyclopenten-1-ol (1) and 2-[2-(tert-butyldimethylsilyloxy)ethyl]-3-cyclopenten-1-ol (4) were
resolved with a variety of enantioselectivities. In the case of alcohol 1, the enantiomeric ratio (the
E value) was increased by changing the acylating agent from vinyl acetate (E ) 30) to vinyl butyrate
(E ) 156) and dropped substantially with longer acyl donors. With vinyl chloroacetate, the reaction
rate was fast and the enantioselectivity was high (E ) 89), whereas the resolution with vinyl
trifluoroacetate resulted in a very poor enantioselectivity (E ) 4). The bulky acylating agent, vinyl
pivalate, gave a moderate enantioselectivity (E ) 15). In the case of alcohol 4, the enantioselec-
tivities were excellent (E > 142) except vinyl pivalate (E ) 12). It is indicated that the acyl group
transiently attached at the active site of the lipase acts as a stereochemical controller. The solvent
effect is also described briefly. A clear correlation was observed between the E values and the log
P values of the organic solvents; the smaller the log P value of the solvent, the higher the E value.
In tr od u ction
and others5 belong to the former (noncovalent bond-
based) strategy. Among them, the solvent engineering
has become one of the most important methods, since
Klibanov et al. have demonstrated that organic solvents
have a marked effect on the enantioselectivity of enzy-
matic reactions.2 The kinetic resolution with (immobi-
lized) enzymes in a variety of organic solvents allows one
to optimize the reaction conditions easily.2,6 However,
satisfactory improvement in the enantioselectivity is not
necessarily attained by changing the solvent. Hence,
other rational strategies to alter the thermodynamic
stability of the enzyme-substrate complex and/or the
transition state also need to be pursued.
The kinetic resolution of racemic alcohols and amines
catalyzed by hydrolases such as lipases and serine
proteases has received considerable attention in recent
years1 and has been utilized in the chemoenzymatic
syntheses of optically active natural products and phar-
maceuticals. The hydrolases have been reported to exert
a broad range of enantioselectivity. Hence, various
methods of artificially improving the enantioselectivity
in the hydrolase-catalyzed asymmetric reactions have
been so far explored,2-11 and they can be classified mainly
into two groups according to the types of perturbations
on an enzyme: the noncovalent and covalent bond-based
strategies.
The site-directed or residue-selective chemical modi-
fication methods7 and the covalent immobilization8 be-
long to the latter (covalent bond-based) strategy. The
site-directed mutagenesis9 can also be included in this
category as a special case. A well-defined chemical
structural change can be brought about in an enzyme by
the site-directed chemical or mutagenetic modifications.
Another covalent bond-based strategy is the active-site-
directed transient chemical modification of an enzyme,
which will be discussed in detail in this paper.
The choice of organic solvent (the solvent engineer-
ing),1h,2 the effect of additives,3 the imprinting method,4
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) For leading reviews and books, see: (a) J ones, J . B. Tetrahedron
1986, 42, 3351. (b) Chen, C.-S.; Sih, C. J . Angew. Chem., Int. Ed. Engl.
1989, 28, 695. (c) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114. (d)
Preparative Biotransformations: Whole Cell and Isolated Enzymes in
Organic Synthesis; Roberts, S. M., Wiggins, K., Casy, G., Eds.; J ohn
Wiley & Sons: Chichester, 1993. (e) Wong, C.-H.; Whitesides, G. M.
Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, 1994.
(f) Enzyme Catalysis in Organic Synthesis; Drauz, K., Waldmann, H.,
Eds.; VCH: New York, 1994; Vol. 1. (g) Faber, K. Biotransformations
in Organic Chemistry; Springer-Verlag: Berlin, 1995. (h) Enzymatic
Reactions in Organic Media; Koskinen, A. M. P., Klibanov, A. M., Eds.;
Blackie Academic: Glasgow, 1996.
(5) (a) Wu, S.-H.; Guo, Z.-W.; Sih, C. J . J . Am. Chem. Soc. 1990,
112, 1990. (b) Kamat, S. V.; Beckman, E. J .; Russell, A. J . J . Am. Chem.
Soc. 1993, 115, 8845.
(6) (a) Nakamura, K.; Takebe, Y.; Kitayama, T.; Ohno, A. Tetrahe-
dron Lett. 1991, 32, 4941. (b) Secundo, F.; Riva, S.; Carrea, G.
Tetrahedron: Asymmetry 1992, 3, 267. (c) Herrado´n, B. Synlett. 1993,
108.
(2) (a) Sakurai, T.; Margolin, A. L.; Russell, A. J .; Klibanov, A. M.
J . Am. Chem. Soc. 1988, 110, 7236. (b) Kitaguchi, H.; Fitzpatrick, P.
A.; Huber, J . E.; Klibanov, A. M. J . Am. Chem. Soc. 1989, 111, 3094.
(c) Fitzpatrick, P. A.; Klibanov, A. M. J . Am. Chem. Soc. 1991, 113,
3166. (d) Tawaki, S.; Klibanov, A. M. J . Am. Chem. Soc. 1992, 114,
1882. (e) Terradas, F.; Teston-Henry, M.; Fitzpatrick, P. A.; Klibanov,
A. M. J . Am. Chem. Soc. 1993, 115, 390. (f) Ke, T.; Wescott, C. R.;
Klibanov, A. M. J . Am. Chem. Soc. 1996, 118, 3366.
(7) Site-directed and residue-selective chemical modifications to alter
the enantioselectivity of hydrolytic enzymes have not been reported
so far, to the best of our knowledge. For chemical modifications of
hydrolytic enzymes to improve their activity and solubility in organic
solvents, see: (a) Takahashi, K.; Ajima, A.; Yoshimoto, T.; Okada, M.;
Matsushima, A.; Tamaura, Y.; Inada, Y. J . Org. Chem. 1985, 50, 3414.
(b) Gaertner, H.; Puigserver, A. Eur. J . Biochem. 1989, 181, 207. For
active-site-directed chemical modifications to alter the reactivity of
hydrolytic enzymes, see: (c) Polgar, L.; Bender, M. L. J . Am. Chem.
Soc. 1966, 88, 3153. (d) Neet, K. E.; Koshland, D. E., J r. Proc. Natl.
Acad. Sci. U.S.A. 1966, 56, 1606.
(3) (a) Guo, Z.-W.; Sih, C. J . J . Am. Chem. Soc. 1989, 111, 6836. (b)
Itoh, T.; Hiyama, Y.; Betchaku, A.; Tsukube, H. Tetrahedron Lett. 1993,
34, 2617.
(4) (a) Sta˚hl, M.; J eppsson-Wistrand, U.; Ma˚nsson, M.-O.; Mosbach,
K. J . Am. Chem. Soc. 1991, 113, 9366. (b) Okahata, Y.; Hatano, A.;
Ijiro, K. Tetrahedron: Asymmetry 1995, 6, 1311.
