The development of new catalytic enantioselective access to stereogenic CF_(3)-containingmolecules is of great interest for expediting the discovery of lead compounds that remain challenging.Specifically,enantioselect...The development of new catalytic enantioselective access to stereogenic CF_(3)-containingmolecules is of great interest for expediting the discovery of lead compounds that remain challenging.Specifically,enantioselective synthesis of valuable ketones featuring stereogenicα-CF_(3) has rarely been reported.We devise a general and modular approach to facilely access enantioenrichedα-CF_(3) ketones via nickel-catalyzed reductive cross-coupling of readily available acid chlorides and racemicα-CF_(3) alkyl bromides in an enantioconvergent fashion under mild conditions.This protocol features neighboring directing group-free,high chemoselectivity,excellent functional group tolerance,facile scale-up,and notable amenability to straightforward downstream elaboration toward pharmaceutically useful enantioenrichedβ-trifluoromethylated secondary and tertiary alcohols,thus constituting a reliable,direct,practical,and efficient synthetic alternative to furnish enantiopureα-CF_(3) carbonyls.Interestingly,an appropriate choice of the phosphine ligand as coligand plays an important role in high efficiency and asymmetric induction.Mechanistic studies suggest a radical chain pathway.展开更多
基金We gratefully acknowledge funding from the Jiangsu Specially Appointed Professor Plan,National Natural Science Foundation of China(grant no.22071111)Natural Science Foundation of Jiangsu Province of China(grant no.BK20201368).
文摘The development of new catalytic enantioselective access to stereogenic CF_(3)-containingmolecules is of great interest for expediting the discovery of lead compounds that remain challenging.Specifically,enantioselective synthesis of valuable ketones featuring stereogenicα-CF_(3) has rarely been reported.We devise a general and modular approach to facilely access enantioenrichedα-CF_(3) ketones via nickel-catalyzed reductive cross-coupling of readily available acid chlorides and racemicα-CF_(3) alkyl bromides in an enantioconvergent fashion under mild conditions.This protocol features neighboring directing group-free,high chemoselectivity,excellent functional group tolerance,facile scale-up,and notable amenability to straightforward downstream elaboration toward pharmaceutically useful enantioenrichedβ-trifluoromethylated secondary and tertiary alcohols,thus constituting a reliable,direct,practical,and efficient synthetic alternative to furnish enantiopureα-CF_(3) carbonyls.Interestingly,an appropriate choice of the phosphine ligand as coligand plays an important role in high efficiency and asymmetric induction.Mechanistic studies suggest a radical chain pathway.
