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Synthesis 2005(8): 1368-1377  
DOI: 10.1055/s-2005-865337
FEATUREARTICLE
© Georg Thieme Verlag Stuttgart · New York

Stereochemical Study on α-Alkylation of β-Branched α-Amino Acid Derivatives­ via Memory of Chirality

Takeo Kawabata*, Jianyong Chen, Hideo Suzuki, Kaoru Fuji
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
Fax: +81(774)383197; e-Mail: kawabata@scl.kyoto-u.ac.jp;
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Publication History

Received 21 March 2005
Publication Date:
25 April 2005 (online)

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Abstract

α-Alkylation of N-Boc-N-MOM amino acid derivatives with an additional chiral center at the β-carbon proceeded with retention of configuration, irrespective of the chirality at the β-carbon. The C-N axial chirality of the enolate intermediates played a decisive role in the stereochemical course of the alkylation, while the central chirality of the β-carbon had little effect. Amino acid derivatives with contiguous quaternary and tertiary stereocenters are readily obtained in a stereochemically expectable manner.

Key words

axial chirality - amino acid - memory of chirality - enolate - quaternary stereocenter

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7

A similar temperature-dependent decrease in ee was also observed in the α-methylation of 19: When enolate formation was performed at -78 °C for 30 min, the subsequent methylation at -78 °C gave a product of 81% ee. When enolate formation was performed at -78 °C for 30 min and then at -40 °C for 30 min, the subsequent methylation at -78 °C gave a product of 5% ee. Enolate formation at -78 °C for 30 min and then at 0 °C for 30 min gave a product of 0% ee. This can be rationalized by temperature-dependent epimerization of the chiral enolate intermediate J via bond rotation of the C(2)-N axis. Details are discussed in reference 2.

8

Enolate F generated from 7 or 10 is not axially chiral along the C(2)-N axis because of the same two substituents on the nitrogen atom, even if the bond rotation is restricted at -78 °C.

9

The stereochemistry of 8 and 9 was determined after their conversion into the corresponding p-nitrobenzamide derivatives, see ref. 6.

10

Similar stereochemical results were observed in the α-allylation of 3 and 6, see reference 6.

11

Enolate G generated from 11 or 14 is not axially chiral along the C(2)-N axis because of the same two substituents on the nitrogen atom, even if the bond rotation is restricted at -78 °C.

13

While N-methylation took place during the transformation from 16 into 27, it did not during that from 17 into 28, probably due to the steric hindrance caused by diaxial 3,4-dimethyl groups in 28.