(8) Berger, B.; Faber, K. J . Chem. Soc., Chem. Commun. 1991, 1198.
(9) Hirose, Y.; Kariya, K.; Nakanishi, Y.; Kurono, Y; Achiwa, K.
Tetrahedron Lett. 1995, 36, 1063.
S0022-3263(96)01144-9 CCC: $12.00 © 1996 American Chemical Society

Kinetic Resolution of Racemic 2-Substituted 3-Cyclopenten-1-ols
J . Org. Chem., Vol. 61, No. 24, 1996 8611
Sch em e 1
Sch em e 2
oyl)methyl]-3-cyclopenten-1-ol (1).12,13 In this paper, we
report in detail the effect of the acyl group of acylating
agents on the enantioselectivity in the lipase-catalyzed
kinetic resolutions of racemic alcohols. Among various
types of acyl donors, enol esters were used, because they
are considered to be the most suitable for our investiga-
tion because of their high reactivity and irreversibil-
ity.10,14
The fact that the hydrolase-catalyzed reactions proceed
through the covalent intermediates such as the acyl-
enzyme and the tetrahedral intermediates provides a clue
to modulate the enantioselectivity. By changing the acyl
group of acylating agents, a hydrolytic enzyme is trans-
formed into a variety of acyl-enzyme intermediates in an
organic solvent. Sih et al. have proposed that various
acyl-enzyme intermediates thus produced in situ, whose
active site structures differ from one another, can in
principle exert various chiral discrimination abilities in
the course of the enantioselective acylation of racemic
alcohols.1b A simplified scheme is shown in Scheme 1,
where R represents a variety of substituents (vide infra).
Thus, the acyl group directly incorporated into the active
site of the hydrolase can act as a stereochemical controller.
Because the serine residue at the active site of the
hydrolases can be easily acylated by using various kinds
of acylating agents in organic solvents, the transiently-
altered enzyme (the acyl-enzyme intermediate) optimal
for an asymmetric acylation can be easily searched.
There have been reported only several systematic studies
to examine this concept,1b,10,11 though this is an easier
method to modify an enzyme (transiently in situ) com-
pared with other covalent bond-based strategies. Much
about the potential of this method evidently remains to
be investigated. A combination of this methodology with
the solvent engineering will help us realize a highly
enantioselective kinetic resolutions of a wide range of
racemic alcohols.
Resu lts a n d Discu ssion
Syn t h esis of R a cem ic Alcoh ols. (1S,5R)-2-Oxa-
bicyclo[3.3.0]oct-6-en-3-one ((1S,5R)-2) is a well-known
chiral building block for prostaglandins,15 and the devel-
opment of its efficient asymmetric synthetic method has
been an important subject.15b-f For examination of the
aforementioned strategy, it was necessary to convert the
lactone 2 to an alcohol derivative. After several attempts,
we found that the aminolysis of 2 with aq dimethylamine
in THF gave alcohol 1 that is convertible back to 2
(Scheme 2).12 We also examined another related alcohol
derived from 2, 2-[2-(tert-butyldimethylsilyloxy)ethyl]-3-
cyclopenten-1-ol (4). Enantiomers (1R,5S)-2 and (1R,2S)-4
are chiral building blocks for natural products such as
pseudomonic acids.16
P r ep a r a tive Kin etic Resolu tion s. Effect of Acyl
Don or on En a n tioselectivity. We examined several
vinyl esters in the kinetic resolutions of 1 using Pseudomo-
nas cepacia lipase (Amano lipase PS) in diisopropyl ether
(Scheme 3). The reactions were monitored by TLC and
stopped by filtration at an appropriate conversion. Al-
cohol 1 and esters 5a -k were separated by column
chromatography, and their optical purities were deter-
mined by capillary gas chromatography after they were
lactonized by saponification (Scheme 2). The enantiose-
lectivities were compared on the basis of the enantiomeric
ratios (E values) calculated according to the literature17
and are shown in Table 1.
Lipases (EC 3.1.1.3) have recently been attracting
great interest because of their (1) broad substrate speci-
ficity, (2) good enantioselectivity, and (3) thermostability
in organic solvents. Recently we have reported the
lipase-catalyzed resolutions of 2-[(N,N-dimethylcarbam-
(10) For the effect of the chain length of acyl donors on the
enantioselectivity in the lipase-catalyzed acylations using enol esters,
see: (a) Wang, Y.-F.; Lalonde, J . J .; Momongan, M.; Bergbreiter, D.
E.; Wong, C.-H. J . Am. Chem. Soc. 1988, 110, 7200. (b) Hiratake, J .;
Inagaki, M.; Nishioka, T.; Oda, J . J . Org. Chem. 1988, 53, 6130. (c)
Inagaki, M.; Hiratake, J .; Nishioka, T.; Oda, J . Agric. Biol. Chem. 1989,
53, 1879. (d) Guo, Z.-W.; Wu, S.-H.; Chen, C.-S.; Girdaukas, G.; Sih,
C. J . J . Am. Chem. Soc. 1990, 112, 4942. (e) Yamazaki, Y.; Hosono, K.
Tetrahedron Lett. 1990, 31, 3895. (f) Miyazawa, T.; Kurita, S.; Ueji,
S.; Yamada, T.; Kuwata, S. J . Chem. Soc., Perkin Trans. 1 1992, 18,
2253. (g) Parida, S.; Dordick, J . S. J . Org. Chem. 1993, 58, 3238. (h)
Tokuyama, S.; Yamano, T.; Aoki, I.; Takanohashi, K.; Nakahama, K.
Chem. Lett. 1993, 741.
(11) For the effect of the chain length of acyl donors on the
enantioselectivity in the lipase-catalyzed acylations using the acyl
donors other than enol esters, see: (a) Sonnet, P. E. J . Org. Chem.
1987, 52, 3477. (b) Stokes, T. M.; Oehlschlager, A. C. Tetrahedron Lett.
1987, 28, 2091. (c) Okahata, Y.; Fujimoto, Y.; Ijiro, K. Tetrahedron
Lett. 1988, 29, 5133. (d) Holmberg, E.; Szmulik, P.; Norin, T.; Hult, K.
Biocatalysis 1989, 2, 217. (e) Guo, Z.-W.; Wu, S.-H.; Chen, C.-S.;
Girdaukas, G.; Sih, C. J . J . Am. Chem. Soc. 1990, 112, 4942.
(12) Sakai, T.; Iida, Y.; Kikuyama, S.; Tsuboi, S.; Utaka, M. Chem.
Lett. 1991, 1651.
(13) Ema, T.; Maeno, S.; Takaya, Y.; Sakai, T.; Utaka, M. Tetrahe-
dron: Asymmetry 1996, 7, 625.
(14) Chen, C.-S.; Wu, S.-H.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1987, 109, 2812.
