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Cooperative Activation of Alkyne and Thioamide Functionalities; Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to α,β‐Unsaturated Thioamides
Author(s) -
Yazaki Ryo,
Kumagai Naoya,
Shibasaki Masakatsu
Publication year - 2011
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201100050
Subject(s) - thioamide , chemistry , catalysis , alkyne , enantioselective synthesis , conjugate , combinatorial chemistry , brønsted–lowry acid–base theory , lewis acids and bases , reactivity (psychology) , ligand (biochemistry) , stereochemistry , medicinal chemistry , organic chemistry , receptor , medicine , mathematical analysis , biochemistry , alternative medicine , mathematics , pathology
A detailed study of the direct catalytic asymmetric conjugate addition of terminal alkynes to α,β‐unsaturated thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst, comprising [Cu(CH 3 CN) 4 ]PF 6 , bisphosphine ligand, and Li(OC 6 H 4 ‐ p ‐OMe) simultaneously activated both substrates to compensate for the low reactivity of copper alkynylide. A series of control experiments revealed that the intermediate copper‐thioamide enolate functioned as a Brønsted base to generate copper alkynylide from the terminal alkyne, thus driving the catalytic cycle through an efficient proton transfer between substrates. These findings led to the identification of a more convenient catalyst using potassium hexamethyldisilazane (KHMDS) as the Brønsted base, which was particularly effective for the reaction of silylacetylenes. Divergent transformation of the thioamide functionality and a concise enantioselective synthesis of a GPR40 receptor agonist AMG‐837 highlighted the synthetic utility of the present catalysis.