7538
J . Org. Chem. 1997, 62, 7538-7539
sponding N-phenylacetyl derivatives of 1 with penicillin
En a n tioselective Biom im etic
acylase.7 Nevertheless, the lure of a direct asymmetric
synthesis of fluoro amino acids via enantioselective PSR,
providing the most efficient access to these biomedicinally
important compounds, has been attracting our attention
for many years.8 The challenge associated with the
asymmetric PSR, in general, is provided by the nature
of the reaction. As it follows from the mechanism of
azomethine-azomethine isomerization, the targeted base-
assisted proton transfer occurs from a less to a more
configurationally unstable stereogenic center and accord-
ingly, under the thermodynamically controlled conditions,
cannot be realized in an asymmetric sense.9 In the series
of fundamental works designed to reveal the mechanism
and stereochemical course of the biological transamina-
tion, Cram et al. have demonstrated that in the certain
model azomethine-azomethine isomerizations of hydro-
carbon imines [1,3]-proton transfer occurs intramolecu-
larly in a suprafacial, stereoselective manner.10 However,
the reversibility of the isomerizations and substantial
racemization of the both starting and resultant com-
pounds were shown to be the problems that would plague
the asymmetric biomimetic transamination methodology.
Recently, we have discovered that, in striking contrast
to the hydrocarbon imines, the Schiff bases derived from
fluoroalkyl ketones and (S)-R-phenylethylamine under
certain reaction conditions could be isomerized to the
corresponding N-(R-phenylethylidene) derivatives with
the enantioselectivity ranging from 88 to 97% ee.3d
However, the first attempt to expand these findings on
the asymmetric synthesis of fluorinated amino acids via
transamination of R-keto perfluorocarboxylic esters gave
totally discouraging results. We have found that the
isomerization of N-(R-phenyl)ethylimine of ethyl trifluo-
ropyruvate, while easily occurring, afforded the virtually
racemic N-(R-phenylethylidene)trifluoroalanine ethyl es-
ter, presumably, through the nonasymmetric reaction
route.3e Thus, with these intriguing successes and
failures we set about the development of enantioselective
transamination of â-keto carboxylic acids, which are
structurally similar to both fluoroalkyl ketones and
R-keto carboxylic acids.
Tr a n sa m in a tion of â-Keto Ca r boxylic Acid
Der iva tives. An Efficien t Asym m etr ic
Syn th esis of â-(F lu or oa lk yl) â-Am in o Acid s
Vadim A. Soloshonok,* Taizo Ono, and
Irina V. Soloshonok
National Industrial Research Institute of Nagoya,
Hirate-cho 1-1, Kita-ku, Nagoya City,
Aichi Prefecture 462, J apan
Received J une 9, 1997
In recent years, â-amino acids have received a great
deal of attention due to a wide range of their potential
biomedicinal and synthetic applications.1 In this context,
considering the exciting benefits of fluorine substitution
for hydrogen disclosed for the family of R-amino acids,2
the development of new synthetic methodology for pre-
paring fluorine-containing and enantiomerically pure
â-amino acids is of particular interest. In this paper, we
report the first practical asymmetric synthesis of â-(fluo-
roalkyl) â-amino acids of high optical purity via enanti-
oselective biomimetic transamination of the correspond-
ing â-keto carboxylic acids derivatives.
A reducing agent-free biomimetic reductive amination,
referred to as [1,3]-proton shift reaction (PSR),3 is emerg-
ing as an efficient, preparatively useful, generalized
method for the synthesis of various fluorine-containing
amino compounds of biomedicinal and synthetic impor-
tance.2,4 To achieve a reductive transformation of a
carbonyl to an amino group, PSR makes use of a
biomimetic5 transposition of an imine functionality via
base-catalyzed azomethine-azomethine isomerization,
an intramolecular reductive-oxidative process, and thus
is conceptually different from the well-tried purely
chemical methodology relying heavily on the use of
external reducing agents.6 In particular, racemic â-(fluo-
roalkyl) â-amino acids 1 can be easily prepared by the
base-assisted isomerization of the corresponding enam-
ines, derived from â-keto carboxylic esters and benzyl-
amine or picolylamines.3a,c For preparing â-amino acids
1 in enantiomerically pure form, we have developed a
biocatalytic approach involving resolution of the corre-
The starting compounds 4a -c and 5 were readily
synthesized by the direct condensation between an ap-
propriate â-keto ester 2a -c and (S)-R-phenylethylamine
3 (Scheme 1). An important characteristic of these
substrates is that they exist as (Z)-enamines, stabilized
by the intramolecular hydrogen bond. First, we have
tried to isomerize enamine 4a under the conditions
previously established for the analogous transformation
of the corresponding N-benzyl derivative.3a However,
after N-(R-phenylethyl)enamine 4a was heated in a
triethylamine (TEA) solution at 100-150 °C for more
than 300 h, starting compound 4a was recovered chemi-
(1) For the most recent reviews on â-amino acids see: Enantiose-
lective Synthesis of â-Amino Acids; J uaristi, E., Ed.; VCH-Wiley: New
York, 1997.