(15) (a) Corey, E. J .; Mann, J . J . Am. Chem. Soc. 1973, 95, 6832. (b)
Partridge, J . J .; Chadha, N. K.; Uskokovic´, M. R. J . Am. Chem. Soc.
1973, 95, 7171. (c) Takano, S.; Tanizawa, K.; Ogasawara, K. J . Chem.
Soc., Chem. Commun. 1976, 189. (d) Irwin, A. J .; J ones, J . B. J . Am.
Chem. Soc. 1977, 99, 1625. (e) Terashima, S.; Yamada, S.; Nara, M.
Tetrahedron Lett. 1977, 1001. (f) Newton, R. F.; Paton, J .; Reynolds,
D. P.; Young, S.; Roberts, S. M. J . Chem. Soc., Chem. Commun. 1979,
908.
(16) Barrish, J . C.; Lee, H. L.; Mitt, T.; Pizzolato, G.; Baggiolini, E.
G.; Uskokovic´, M. R. J . Org. Chem. 1988, 53, 4282.
(17) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294.

8612 J . Org. Chem., Vol. 61, No. 24, 1996
Ema et al.
Sch em e 3
Sch em e 4
Ta ble 2. En a n tioselective Lip a se-Ca ta lyzed Acyla tion of
Alcoh ol 4 w ith Va r iou s Acyla tin g Agen ts
(RCO2CHdCH2)a
Ta ble 1. En a n tioselective Lip a se-Ca ta lyzed Acyla tion of
Alcoh ol 1 w ith Va r iou s Acyla tin g Agen ts
(RCO2CHdCH2)a
% yieldc (% eed)
% yieldc (% eed)
vinyl
ester (R) time (h) c (%)b
(1R,2S)-6
6a 44 (>99) 52 (77)
6b 46 (98) 53 (87)
(1S,2R)-4 E value e
vinyl ester (R) time (h) c (%)b (1R,2S)-5 (1S,2R)-1 E value e
CH3
2.5
6
9
1
48
144
44
47
40
50
-
>466
283
CH3
C2H5
3
3
3
3
50
42
45
51
55
49
51
20
24
14
7
5a 47 (84) 46 (83)
5b 41 (95) 48 (69)
5c 42 (97) 51 (78)
5d 43 (70) 47 (72)
5e 51 (70) 40 (86)
5f 44 (89) 42 (84)
5g 48 (92) 43 (95)
5h 18 (52) 43 (13)
5i 19 (84) 10f (27)
5j 19 (89) 53f (15)
5k 12 (92) 16f (7)
30
81
156
12
15
45
89
4
n-C3H7
n-C9H19
ClCH2
t-C4H9
C6H5
6c 40 (>99) 58 (67)
>402
n-C3H7
n-C5H11
n-C7H15
n-C9H19
ClCH2
CF3
t-C4H9
C6H5
CH3CHdCH
6d 46 (>99) 50 (>99)
>1057
6e 40 (-f)
6f 40 (97)
59 (52)
55 (72)
12 g
2
43
142
1.5
0.5
0.75
48
48
48
a
Conditions: lipase PS (200 mg), 4 (0.41 mmol), vinyl ester (0.82
b
mmol), dry (i-Pr)2O (10 mL), 30 °C. Conversion calculated from
c ) 100 × ee(4)/(ee(4) + ee(6)) according to ref 17. c Isolated yield.
15
20
26
Determined by 1H NMR spectra, after 4 and 6 were converted
d
to the MTPA ester. e Calculated from E ) ln {1 - c(1 + ee(6))}/ln
{1 - c(1 - ee(6))} according to ref 17. f Not determined due to the
a
Conditions: lipase PS (400 mg), 1 (1.2 mmol), vinyl ester (2.4
g
tolerance of the pivalic ester for saponification. Calculated from
b
mmol), dry (i-Pr)2O (10 mL), 30 °C. Conversion calculated from
E ) ln {(1 - c)(1 - ee(4))}/ln {(1 - c)(1 + ee(4))} by using the %
yield and % ee of the alcohol 4 recovered.
c ) 100 × ee(1)/(ee(1) + ee(5)) according to ref 17. c Isolated yield.
d
Determined by capillary GC with Chrompack CP-cyclodextrin-
â-2,3,6-M-19, after 1 and 5 were lactonized. e Calculated from E
) ln {1 - c(1 + ee(5))}/ln {1 - c(1 - ee(5))} according to ref 17.
f Large amounts of lactone 2 were obtained due to the prolonged
reaction time.
show no reactivity in the lipase-catalyzed (trans)esteri-
fications. The enantioselectivity was moderate in this
particular case, but the steric effect of the pivaloyl group
may be effective for other substrates not examined. The
reactions using vinyl benzoate and vinyl crotonate were
very slow, probably because of the low reactivity of the
conjugated esters, and the prolonged reaction time led
to the spontaneous lactonization of 1. It is interesting
to note that the resolution using vinyl crotonate resulted
in a drop in the E value as compared with that using
vinyl butyrate, although both of them have the C4 chain
lengths in the acyl moieties.
Next, we examined alcohol 4 in the lipase-mediated
kinetic resolutions (Scheme 4). The enantioselectivities
were excellent when linear acyl donors with various alkyl
chain lengths were used (Table 2). The side chain (CH2-
CH2OTBDMS) of 4 appears to be recognized by the lipase
more strictly than that (CH2CON(CH3)2) of alcohol 1, and
so the magnitudes of the perturbations caused by various
alkyl chains of the linear vinyl esters against 4 are
difficult to evaluate. On the other hand, vinyl pivalate
altered the E value markedly. Severe steric repulsion
seems to operate between the tertiary butyl group of vinyl
pivalate and the TBDMS group of 4 in the course of the
lipase-catalyzed transesterification, which can also be
indirectly suggested by the fact that the pivalic ester 6e
obtained by the lipase-catalyzed reaction using vinyl
pivalate could not be hydrolyzed at all by aq KOH in
refluxing EtOH overnight. The transesterification with
The racemic alcohol (()-1 was found to be resolved into
the enantiomers with a variety of optical purities. It is
interesting to note that a slight elongation of the alkyl
chain of the vinyl esters caused dramatic changes in the
enantioselectivity. The enantioselectivity was success-
fully improved by changing the acylating agent from vinyl
acetate (E ) 30) to vinyl butyrate (E ) 156) and dropped
substantially with longer acyl donors. The reaction time
became shorter as the acyl donor was longer, because the
rate of the acylation with longer vinyl ester was faster.13
This trend can be ascribed to the inherently high affinity
of the lipase toward the long-chain acyl group (natural
substrates of lipases are triacyl glycerides of long-chain
fatty acids) and indicates that the lipase in dry organic
solvent retains its native molecular recognition property
to some degree. We further investigated other types of
vinyl esters (Table 1). With vinyl chloroacetate, the
reaction rate was found to be fast and the enantioselec-
tivity was excellent, which can be ascribed, respectively,
to the electronegativity and to the size of the chlorine
atom (vide infra). This trend is different from the results
reported by Miyazawa et al. that the use of vinyl
chloroacetate caused the inversion of the stereo-
selectivity.10f On the contrary, the resolution with vinyl
trifluoroacetate resulted in a very poor enantioselectivity.
