title: 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.
authors.affiliation: Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yazaki
authors.forename: Naoya
authors.initials: N
authors.lastname: Kumagai
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D002384:Catalysis; D056831:Coordination Complexes / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D008094:Lithium / Q000737:chemistry; D008968:Molecular Conformation; D011522:Protons; D013854:Thioamides / Q000737:chemistry*
chemical_list: D000480:Alkynes; D056831:Coordination Complexes; D011522:Protons; D013854:Thioamides; D003300:Copper; D008094:Lithium