Hydrogen Bonding Interaction Enabled Asymmetric C─H Acylation of Trifluoroethanol by Dual Nickel/Photoredox Catalysis

Abstract Serving as a bioisostere for methyl groups, the incorporation of the trifluoromethyl group (CF 3 ) has become a key area of interest in pharmaceutical lead optimization for its unique combination of steric bulk and high electronegativity. Recognizing the widespread application of optically pure α‐methyl‐α‐hydroxy carbon centers in drug molecules, the introduction of α‐hydroxytrifluoroethyl groups into stereogenic centers holds significant potential. Herein, we describe an asymmetric trifluoroalkylation protocol utilizing nickel/photoredox cocatalysis to synthesize enantioenriched α‐trifluoromethyl acyloins via a 1,2‐hydrogen atom migration strategy. Density functional theory calculations guided the reaction design, revealing hydrogen‐bonding interactions within the transition state that control the chiral outcome. The resulting products can be further reduced through a one‐pot process to yield fluoroalkyl‐1,2‐ anti ‐diols with adjacent stereocenters. This hydrogen‐bonding synergistic methodology demonstrates excellent stereochemical control, mild conditions, and broad functional group tolerance, enabling the efficient asymmetric trifluoroalkylation of complex molecules and offering new avenues for chiral drug development.