Hydrogen Bonding Interaction Enabled Asymmetric C─H Acylation of Trifluoroethanol by Dual Nickel/Photoredox Catalysis
Yuanbo Li, Duo‐Duo Hu, Wei‐Ran Ren, Hang Liu, Yulin Wang, Kuiliang Li, Wen‐Chang Ke, Ruo‐Xing Jin, Xi‐Sheng Wang
Abstract
) 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.