Synthesis of polysubstituted cyclobutanes through a photoredox strain-release/[3,3]-rearrangement cascade

Abstract

Small saturated carbocycles, such as cyclobutanes, with elevated three-dimensionality and rich C_sp3 centers are privileged scaffolds in naturally occurring molecules and drug discovery. It remains highly desirable and challenging to develop modular and straightforward strategies to craft densely substituted cyclobutanes. Herein, a photoredox-catalyzed radical strain-release/[3,3]-rearrangement cascade (SRRC) strategy for efficient synthesis of polysubstituted cyclobutanes is disclosed. This protocol operates with readily available α-silylamines as radical precursors, and strained bicyclo[1.1.0]butanes (BCBs) and cyclobutenes as radical acceptors, to access an array of structurally diverse 1,1,3- and 1,1,2-trisubstituted cyclobutanes containing a unique non-natural amino acid scaffold. Mechanistic studies reveal the pivotal reactivity of the silylketene acetal intermediate and the origin of diastereoselectivity. The power and utility of this method are illustrated with diverse transformations and preliminary anticancer assessment.