Cooperative Activation of Alkyne and Thioamide Functionalities; Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to α,β‐Unsaturated Thioamides

Abstract

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.

Cooperative Asymmetric Catalysis Using Thioamides toward Truly Practical Organic Syntheses

“…Thus, a simple mesitylcopper/ 16 catalytic system emerged as the second‐generation catalyst for this transformation, in which mesitylcopper irreversibly deprotonated the terminal alkyne 3 to enter into the catalytic cycle with the concomitant generation of mesitylene. This catalytic cycle proceeded smoothly to produce the β‐alkynyl thioamides 17 with yields and enantioselectivities comparable to those observed with the first‐generation catalyst 21…”

“…In‐depth analysis of the proton transfer process in the catalytic cycle with the first‐generation catalyst [Cu(CH 3 CN) 4 ]PF 6 / 16 /Li(OC 6 H 4 ‐ p ‐OMe) revealed an intriguing clue toward refining the catalytic system (Scheme ) 21. In the catalytic cycle of the first‐generation catalyst, the Cu/ 16 complex and Li(OC 6 H 4 ‐ p ‐OMe) cooperatively deprotonated the terminal alkyne 3 to generate Cu‐alkynylide 19 with concomitant formation of HOC 6 H 4 ‐ p ‐OMe (Scheme , cycle A).…”

Catalytic Asymmetric Conjugate Addition of Thiols to α,β‐Unsaturated Thioamides: Expeditious Access to Enantioenriched 1,5‐Benzothiazepines

“…Our previous investigations revealed that a mesitylcopper/chiral bisphosphine catalyst forms an active copper nucleophile with the liberation of mesitylene 6b,d. An analogous catalytic cycle can be delineated for the conjugate addition of thiols 2 (Scheme ).…”

GPR40: A therapeutic target for mediating insulin secretion

“…However, the latter, including a variety of monounsaturated fatty acids such as 9Z-palmitoleic acid (C16:1) and 9Z-oleic acid (C18:1) and polyunsaturated fatty acids such as 9Z,12Z-linoleic acid (C18:2) and 5,8,11-eicosatrienoic acid (C20:3), do not appear to be dependent on carbon chain length or the degree of saturation (44). Additionally, a series of synthetic agonists such as GW9508, AMG 837 and 3-substituted 3-(4-aryloxyaryl)propanoic acids have been recently reported (47)(48)(49)(50). Several synthetic GPR40 antagonists have also been well described, including DC260126 and GW1100 (51-54).…”