Asymmetric Remote Leaving Group-Promoted Propargylic Substitution

Propargylic substitution is a basic type of transformation in organic synthesis but relies on the existence of an α-leaving group. Thus, alkyne bearing an alkyl-linked remote leaving group is not considered as a suitable substrate for propargylation, and related remote substitution is unexplored. Here, we show that such a remote propargylation model can be established stereoselectively via copper catalysis. By combining the positive effects of d-orbital electron donation of alkynyl copper, ring strain release, and the cleaving tendency of the remote leaving group, propargylic cyclopropane fragmentation and functionalization is achieved in good yield and with high enantioselectivity. A set of modified chiral PPBOX ligands are developed to guarantee stereocontrol of the transformation. Both the amination and alkylation processes have been established to demonstrate the reliability of the design. Mechanistic studies show the necessity of Cu metal, ring strain, and remote leaving group in promoting C–C bond cleavage and that propargylic substitution might be the turnover-limiting step.