Convenient Enzymatic Resolution of Alcohols Using Highly Reactive, Nonharmful Acyl Donors, 1-Ethoxyvinyl Esters

Article abstract of DOI:10.1021/jo9910785

1-Ethoxyvinyl esters 3, a new type of acyl donors for enzymatic resolution of racemic alcohols, were disclosed to be superior to the contemporary major reagents, vinyl esters 1 and isopropenyl esters 2. Three features of 3 are noticeable: (1) 3 generates ethyl acetate as a single coproduct, which does not affect any enzymes, while acetaldehyde liberated from 1 deactivates some kinds of lipases. (2) The reactivity of 3 was not less than that of 1 and much higher than that of 2, and the optical purity of the products was as high as that of 1 and 2. Especially, it was generally observed that 3 showed higher reactivity than 1 for reactions using Candida rugosa lipases, one of the most commonly employed lipases, having liberal applicability to substrates but sensitive to acetaldehyde. Twelve examples of the kinetic resolution of racemic secondary alcohols (5 and 10) and one desymmetrization of meso-alcohol 7 were presented employing the acetate 3a or the octanoate 3b and four types of lipases. (3) A one-pot procedure for the preparation of 3 from the corresponding carboxylic acid and the subsequent enzymatic resolution of alcohols, which has not been reported using 1 or 2, was elucidated. The chemical and optical yields of the products by this procedure were similar to those obtained using isolated 3.

Full text of DOI:10.1021/jo9910785

J . Org. Chem. 2000, 65, 83-88
83
Con ven ien t En zym a tic Resolu tion of Alcoh ols Usin g High ly
Rea ctive, Non h a r m fu l Acyl Don or s, 1-Eth oxyvin yl Ester s
Yasuyuki Kita,* Yasushi Takebe, Kenji Murata, Tadaatsu Naka, and Shuji Akai
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita,
Osaka 565-0871, J apan
Received J uly 6, 1999
1-Ethoxyvinyl esters 3, a new type of acyl donors for enzymatic resolution of racemic alcohols,
were disclosed to be superior to the contemporary major reagents, vinyl esters 1 and isopropenyl
esters 2. Three features of 3 are noticeable: (1) 3 generates ethyl acetate as a single coproduct,
which does not affect any enzymes, while acetaldehyde liberated from 1 deactivates some kinds of
lipases. (2) The reactivity of 3 was not less than that of 1 and much higher than that of 2, and the
optical purity of the products was as high as that of 1 and 2. Especially, it was generally observed
that 3 showed higher reactivity than 1 for reactions using Candida rugosa lipases, one of the most
commonly employed lipases, having liberal applicability to substrates but sensitive to acetaldehyde.
Twelve examples of the kinetic resolution of racemic secondary alcohols (5 and 10) and one
desymmetrization of meso-alcohol 7 were presented employing the acetate 3a or the octanoate 3b
and four types of lipases. (3) A one-pot procedure for the preparation of 3 from the corresponding
carboxylic acid and the subsequent enzymatic resolution of alcohols, which has not been reported
using 1 or 2, was elucidated. The chemical and optical yields of the products by this procedure
were similar to those obtained using isolated 3.
In tr od u ction
acetaldehyde as a single coproduct and thereby produced
optically active compounds in high optical as well as
chemical yields in short reaction periods. However,
acetaldehyde is known to deactivate some kinds of
enzymes [e.g., lipases from Candida rugosa and Geotri-
chum candidum] through, for example, formation of
Schiff bases with ꢀ-amino groups of lysine residues, which
limits the reliable use of 1.4 Although immobilization of
the enzyme on a support was reported to overcome this
problem,4a this technique seems to become laborious
when one surveys a suitable catalyst from a variety of
readily available enzymes. On the other hand, isoprope-
nyl esters 2 are the second most often employed reagents,
which also feature an irreversible system generating
nonharmful acetone as a coproduct; however, they are
generally less reactive than 1.3f Therefore, use of an
alternative, highly reactive acyl donor which does not
produce any enzyme inhibitors must become the best
method facilitating the use of enzymes without any
modification.
Recently we briefly communicated that 1-ethoxyvinyl
acetate (3a )5 is such a reagent suitable for this require-
ment, providing high chemical and optical yields of the
products with release of nonharmful volatile ethyl acetate
as a single coproduct (Scheme 1).6,7
We have further evaluated the advantages of 3 over 1
and 2, i.e., general applicability to enzymatic esterifica-
tion of alcohols, higher reactivity for reactions using li-
pases from C. rugosa, and a novel one-pot procedure for
the preparation of 3 and the subsequent enzymatic
resolution of alcohols, which has not been reported using
1 or 2. In this paper, we present full details of these
results in addition to those of our previous communica-
tion.
