Synthesis 2016; 48(14): 2191-2200
DOI: 10.1055/s-0035-1561620
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© Georg Thieme Verlag Stuttgart · New York

Ex Situ Enantioconvergent Approaches for the Effective Use of Undesired­ Isomers: Stereochemical Convergence of a Substrate with Multiple Chiral Centers and Recycling of a Decarboxylated Byproduct

Yasunobu Yamashita
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan   Email: hanaya-kn@pha.keio.ac.jp
,
Tohru Kurihara
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan   Email: hanaya-kn@pha.keio.ac.jp
,
Takanobu Horiguchi
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan   Email: hanaya-kn@pha.keio.ac.jp
,
Atsushi Miki
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan   Email: hanaya-kn@pha.keio.ac.jp
,
Mitsuru Shoji
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan   Email: hanaya-kn@pha.keio.ac.jp
,
Takeshi Sugai
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan   Email: hanaya-kn@pha.keio.ac.jp
,
Kengo Hanaya*
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan   Email: hanaya-kn@pha.keio.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 05 January 2016

Accepted after revision: 16 March 2016

Publication Date:
11 May 2016 (online)

Abstract

Enzyme-mediated kinetic resolution of racemic starting materials is a valuable and convenient tool for the preparation of enantioenriched compounds. To overcome the 50% yield limitation in conventional kinetic resolution, diverse enantioconvergent approaches have been developed. After a brief introduction of the recently developed ‘in situ deracemization’ and ‘ex situ enantioconvergent approach’, we present unique ex situ enantioconvergent approaches to solve two difficult cases: 1) In the synthesis of ethyl (3R,4S,5R)-shikimate, a diastereomeric (3R*,4S*,5S*)-substrate containing multiple chiral centers was applied in an enzyme-catalyzed acetylation, and both the enzyme-catalyzed product and unreacted substrate converted into ethyl (3R,4S,5R)-shikimate via partial stereochemical inversions. 2) The enzyme-catalyzed kinetic resolution of a ranirestat precursor and the regeneration of the racemic substrate from a decarboxylated byproduct are described in detail. Since in the latter study, the products spontaneously decarboxylated after hydrolysis of the ester groups, the in situ regeneration of the racemic substrates was of significant difficulty. We successfully installed an ethoxycarbonyl group on the byproduct by ex situ sequential derivatization to overcome the 50% yield limitation.

1 Short Review of Enantioconvergent Approaches

2 Resolution of a Substrate with Multiple Chiral Centers

3 Resolution Based on Enzyme-Mediated Hydrolysis Accompanied by Nonenzymatic C–C Bond Cleavage

4 Conclusions

Supporting Information

 
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