792
S.-k. Lee et al.
LETTER
(7) (a) For a quantitative analysis of the reactions of two
References
interconverting diastereomeric species that lead to different
products by a Curtin–Hammett–Winstein–Holness prin-
ciple, see: Seeman, J. I. Chem. Rev. 1983, 83, 83. (b) For
cases in which the stereoselectivity of the product reflects
the thermodynamic ratios of diastereomeric intermediates,
see: Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1996,
118, 3479. (c) Also see: Basu, A.; Gallagher, D. J.; Beak, P.
J. Org. Chem. 1996, 61, 5718.
(1) (a) Lee, S.-k.; Lee, S. Y.; Park, Y. S. Synlett 2001, 1941.
(b) Caddick, S.; Afonso, C. A. M.; Candeias, S. X.;
Hitchcock, P. B.; Jenkins, K.; Murtagh, L.; Pardoe, D.;
Santos, A. G.; Treweeke, N. R.; Weaving, R. Tetrahedron
2001, 57, 6589. (c) Ben, R. N.; Durst, T. J. Org. Chem.
1999, 64, 7700. (d) Kubo, A.; Kubota, H.; Takahashi, M.;
Nunami, K. J. Org. Chem. 1997, 62, 5830. (e) Ward, R. S.;
Pelter, A.; Goubet, D.; Pritchard, M. C. Tetrahedron:
Asymmetry 1995, 6, 93.
(2) This term was used by Prof. Peter Beak and coworkers for
their mechanistic studies of electrophilic asymmetric
substitution reaction: Beak, P.; Basu, A.; Gallagher, D. J.;
Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29,
552.
(3) (S,S)-N-Methyl pseudoephedrine is commercially available
and can also be easily prepared by N-methylation of (S,S)-
pseudoephedrine with MeI and NaH.
(4) When a solution of 1 ( S: R = 67:33) in CH3CN was stirred
for 1.5 h, spontaneous epimerization provided 1 with a ratio
of 80:20 ( S: R).
(5) The absolute configurations of ( S)-1 was assigned by com-
parison to the 1H NMR of authentic diastereomer prepared
from commercially available (S)- -bromo-propionic acid.
The absolute configuration of (R)-2 was assigned by com-
parison of CSP-HPLC retention time with authentic material
prepared from (R)-alanine.
(6) It has been proposed by several examples that the epimeri-
zation of -halo ester and -halo amide can be promoted by
a base via keto-enol tautomerism and/or by a halide source
via nucleophilic displacement of the bromide ion.1
(8) The absolute configuration of (R)-7 was assigned by
comparison of CSP-HPLC retention time with authentic
material prepared from commercially available (R)-2-
aminobutyric acid. The absolute configuration of (R)-8 was
assigned by analogy to the formation of (R)-2 and (R)-7.
(9) General procedure for the asymmetric synthesis of
methyl-N-benzyl alaninate [(R)-2]: To a solution of ( RS)-
1 ( S: R = 60:40) in CH3CN (ca. 0.1 M) at r.t. was added
Et3N (1.2 equiv). The resulting reaction mixture was stirred
at r.t. for 1.5 h, and then benzylamine (1.2 equiv) was added.
After 4 h, the mixture was filtered and the solvent eva-
porated. The crude mixture and p-toluenesulfonic acid (0.1
equiv) in methanol were refluxed for 24 h. The solvent was
evaporated and the crude material was purified by column
chromatography to give methyl-N-benzyl alaninate [(R)-2].
From 100 mg of 1, 53 mg (86% isolated yield) of 2 was
obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz)
7.32–7.23 (m, 5 H), 3.80 (d, J = 12.8 Hz, 1 H), 3.72 (s, 3 H),
3.67 (d, J = 12.8 Hz, 1 H), 3.39 (q, J = 7.0 Hz, 1 H), 1.85 (br,
1 H), 1.32 (d, J = 7.0 Hz, 3 H); 13C NMR (CDCl3, 100 MHz)
176.6, 140.1, 128.8, 128.6, 127.5, 56.3, 52.4, 52.2, 19.5. The
enantiomeric ratio of 2 was determined to be 98:2 in favor of
the R enantiomer by chiral HPLC using racemic material as
a standard and the absolute configuration was assigned by
comparison of CSP-HPLC retention time with authentic
material prepared from (R)-alanine. [Chiralcel OD column;
10% 2-propanol in hexane; 0.9 mL/min; the R-enantio-
mer(major) had a retention time of 6.0 min, and the
S-enantiomer(minor) had a retention time of 5.4 min].
Synlett 2002, No. 5, 790–792 ISSN 0936-5214 © Thieme Stuttgart · New York