As well as hydrolysis of esters catalyzed by lipases and
esterases, transesterifications of alcohols with acylating
reagents (acyl donors) catalyzed by the same enzymes
in organic media have been established as efficient
asymmetric syntheses in this decade.1 Important progress
in this method can be mainly attributed to the develop-
ment of effective acyl donors. Among diverse reagents
involving 2-haloethyl esters,2a cyanomethyl esters,2b oxime
esters,2c-g acid anhydrides,2h,i vinyl esters 1,3 and isopro-
penyl esters 2,3 currently 1 is the best reagent and
employed to a major extent. This is because 1 has realized
an irreversible system by generating neutral volatile
(1) For recent reviews, see: (a) Faber, K.; Riva, S. Synthesis 1992,
895-910. (b) Wong, C. H.; Whitesides, G. M. Enzymes in Synthetic
Organic Chemistry; Pergamon: Oxford, 1994; pp 41-130. (c) Naka-
mura, K.; Hirose, Y. J . Synth. Org. Chem. J pn. 1995, 53, 668-677. (d)
Theil, F. Chem. Rev. 1995, 95, 2203-2227. (e) Schoffers, E.; Golebio-
wski, A.; J ohnson, C. R. Tetrahedron 1996, 52, 3769-3826. (f) Faber,
K. Biotransformations in Organic Chemistry, 3rd ed.; Springer-
Verlag: Berlin, 1997. (g) Schmid, R. D.; Verger, R. Angew. Chem., Int.
Ed. Engl. 1998, 37, 1608-1633.
(2) Trifluoroethyl esters and chloroethyl esters: (a) Kirchner, G.;
Scollar, M. P.; Klibanov, A. M. J . Am. Chem. Soc. 1985, 107, 7072-
7076. Cyanomethyl esters: (b) West, J . B.; Scholten, J .; Stolowich, N.
J .; Hogg, J . L.; Scott, A. I.; Wong, C.-H. J . Am. Chem. Soc. 1988, 110,
3709-3710. Oxime esters: (c) Ghogare, A.; Kumar, G. S. J . Chem. Soc.,
Chem. Commun. 1989, 1533-1535. (d) Gotor, V.; Pulido, R. J . Chem.
Soc., Perkin Trans. 1 1991, 491-492. (e) Mischitz, M.; Po¨schl, U.;
Faber, K. Biotechnol. Lett. 1991, 13, 653-656. (f) Pulido, R.; Ortiz, F.
L.; Gotor, V. J . Chem. Soc., Perkin Trans. 1 1992, 2891-2898. (g) Gotor,
V.; Moris, F. Synthesis 1992, 626-628. Acid anhydrides: (h) Bianchi,
D.; Cesti, P.; Battistel, E. J . Org. Chem. 1988, 53, 5531-5534. (i)
Uemura, A.; Nozaki, K.; Yamashita, J .; Yasumoto, M. Tetrahedron Lett.
1989, 30, 3817-3818.
(3) (a) Degueil-Castaing, M.; J eso, B. D.; Drouillard, S.; Maillard,
B. Tetrahedron Lett. 1987, 28, 953-954. (b) Wang, Y.-F.; Wong, C.-H.
J . Org. Chem. 1988, 53, 3127-3129. (c) Terao, Y.; Murata, M.; Achiwa,
K.; Nishio, T.; Akamtsu, M.; Kamimura, M. Tetrahedron Lett. 1988,
29, 5173-5176. (d) Laumen, K.; Breitgoff, D.; Schneider, M. P. J . Chem.
Soc., Chem. Commun. 1988, 1459-1461. (e) Wang, Y.-F.; Lalonde, J .
J .; Momongan, M.; Bergbreiter, D. E.; Wong, C.-H. J . Am. Chem. Soc.
1988, 110, 7200-7205. (f) Hiratake, J .; Inagaki, M.; Nishioka, T.; Oda,
J . J . Org. Chem. 1988, 53, 6130-6133.
(4) (a) Berger, B.; Faber, K. J . Chem. Soc., Chem. Commun. 1991,
1198-1200. (b) Weber, H. K.; Zuegg, J .; Faber, K.; Pleiss, J . J . Mol.
Catal., B 1997, 3, 131-138.
10.1021/jo9910785 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/07/2000

84 J . Org. Chem., Vol. 65, No. 1, 2000
Kita et al.
Sch em e 1
3a using lipases AY and CRL (both from C. rugosa) were
about 2-3 times faster than those of 1a (Figure 1d,e).
In all reactions of 3a , the alcohol was completely con-
verted to the corresponding acetate 4. Thus, excellent
applicability of the new acyl donor 3a to the enzymatic
reactions was disclosed.
We next compared 1a and 3a on the kinetic resolution
of a racemic secondary alcohol 5 using lipase AY. The
results summarized in Table 1 reveal two advantages of
3a : First, 3a was much more reactive than 1a ; viz.,
reaction using 3a reached 50% conversion after 2.5 h,
while the similar reaction using 1a took 120 h to reach
30% conversion. The E values9 for both reactions were
equal (runs 1 and 3). Second, a striking contrast between
1a and 3a was observed about the reproducibility of
recovered lipases: the recovered lipase from run 1
retained similar reactivity with even higher enantiose-
lectivity (run 2), whereas the lipase recovered from run
3 completely lost its reactivity (run 4).
Sch em e 2
Sch em e 3
Comparison of three acetyl donors, 1a , 2a , and 3a , on
desymmetrization of a meso-diol (7) employing lipase AY
was also studied under the same reaction conditions
(Table 2). It is obvious that the relative reactivity was in
the order 3a > 1a > 2a , and 3a afforded the best
chemical and optical yields of the product (-)-8, although
the differences were small.
The kinetic resolution of various types of racemic
secondary alcohols 10 by 3a or the octanoate 3b was
investigated employing lipases PS, PS-D (PS immobilized
on diatomaceous earth), AK, and CAL-B (Table 3). In
every run, the reaction proceeded within a reasonable
period using only a slight excess amount (0.7 equiv) of 3.
