4736
J . Org. Chem. 2001, 66, 4736-4738
Sch em e 1
Sch em e 2
Lip a se/Ru th en iu m -Ca ta lyzed Dyn a m ic
Kin etic Resolu tion of Hyd r oxy Acid s, Diols,
a n d Hyd r oxy Ald eh yd es P r otected w ith a
Bu lk y Gr ou p
Mahn-J oo Kim,* Yoon Kyung Choi, Min Young Choi,
Mi J ung Kim, and J aiwook Park*
National Research Laboratory of Chirotechnology,
Department of Chemistry, Division of Molecular and Life
Sciences, Pohang University of Science and Technology,
San 31 Hyojadong, Pohang, Kyungbuk 790-784, Korea
mjkim@postech.ac.kr
Received March 21, 2001
Kinetic resolutions of racemic mixtures based on lipase
catalysis provide a useful methodology for the synthesis
of optically active compounds such as chiral alcohols,
acids, and their esters.1 However, the enzymatic kinetic
resolutions often suffer from two major problems: un-
satisfactory enantioselectivity and low yield (the theoreti-
cal maximum yield is 50%). One of the useful strategies
for enhancing the enzyme enantioselectivity is the use
of structurally modified substrates.2,3 The counterpart for
improving the yield is the dynamic kinetic resolution
(DKR),4 allowing for the complete transformation of
racemic mixtures to single enantiomers. In this work,
these two strategies have been combined for the efficient
resolution of versatile difunctional molecules such as
hydroxy acids, diols, and hydroxy aldehydes. The racemic
substrates were modified with a bulky protecting group5
and then subjected to the lipase/ruthenium-catalyzed
DKR (Scheme 1).6,7 In most cases, both optical purities
and yields of products reached a satisfactory level.
The first series of illustrative examples is the DKRs
of protected â-hydroxybutyrates 1a -d 8 (Scheme 2), in
which the carboxy functionality is protected with four
different bulky groups including benzyl (1a ), (p-methoxy-
phenyl)methyl (1b), biphenylmethyl (1c), and tert-butyl
(1d ). Initially, the DKR of 1a were examined with
Candida antarctica lipase B (CALB, immobilized; trade
name, Novozym-4359), which gave poor enantiomeric
excesses. However, the DKR tested with Pseudomonas
cepacia lipase (PCL, immobilized; trade name, Lipase PS-
D10) provided better optical purity. Accordingly, the
further DKR reactions were carried out with PCL. In the
reactions of 1a -c, a significant amount (15 mol %) of
ruthenium catalysts were used with small amounts (0.05
mass equiv) of enzymes to get higher ee’s. The reaction
(1) (a) Chen, C.-S. and Sih, C. J . Angew. Chem., Int. Ed. Engl. 1989,
28, 695. (b) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114. (c)
Santaniello, E.; Fetrizia, P.; Grisenti, P.; Manzocchi, A. Chem. Rev.
1992, 92, 1071. (d) Wong, C.-H.; Whitesides, G. M. Enzymes in
Synthetic Organic Chemistry; Pergamon: Oxford, 1994.
(2) (a) Scilimati, A.; Ngooi, T. K.; Sih, C. J . Tetrahedron Lett. 1988,
29, 4927. (b) Goergens, U.; Schneider, M. P. J . Chem. Soc., Chem.
Commun. 1991, 1064 and 1066. (c) Kim, M.-J .; Choi, Y. K. J . Org.
Chem. 1992, 57, 1065. (d) Kim, M.-J .; Lim, I. T.; Choi, G.-B.; Whang,
S.-Y.; Ku, B.-C.; Choi, J .-Y. Bioorg. Med. Chem. Lett. 1996, 6, 71. (e)
Gupta, A. K.; Kazlauskas, R. J . Tetrahedron: Asymmetry 1993, 4, 879.
(3) The other strategies includeenzyme modification,a,b molecular
imprinting,c-g and additive additionh-m. (a) Gu, Q.-M.; Sih, C. J .
Biocatalysis 1992, 6, 115-126. (b) Tuomi, W. V.; Kazlauskas, R. J . J .
