ORGANIC
LETTERS
2002
Vol. 4, No. 12
2021-2023
A New and Efficient Chemoenzymatic
Route to Both Enantiomers of
4-Hydroxycyclohex-2-en-1-one
Ayhan S. Demir* and Ozge Sesenoglu
Department of Chemistry, Middle East Technical UniVersity, 06531 Ankara, Turkey
Received March 9, 2002
ABSTRACT
A chemoenzymatic synthesis of both enantiomers of the pharmacologically interesting 4-hydroxycyclohex-2-en-1-one in three steps starting
from 3-methoxycyclohex-2-en-1-one is described. Manganese(III) acetate-mediated acetoxylation followed by enzyme-mediated hydrolysis of
r-acetoxy enone affords acetoxy enone 3 and hydroxy enone 4 with high enantiomeric excesses and in good yields. The reduction of the
acetoxy and hydroxy enones furnished both enantiomers of 4-hydroxycyclohex-2-en-1-one in high enantiomeric excess.
Chiral R-hydroxy ketones are important structural units in
many biologically active compounds, and they are also
important synthons for the asymmetric synthesis of natural
products.1 During the past several years, there has been an
increasing interest in the biological and pharmacological
properties of members of the compactin-mevinolin family
of natural products,2 koninginine,3 phyllanthurino lactone and
related compounds.4 Optically active 4-hydroxycyclohex-2-
en-1-one (1) has been employed in several laboratories as a
starting material for the synthesis of such kinds of com-
pounds. It is, therefore, of considerable interest to develop
efficient methods for preparing optically active 4-hydroxy-
cyclohex-2-en-1-one (1) that minimize the number of
required synthetic steps while maximizing the overall chemi-
cal and optical yield of this important intermediate.
Several preparations of (S)-1 and (R)-1 have been pub-
lished by using either chemical5 or enzymatic6 transforma-
tions. Many of these syntheses involve multistep sequence
with low overall yields and poor enantioselectivities. Dan-
ishefsky and co-workers developed a multistep procedure
for the preparation of (S)-1 from a homochiral natural
product, quinic acid.5a Starting from the same acid, Bru¨ckner
et al. reported the synthesis of the other enantiomer, (R)-1,
in six steps with 18% overall yield and 100% enantiomeric
(1) (a) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in Enantio-
selectiVe Synthesis; VCH: Weinheim, 1997. (b) Davies, F. A.; Chen, B. C.
Chem. ReV. 1992, 92, 919. (c) Hashiyama, T.; Morikawa, K.; Sharpless,
K. B. J. Org. Chem. 1992, 57, 5067. (d) Knight, R. L.; Leeper, F. J. J.
Chem. Soc., Perkin Trans. 1 1998, 1891. (e) Enders, D.; Breuer, K.; Teles,
J. H. HelV. Chim. Acta 1996, 79, 1217. (f) Enders, D.; Breuer K. In
ComprehensiVe Asymmetric Catalysis, Vol. 2; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 1093. (g) Koike, T.;
Murata, K.; Ikariya, T. Org. Lett. 2000, 2, 3833.
(2) (a) Yamamoto, A.; Sudo, H.; Endo, A. Atherosclerosis 1980, 35,
259. (b) Mabuchi, H.; Haba, T.; Tatami, R.; Miyamoto, S.; Sakai, Y.;
Wakasugi, T.; Watanabe, A.; Koizumi, J.; Takeda, R. New Engl. J. Med.
1981, 305, 478. (c) Brown, M. S.; Goldstein, J. L. J. Lipid Res. 1980, 21,
505. (d) Arseniyadis, S.; Brondi Alves, R.; Wang, Q.; Yashunsky, D. V.;
Potier, P. Tetrahedron Lett. 1994, 35, 7949. (e) Arseniyadis, S.; Brondi
Alves, R.; Yashunsky, D. V.; Potier, P.; Toupet, L. Tetrahedron 1997, 53,
1003.
(5) (a) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738. (b) Carren˜o, M. C.; Garc´ıa
Ruano, J. L.; Garrido, M.; Ruiz, M. P.; Solladie´, G. Tetrahedron Lett. 1990,
31, 6653. (c) Bru¨njes, R.; Tiltsan, U.; Winterfeldt, E. Chem. Ber. 1991,
124, 1677. (d) Gebauer, O.; Bru¨ckner, R. Liebigs Ann. 1996, 1559. (e)
Maruoka, K.; Saito, S.; Ooi, T.; Yamamoto, H. Synlett 1991, 579. (f) Yu,
L.; Zhang, R.; Wang, Z. J. Chem. Soc., Perkin Trans. 1 2001, 2958. (g) de
March, P.; Escoda, M.; Figueredo, M.; Font, J.; Garcia, E.; Rodriguez, S.
Tetrahedron:Asymmetry 2000, 11, 4473. (h) Chang, S.; Heid, M. R.;
Jacobsen, E. N. Tetrahedron Lett. 1994, 35, 669. (i) Hiroya, K.; Kurihara,
Y.; Ogasawara, K. Angew. Chem. 1995, 107, 2445.
(3) (a) Dunlop, R.; Simon, A.; Sivasithamparam, K.; Ghisalberti, E. J.
Nat. Prod. 1989, 52, 67. (b) Ghisalberti, E.; Rowland, C. J. Nat. Prod.
1993, 56, 1799. (c) Parker, S.; Cutler, H.; Schreiner, P. Biosci., Biotechnol.,
Biochem. 1995, 59, 1747. (d) Liu, G.; Wang, Z. Q. Synthesis 2001, 119.
(4) Mori, K.; Audran, G.; Nakahara, Y.; Bundo, M.; Kido, M. Tetra-
hedron Lett. 1997, 38, 575.
(6) (a) Marchand, A. P.; Xing, D.; Wang, Y.; Bott, S. G. Tetrahedron:
Asymmetry 1995, 6, 2709. (b) Kazlauskas, R. J.; Weissfloch, A. N. E.;
Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656. (c) Suzuki,
H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 2001, 66, 1494.
10.1021/ol025847+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/18/2002