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Synlett 2008(16): 2487-2490  
DOI: 10.1055/s-2008-1078259
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Asymmetric 1,4-Addition of Arylboronic Acids to α,β-Unsaturated Esters Catalyzed by Dicationic Palladium(II)-Chiraphos Complex for Short-Step Synthesis of SmithKline Beecham’s Endothelin Receptor Antagonist

Takashi Nishikataa, Shunsuke Kiyomurab, Yasunori Yamamotob, Norio Miyaura*b
a Innovation Plaza Hokkaido, Japan Science and Technology Agency, Sapporo 060-0819, Japan
b Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax: +81(11)7066561; e-Mail: miyaura@eng.hokudai.ac.jp;
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Publication History

Received 13 June 2008
Publication Date:
21 August 2008 (online)

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Abstract

An asymmetric 1,4-addition of arylboronic acids to RCH=CHCO2Ar (Ar = Ph or 4-acetylphenyl) was carried out at 50 ˚C in aqueous acetone in the presence of [Pd(chiraphos)(PhCN)2](SbF6)2. The reaction gave optically active β-aryl esters in up to 98% ee. The protocol provided a simple access to an endothelin receptor antagonist reported by SmithKline Beecham.

Key words

arylboronic acids - palladium catalyst - asymmetric reaction - conjugate addition - β-arylalkanoate - bioactive compound

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General Procedure: A flask charged with [Pd((S,S)-chiraphos)(PhCN)2](SbF6)2 [(S,S)-3; 1 mol%], ArB(OH)2 (1.5 mmol) and 1 (0.5 mmol) was flushed with nitrogen. Acetone (2 mL) and H2O (0.2 mL) were then added. After stirring for 20 h at 50 ˚C, the product was isolated by chromatography on silica gel. The enantiomer excess was determined by Chiral HPLC using Daicel Chiralpak IA, IB or IC.