enol and the acetylated lipase, keto-enol tautomerization
for the formation of ketone 2, reduction of ketone 2 to the
racemic mixture of alcohols (R)-3 and (S)-3, enantioselective
acetylation of (R)-3 with the acetylated lipase to produce
chiral acetate (R)-4, and reversible transformation between
(S)-3 and (R)-3. The ruthenium-catalyzed steps, reduction
of ketone 2 and reversible transformation between (S)-3 and
(R)-3, are common to the ketone-conversion process, which
requires independent acyl donors (Scheme 2). The common
Table 1. Conversion of Ketones to Chiral Acetatesa
Scheme 2. Concerted Catalytic Reactions for the Conversion
of Ketones to Chiral Acetates
steps constitute a catalytic transfer-hydrogenation reaction
of ketone, with alcohol acting as a hydrogen donor.6
Therefore, both processes need a proper catalyst for the
transfer-hydrogenation reaction and a hydrogen donor com-
patible with lipase-catalyzed acyl-transfer reactions.
a The reactions were carried out on a 0.25 mmol scale with 2 mol % of
5, 7.5 mg of Novozym 435, 1.5 equiv of 2,6-dimethylheptan-4-ol, and 3
equiv of 4-chlorophenyl acetate in 0.8 mL of toluene at 70 °C for 44 h
under an argon atmosphere. b The yields were estimated by 1H NMR. c The
% ee values of acetates were determined by HPLC carried out with a chiral
column ((R,R) Whelk-01, Merck). d The yields and optical purities were
determined by GC carried out with a chiral capillary column (Chiraldex
B-PH, Altech).
We surveyed many transition-metal complexes used in
transfer-hydrogenation reactions and found complex 5 as an
excellent procatalyst for our processes. In fact complex 5
has been used in many catalytic reactions, including transfer-
hydrogenation reactions and DKR of alcohols.2b-d,7 For a
hydrogen donor compatible with the lipase-catalyzed acyl-
transfer reactions, 2,6-dimethylheptan-4-ol (6) was chosen,
since it is a poor substrate against lipases and is commercially
available.
acetates (R)-4 were produced in high yields (94-100%) with
high enantioselectivities (95-99% ee) not only from aromatic
ketones but also from aliphatic ones.10 In all cases ketones
2 were left only in less than a 5% amount, regardless of
their oxidation potentials.11 Moreover, intermediate alcohols
3 were not detected in all but the reaction of 2e, in which a
considerable amount of 3e (13% yield) remained, and chiral
acetate 4e was formed in a lower yield (82%) with a lower
optical purity (90% ee).
The scope of the ketone-conversion process was investi-
gated with ketones 2a-h by using complex 5, an im-
mobilized lipase,8 hydrogen donor 6, and 4-chlorophenyl
acetate as an acyl donor in toluene at 70 °C (Table 1).9 Chiral
(3) (a) Allen, J. V.; Williams, J. M. J. Tetrahedron Lett. 1996, 37, 1859.
(b) Choi, C. K.; Suh, J. H.; Lee, D.; Lim, I. T.; Jung, J. Y.; Kim, M.-J. J.
Org. Chem. 1999, 64, 8423
(4) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668.
Enol acetates 1a-h, corresponding to ketones 2a-h, were
prepared and tested for the conversion to chiral acetates 4
under the same reaction conditions as in Table 1 but without
4-chlorophenyl acetate.12 Initial results were not satisfactory,
due to the production of ketones 2 and alcohols 3 in large
amounts. However, we found that the purity of hydrogen
(5) Reviews for DKR: (a) Ward, R. S. Tetrahedron: Asymmetry 1995,
6, 1475. (b) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc.
Jpn. 1995, 68, 36. (c) Caddick, S.; Jenkins, K. Chem. Soc. ReV. 1996, 447.
(d) Stu¨rmer, R. Angew. Chem. 1997, 109, 1221; Angew. Chem., Int. Ed.
Engl. 1997, 36, 1173. (e) Strecher, H.; Faber, K. Synthesis 1997, 1. (f)
Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M.; Bruggink, A.;
Zwanenburg, B. Tetrahedron 1997, 53, 9417. (g) Strauss, U. T.; Felfer,
U.; Faber, K. Tetrahedron: Asymmetry 1999, 10, 107. (h) Gihani, M. T.
E.; Williams, J. M. J. Curr. Opin. Chem. Biol. 1999, 3, 11.
(6) Recent reviews: (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem.
ReV. 1992, 92, 1501. (b) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.;
Huskens, J. Synthesis 1994, 1007. (c) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97.
(7) (a) Blum, Y.; Czarkie, D.; Rahamim, Y.; Shvo, Y. Organometallics
1985, 4, 1459. (b) Shvo, Y.; Czarkie, D.; Rahamim, Y. J. Am. Chem. Soc.
1986, 108, 7400. (c) Shvo, Y.; Czarkie, D. J. Organomet. Chem. 1986,
315, C25. (d) Menashe, N.; Shvo, Y. Organometallics 1991, 10, 3885. (e)
Menashe, N.; Salant, E.; Shvo, Y. J. Organomet. Chem. 1996, 514, 97. (f)
Almeida, M. L. S.; Beller, M.; Wang, G.-Z.; Ba¨ckvall, J.-E. Chem. Eur. J.
1996, 2, 1533 and references therein. (g) Shvo, Y.; Goldberg, I.; Czerkie,
D.; Reshef, D.; Stein, Z. Organometallics 1997, 16, 133.
(9) Ba¨ckvall and co-workers selected 4-chlorophenyl acetate as a suitable
acyl donor after surveying various alkenyl acetates and activated esters.
However, the separation of the product from unreacted 4-chlorophenyl
acetate is difficult in some cases.2c
(10) The absolute configuration of the acetates was determined by
comparing their optical rotations with known data. See: (a) Naemura, K.;
Murata, M.; Tanaka, R.; Yano, M.; Hirose, K.; Tobe, Y. Tetrahedron:
Asymmetry 1996, 7, 3285-3294. (b) Laumen, K.; Schneider, M. P. J. Chem.
Soc., Chem. Commun. 1988, 598-600.
(11) Adkins, H.; Elofson, R. M.; Rossow, A. G.; Robinson, C. C. J.
Am. Chem. Soc. 1949, 71, 3622.
(8) The lipase from Candida antarctica is immobilized on acrylic resin
(trade name: Novozym 435, Nordisk Korea).
(12) For the synthesis of enol acetates, see: Larock, R. C. ComprehensiVe
Organic Transformations; VCH: New York, 1989.
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Org. Lett., Vol. 2, No. 3, 2000