J . Org. Chem. 1999, 64, 8423-8424
8423
Sch em e 1
Dyn a m ic Kin etic Resolu tion of Acyclic
Allylic Aceta tes Usin g Lip a se a n d
P a lla d iu m
Yoon Kyung Choi, J ong Hwa Suh, Donghyun Lee,
In Taek Lim, J ae Yoon J ung,1 and Mahn-J oo Kim*
Sch em e 2
Department of Chemistry and Center for Biofunctional
Molecules, Pohang University of Science and Technology,
San 31 Hyojadong, Pohang, Kyungbuk 790-784, Korea
Received J une 14, 1999
The complete transformation of a racemic mixture into
a single enantiomer is one of the current challenging
problems in asymmetric synthesis.2 As a useful approach
for such transformation, we have studied the dynamic
kinetic resolution using enzymes and transition metal
complexes.3,4 In this manuscript, we report the first
successful dynamic kinetic resolution of acyclic allylic
acetates using a lipase and a palladium complex, leading
to the synthesis of allylic alcohols with high optical
purity.
Sch em e 3
The Williams group recently reported the first example
for the dynamic kinetic resolution of allylic acetate using
a lipase and a palladium complex.4a In this procedure,
allylic acetate is resolved through the lipase-catalyzed
hydrolysis, and the enzymatically unreactive enantiomer
is racemized in situ through the palladium(II)-catalyzed
rearrangement. The resolution is performed in phosphate
buffer at 37-40 °C. The successful resolution was achieved
only for a cyclic allylic acetate and required a long
reaction time (19 days) due to the slow Pd-catalyzed step.
The dynamic kinetic resolution would be more useful if
it could be applicable to the resolution of acyclic allylic
substrates which are readily available. For this goal, we
explored a conceptually similar but chemically different
approach: the resolution through the lipase-catalyzed
transesterification coupled with the Pd(0)-catalyzed ra-
cemization in organic solvent (Scheme 1).
As the substrates to be resolved, 1,3-disubstituted
allylic acetates 1a -e with a methyl group at the 1-posi-
tion and an aryl group at the 3-position were chosen. The
lipases from Pseudomonas cepacia (PCL) and Candida
antarctica (CAL), which are available in the immobilized
forms,5 were employed as the enzymes for the resolution.
Both enzymes showed high enantioselectivity in the
screening experiments: in the kinetic resolution of 1a ,
the products of >99% ee were obtained at 45-48%
conversion for both of them. As the acyl acceptor in the
transesterification reaction, 2-propanol was chosen be-
cause it and its acetate can be readily removed after the
reaction is complete. It was used in a 10-fold excess to
shift the position of the equilibrium toward the resolved
products. It was observed that, in the transesterification
using only the enzymatically reactive enantiomer (R)-
1a as the substrate, over 90% of the substrates was
converted to the products in the presence of a 10-fold
excess of 2-propanol. As the catalyst for the racemiza-
tion of the enzymatically unreactive enantiomer,6 tet-
rakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] was
used together with 1,1′-bis(diphenylphosphino)ferrocene
(dppf).7 The Pd-catalyzed racemization in the presence
of 2-propanol in THF is accompanied by two side reac-
tions, elimination and substitution, to yield 3 and 4,
respectively (Scheme 2). Accordingly, the unwanted reac-
tions must be depressed without affecting the racemiza-
tion for higher yield. This was achieved more effectively
when the Pd complex was used together with 3 equiv of
dppf.
In typical experiments, the reactions were carried out
at room temperature under argon atmosphere on 0.5
mmol scale using substrate (0.1-0.3 M), 2-propanol (10
equiv), CAL (0.2-0.4 g/mmol substrate) or PCL (0.5-0.8
g/mmol substrate), Pd(PPh3)4 (5 mol %), and DPPF (15
mol %) in THF. The reactions started initially without
(1) Undergraduate research participant.
(2) Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry
1999, 10, 107.
(3) Review on dynamic kinetic resolution: Ward, R. S. Tetrahedron:
Asymmetry 1995, 6, 1475.
(4) Previous reports: (a) Allen, J . V.; Williams, J . M. J . Tetrahedron
Lett. 1996, 37, 1859. (b) Dinh, P. M.; Howarth, J . A.; Hudnott, A. R.;
Williams, J . M. J .; Harris, W. Tetrahedron Lett. 1996, 37, 7623-26.
(c) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668. (d) Persson, B.
A.; Larsson, A. L. E.; Ray, M. L.; Ba¨ckvall, J .-E. J . Am. Chem. Soc.
1999, 121, 1645.
(5) PCL immobilized on ceramic particles (trade name, Lipase PS-C
(type II), Amano, J apan) and CAL immobilized on acrylic resin (trade
name, Novozym 435, Novo Nordisk Korea) were used.
(6) Most likely this racemization proceeds via cis-migration of
coordinated acetate in the intermediate (π-allyl)palladium complex
(Trost. B. M.; Verhoeven, T. R.; Fortunak, J . M. Tetrahedron Lett. 1979,
130. Ba¨ckvall, J . E.; Nordberg, R. E.; Bjo¨rkman, E. E.; Moberg, C. J .
Chem. Soc., Chem. Commun. 1980, 943. Ba¨ckvall, J . E.; Nordberg, R.
E.; Wilhelm, D. J . Am. Chem. Soc. 1985, 107, 6892). It may also proceed
via a Pd-to-Pd displacement (Granberg, K. L.; Ba¨kvall, J . E. J . Am.
Chem. Soc. 1992, 114, 6858).
(7) Dppf was the most effective among the diphosphine ligands,
including dppf, 1,2-bis(diphenylphosphino)ethane (dppe), and 1,4-bis-
(diphenylphosphino)butane (dppb), that were screened for the racem-
ization of (S)-1a by Pd(PPh3)4.
10.1021/jo990956w CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/07/1999