This is partly because nonenzymatic reactions occurred
dominantly.18 The transesterification with the bulky
acylating agent, vinyl pivalate, did proceed, although the
reaction rate was very slow. This result presents a
striking contrast to the fact that tertiary alcohols usually
(18) The acylation with vinyl trifluoroacetate in the absence of the
lipase did proceed, and small amounts of trifluoroacetic acid generated
in situ seemed to induce the lactonization of 1 during the reaction;
isolated yield of 2 27% (13% ee for (1S,5R)-form).

Kinetic Resolution of Racemic 2-Substituted 3-Cyclopenten-1-ols
J . Org. Chem., Vol. 61, No. 24, 1996 8613
Sch em e 5
enantiomers in the Michaelis complex and/or in the
subsequent transition state will influence the enantiose-
lectivity.24
F igu r e 1. Schematic representations of the complex of the
acyl-lipase intermediate with the substrate. A differential
degree of additional spatial constraint (steric bias) imposed
by the acyl moiety against the fast- and slow-reacting enan-
tiomers in the Michaelis complex and/or in the subsequent
transition state will influence the enantioselectivity. (a) The
binding site of the lipase is not crowded, and the substrate
can freely rotate, adopting a favorable conformation. (b) Both
the orientation and conformation of the substrate are restricted
by the spatial constraint caused by the large acyl group.
Indeed, the results in Tables 1 and 2 indicate that such
steric bias with respect to each enantiomer of 1 (or 4)
operates when the acyl donor was changed. For example,
the steric hindrance of vinyl pivalate retarded the reac-
tion of the fast-reacting enantiomer more than that of
the slow-reacting enantiomer, leading to the dropped E
values compared with those obtained by using vinyl
acetate. This effect seems important especially for 4,
which is considered to experience severer spatial con-
straint than 1, judging from the long reaction time and
the large decrease in the E value. On the other hand, in
the case of vinyl chloroacetate, the acylation of the fast-
reacting enantiomer of 1 (or 4) was accelerated by the
electronegative chlorine atom, whereas the acylation of
the slow-reacting enantiomer was suppressed by the
increased steric hindrance in comparison with vinyl
acetate, resulting in excellent enantioselectivities. Hence,
we propose that the bulky and moderately activated vinyl
esters such as vinyl chloroacetate may be good candidates
to exert high enantioselectivities for a wide range of
racemic alcohols. The fact that the reaction using vinyl
crotonate resulted in a lower enantioselectivity than that
using vinyl butyrate having the same chain length (C4)
in the acyl moiety (Table 1) may suggest that the
conformation of the acyl moiety in the acyl-lipase is
important. As for the crotonate moiety, only two con-
formers (s-cis and s-trans) are possible, and the s-cis (less
hindered) conformation may predominate in the acyl-
lipase intermediate as shown in Scheme 5. On the other
hand, the butyrate moiety can take many conformations,
among which the U-shaped (more hindered) conformation
could retard the acylation of the slow-reacting enanti-
omer of 1 more efficiently than the crotonate (s-cis)
moiety (Scheme 5).
vinyl chloroacetate showed both the highest reactivity
and the highest enantioselectivity (E > 1057) and re-
sulted in a perfect resolution.
Thus, various acyl groups were adopted because of the
high enzymatic activity of the lipase in diisopropyl ether;
the total turnover number (TTN)1e is calculated to be ca.
5000 when the reaction was stopped at 50% conversion.19
A wide variety of the enantioselectivities shown in Tables
1 and 2 demonstrates that the present strategy has a
good potential to alter the enantioselectivity and indi-
cates that the acyl group directly incorporated into the
active site of the lipase acts as a stereochemical control-
ler.20
Ster eoch em ica l Role of th e Acyl Moiety in th e
En a n tiom er -Differ en tia tin g Step . The enantioselec-
tivity in the lipase-catalyzed transesterification results
from the diastereomeric interaction in the acyl-lipase-
substrate complex and/or in the following transition state
(Scheme 1).22 It is evident from the above results that
not only the chiral binding site of the lipase itself but
also the acyl moiety covalently linked to the active site
of the lipase play an important role in the enantioselec-
tive acylation of 1 and 4. Figure 1 shows schematic
representations of the complex between the slow-reacting
enantiomer of 1 (or 4) and the acyl-lipase intermediate,
where direct (attractive or repulsive23) interactions are
assumed to occur between the acyl substituent of the
intermediate and the substrate. A larger acyl moiety
makes the binding cavity more crowded than a smaller
acyl moiety does. A differential degree of such additional
spatial constraint against the fast- and slow-reacting
Solven t Effect. To investigate the usefulness of a
combination of the present methodology with the solvent
engineering,10g we examined various organic solvents for
the lipase-catalyzed resolution of 1 using vinyl butyrate.
As a result, we obtained higher E values in hydrophilic
(19) Lipase PS powder contains 1% (w/w) lipase in Celite, whose
molecular weight is ca. 33000 (private communication with Dr. Y.
Hirose). A kinetic measurement indicated that in the absence of the
lipase the reaction rate was too slow to determine, and that the
apparent rate-acceleration by the lipase catalysis in diisopropyl ether
was at least .105.
(20) Although the enantioselectivity was dramatically altered by
changing the acyl donor, the stereochemical preference obeyed Ka-
zlauskas’s rule,21 indicating that the stereochemistry is governed
primarily by the size and shape of the binding pocket of the lipase.
(21) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J . Org. Chem. 1991, 56, 2656.
(23) It should be noted here that the present strategy is quite
different from the enzymatic hydrolysis of racemic esters in water,
where ester derivatives of a racemic alcohol with various acyl groups
are examined; e.g. Ehrler, J .; Seebach, D. Liebigs Ann. Chem. 1990,
379. By changing the solvent from water to organic solvents, attractive
interactions such as hydrophobic interaction change to another types
of interactions such as steric repulsion. Such transition of the
intermolecular force will change the thermodynamic stability of the
intermediates, and hence can potentially lead to a drastically altered
enantioselectivity as compared with the reaction in water.
(24) This tactics was also found to be effective for the kinetic
resolution of other types of racemic alcohols such as linear aliphatic
alcohol.
(22) Fersht, A. Enzyme Structure and Mechanism, 2nd ed.; Free-
man: New York, 1985; Chapters 3 and 13.

8614 J . Org. Chem., Vol. 61, No. 24, 1996
Ema et al.
resolution of racemic alcohols is an important subject.
