K. Takabe et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2295–2297
2297
obtained from N-monoalkylbutanamide (entries 8–11).
References and Notes
These tendencies were in good accord with the results of
stereoselectivity in the lipase-catalyzed asymmetric
desymmetrization of the 2-carbamoylmethyl-1,3-diols 5.5
1. Isolation: Kleiner, E. M.; Pilner, S. A.; Soifer, V. S.; Ono-
prienko, V. V.; Balasheva, T. A.; Rozynov, B. V.; Khoklov,
S. A. Bioorg. Khim. 1976, 2, 1142.
2. (a) Asymmetric synthesis: Crawforth, J. M.; Fawcett, J.;
Rawlings, B. J. J. Chem. Soc., Perkin Trans. 1 1998, 1721. (b)
Parsons, P. J.; Lacrouts, P.; Buss, A. D. J. Chem. Soc., Chem.
Commun. 1995, 437. (c) Mori, K.; Chiba, N. Liebigs Ann.
Chem. 1990, 31. (d) Posner, G. H.; Weitzberg, M.; Jew, S.-s.
Synth. Commun. 1987, 17, 611. (e) Mori, K.; Yamane, K.
Tetrahedron 1982, 38, 2919.
3. (a) Kondo, K.; Higuchi, Y.; Sakuda, S.; Nihira, T.;
Yamada, Y. J. Antibiotics 1989, 42, 1873. (b) Nihira, T.; Shi-
mizu, Y.; Kim, H. S.; Yamada, Y. J. Antibiotics 1988, 41,
1828. (c) Yamada, Y.; Sugamura, K.; Kondo, K.; Yanagi-
moto, M.; Okada, H. J. Antibiotics 1987, 40, 496.
4. Sato, K.; Nihira, T.; Sakuda, S.; Yanagimoto, M.;
Yamada, Y. J. Ferment. Bioeng. 1989, 68, 170.
5. Takabe, K.; Iida, Y.; Hiyoshi, H.; Ono, M.; Hirose, Y.;
Fukui, Y.; Yoda, H.; Mase, N. Tetrahedron: Asymmetry 2000,
11, 4825.
6. Typical procedure: a solution of the butanamide 10a
(100 mg, 0.358 mmol) and Lipase PS (10.7 mg, 30 mg/mmol of
10a) in vinyl acetate (2equiv) was stirred at 25 ꢁC for an appro-
priate time; then, Lipase PS was removed through filtration, and
concentrated to give a crude oil, which was purified by column
chromatography (silica gel, eluent: hexane–AcOEt) to give the
monoacetate 11a and the recovered alcohol 10a.
The enantiomerically pure alcohol (S)-10a was obtained
by kinetic resolution repeatedly (11a: 1st 60% ee; 2nd
94% ee, 3rd >99%ee, total yield 21%) followed by
hydrolysis, which was employed in the synthesis of vir-
giniae butanolide C (VB C) as shown in Scheme 2.
Cyclization of the (S)-alcohol 10a gave (R)-3-benzyloxy-
methyl-4-butanolide (R)-9 in 77% yield without race-
mization as revealed by a chiral HPLC analysis. The
butanolide (R)-9 was treated with LDA at ꢀ78 ꢁC, and
the resulting anion was reacted with hexanoyl chloride
to give the butanolide (3R)-12 in 68% yield. An ana-
logue of A-factor (3R)-13 was obtained by deprotection
of the benzyl group in 78% yield. Reduction/deprotec-
tion of (3R)-12 gave a diastereomeric mixture of 14,
which was readily separated by column chromato-
graphy to afford VB C (2R,3R,10S)-14 and its epimer
(2R, 3R,10R).11 A higher value of the optical rotation of
synthetic VB C was observed compared with that
reported in the literature,2c therefore, it is suggested that
partial racemization via NaBH4 reduction of 13 might
have occurred in a previous preparation of VB C.2c
7. We also examined the enantioselective hydrolysis and
transesterification of the acetate 11a,b in the presence of
Lipase PS in a buffer and ethanol solution, respectively; how-
ever, low enantioselectivities (11–57% ee) was observed.
8. The enantioselectivities were dependent upon the nature of
the lipase used, for instance, Lipase A (Aspergillus niger,
Amano) showed reverse enantioselectivity to give (S)-acetate
11a (57% ee).
In conclusion, we have shown high enantioselectivity in
the kinetic resolution of the butanamide 10. This pres-
ent reaction would provide a practical strategy for
asymmetric synthesis of natural products including
3-alkoxymethyl butanolide skeleton.
9. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294.
Acknowledgements
10. High enantiomeric excess of the acetate 11 was not
obtained, because acetylation of the alcohol 10 slowly pro-
ceeded in the absence of Lipase PS. See Hyatt, J. A.; Skelton,
C. Tetrahedron: Asymmetry 1997, 8, 523.
11. Revised structure of the virginiae butanolides is reported
by Yamada et al.; see: Sakuda, S.; Yamada, Y. Tetrahedron
Lett. 1991, 32, 1817.
We thank Professor Yasuhiro Yamada of Osaka Uni-
versity for scientific discussion. We are also grateful to
Amano Pharmaceutical Co., Ltd. for a generous gift of
some enzymes. This work was supported by a Grant-in-
Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture of Japan.