After the conversion reached about 50%, the reaction
mixture was filtered, and the filtrate was concentrated.
Purification by SiO2 chromatography gave the unreacted
alcohol 10 and the ester 11 (method A).10 The E values
of these reactions were good to excellent and were by no
means inferior to the reported values using 1a .
On e-P ot P r oced u r e for th e P r ep a r a tion of
Eth oxyvin yl Ester s 3 fr om Ca r boxylic Acid s a n d
Su bsequ en t En zym a tic Resolu tion of Ra cem ic Al-
coh ols. In the previous section, we used 3 purified by
distillation or chromatography (method A). On the other
hand, one-pot operation for the preparation and subse-
quent enzymatic reaction of 3 (method B) also provided
the same products with retention of the high reactivity
and enantioselectivity (Scheme 4).
A typical procedure is presented for the resolution of
10a by 3a : According to the standard preparation of 3,8
a solution of acetic acid (1.6 mmol, 0.8 equiv compared
to 10a ) in i-Pr2O (0.8 mL) was added to a mixture of
ethoxyacetylene (2.1 mmol) and [RuCl2(p-cymene)]2 (6
µmol) in i-Pr2O (2.2 mL) at 0 °C. The reaction mixture
was stirred at 0 °C for 0.5 h and at room temperature
for 1 h and then was added to a mixture of (()-10a (2.0
mmol) and lipase PS-D (80 mg) in i-Pr2O (2.9 mL). The
whole mixture was stirred at 30 °C for 6 h. Usual workup
and purification gave (S)-10a (45%, >99% ee) and (R)-
11a (46%, 96% ee) (Table 4, run 1). This method was
similarly applied to the resolution of 10a by lipase AK
and 3a and that of 10g by CAL-B and 3b to give (S)-
Resu lts a n d Discu ssion
Ap p lica bility, Rea ctivity, a n d Ster eoselectivity of
1-Eth oxyvin yl Ester s 3 Com p a r ed w ith Th ose of
Vin yl Ester s 1 a n d Isop r op en yl Ester s 2. 1-Ethoxy-
vinyl esters 3 are readily available by the addition of the
corresponding carboxylic acids to ethoxyacetylene in the
presence of a catalytic amount (e0.5 mol % equiv) of
[RuCl2(p-cymene)]2 in high yields,8 easy to handle, and,
in most cases, storable in a freezer over a year without
any significant decomposition (Scheme 2).
At first, general applicability and reactivity of the
acetate 3a for the enzymatic reactions were examined
by esterification of 1-octanol, comparing with those of
corresponding 1a and 2a (Scheme 3 and Figure 1). As
shown in Figure 1a, 3a showed reactivity almost equal
to that of 1a and approximately 4 times higher reactivity
than 2a for the reaction using lipase PS (from Pseudomo-
nas cepacia). Similar reactivity of 3a to 1a was also
observed for the reactions using lipases AK (from
Pseudomonas fluorescens) and CAL-B (from Candida
antarctica) (Figure 1b,c). Interestingly, the reactions of
(5) We have disclosed various types of very mild and convenient
reactions utilizing the ketene acetal reagents I. Thus, the reactions
with nucleophiles (Nu-H) proceed in inert solvents at room-to-moderate
temperature to give the products II accompanied by formation of
volatile esters III as the only coproducts. Simple concentration of the
reaction mixture gives pure II in high yields. For reviews, see: Kita,
Y.; Tamura, O.; Tamura, Y. J . Synth. Org. Chem. J pn. 1986, 44, 1118-
1133. Kita, Y.; Shibata, N. Synlett 1996, 289-296.
(6) Kita, Y.; Takebe, Y.; Murata, K.; Naka, T.; Akai, S. Tetrahedron
Lett. 1996, 37, 7369-7372.
(7) Application of 1-ethoxyvinyl acetate (3a ) to enzymatic esterifi-
cation was also presented by another group; see: Schudok, M.;
Kretzschmar, G. Tetrahedron Lett. 1997, 38, 387-388.
(8) Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. J . Chem.
Soc., Perkin Trans. 1 1993, 2999-3005. Shibata N.; Matsugi M.;
Kawano N.; Fukui S.; Fujimori C.; Gotanda K.; Murata K.; Kita Y.
Tetrahedron: Asymmetry 1997, 8, 303-310.
(9) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294-7299.
(10) A blank experiment of run 1 was run without the lipase (other
conditions are the same), resulting in only 5% conversion after 7 d.

Enzymatic Resolution of Alcohols
J . Org. Chem., Vol. 65, No. 1, 2000 85
F igu r e 1. Time course of the reaction of 1-octanol (0.77 mmol) with the acetyl donor 1a , 2a , or 3a catalyzed by (a) lipase PS, (b)
lipase AK, (c) CAL-B, (d) lipase AY, and (e) CRL. Reaction conditions: for (a), lipase PS (50 mg), acyl donor (1.5 mmol), i-Pr2O (20
mL), 30 °C; for (b), lipase AK (15 mg), acyl donor (1.5 mmol), i-Pr2O (20 mL), 30 °C; for (c), CAL-B (5 mg), acyl donor (1.5 mmol),
i-Pr2O (20 mL), 30 °C; for (d), lipase AY (500 mg), acyl donor (2.3 mmol), i-Pr2O-H2O (1000:1, 20 mL), 30 °C; for (e), CRL (500
mg), acyl donor (1.5 mmol), i-Pr2O-H2O (1000:1, 20 mL), 30 °C.
