EtOD, the product (S)-4a was obtained typically with 85% ee and
>95% deuterium incorporation at the a-position.10 The optical
purity was simply enriched to >99% ee by a single recrystallization
from methyl cyclohexane (entry 4, Table 1).
of a variety of enantiomerically pure natural and non-natural a-
deuterium labelled chiral amino acids.
Acknowledgements
The generality of this protocol was then demonstrated by
synthesizing ten a-carbon deuterium-labelled a-N-acyl amino
esters (S)-4a–j. As shown from the results in Table 2, in all
cases, the DKR products 4a–j were obtained typically with >95%
deuterium incorporation at the a-position. In addition, high levels
of asymmetric induction were also obtained with most substrates.
Here again, all products 4a–j were obtained in the enantiomerically
pure form (>99% ee) after a single recrystallization from methyl
cyclohexane.
The N-protected amino esters 4 could also be successfully
transformed into the more valuable optically pure amino acids 1 by
hydrolysis without any loss of their deuterium labeling or optical
purity. For example, gram quantities of optically pure (>99.9%
ee) a-deuterated L-m-tyrosine11 could be obtained in one-step by
hydrolysis of (S)-4g with HBr/AcOH (see ESI†) (Scheme 1).
This work was supported by grants NRF-20090085824 (Basic
Science Research Program, MEST), NRF-2010-0029698 (Priority
Research Centers Program, MEST), 2011-0001334 (SRC program,
MEST), R31-2008-10029 (WCU program, MEST) and B551179-
10-03-00 (Cooperative R&D Program, Korea Research Council
Industrial Science and Technology).
Notes and references
1 For a general review of this research area see, R. Vogues, in Synthesis
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Allen, Ed., John Wiley & Sons, Inc., New York, 1994, p 1.
2 For a recent review on the synthesis of labelled amino acids see, C.
M. Reid and A. Sutherland, in Amino Acids, Peptides and Proteins in
Organic Chemistry, Vol. 1; A. B. Hughes, Ed., Wiley-VCH: Weinheim,
2009, Chapter 11, pp 473–494.
3 For example, see: (a) O. V. Mosin, D. A. Skladnev and V. I. Shvets,
Biosci., Biotechnol., Biochem., 1998, 62, 225–229; (b) J. J. Milne and J.
P. G. Malthouse, Biochem. Soc. Trans., 1996, 24, 133S; (c) N. G. Faleev,
S. B. Ruvinov, M. B. Saporovskaya, V. M. Belikov, L. N. Zakomyrdina,
I. S. Sakharova and Y. M. Torchinsky, Tetrahedron Lett., 1990, 31,
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S. Hexspoor, U. Kragl and J. Lugtenburg, Eur. J. Org. Chem., 1999, 10,
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4 (a) J. T. Kendall, J. Labelled Compd. Radiopharm., 2000, 43, 917–924;
(b) T. Torizawa, A. M. Ono, T. Terauchi and M. Kainosho, J. Am.
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5 J. W. Lee, T. H. Ryu, J. S. Oh, H. Y. Bae, H. B. Jang and C. E. Song,
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6 CCDC 837463.
7 J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am. Chem. Soc., 2008,
130, 14416–14417; See the CIF-file in the Supporting Information of
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Scheme 1 A gram-scale synthesis of a-deuterated L-m-tyrosine.
In conclusion, we have developed a convenient and general
method for the synthesis of a-deuterium labelled chiral amino
acids. This procedure involves the organocatalytic DKR reaction
of racemic azlactones 3 with EtOD as a nucleophile as well as
a deuterium source. In most cases, the N-protected a-deuterated
amino esters 4 were obtained with a deuterium content greater
than 95% and, moreover, their optical purity was enriched to
>99% ee by a single recrystallization. The N-protected amino
esters 4 could also be successfully transformed into the optically
pure amino acids 1 by hydrolysis, without any loss of their
deuterium labeling or optical purity. We believe that our protocol is
one of the most general and effective strategies for the preparation
9 J. D. Jersey and B. Zerner, Biochemistry, 1969, 8, 1967–1974.
10 The opposite enantiomer (R)-4a was obtained at a lower level of ee (55%
ee) using the hydroquinidine-derived catalyst, Bis-HQD-SQA (2c).
11 C. E. Humphrey, M. Furegati, K. Laumen, L. L. Veccjia, T. Leutert, J.
C. Mu¨ller-Hartwieg and M. Vo¨gtle, Org. Process Res. Dev., 2007, 11,
1069–1075.
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