Org. Chem. 1999, 64, 2638. (c) Russell, A. J .; Klibanov, A. M. J . Biol.
Chem. 1988, 263, 11624. (d) Sta¨hl, M.; J eppsson-Wistrand, U.; Mans-
son, M. O.; Mosbach, K. J . Am. Chem. Soc. 1991, 113, 9366. (e) Rich,
J . O.; Dordick, J . S. J . Am. Chm. Soc. 1997, 119, 3245. (f) Ke, T.;
Klibanov, A. M. Biotechnol. Bioeng. 1998, 57, 764. (g) Lee, D.; Choi,
Y. K.; Kim, M.-J . Org. Lett. 2000, 2, 2553. (h) Guo, Z.-W.; Sih, C. J . J .
Am. Chem. Soc. 1989, 111, 6839. (i) Khmelnitsky, Y. L.; Welch, S. H.;
Clark, D. S.; Dordick, J . S. J . Am. Chem. Soc. 1994, 116, 2647. (j)
Paradkar, V. M.; Dordick, J . S. J . Am. Chem. Soc. 1994, 116, 5009. (k)
Itoh, T.; Tagaki, Y.; Murakami, T.; Hiyama, Y.; Tsukuba, H. J . Org.
Chem. 1996, 61, 2158. (l) Parker, M. C.; Brown, S. A.; Robertson, L.;
Turner, N. J . Chem. Commun. 1998, 2247. (m) Griebenow, K.;
Laureano, Y. D.; Santos, A. M.; Clemente, I. M.; Rodr´ıguez, L.; Vidal,
M. W.; Barletta, G. J . Am. Chem. Soc. 1999, 121, 8157
(6) (a) Persson, B. A.; Larsson, A. L. E.; Ray, M. L.; Ba¨ckvall, J .-E.
J . Am. Chem. Soc. 1999, 121, 1645. (b) Koh, J . H.; J ung, H. M.; Kim,
M.-J .; Park, J . Tetrahedron Lett. 1999, 40, 6281. (c) J ung, H. M.; Koh,
J . H.; Kim, M.-J .; Park, J . Org. Lett. 2000, 2, 409 and 2487. (c) Huerta,
F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J .-E. Org. Lett. 2000, 2, 1037. (d) Lee,
D.; Huh, E. A.; Kim, M.-J .; J ung, H. M.; Koh, J . H.; Park, J . W. Org.
Lett. 2000, 2, 2377.
(7) For other enzyme/metal-catalyzed DKRs, see: (a) Dinh, P. M.;
Howarth, J . A.; Hudnott, A. R.; Williams, J . M. J .; Harris, W.
Tetrahedron Lett. 1996, 37, 7623. (b) Reetz, M. T.; Schimossek, K.
Chimia 1996, 50, 668. (c) Allen, J . V.; Williams, J . M. J . Tetrahedron
Lett. 1996, 37, 1859. (a) Choi, Y.-K.; Suh, J . H.; Lee, D.; Lim, I.; J ung,
J . Y.; Kim, M.-J . J . Org. Chem. 1999, 64, 8423.
(8) The protected substrates except commercially available 1d were
readily prepared by the enzymatic reactions of diketene with the
corresponding alcohols followed by reduction in the presence of 3 and
2,6-dimethyl-4-heptanol.
(9) Provided by Novo Nordisk Korea.
(10) Provided by Amano, J apan.
(4) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475.
(5) The empirical rules, previously proposed by the Kazulauskas
group and others, suggest that the lipase substrates should have one
small and one significantly larger substituents at the hydroxymethine
center to be resolved with high enantioselectivity in lipase-catalyzed
reactions. (a) Kazlauskas, J . J .; Weissfloch, A. W. E.; Rapport, A. T.;
Cuccia, L. A. J . Org. Chem. 1991, 56, 2656. (b) Burgess, K.; J ennings,
L. D. J . Am. Chem. Soc. 1991, 113, 6129. (c) Kim, M.-J .; Cho, H. J .
Chem. Soc. Chem. Commun. 1992, 1411.
10.1021/jo0156417 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/02/2001