10a ,g and (R)-11a ,h in high chemical and optical yields
(runs 2 and 3). In Table 4, a comparison of methods A
and B is also given to show no particular difference in
terms of the reaction time and chemical and optical yields
of the products.
to its native high reactivity, use of 3 for enzymatic
esterification reactions should enhance their practical
efficacy.
On the other hand, selection of the acyl moiety of an
acyl donor is well-known to be crucial to improve chemi-
cal and optical yields13 and also the stability of the
products.14 However, reported examples were limited to
commercially available 1 involving linear aliphatic acyl
groups and a few simple unsaturated acyl groups.13,15,16
Con clu sion s
1-Ethoxyvinyl esters 3, readily prepared and easy-to-
handle acylating donors, feature reactivity similar to and
enantioselectivity at least as high as those of 1 and 2 for
enzymatic resolution of a wide range of alcohols. Espe-
cially, 2-3 times higher reactivity of 3 than 1 was
generally observed from the reactions using C. rugosa
lipases. It is worth mentioning that C. rugosa lipases
have often been employed in recent years due to their
liberal applicability to bulky substrates despite their
sensitivity to acetaldehyde.1b,12 Considering that 3 pro-
duces a nonharmful coproduct, ethyl acetate, in addition
(12) For examples, see: Lautens, M.; Ma, S.; Yee, A. Tetrahedron
Lett. 1995, 36, 4185-4188. Nair, M. S.; Anilkumar, A. T. Tetrahe-
dron: Asymmetry 1996, 7, 511-514. Cheˆnevert, R.; Goupil, D.; Rose,
Y. S.; Be´dard, E. Tetrahedron: Asymmetry 1998, 9, 4285-4288.
(13) For examples, see: Stokes, T. M.; Oehlschlager, A. C. Tetra-
hedron Lett. 1987, 28, 2091-2094. Ema, T.; Maeno, S.; Takaya, Y.;
Sakai, T.; Utaka, M. Tetrahedron: Asymmetry 1996, 7, 625-628; J .
Org. Chem. 1996, 61, 8610-8616. Nakamura, K.; Takenaka, K.; Ohno,
A. Tetrahedron: Asymmetry 1998, 9, 4429-4439. For the use of vinyl
benzoate and vinyl phenylacetate, see: Holla, E. W. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 220-221. Delinck, D. L.; Margolin, A. L.
Tetrahedron Lett. 1990, 31, 3093-3096. Margolin, A. L.; Delinck, D.
L.; Whalon, M. R. J . Am. Chem. Soc. 1990, 112, 2849-2854.
(14) For an example, see: Akai S.; Naka T.; Takebe Y.; Kita Y.
Tetrahedron Lett. 1997, 38, 4243-4246.
(11) Nakamura, K.; Kinoshita, M.; Ohno, A. Tetrahedron 1995, 51,
8799-8808.

86 J . Org. Chem., Vol. 65, No. 1, 2000
Kita et al.
Ta ble 1. Kin etic Resolu tion of (()-5 Usin g 1a or 3a
column (250 mm × 4.6 mm, eluent: hexane-i-PrOH). Column
chromatographic purification was done using silica gel 60 (70-
230 mesh, Merck Co., Ltd.) or silica gel BW-300 (200-400
mesh, Fuji Silysia Chemical Co., Ltd., J apan). Lipases PS (from
P. cepacia), PS-D (PS immobilized on diatomaceous earth), AK
(from P. fluorescens), and AY (from C. rugosa) were gifts from
Amano Pharmaceutical Co., Ltd., J apan. CAL-B (CHIRA-
ZYME L2, from C. antarctica, fraction B) was a gift from Roche
Diagnostics. CRL (LIPASE type VII, from C. rugosa) was
purchased from Aldrich. Enzymes were dried (1 mmHg, room
temperature, overnight) prior to use. Yields refer to isolated
material of g95% purity as determined by 1H NMR. All the
products (5, 6, 8, 9, 10, and 11), except for 11i, are known
and well identified by spectroscopic data.
Ca ta lyzed by Lip a se AY
ee (%)a
acyl
donor
reaction
time
conversion
(%)
E
run
(-)-5
(+)-6
value
1
3a
3a
1a
1a
2.5 h
12 h
120 h
11 d
52
51
31
78
81
40
72
79
81
14
21
14
2b
3
4c
e10
1-Eth oxyvin yl a ceta te (3a ) was prepared by the reported
method.8
a
Determined by HPLC using Daicel CHIRALCEL OD (hexane-
i-PrOH) after conversion to the corresponding 3,5-dinitrobenzoate.
Conversion of 6 to the 3,5-dinitrobenzoate was run by alkaline
hydrolysis followed by esterification. b The enzyme recovered from
run 1 was reused after drying (<0.1 mmHg, room temperature, 2
d). c The enzyme recovered from run 3 was reused after drying
(same as footnote b).