This paper presents that the effect of the acyl group of
acylating agents on the enantioselectivity in the lipase-
catalyzed acylations of racemic alcohols is large. By
using this method, the versatile chiral building blocks,
1, 2, and 4, have been successfully resolved into their
enantiomers with high optical purities. The results
strongly indicates that the acyl group transiently at-
tached at the active center of the lipase participates in
the alteration of the enantioselectivity as a stereochem-
ical controller. The efficient conditions for the kinetic
resolution of a racemic alcohol can be easily searched
simply by changing the acyl group of the vinyl ester. The
present method has been combined with the solvent
engineering to effectively optimize the reaction condi-
tions. It can also be potentially used even in the solvent-
free system and in the supercritical carbon dioxide,26 both
of which are very important from the environmental as
well as the economical viewpoints and may also be
effective for controlling the regioselectivity in the acyla-
tion of polyols such as sugars.27 The results in this paper
will provide us with useful hints to develop new acylating
agents in the future.
F igu r e 2. The correlation between the enantioselectivities (E
values) in the Pseudomonas cepacia lipase-catalyzed acylations
of the alcohol 1 and the log P values of the solvents. Condi-
tions: lipase PS (400 mg), 1 (1.2 mmol), vinyl butyrate (2.4
mmol), dry organic solvent (10 mL), 30 °C. The log P values
were taken from ref 25. Solvents (reaction time, conversion):
(a) 1,4-dioxane (23 h, 47%), (b) acetonitrile (12 h, 43%), (c)
acetone (9 h, 32%), (d) THF (7 h, 24%), (e) ether (6 h, 50%), (f)
diisopropyl ether (5 h, 42%), (g) benzene (7 h, 25%), (h) toluene
(7 h, 30%), (i) cyclohexane (2 h, 35%), (j) hexane (2 h, 33%),
(k) isooctane (2 h, 49%). The log P value of isooctane was taken
from that of octane.
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra measured in CDCl3 at
200 and 50 MHz, respectively, are reported. Column chro-
matography was carried out using Nacalai silica gel 60 (70-
230 mesh) or Fuji Silysia BW-127 ZH (100-270 mesh), and
thin layer chromatography (TLC) was performed on Merck
solvents, and significantly, a clear correlation was ob-
served between the E values and the log P values25 of
the solvents as shown in Figure 2; the smaller the log P
value of the solvent, the higher the E value. Clear
correlations between the E values and the log P values
have been so far reported.2,6 On the other hand, no
correlation between the dielectric constants of the sol-
vents and the E values was observed (not shown). The
reaction rate was slow in hydrophilic solvents (log P <
0.5).
Klibanov et al. have reported that the enantioselec-
tivities in hydrolase-catalyzed reactions in various or-
ganic solvents correlate well with the solvent hydro-
phobicity2a,d,e (log P), or with the solvent polarity2c (the
dielectric constant and the dipole moment). They have
suggested that the former physicochemical parameter is
related to the driving force of the binding, and the latter
parameters are related to the steric constraint that stems
from the rigidity of the enzyme. Applying their explana-
tion to the present study, the rigidity of the lipase is not
important for the enantioselectivity, whereas tight bind-
ing of the substrate in the hydrophobic pocket of the
lipase occurs in hydrophilic solvents, leading to high
enantioselectivity. Because hydrophilic solvents desta-
bilize the lipase and lower its activity to some degree by
disordering or stripping off the “essential water” from the
lipase,1b,25b the organic solvents with moderate hydro-
phobicity such as ether and diisopropyl ether, where both
the enantioselectivity of the reaction and the activity of
the lipase are high, are optimal in this case.
silica gel 60 F254
. Mass spectra were measured by Dr. S.
Nakajima (Okayama University). Lactone 2 and diol 3 were
prepared according to the literature.15a Lipase PS provided
by Amano Pharmaceutical Co. was used without further
purification. The dry organic solvents used in the lipase-
catalyzed kinetic resolutions were prepared as follows. Hex-
ane, cyclohexane, isooctane, toluene, ether, diisopropyl ether,
THF, and 1,4-dioxane were distilled from sodium. Benzene
was distilled from CaH2, and acetone was dried over 4 Å
molecular sieves. Anhydrous acetonitrile purchased from
Wako Pure Chemical Industries was used without further
purification.
(()-2-[(N,N-Dim eth ylcar bam oyl)m eth yl]-3-cyclopen ten -
1-ol (1). To a solution of lactone 2 (2.00 g, 16.1 mmol) in THF
(40 mL) was added slowly aq 50% dimethylamine solution (80
mL) at room temperature, and the reaction mixture was
stirred for 4 h. The solution was cooled in an ice bath and
adjusted to pH 7 by adding concd HCl slowly. The resulting
solution was extracted with ethyl acetate (50 mL × 8), dried
over MgSO4, and then concentrated. The crude product was
purified by column chromatography on silica gel (hexane/
EtOAc (2:1)-(0:1)) to give alcohol 1 (1.80 g, 59%) as a colorless
viscous oil. The product 1 was used without distillation to
prevent lactonization and can be stored in a refrigerator at
least for a week without lactonization: 1H NMR δ 2.32-2.73
(m, 4H), 3.01 (m, 1H), 2.96 (s, 3H), 3.06 (s, 3H), 4.52-4.63 (m,
1H), 5.47-5.77 (m, 2H); 13C NMR δ 31.7, 35.6, 37.7, 40.5, 46.5,
72.0, 129.3, 131.8, 173.7; IR (neat) 3406, 1626 cm-1
. For
(1S,2R)-1: 95% ee after the lipase-catalyzed kinetic resolution;
[R]27 ) -24.2 (c 1.12, CHCl3).
D
(()-2-[2-(ter t-Bu tyldim eth ylsilyloxy)eth yl]-3-cyclopen t-
en -1-ol (4). To a solution of diol 3 (1.00 g, 7.8 mmol) and
imidazole (1.29 g, 19.0 mmol) in dry THF (20 mL) was slowly
added dropwise a solution of t-BuMe2SiCl (1.14 g, 7.6 mmol)
in dry THF (10 mL) in an ice bath. The reaction mixture was
stirred in an ice bath for 1 h and then stirred at room
temperature for 19 h. After the reaction was quenched with
H2O (2 mL), the resulting solution was extracted with ethyl
Con clu sion s
Development of the strategies for effectively improving
the enantioselectivity of the lipase-catalyzed kinetic
(25) The parameter P represents the partition coefficient of a solvent
between 1-octanol and water. (a) Leo, A.; Hansch, C.; Elkins, D. Chem.
Rev. 1971, 71, 525. (b) Laane, C.; Boeren, S.; Vos, K.; Veeger, C.
Biotechnol. Bioeng. 1987, 30, 81.
(26) Nakamura, K. Trends Biotechnol. 1990, 8, 288.
(27) Panza, L.; Brasca, S.; Riva, S.; Russo, G. Tetrahedron: Asym-
metry 1993, 4, 931.

