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, Tohru Kurihara, Takanobu Horiguchi, Atsushi Miki, Mitsuru Shoji, Takeshi Sugai, Kengo Hanaya

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

Original languageEnglish
JournalSynthesis (Germany)
DOIs
Publication statusAccepted/In press - 2016 Mar 16

Fingerprint

Isomers
Byproducts
Recycling
Substrates
Enzyme kinetics
Enzymes
Hydrolysis
Acetylation
Esters

Keywords

  • convergence
  • enzyme catalysis
  • kinetic resolution
  • undesired stereoisomers

ASJC Scopus subject areas

  • Organic Chemistry
  • Catalysis

Cite this

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title = "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",
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",
keywords = "convergence, enzyme catalysis, kinetic resolution, undesired stereoisomers",
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T2 - Stereochemical Convergence of a Substrate with Multiple Chiral Centers and Recycling of a Decarboxylated Byproduct

AU - Yamashita, Yasunobu

AU - Kurihara, Tohru

AU - Horiguchi, Takanobu

AU - Miki, Atsushi

AU - Shoji, Mitsuru

AU - Sugai, Takeshi

AU - Hanaya, Kengo

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N2 - 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

AB - 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

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