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Synlett 2002(5): 0790-0792
DOI: 10.1055/s-2002-25373
LETTER
© Georg Thieme Verlag Stuttgart · New York

Dynamic Resolution of α-Bromo-α-Alkyl Esters Using N-Methyl Pseudo-ephedrine as a Chiral Auxiliary: Asymmetric Syntheses of α-Amino Acid Derivatives

Sang-kuk Lee, Jiyoun Nam, Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, Korea
Fax: +82(2)34365382; e-Mail: parkyong@kkucc.konkuk.ac.kr;
Further Information

Publication History

Received 27 February 2002
Publication Date:
07 February 2007 (online)

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Abstract

N-Methyl pseudoephedrine mediated dynamic resolution of α-bromo-α-alkyl esters in nucleophilic substitution reaction has been investigated. Best results are obtained when α-bromo-α-alkyl esters 1, 4 and 5 are allowed to equilibrate before the addition of nucleophile. This simple epimerization-substitution sequence provides a practical protocol for asymmetric syntheses of α-amino acid derivatives 2, 7 and 8 up to 98:2 enantiomeric ratio.

Key words

asymmetric synthesis - chiral auxiliaries - amino acids - kinetic resolution - nucleophiles

    References

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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 (αS:αR = 67:33) in CH3CN was stirred for 1.5 h, spontaneous epimerization provided 1 with a ratio of 80:20 (αS:αR).

5

The absolute configurations of (αS)-1 was assigned by com-parison to the 1H NMR of authentic diastereomer prepared from commercially available (S)-α-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 α-halo ester and α-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 (αRS)-1 (αS:αR = 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].