Kinetic Resolution of Racemic 2-Substituted 3-Cyclopenten-1-ols
J . Org. Chem., Vol. 61, No. 24, 1996 8615
acetate, dried over MgSO4, and then concentrated. The
residue was purified by column chromatography on silica gel
(hexane/EtOAc (10:1)) to give alcohol 4 (1.25 g, 66%) as a
colorless viscous oil: 1H NMR δ 0.09 (s, 6H), 0.91 (s, 9H), 1.69-
2.02 (m, 2H), 2.29-2.45 (m, 1H), 2.56-2.77 (m, 2H), 3.55 (br
s, 1H), 3.65 (dt, J ) 9.8, 3.0 Hz, 1H), 3.77-3.90 (m, 1H), 4.44
(t, J ) 6.1 Hz, 1H), 5.45-5.78 (m, 2H); 13C NMR δ -5.6, 18.2,
25.8, 30.4, 41.6, 50.6, 63.2, 71.6, 128.4, 132.9; IR (neat) 3435
+26.1 (c 1.24, CHCl3); 1H NMR δ 0.88 (t, J ) 6.7 Hz, 3H),
1.20-1.40 (m, 4H), 1.59 (quintet, J ) 7.3 Hz, 2H), 2.24 (t, J )
7.9 Hz, 2H), 2.30-2.40 (m, 2H), 2.55 (dd, J ) 15.8, 7.0 Hz,
1H), 2.68-2.83 (m, 1H), 2.94 (s, 3H), 3.00 (s, 3H), 3.28-3.44
(m, 1H), 5.45 (dt, J ) 6.5, 3.0 Hz, 1H), 5.73 (s, 2H); 13C NMR
δ 13.9, 22.3, 24.7, 31.3, 32.0, 34.5, 35.4, 37.2, 39.4, 44.4, 74.8,
128.2, 133.0, 171.7, 173.3; IR (neat) 1732, 1651 cm-1; HRMS
(EI) calcd for C15H25O3N 267.1834, found 267.1809.
cm-1
. For (1S,2R)-4: >98% ee after the lipase-catalyzed
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
kinetic resolution; [R]23 ) -48.9 (c 1.10, CHCl3).
p en ten -1-yl Octa n oa te (5e). Colorless oil; 70% ee; [R]25
)
D
D
+29.7 (c 1.18, CHCl3); 1H NMR δ 0.87 (t, J ) 6.7 Hz, 3H),
1.19-1.40 (m, 8H), 1.50-1.70 (m, 2H), 2.25 (t, J ) 7.9 Hz, 2H),
2.30-2.40 (m, 2H), 2.54 (dd, J ) 15.8, 6.9 Hz, 1H), 2.67-2.82
(m, 1H), 2.95 (s, 3H), 3.01 (s, 3H), 3.28-3.44 (m, 1H), 5.44 (dt,
J ) 7.6, 2.7 Hz, 1H), 5.73 (s, 2H); 13C NMR δ 14.0, 22.5, 25.0,
28.9, 29.1, 31.6, 32.0, 34.5, 35.4, 37.2, 39.4, 44.4, 74.8, 128.1,
133.0, 171.6, 173.2; IR (neat) 1733, 1653 cm-1; HRMS (EI)
calcd for C17H29O3N 295.2147, found 295.2169.
Gen er a l P r oced u r e for th e P r ep a r a tive Kin etic Reso-
lu tion s. A heterogeneous solution of lipase PS (400 mg), 1
(200 mg, 1.18 mmol), and vinyl ester (2.36 mmol) in dry organic
solvent (10 mL) were stirred at 450 rpm in a test tube with a
rubber septum in a thermostat at 30 °C. The progress of the
reaction was monitored by TLC, and stopped by filtration at
an appropriate conversion (typically 40-50%). Alcohol 1 and
esters 5a -k were separated by column chromatography (SiO2,
hexane/EtOAc (2:1)-(0:1)). The reaction conditions for 4 were
similar to those for 1: lipase PS (200 mg), 4 (100 mg, 0.41
mmol), vinyl ester (0.82 mmol), dry diisopropyl ether (10 mL).
Deter m in a tion of th e Op tica l P u r ity a n d th e Absolu te
Con figu r a tion . A solution of the optically active alcohol 1
(or esters 5a -k ) (0.15 mmol) in 1 N aq KOH (3 mL)/MeOH
(0.2 mL) was stirred at room temperature overnight and then
adjusted to pH 7 by adding 10% HCl. The resulting solution
was extracted with ethyl acetate (1 mL × 3), dried over MgSO4,
and concentrated to give lactone 2 (89-100%). The optical
purity of 2 was determined by capillary gas chromatography
fitted with Chrompack CP-cyclodextrin-â-2,3,6-M-19 column
(injection temperature, 250 °C; column temperature, 120 °C;
carrier gas, He). The optical purities of 4 and 6a -f except 6e
were determined by conversion to the corresponding MTPA
ester.28 The signals of an allyl proton (2.32-2.47 ppm) were
integrated. Both of the absolute configurations of alcohols 1
and 4 obtained in the lipase-catalyzed resolutions were
determined to be (1S,2R) by comparison with the signs of the
reported optical rotations after the optically active alcohols 1
and 4 were converted to lactone 2 with >99% ee ([R]26D ) -109
(c 1.34, MeOH), lit.15b [R]25D ) -106 (c 1.00, MeOH) for (1S,5R)-
2) and diol 3 with >99% ee ([R]26D ) -62 (c 1.02, MeOH), lit.15b
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl Deca n oa te (5f). Colorless oil; 89% ee; [R]28
)
D
+23.6 (c 1.21, CHCl3); 1H NMR δ 0.87 (t, J ) 6.9 Hz, 3H),
1.18-1.40 (m, 12H), 1.50-1.70 (m, 2H), 2.25 (t, J ) 7.8 Hz,
2H), 2.27-2.39 (m, 2H), 2.55 (dd, J ) 15.8, 7.0 Hz, 1H), 2.68-
2.83 (m, 1H), 2.95 (s, 3H), 3.00 (s, 3H), 3.29-3.44 (m, 1H), 5.47
(dt, J ) 6.2, 2.8 Hz, 1H), 5.73 (s, 2H); 13C NMR δ 14.1, 22.6,
25.0, 29.1, 29.2, 29.3, 29.4, 31.8, 32.0, 34.5, 35.4, 37.2, 39.4,
44.4, 74.8, 128.1, 133.0, 171.7, 173.3; IR (neat) 1733, 1653 cm-1
HRMS (EI) calcd for C19H33O3N 323.2460, found 323.2450.
