Cooperative Catalysis of Metal and O-HO/sp super(3)-C-HO Two-Point Hydrogen Bonds in Alcoholic Solvents: Cu-Catalyzed Enantioselective Direct Alkynylation of Aldehydes with Terminal Alkynes

Catalyst-substrate hydrogen bonds in artificial catalysts usually occur in aprotic solvents, but not in protic solvents, in contrast to enzymatic catalysis. We report a case in which ligand-substrate hydrogen-bonding interactions cooperate with a transition-metal center in alcoholic solvents for enantioselective catalysis. Copper(I) complexes with prolinol-based hydroxy amino phosphane chiral ligands catalytically promoted the direct alkynylation of aldehydes with terminal alkynes in alcoholic solvents to afford nonracemic secondary propargylic alcohols with high enantioselectivities. Quantum-mechanical calculations of enantiodiscriminating transition states show the occurrence of a nonclassical sp super(3)-C-HO hydrogen bond as a secondary interaction between the ligand and substrate, which results in highly directional catalyst-substrate two-point hydrogen bonding. Efficient enantioselective direct carbonyl addition of terminal alkynes is achieved through ligand-substrate two-point hydrogen bonds consisting of O-HO and sp super(3)-C-HO interactions that cooperate with copper in alcoholic solvents (see picture).