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Synthesis 2008(7): 1017-1022  
DOI: 10.1055/s-2008-1032123
PAPER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Synthesis of the PPARα Agonist (R)-K-13675 via (S)-2-Hydroxybutyrolactone

Yukiyoshi Yamazaki*, Takaaki Araki, Minoru Koura, Kimiyuki Shibuya
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co. Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
Fax: +81(42)3950312; e-Mail: y-yamazk@kowa.co.jp;
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Publication History

Received 2 November 2007
Publication Date:
06 March 2008 (online)

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Enantioselective Synthesis of the PPARα Agonist (R)-K-13675 via (S)-2-HydroxybutyrolactoneSynthesis 2008; 2008(13): 2154-2154
DOI: 10.1055/s-2008-1067138

Abstract

Enantioselective synthesis of enantiomerically pure PPARα agonist (R)-K-13675 can be achieved starting from (S)-2-hydroxybutyrolactone. An important intermediate, 2-(aryloxy)butyrolactone, was prepared by reaction of the phenol with (S)-2-hydroxybutyrolactone in excellent yield without loss of enantiomeric purity using the Mitsunobu reaction, followed by conversion into the 2-(aryloxy)butanoic acid via the 2-(aryloxy)-4-iodobutanoate by cleavage of the lactone on exposure to iodotrimethylsilane, followed by hydrogenolysis and hydrolysis.

Key words

Mitsunobu reaction - ethers - ring opening - enantioselective synthesis - PPARα agonist

4

When we used 0.1 equiv Amberlyst 15 instead of 1.0 equiv TFA or TsOH, we could reduce the scale of silica gel from 40-fold weight of 5 to 5-fold.

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In the case of tert-butyl (S)-2-hydroxybutanoate, DEAD gave better results than DIAD or DBAD; the yield was 60% and enantiomeric purity was 94.0% ee.