;
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl Ch lor oa ceta te (5g). Colorless oil; 92% ee; [R]26
D
1
) +26.4 (c 1.24, CHCl3); H NMR δ 2.31-2.47 (m, 2H), 2.60
(dd, J ) 16.1, 7.7 Hz, 1H), 2.72-2.87 (m, 1H), 2.95 (s, 3H),
3.00 (s, 3H), 3.34-3.50 (m, 1H), 4.00 (s, 2H), 5.57 (dt, J ) 6.9,
2.6 Hz, 1H), 5.73 (s, 2H); 13C NMR δ 32.1, 35.6, 37.4, 39.4,
41.2, 44.7, 128.1, 133.0, 166.8, 171.7; IR (neat) 1752, 1643 cm-1
;
HRMS (EI) calcd for C11H16O3NCl 245.0819, found 245.0826.
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl Tr iflu or oa ceta te (5h ). The trifluoroacetate
ester was relatively unstable and was gradually changed to
lactone 2. 1H NMR δ 2.37-2.85 (m, 4H), 2.93 (s, 3H), 2.98 (s,
3H), 3.44-3.60 (m, 1H), 5.66-5.82 (m, 3H).
[R]25 ) -74 (c 1.00, MeOH) for (1S,2R)-3), respectively.
D
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl P iva la te (5i). Mp 54-55 °C; 84% ee; [R]24
)
p en ten -1-yl Aceta te (5a ). Colorless oil; 84% ee; [R]25
)
D
D
1
1
+33.0 (c 1.03, CHCl3); H NMR δ 1.16 (s, 9H), 2.22-2.42 (m,
2H), 2.56 (dd, J ) 16.0, 6.9 Hz, 1H), 2.70-2.83 (m, 1H), 2.94
(s, 3H), 2.99 (s, 3H), 3.30-3.44 (m, 1H), 5.43 (dt, J ) 6.4, 2.8
Hz, 1H), 5.72 (s, 2H); 13C NMR δ 27.0, 32.3, 35.3, 37.1, 38.8,
39.6, 44.4, 74.6, 128.1, 132.9, 171.6, 177.8; IR (KBr) 1717, 1637
cm-1; HRMS (EI) calcd for C14H23O3N 253.1678, found 253.1665.
+48.9 (c 1.57, CHCl3); H NMR δ 2.01 (s, 3H), 2.28-2.40 (m,
2H), 2.56 (dd, J ) 15.8, 7.0 Hz, 1H), 2.65-2.82 (m, 1H), 2.95
(s, 3H), 3.01 (s, 3H), 3.30-3.44 (m, 1H), 5.45 (dt, J ) 6.5, 3.1
Hz, 1H), 5.73 (s, 2H); 13C NMR δ 21.1, 31.9, 35.4, 37.2, 39.2,
44.3, 75.0, 128.1, 133.0, 170.5, 171.6; IR (neat) 1734, 1644 cm-1
;
HRMS (EI) calcd for C11H17O3N 211.1208, found 211.1193.
Anal. Calcd for C11H17O3N: C, 62.56; H, 8.06; N, 6.64.
Found: C, 62.75; H, 8.33; N, 6.70.
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl Ben zoa te (5j). Colorless oil; 89% ee; [R]19
)
D
+52.1 (c 1.31, CHCl3); 1H NMR δ 2.37-2.53 (m, 2H), 2.68 (dd,
J ) 15.9, 7.0 Hz, 1H), 2.81-3.00 (m, 1H), 2.85 (s, 3H), 2.94 (s,
3H), 3.44-3.58 (m, 1H), 5.72 (dt, J ) 6.1, 2.8 Hz, 1H), 5.79 (s,
2H), 7.37-8.04 (m, 5H); 13C NMR δ 32.2, 35.3, 37.2, 39.3, 44.7,
75.6, 128.2, 128.3, 129.4, 130.5, 132.8, 133.0, 166.0, 171.5; IR
(neat) 1716, 1647 cm-1; HRMS (EI) calcd for C16H19O3N
273.1365, found 273.1370.
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl P r op a n oa te (5b). Colorless oil; 95% ee; [R]25
D
1
) +36.2 (c 1.20, CHCl3); H NMR δ 1.11 (t, J ) 7.6 Hz, 3H),
2.26 (t, J ) 7.6 Hz, 2H), 2.27-2.39 (m, 2H), 2.55 (dd, J ) 15.8,
7.0 Hz, 1H), 2.68-2.82 (m, 1H), 2.94 (s, 3H), 3.00 (s, 3H), 3.28-
3.46 (m, 1H), 5.47 (dt, J ) 7.0, 3.1 Hz, 1H), 5.73 (s, 2H); 13C
NMR δ 9.1, 27.7, 31.9, 35.3, 37.1, 39.3, 44.3, 74.7, 128.1, 132.9,
171.6, 173.8; IR (neat) 1733, 1652 cm-1; HRMS (EI) calcd for
C12H19O3N 225.1365, found 225.1370.
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl Cr oton a te (5k ). Colorless oil; 92% ee; [R]24
)
D
+30.5 (c 1.02, CHCl3); 1H NMR δ 1.84-1.93 (m, 3H), 2.28-
2.44 (m, 2H), 2.56 (dd, J ) 14.1, 6.6 Hz, 1H), 2.69-2.84 (m,
1H), 2.94 (s, 3H), 3.00 (s, 3H), 3.30-3.45 (m, 1H), 5.51 (dt, J
) 6.5, 3.1 Hz, 1H), 5.75 (s, 2H), 5.77-5.84 (m, 1H), 6.85-7.04
(m, 1H); 13C NMR δ 17.9, 31.9, 35.4, 37.2, 39.1, 44.5, 74.7,
122.6, 128.1, 132.9, 144.6, 165.9, 171.7; IR (neat) 1716, 1652
cm-1; HRMS (EI) calcd for C13H19O3N 237.1365, found 237.1325.
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl Bu ta n oa te (5c). Colorless oil; 97% ee; [R]26
)
D
+29.6 (c 1.24, CHCl3); 1H NMR δ 0.93 (t, J ) 7.4 Hz, 3H),
1.53-1.72 (m, 2H), 2.23 (t, J ) 7.4 Hz, 2H), 2.31-2.40 (m, 2H),
2.55 (dd, J ) 15.8, 7.0 Hz, 1H), 2.68-2.83 (m, 1H), 2.94 (s,
3H), 3.00 (s, 3H), 3.27-3.45 (m, 1H), 5.47 (dt, J ) 6.5, 2.9 Hz,
1H), 5.73 (s, 2H); 13C NMR δ 13.6, 18.4, 32.0, 35.3, 36.3, 37.1,
39.4, 44.3, 74.7, 128.1, 132.9, 171.6, 173.0; IR (neat) 1731, 1651
cm-1; HRMS (EI) calcd for C13H21O3N 239.1521, found 239.1531.
Anal. Calcd for C13H21O3N: C, 65.25; H, 8.84; N, 5.85.
Found: C, 64.81; H, 8.69; N, 5.79.