1-Eth oxyvin yl octa n oa te (3b) was prepared from octanoic
acid (1.08 g, 7.5 mmol), ethoxyacetylene (840 mg, 12 mmol),
and [RuCl2(p-cymene)]2 (14 mg, 23 µmol) in i-Pr2O (30 mL)
similarly to the reported procedure.8 The crude product was
purified by distillation under reduced pressure to give 1.09 g
(68%) of pure 3b as a colorless oil: bp 65-67 °C (0.6 mmHg);
1H NMR (300 MHz, CDCl3) δ 0.88 (3H, t, J ) 7.0 Hz), 1.27-
1.45 (11H, m), 1.60-1.75 (2H, m), 2.42 (2H, t, J ) 7.5 Hz),
3.76 (1H, d, J ) 3.5 Hz), 3.81 (1H, d, J ) 3.5 Hz), 3.87 (2H, q,
J ) 7.0 Hz); IR (CHCl3) 1767, 1674 cm-1. Anal. Calcd for
Ta ble 2. Desym m etr iza tion of 7 Usin g 1a -3a Ca ta lyzed
by Lip a se AY
C
12H22O3: C, 67.29; H, 10.35. Found: C, 67.16; H, 10.14.
Lip a se-Ca ta lyzed Ester ifica tion of 1-Octa n ol by 1a -
3a for Com p a r ison of Th eir Rea ctivity. Gen er a l P r oce-
d u r e. A mixture of 1-octanol (0.77 mmol) and an acyl donor
(1a -3a ) in a solvent was stirred at 30 °C for 10 min, to which
was added a lipase. The reaction mixture was stirred at the
same temperature, and the conversion was determined by GLC
using a G-100 column. The results are shown in Figure 1. The
reaction conditions for each run are listed in the caption.
Kin etic Resolu tion of (()-en d o-Bicyclo[2.2.1]h ep t-5-en -
2-ol (5). To a solution of (()-5 (165 mg, 1.5 mmol) in hexane-
H2O (1000:1, 5 mL) were added lipase AY (165 mg) and an
acyl donor (1a or 3a ) (1.5 mmol). The reaction mixture was
stirred at 30 °C for the time shown in Table 1 and filtered
through a Celite pad. The filtrate was concentrated in vacuo,
and the residue was purified by column chromatography
(hexanes-Et2O, 1:1) to give (-)-5 (76 mg, 46% for run 1, and
90 mg, 55% for run 3) as colorless oil and (+)-6 (90 mg, 55%
for run 1, and 55 mg, 24% for run 3). The optical purities of
(-)-5 and (+)-6 and their determination method are shown in
Table 1.
(-)-8
acyl
donor
reaction
time (h)
isolated
yield (%)
ee
yield
of 9 (%)
run
(%)a
1
2
3
3a
1a
2a
7
31
170
75
74
70
86
84
78
13
14
18
Determined by 1H NMR analysis with Eu(hfc)3.
a
We believe the present procedures (methods A and B)
offer not only a convenient screening protocol of a wide
range of acyl moieties14 but also extensive application of
tailor-made and/or unstable 3 for rarely developed new
variants of enzyme-catalyzed asymmetric synthesis.17
(1S,2S,4S)-Bicyclo[2.2.1]h ep t-5-en -2-ol (5): 78% ee, [R]22
D
-113 (CHCl3, c 1.7) {lit.18 [R]20 +162 (CHCl3, c 19) for >97%
D
ee of the (1R,2R,4R)-isomer}; 1H NMR (200 MHz, CDCl3) δ
0.70-0.82 (1H, m), 1.05-1.37 (3H, m), 2.00-2.18 (1H, m), 2.83
(1H, br s), 3.13 (1H, br s), 4.40-4.50 (1H, m), 6.05-6.08 (1H,
Exp er im en ta l Section
m), 6.40-6.47 (1H, m); IR (CHCl3) 3550 cm-1
.
Gen er a l Meth od . GLC analyses were carried out using a
column (2 m × 3 mm) filled with 5% PEG-20M or a G-100
column (40 m × 1.2 mm, Chemical Inspection and Testing
Institute, J apan). 1H NMR spectra were measured at 200-
300 MHz with TMS as an internal standard. IR spectra were
recorded by diffuse reflectance measurement of samples
dispersed in KBr powder or as a CHCl3 solution. Chiral HPLC
analyses were carried out using a Daicel CHIRALCEL OD
(1R,2R,4R)-Bicyclo[2.2.1]h ep t-5-en -2-yl Aceta te (6): 1H
NMR (200 MHz, CDCl3) δ 0.85-0.93 (1H, m), 1.15-1.40 (3H,
m), 1.40-1.52 (1H, m), 1.98 (3H, s), 2.02-2.20 (1H, m), 2.84
(1H, br s), 3.13 (1H, br s), 5.20-5.32 (1H, m), 5.90-6.00 (1H,
m), 6.30-6.40 (1H, m); IR (KBr) 1725 cm-1
.
Desym m etr iza tion of cis-exo-2,3-Bis(h yd r oxym eth yl)-
7-oxa bicyclo[2.2.1]h ep ta n e (7). To a solution 7 (158 mg, 1.0
mmol) in i-Pr2O-H2O (1000:1, 10 mL) were added lipase AY
(300 mg) and an acyl donor (1a -3a ) (5.0 mmol). The reaction
mixture was stirred at 30 °C for the time shown Table 2 and
filtered through a Celite pad. The filtrate was concentrated
in vacuo, and the residue was purified by column chromatog-
raphy (hexanes-EtOAc, 2:1) to give (-)-8 and 9. The yields of
8 and 9 and optical purity of 8 are shown in Table 2.
