Lipase-mediated resolution of racemic benzo-15-crown-5 ether derivatives

Article abstract of DOI:10.1016/S0040-4039(00)00089-7

Racemic large secondary alcohol, 4'-hydroxyethyl-benzo-15-crown-5-ether, (±)-1 was kinetically resolved in high optical yield by asymmetric transformation with Candida antarctica lipase and Pseudomonas cepacia lipase. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00089-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2125–2127
Lipase-mediated resolution of racemic benzo-15-crown-5
ether derivatives
∗
Tatsuro Kijima, Takanori Moriya, Eiki Kondoh and Taeko Izumi
Department of Materials Science and Technology, Faculty of Engineering, Yamagata University Jonan, Yonezawa,
Yamagata, 992-8510, Japan
Received 26 November 1999; revised 5 January 2000; accepted 7 January 2000
Abstract
0
Racemic large secondary alcohol, 4 -hydroxyethyl-benzo-15-crown-5-ether, (±)-1 was kinetically resolved in
high optical yield by asymmetric transformation with Candida antarctica lipase and Pseudomonas cepacia lipase.
©
2000 Elsevier Science Ltd. All rights reserved.
Keywords: crown ether; enzyme and enzyme reaction; transesterification; resolution.
Lipases have recently been recognized as effective catalysts in synthetic organic reactions as well as in
1
biological reactions and provide an interesting alternative method for resolution of enantiomers. They
catalyze esterification and hydrolysis of various alcohol substrates having fluorinated, organometallic,
2
and other exotic functional groups. Optically active crown compounds are of great interest in view of
3
their pathological and physiological properties. Recently, lipase was observed to resolve crown ether
4
compounds. We now report that Candida antarctica (CA) and Pseudomonas cepacia (PS) lipases are
an effective catalyst for resolution of racemic large secondary alcohol having a crown ether ring as a
variation of 1-phenylethanol.
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Among several enzymes, CA lipase (CAL) and lipase PS were found to accelerate transesterification
6
,11
of crown (±)-1
in toluene at 30°C in the presence of vinyl acetate to give the corresponding ester
2
a in excellent yield and ee (enantiomeric excess), Scheme 1. Other lipases such as lipase MY, lipase
OF, lipase AY, CCL (Candida cylindracea lipase) and PPL (Porcine pancreas lipase) were less reactive
than CAL and lipase PS under the same reaction conditions. Commercially available acyl donors (vinyl
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butyrate, vinyl hexanoate and vinyl octanoate) were effective under the present reaction conditions. The
reaction can be carried out in THF using CAL as catalyst. The results are summarized in Table 1.
As a typical experiment, CAL (200 mg) and vinyl acetate (3 mmol) were added to a solution of (±)-1
(
0.6 mmol) in toluene (10 ml) and the mixture was vigorously stirred at 30°C. The reaction was quenched
by filtering off the enzyme, and the enzyme portion was washed with 30 ml of chloroform. Standard
∗
Corresponding author. Fax: +81-238-26-3413; e-mail: kijima@chem.yz.yamagata-ac.jp (T. Kijima)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00089-7
tetl 16376

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Scheme 1.
Table 1
Lipase-catalyzed enantioselective transesterification of (±)-1
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work-up and column chromatography of silica gel (chloroform) gave (R)-(+)-2a in 48% yield (99% ee)
together with (S)-(−)-1 in 45% yield (96% ee).
The enantiomeric excess (% ee) values of 1 and 2 obtained by the kinetic resolutions were determined
by means of HPLC (Daicel, Chiralcel OD column, hexane:2-propanol 9:1). The E values were calculated
9
according to the literature. It was confirmed by a control experiment without lipase that the crown
compound 1 itself cannot function as a catalyst for the transesterification. The absolute configurations
of the ester 2 and the remaining alcohol 1, the former of which was converted into the alcohol, were
1
determined by H NMR (500 MHz) CDCl , from the diastereomeric differences in chemical shifts made
3
10
by the methyl group in (S)-O-methylmanderate esters.
In conclusion, CAL is an excellent catalyst for the transesterification of crown (±)-1 in organic media.
Considering the broad substrate specificity of lipases, this approach is expected to be synthetically useful
for asymmetric preparation of other optically pure alcohols. Further work is under way to resolve crown
compounds of different ring size.
Acknowledgements
We are grateful to Novo Nordisk Bio Industry Co. Ltd, and Amano Pharmaceutical Co. Ltd, for
®
providing us with Novozyme 435 and lipase PS, AY, respectively.

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6
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. Compound (±)-1 was prepared from benzo 15-crown-5 ether, by acetylation (see Ref. 11) with acetic anhydride-
polyphosphoric acid and reduction with NaBH
compound (benzo-15-crown-5 ether) and confirmed by its spectroscopic properties. H NMR (500 MHz, CDCl
4
, subsequently. (±)-1 was obtained in 77% yield of the starting crown
1
3
) δ
6
.83–6.94 (m, 3H, Cp), 4.83 (q, 1H, J=3 Hz, CH), 3.74–4.15 (m, 16H, -O-CH
2
2
-CH -), 3.44 (s, 1H, OH), 1.47 (d, 3H,
−1
J=6.5 Hz, CH
m/z: 312 M .
3
), IR ν (neat), cm : 3400 (OH), 2964 (CH
2
), 1138 (C-O-C), 941 and 860 (1,2,4-substituted benzene), MS
+
7
8
. Kazlauskas, R. J. Biotechnology; Wiley-VCH: Weinheim, 1998; Vol. 8a, pp. 37–192.
1
. H NMR (500 MHz, CDCl
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. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299.
3
) δ 6.80–6.89 (m, 3H, Cp), 5.80 (q, 1H, J=7 Hz, CH
2 2 2
), 3.74–4.18 (m, 16H, -O-CH -CH -), 2.10
(
3
3
).
9
1
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