(1R,2S)-2-[2-(ter t-Bu tyld im eth ylsilyloxy)eth yl]-3-cyclo-
p en ten -1-yl Aceta te (6a ). Colorless oil; >99% ee; [R]20
)
D
+24.3 (c 1.36, CHCl3); 1H NMR δ 0.05 (s, 6H), 0.89 (s, 9H),
1.50-1.83 (m, 2H), 2.04 (s, 3H), 2.28-2.40 (m, 1H), 2.60-2.79
(m, 1H), 2.85-2.97 (m, 1H), 3.67 (t, J ) 6.7 Hz, 2H), 5.39 (dt,
J ) 6.3, 3.0 Hz, 1H), 5.73 (s, 2H); 13C NMR δ -5.3, 18.3, 21.2,
26.0, 31.4, 39.3, 44.7, 61.9, 75.3, 127.6, 133.2, 170.9; IR (neat)
(1R,2S)-2-[(N,N-Dim et h ylca r b a m oyl)m et h yl]-3-cyclo-
p en ten -1-yl Hexa n oa te (5d ). Colorless oil; 70% ee; [R]26
)
D
(28) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
1736 cm-1
.

8616 J . Org. Chem., Vol. 61, No. 24, 1996
Ema et al.
(1R,2S)-2-[2-(ter t-Bu tyld im eth ylsilyloxy)eth yl]-3-cyclo-
(1R,2S)-2-[2-(ter t-Bu tyld im eth ylsilyloxy)eth yl]-3-cyclo-
p en ten -1-yl Bu ta n oa te (6b). Colorless oil; 98% ee; [R]20
)
p en ten -1-yl Ben zoa te (6f). Colorless oil; 97% ee; [R]22
)
D
D
+16.5 (c 1.08, CHCl3); 1H NMR δ 0.04 (s, 6H), 0.89 (s, 9H),
0.93 (t, J ) 7.4 Hz, 3H), 1.50-1.83 (m, 4H), 2.26 (t, J ) 7.3
Hz, 2H), 2.27-2.39 (m, 1H), 2.60-2.76 (m, 1H), 2.86-2.98 (m,
1H), 3.66 (t, J ) 6.6 Hz, 2H), 5.40 (dt, J ) 6.4, 2.8 Hz, 1H),
5.72 (s, 2H); 13C NMR δ -5.3, 13.7, 18.3, 18.5, 25.9, 31.4, 36.4,
+17.3 (c 1.15, CHCl3); 1H NMR δ 0.01 (s, 6H), 0.87 (s, 9H),
1.62-1.97 (m, 2H), 2.41-2.55 (m, 1H), 2.75-2.88 (m, 1H),
2.99-3.11 (m, 1H), 3.70 (t, J ) 6.5 Hz, 2H), 5.63 (dt, J ) 6.4,
2.9 Hz, 1H), 5.74-5.83 (m, 2H), 7.38-8.06 (m, 5H); 13C NMR
δ -5.3, 18.3, 25.9, 31.6, 39.5, 45.1, 61.9, 75.9, 127.7, 128.3,
39.4, 44.7, 61.9, 75.0, 127.6, 133.2, 173.5; IR (neat) 1735 cm-1
.
129.6, 130.6, 132.8, 133.2, 166.3; IR (neat) 1719 cm-1
.
(1R,2S)-2-[2-(ter t-Bu tyld im eth ylsilyloxy)eth yl]-3-cyclo-
p en ten -1-yl Deca n oa te (6c). Colorless oil; >99% ee; [R]24
D
1
Ack n ow led gm en t. We thank Amano Pharmaceuti-
cal Co. and Shin-etsu Vinyl Acetate Co. for providing
us with the lipase PS and various vinyl esters, respec-
tively. We thank Dr. Y. Hirose (Amano Pharmaceutical
Co.) for providing information about lipase PS. We
thank Dr. S. Nakajima (Okayama University) for kindly
measuring mass spectra. We are grateful to the SC-
NMR Laboratory of Okayama University for the mea-
surement of NMR spectra. This work was financially
supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science and
Culture of J apan.
) +4.49 (c 1.38, CHCl3); H NMR δ 0.04 (s, 6H), 0.87 (t, J )
6.8 Hz, 3H), 0.88 (s, 9H), 1.20-1.34 (m, 12H), 1.48-1.81 (m,
4H), 2.27 (t, J ) 7.7 Hz, 2H), 2.33-2.38 (m,1H), 2.62-2.76
(m, 1H), 2.84-2.98 (m, 1H), 3.66 (t, J ) 6.6 Hz, 2H), 5.39 (dt,
J ) 6.4, 2.8 Hz, 1H), 5.72 (s, 2H); 13C NMR δ -5.3, 14.1, 18.3,
22.7, 25.0, 25.9, 29.2, 29.3, 29.4, 31.4, 31.8, 34.6, 39.4, 44.7,
61.9, 75.0, 127.6, 133.2, 173.7; IR (neat) 1735 cm-1
.
(1R,2S)-2-[2-(ter t-Bu tyld im eth ylsilyloxy)eth yl]-3-cyclo-
p en ten -1-yl Ch lor oa ceta te (6d ). Colorless oil; >99% ee;
[R]20D ) +12.0 (c 1.15, CHCl3); 1H NMR δ 0.05 (s, 6H), 0.89 (s,
9H), 1.54-1.84 (m, 2H), 2.33-2.46 (m, 1H), 2.66-2.80 (m, 1H),
2.92-3.04 (m, 1H), 3.68 (t, J ) 6.5 Hz, 2H), 4.03 (s, 2H), 5.48
(dt, J ) 6.2, 2.8 Hz, 1H), 5.74 (s, 2H); 13C NMR δ -5.3, 18.3,
25.9, 31.1, 39.3, 41.0, 44.9, 61.7, 127.4, 133.0, 167.1; IR (neat)
1757 cm-1
.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 1-6 and detailed data for the solvent effect in
Figure 2 (22 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(1R,2S)-2-[2-(ter t-Bu tyld im eth ylsilyloxy)eth yl]-3-cyclo-
p en ten -1-yl P iva la te (6e). Colorless oil; % ee not deter-
mined; [R]22 ) +10.1 (c 1.78, CHCl3); 1H NMR δ 0.04 (s, 6H),
D
0.88 (s, 9H), 1.18 (s, 9H), 1.48-1.84 (m, 2H), 2.20-2.33 (m,
1H), 2.62-2.77 (m, 1H), 2.86-3.02 (m, 1H), 3.66 (t, J ) 6.5
Hz, 2H), 5.35 (dt, J ) 6.5, 2.8 Hz, 1H), 5.71 (s, 2H); 13C NMR
δ -5.3, 18.3, 25.9, 27.1, 31.4, 38.9, 39.5, 44.8, 61.8, 74.8, 127.5,
133.1, 178.2; IR (neat) 1728 cm-1
.
J O961144S