(15) Examples of the preparation of some specified vinyl esters and
their use for enzymatic reaction have been reported. However,
preparation of the vinyl esters was run by transesterification between
large amounts of vinyl acetate and the carboxylic acids under strong
basic conditions in moderate-to-high yields (59-90%). Enzymatic
reactions were carried out after purification of the vinyl esters. See:
Lobell, M.; Schneider, M. P. Tetrahedron: Asymmetry 1993, 4, 1027-
1030; Synthesis 1994, 375-377. A similar preparation of vinyl esters
was also reported by the use of catalytic amounts of Hg(OAc)2 and
100% H2SO4. See: Swern, D.; J ordan, E. F., J r. Organic Syntheses;
Wiley: New York, 1963, Collect. Vol. 4, pp 977-980.
(16) For the preparation of functionalized isopropenyl esters, see:
Kita, Y.; Maeda, H.; Takahashi, F.; Fukui, S. J . Chem. Soc., Perkin
Trans. 1 1993, 2639-2649.
(17) For an example, see: Kita, Y.; Naka, T.; Imanishi, M.; Akai,
S.; Takebe, Y.; Matsugi, M. Chem. Commun. 1998, 1183-1184.
(2R,3S)-2-[(Acet yloxy)m et h yl]-3-(h yd r oxym et h yl)-7-
oxa bicyclo[2.2.1]h ep ta n e (8): 86% ee, [R]22D -10.8 (EtOAc,
c 0.24) {lit.19 [R]20 -14.6 (EtOAc, c 0.2) for 96.5% ee of the
D
(18) Oberhauser, Th.; Bordenteich, M.; Faber, K.; Penn, G.; Griengl.
H. Tetrahedron 1987, 43, 3931-3944.
(19) Andreu, C.; Marco, J . A.; Asencio, G. J . Chem. Soc., Perkin
Trans. 1 1990, 3209-3210.

Enzymatic Resolution of Alcohols
J . Org. Chem., Vol. 65, No. 1, 2000 87
Ta ble 3. Lip a se-Ca ta lyzed Kin etic Resolu tion of (()-10 Usin g 3a ,b (Meth od A)
a
b
Determined by HPLC using Daicel CHIRALCEL OD (hexane-i-PrOH). The absolute configuration was determined by comparison
of the specific rotation of the recovered 10 with that of an authentic sample. c Determined after saponification of 11 to corresponding 10.
Determined after conversion to the corresponding 3,5-dinitrobenzoate. Conversion of 11g,h to the 3,5-dinitrobenzoate was run by
d
saponification followed by esterification.
mg, 48%, >99% ee) and (R)-11a (155 mg, 47%, 96% ee). The
reaction conditions, the conversion, and the optical purity of
the products 10 and 11 for other cases are summarized in
Table 3. The optical purity and the absolute configuration of
the products were determined as shown in the footnotes of
Table 3.
Sch em e 4
(S)-1-P h en yleth a n ol (10a ): [R]22 -58.8 (c-C5H10, c 1.1)
D
{lit.20 [R]D -49.7 (c-C5H10, c 2.0) for 91% ee}; 1H NMR (270
MHz, CDCl3) δ 1.49 (3H, d, J ) 6.0 Hz), 1.90 (1H, br s), 4.89
(1H, q, J ) 6.0 Hz), 7.25-7.37 (5H, m); IR (KBr) 3358 cm-1
.
(R)-1-P h en yleth yl Aceta te (11a ): 1H NMR (270 MHz,
CDCl3) δ 1.53 (3H, d, J ) 6.5 Hz), 2.07 (3H, s), 5.88 (1H, q, J
) 6.5 Hz), 7.27-7.36 (5H, m); IR (KBr) 1732 cm-1
.
(S)-1-(4-Met h oxyp h en yl)et h a n ol (10b ): [R]22 -52.5
1
(2R,3S)-form}; H NMR (270 MHz, CDCl3) δ 1.48-1.58 (2H,
m), 2.06 (3H, s), 2.00-2.25 (2H, m), 3.50-3.70 (2H, m), 3.92-
D
(CHCl3, c 0.7) {lit.21 [R]21 +47.2 (CHCl3, c 0.9-1.1) for 89%
D
ee of the (R)-form}; 1H NMR (200 MHz, CDCl3) δ 1.49 (3H, d,
J ) 6.5 Hz), 1.75 (1H, br s), 3.81 (3H, s), 4.86 (1H, q, J ) 6.5
Hz), 6.86-6.91 (2H, m), 7.26-7.33 (2H, m); IR (KBr) 3382
4.20 (2H, m), 4.38-4.52 (2H, m); IR (KBr) 1740 cm-1
.
(2R,3S)-2,3-Bis[(a cetyloxy)m eth yl]-7-oxa bicyclo[2.2.1]-
h ep ta n e (9): 1H NMR (300 MHz, CDCl3) δ 1.50-1.56 (2H,
m), 1.72-1.83 (2H, m), 2.07 (6H, s), 2.18-2.28 (2H, m), 3.90-
4.03 (2H, m), 4.07-4.18 (2H, m), 4.40-4.46 (2H, m); IR (KBr)
cm-1
.
