Synthesis of Chiral Tertiary α,α-Difluoromethyl Carbinols by Cu-Catalyzed Asymmetric Propargylation

Chiral alpha,alpha-difluoromethyl carbinols are recurring structural motifs in many therapeutic agents. Despite the indubitable interest in the catalytic asymmetric synthesis of such compounds, this research field still remains largely underexplored. Herein, an efficient approach to a range of chiral homopropargylic alpha,alpha-difluoromethyl carbinols has been developed, through a Cu-catalyzed enantioselective propargylation of alpha,alpha-difluoroketones with (pinacolato)allenylboron. In the presence of a cuprous complex, generated in situ from CuCl and a spiroketal-based diphosphine (SKP) ligand, a variety of aryl-, heteroaryl-, alkyl-, alkynyl, alkenyl, or benzyloxycarbonyl-substituted alpha,alpha-difluoromethyl carbinols were obtained in 75-99 % yields with 84-98 % ee values. The catalytic system was further investigated using a combined dynamic NMR spectroscopic, X-ray crystallographic, and non-linear effect studies. The origin of the enantioselectivity was rationalized based on DFT calculations. Finally, several efficient transformations were showcased to highlight the utilities of the protocol in synthesis of complex compounds bearing an alpha,alpha-difluoromethyl carbinol moiety.