Efficient route to (S)-azetidine-2-carboxylic acid

Yasuhiko Futamura, Masayuki Kurokawa, Rika Obata, Shigeru Nishiyama, Takeshi Sugai

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

A new and efficient route to (S)-azetidine-2-carboxylic acid (>99.9% ee) in five steps and total yield of 48% via malonic ester intermediates was established. As the key step, efficient four-membered ring formation (99%) was achieved from dimethyl (S)-(1′-methyl)benzylaminomalonate by treating with 1,2-dibromoethane (1.5 eq) and cesium carbonate (2 eq) in DMF. Krapcho dealkoxycarbonylation of dimethyl (1′S)-1-(1′-methyl) benzylazetidine-2,2-dicarboxylate, the product of this cyclization procedure, proceeded with preferential formation (2.7:1, 78% total yield) of the desired (2S,1′S)-monoester, with the help of a chiral auxiliary which was introduced on the nitrogen atom. The undesired (2R,1′S)-isomer could be converted to that with proper stereochemistry, by a deprotonation and subsequent reprotonation step. Finally, lipase-catalyzed preferential hydrolysis of the (2S,1′S)-monoester and subsequent deprotection provided enantiomerically pure (S)-azetidine-2-carboxylic acid in a 91% yield from the mixture of (2S,1′S)- and (2R,1′S)-isomers.

Original languageEnglish
Pages (from-to)1892-1897
Number of pages6
JournalBioscience, Biotechnology and Biochemistry
Volume69
Issue number10
DOIs
Publication statusPublished - 2005 Oct 23

Keywords

  • Azetidine-2-carboxylate
  • Azetidine-ring formation
  • Cyclic amino acid
  • Diastereofacially selective protonation
  • Krapcho dealkoxycarbonylation

ASJC Scopus subject areas

  • Biotechnology
  • Analytical Chemistry
  • Biochemistry
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Organic Chemistry

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