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SCHEME 1. Two Approaches for Dynamic Kinetic Resolution
of Amino Acid Amides
Synthesis of Optically Active Amino Acid Derivatives
via Dynamic Kinetic Resolution
Yoon Kyung Choi, Yunwoong Kim, Kiwon Han,
Jaiwook Park,* and Mahn-Joo Kim*
Department of Chemistry, Pohang University of Science and
Technology, San-31 Hyojadong, Pohang 790-784, Korea
yields approaching 100%.3 Recently, several groups have
developed some useful procedures for the DKR of amino
acids.4,5 In most cases, DKR was accomplished via the
enzymatic enantioselective hydrolysis of amino acid deriva-
tives such as oxazolones4 and hydantoins5 which were prone
to spontaneous racemization under weakly basic conditions.
Lately, a purely enzymatic method was reported for the
DKR of amino acid amides.6 In this procedure, a D-selective
peptide hydrolase and a racemase were coupled for the
dynamic enantioselective hydrolysis of racemic amino acid
amides to D-amino acids (Scheme 1, top). We herein wish to
report a different approach for the DKR of amino acid
amide: dynamic enantioselective acylation by the coupling of
a lipase and a palladium catalyst (Scheme 1, bottom).
Previously, we reported the DKR of primary amines with
a lipase-Pd couple as the catalysts.7,8 In the lipase/Pd-
catalyzed DKR, a variety of benzylic and aliphatic amines
were converted to single enantiomeric products with good
yields. As a part of the previous work, we also observed
that phenylalanine amide was eligible as the substrate for
the lipase/Pd-catalyzed DKR although a harsh condition
(100 °C) was necessary for satisfactory DKR. Subsequently,
we envisioned that the DKR of amino acid amides should
provide a useful route to optically active amino acid derivatives.
Received September 21, 2009
The complete conversion of racemic amino acid amides to
optically active amino acid derivatives was accomplished
via lipase/palladium-catalyzed dynamic kinetic resolu-
tion (DKR). In the DKR, a lipase catalyzes the selective
acylation of L-substrate in the presence of acyl donor
while unreacted D-substrate is isomerized by a Pd nano-
catalyst to L-substrate. The DKR reactions provided
good yields (80-98%) and high enantiomeric excess
(95-98% ee). Interestingly, the DKR reactions of phe-
nylglycine amide in the presence of Z-Gly-OMe or Z-Gly-
Gly-OMe yielded optically active di- and tripeptide .
Enantiopure amino acids and their derivatives are versa-
tile building blocks for the asymmetric synthesis of a wide
range of natural products and pharmaceuticals.1,2 Although
numerous methods have been developed for their synthesis,
the resolutions of their racemic forms via enzymatic kinetic
resolution or fractional recrystallization of their diastereo-
meric salts still provide useful routes to them. These proce-
dures, however, suffer from the intrinsic limitation that the
theoretical maximum yield for a single enantiomer cannot
exceed 50%. Alternatively, dynamic kinetic resolution
(DKR), in which the kinetic resolution and racemization of
substrate take place simultaneously in one pot, provides high
(4) (a) Roff, G. J.; Lloyd, R. C.; Turner, N. J. J. Am. Chem .Soc. 2004,
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Asymmetry 2000, 11, 1687–1690. (c) Turner, N. J.; Winterman, J. R.;
McCague, R.; Parrat, J. S.; Taylor, S. J. C. Tetrahedron Lett. 1995, 36,
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(5) Suzuki, M.; Yamazaki, T.; Ohta, H.; Shima, K.; Ohi, K.; Nishiyama,
S.; Sugai, T. Synlett 2000, 189–192.
(6) Asano, Y.; Yamaguchi, S. J. Am. Chem. Soc. 2005, 127, 7696–7697.
(7) Kim, M.-J.; Kim, W.-H.; Han, K.; Choi, Y. K.; Park, J. Org. Lett.
2007, 9, 1157–1159.
(8) The first DKR of amine by the coupling of lipaseand Pd/C was
reported by the Reetz group8l and then more practical procedures with Pd/
alkaline earth salts (BaSO4 and CaCO3),8h,j Pd/Raney metals (Ni and Co),8d
Ru complex,8a,j or Ir complex8g as the racemization catalyst were developed.
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For these and additional developments, see: (a) Thalen, L. K.; Zhao, D.;
Sortais, J.-B.; Pasetzold, J.; Hoben, C.; Backvall, J.-E. Chem.;Eur. J. 2009,
€
15, 3403–3410. (b) leandro, L. H.; Alexandre, A. V.; Pedrozo, E. C.
Tetrahedron Lett. 2009, 50, 4331–4334. (c) Blidi, L. E.; Nechab, M.;
Vanthuyne, N.; Gastaldi, S.; Bertrand, M. P.; Gil, G. J. Org. Chem. 2009,
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Synth. Catal. 2008, 350, 113–121. (e) Veld, M. A. J.; Hult, K.; Palmans, R. A.;
Meijer, E. W. Eur. J. Org. Chem. 2007, 5416–5421. (f) Stirling, M. J.; Blacker,
A. J.; Page, M. I. Tetrahedron Lett. 2007, 48, 1247–1250. (g) Blacker, A. J.;
Stirling, M. J.; Page, M. I. Org. Process Res. Dev. 2007, 11, 642–648. (h)
Parvulescu, A. N.; Jacobs, P. A.; De Vos, D. E. Chem.;Eur. J. 2007, 13,
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*To whom correspondence should be addressed.
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DOI: 10.1021/jo902034x
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Published on Web 11/17/2009
2009 American Chemical Society