(R)-1-(4-Meth oxyp h en yl)eth yl Aceta te (11b): 1H NMR
(200 MHz, CDCl3) δ 1.52 (3H, d, J ) 6.5 Hz), 2.05 (3H, s),
3.80 (3H, s), 5.85 (1H, q, J ) 6.5 Hz), 6.85-6.92 (2H, m), 7.25-
1732 cm-1
.
Lip a se-Ca ta lyzed Kin etic Resolu tion s of (()-10a . Typ i-
ca l P r oced u r e for Meth od A. A mixture of (()-10a (246 mg,
2.0 mmol), 3a (182 mg, 1.4 mmol), and lipase PS (80 mg) in
i-Pr2O (6.0 mL) was stirred at 30 °C for 5.5 h. The lipase
powder was filtered off through a Celite pad, and the filtrate
was concentrated in vacuo. The crude product was purified
by chromatography (hexanes-Et2O, 3:1) to give (S)-10a (117
7.33 (2H, m); IR (KBr) 1734 cm-1
.
(20) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem.
Soc. 1986, 108, 6071-6072.
(21) Hayashi, T.; Matsumoto, Y.; Ito, Y. J . Am. Chem. Soc. 1989,
111, 3426-3428.

88 J . Org. Chem., Vol. 65, No. 1, 2000
Ta ble 4. Kin etic Resolu tion of (()-10 by a On e-P ot P r oced u r e (Meth od B)a
Kita et al.
a
b
Results by method A are cited from Table 1. The ee value for 10 was determined by HPLC using Daicel CHIRALCEL OD (hexane-
i-PrOH). The ee value for 11 was determined after saponification of 11 into corresponding 10 otherwise noted. c Th ee value was determined
after conversion to the corresponding 3,5-dinitrobenzoate. Conversion of 11h to the 3,5-dinitrobenzoate was run by saponification followed
by esterification.
(S)-1-(4-Ch lor op h en yl)eth a n ol (10c): [R]22D -49.6 (Et2O,
(R)-6-Meth yl-5-h ep ten -2-yl Octa n oa te (11h ): 1H NMR
(300 MHz, CDCl3) δ 0.88 (3H, t, J ) 6.0 Hz), 1.20-1.40 (11H,
m) 1.40-1.75 (10H, m), 2.00 (2H, q, J ) 7.0 Hz), 2.26 (2H, t,
J ) 7.0 Hz), 4.80-4.95 (1H, m), 5.00-5.10 (1H, m); IR (CHCl3)
c 1.8) {lit.21 [R]21 +46.1 (Et2O, c 0.9-1.1) for 91% ee of the
D
1
(R)-form}; H NMR (200 MHz, CDCl3) δ 1.48 (3H, d, J ) 6.5
Hz), 1.81 (1H, d, J ) 3.5 Hz), 4.89 (1H, dd, J ) 6.5, 3.5 Hz),
7.31 (4H, s); IR (KBr) 3329 cm-1
.
1720 cm-1
.
(R)-1-(4-Ch lor op h en yl)eth yl Aceta te (11c): 1H NMR
(200 MHz, CDCl3) δ 1.51 (3H, d, J ) 6.5 Hz), 2.06 (3H, s),
5.83 (1H, q, J ) 6.5 Hz), 7.29-7.35 (4H, m); IR (KBr) 1740
(S)-1-Octyn -3-ol (10h ): [R]24 -6.0 (pentane, c 1.0) {lit.24
D
[R]20D -3.57 (pentane, c 5.39) for 21% ee}; 1H NMR (300 MHz,
CDCl3) δ 0.90 (3H, t, J ) 6.5 Hz), 1.30-1.80 (9H, m), 2.47 (1H,
cm-1
.
d, J ) 2.0 Hz), 4.30-4.40 (1H, m); IR (CHCl3) 3300 cm-1
.
(S)-1-P h en yl-1-p r op a n ol (10d ): [R]22D -43.9 (CHCl3, c 1.7)
{lit.20 [R]D -47.6 (CHCl3, c 6.1) for 98% ee}; 1H NMR (200 MHz,
CDCl3) δ 0.93 (3H, t, J ) 7.5 Hz), 1.70-1.90 (3H, m), 4.55-
(R)-1-Octyn -3-yl Octa n oa te (11i): [R]24D -36.9 (pentane,
1
c 1.1); H NMR (300 MHz, CDCl3) δ 0.88 (3H, t, J ) 7.0 Hz),
0.90 (3H, t, J ) 6.5 Hz), 1.30-1.80 (18H, m), 2.33 (2H, t, J )
7.5 Hz), 2.44 (1H, d, J ) 2.0 Hz), 5.36 (1H, td, J ) 6.5, 2.0
Hz); IR (CHCl3) 1732 cm-1. Anal. Calcd for C16H28O2: C, 76.14;
H, 11.18. Found: C, 76.12; H, 11.13.
4.68 (1H, m), 7.20-7.40 (5H, m); IR (KBr) 3354 cm-1
.