(2) For general reviews on fluorine-containing amino acids see:
Fluorine-Containing Amino Acids: Synthesis and Properties; Kukhar,
V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, 1995.
(3) (a) Soloshonok, V. A.; Kukhar, V. P. Tetrahedron 1996, 52, 6953.
(b) Ono, T.; Kukhar, V. P.; Soloshonok, V. A. J . Org. Chem. 1996, 61,
6563. (c) Soloshonok, V. A.; Ono, T. Tetrahedron 1996, 52, 14701. (d)
Soloshonok, V. A.; Ono, T. J . Org. Chem. 1997, 62, 3030. (e) Soloshonok,
V. A.; Kukhar, V. P. Tetrahedron 1997, 53, 8307 and other references
on PSR cited therein.
(4) For general discussion on biological activity and synthetic
importance of fluorinated amino compounds see these monographs:
(a) Welch, J . T.; Eswarakrischnan, S. Fluorine in Bioorganic Chemistry;
Wiley: New York, 1991. (b) Biomedicinal Aspects of Fluorine Chem-
istry; Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier:
Amsterdam, 1993. (c) Biomedical Frontiers of Fluorine Chemistry;
Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; American Chemical
Society: Washington, D.C., 1996. For the most recent publications
see: (d) Fluoroorganic Chemistry: Synthetic Challenges and Biomedi-
cal Rewards; Resnati, G., Soloshonok, V. A., Eds.; Tetrahedron
Symposium-in-Print No. 58; Tetrahedron 1996, 52, 1-330.
(5) (a) Snell, E. E. In Chemical and Biological Aspects of Pyridoxal
Catalysis; Fasella, P. M., Braunstein, A. E., Rossi-Fanelli, A., Eds.;
Macmillan: New York, 1963. (b) Pyridoxal Catalysis: Enzymes and
Model Systems; Snell, E. E., Braunstein, A. E., Severin, E. S.,
Torchinsky, Yu, M., Eds.; Interscience: New York, 1968.
(7) (a) Soloshonok, V. A.; Kirilenko, A. G.; Fokina, N. A.; Shishkina,
I. P.; Galushko, S. V.; Kukhar, V. P.; Svedas, V. K.; Kozlova, E. V.
Tetrahedron: Asymmetry 1994, 5, 1119. (b) Soloshonok, V. A.; Kir-
ilenko, A. G.; Fokina, N. A.; Galushko, S. V.; Kukhar, V. P.; Svedas,
V. K.; Resnati, G. Tetrahedron: Asymmetry 1994, 5, 1225.
(8) (b) Kukhar, V. P.; Soloshonok, V. A.; Galushko, S. V.; Rozhenko,
A. B. Dokl. Akad. Nauk SSSR 1990, 310, 886. (d) Soloshonok, V. A.;
Kirilenko, A. G.; Galushko, S. V.; Kukhar, V. P. Tetrahedron Lett. 1994,
35, 5063.
(9) (a) Cram, D. J .; Guthrie, R. D. J . Am. Chem. Soc. 1966, 88, 5760.
(b) Smith, P. A. S.; Dang, C. V. J . Org. Chem. 1976, 41, 2013.
(10) (a) J aeger, D. A.; Broadhurst, M. D.; Cram, D. J . J . Am. Chem.
Soc. 1979, 101, 717. (b) Guthrie, R. D.; J aeger, D. A.; Meister, W.;
Cram, D. J . J . Am. Chem. Soc. 1971, 93, 5137. (c) J aeger, D. A.; Cram,
D. J . J . Am. Chem. Soc. 1971, 93, 5153 and other references of this
group cited therein.
(6) Abdel-Magid, A.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J . Org. Chem. 1996, 61, 3849 and references cited therein.
S0022-3263(97)01023-2 CCC: $14.00 © 1997 American Chemical Society