(R)-1-P h en yl-1-p r op yl Aceta te (11d ): 1H NMR (200
MHz, CDCl3) δ 0.88 (3H, t, J ) 7.5 Hz), 1.78-1.95 (2H, m),
2.08 (3H, s), 5.66 (1H, t, J ) 7.5 Hz), 7.30-7.34 (5H, m); IR
Lip a se-Ca ta lyzed Kin etic Resolu tion of (()-10a by a
On e-P ot P r oced u r e. Typ ica l P r oced u r e for Meth od B.
To an ice-cooled solution of ethoxyacetylene (168 mg, 2.1 mmol)
and [RuCl2(p-cymene)]2 (3.9 mg, 6.4 µmol) in anhydrous i-Pr2O
(2.2 mL) was added dropwise a solution of acetic acid (96 mg,
1.6 mmol) in anhydrous i-Pr2O (0.8 mL). The reaction mixture
was stirred at 0 °C for 0.5 h, warmed to room temperature,
and stirred for an additional 1 h. This mixture was added to
a mixture of (()-10a (244 mg, 2.0 mmol) and lipase PS-D (80
mg) in anhydrous i-Pr2O (2.9 mL). The remainder of the
procedure is the same as described in method A to give (S)-
10a (109 mg, 45%, >99% ee) and (R)-11a (152 mg, 46%, 96%
ee). The reaction conditions, isolated yields, and optical purity
of the products 10 and 11 for other cases are summarized in
Table 4. All products obtained by this method are identical,
except for the optical purity, with the compounds obtained by
(KBr) 1736 cm-1
.
(R)-2-Ch lor o-1-p h en yleth a n ol (10e): [R]22 -58.9 (c-
D
C6H12, c 1.3) {lit.22 [R]D +53.3 (c-C6H12, c 2) for the (S)-form};
1H NMR (200 MHz, CDCl3) δ 2.65 (1H, d, J ) 3.0 Hz), 3.60-
3.80 (2H, m), 4.86-4.96 (1H, m), 7.26-7.43 (5H, m); IR (KBr)
3320 cm-1
.
(S)-2-Ch lor o-1-p h en yleth yl Aceta te (11e): 1H NMR (200
MHz, CDCl3) δ 2.14 (3H, s), 3.60-3.90 (2H, m), 5.96 (1H, dd,
J ) 7.5, 5.0 Hz), 7.37 (5H, s); IR (KBr) 1748 cm-1
.
(S)-1-In d a n ol (10f): [R]22 +30.8 (CHCl3, c 0.8) {lit.23 [R]D
D
1
+24.4 (CHCl3, c 2) for 71% ee}; H NMR (200 MHz, CDCl3) δ
1.70 (1H, d, J ) 7.0 Hz), 1.87-2.03 (1H, m), 2.42-2.58 (1H,
m), 2.75-2.90 (1H, m), 3.00-3.12 (1H, m), 5.21-5.30 (1H, m),
7.21-7.45 (4H, m); IR (KBr) 3339 cm-1
.
(R)-1-In d a n yl Aceta te (11f): 1H NMR (200 MHz, CDCl3)
δ 2.00-2.43 (1H, m), 2.06 (3H, s), 2.43-2.54 (1H, m), 2.82-
2.93 (1H, m), 3.05-3.15 (1H, m), 6.20 (1H, dd, J ) 4.0, 7.0
method A. 10a (run 1), [R]24 -54.1 (c-C5H10, c 1.8); 10a (run
D
2), [R]23D -50.3 (c-C5H10, c 1.9); 10g (run 3); [R]22D +13.1 (EtOH,
Hz), 7.12-7.43 (4H, m); IR (KBr) 1734 cm-1
.
c 1.0).
(S)-6-Meth yl-5-h ep ten -2-ol (10g): [R]22 +14.0 (EtOH, c
D
0.7) {lit.11 [R]D +16.6 (EtOH, c 1.0) for 99.9% ee}; 1H NMR
(250 MHz, CDCl3) δ 1.19 (3H, d, J ) 7.0 Hz), 1.38-1.60 (2H,
m), 1.63 (3H, s), 1.69 (3H, s), 1.90-2.20 (2H, m), 3.70-3.85
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research No. 09557180 from
the Ministry of Education, Science, Sports, and Culture,
J apan. We thank Noriyuki Kawano for technical as-
sistance. Amano Pharmaceutical Co., Ltd., J apan, and
Roche Diagnostics K. K., J apan, are thanked for their
generous gifts of lipases.
(1H, m), 5.05-5.20 (1H, m); IR (CHCl3) 3611 cm-1
.
(R)-6-Meth yl-5-h ep ten -2-yl Aceta te (11g): 1H NMR (200
MHz, CDCl3) δ 1.21 (3H, d, J ) 5.0 Hz), 1.40-1.70 (2H, m),
1.60 (3H, s), 1.68 (3H, s), 1.90-2.10 (2H, m), 2.03 (3H, s), 4.80-
4.95 (1H, m), 5.00-5.12 (1H, m); IR (CHCl3) 1724 cm-1
.
J O9910785
(22) Kutsuki, H.; Sawa, I.; Hasegawa, J .; Watanabe, K. Agric. Biol.
Chem. 1986, 50, 2369-2373.
(23) Terashima, S.; Tanno, N.; Koga, K. Chem. Lett. 1980, 981-
984.
(24) Kamezawa, M.; Raku, T.; Tachibana, H.; Ohtani, T.; Naoshima,
Y. Biosci. Biotechnol. Biochem. 1995, 59, 549-551.