Difunctionalization of C–C σ-Bonds Enabled by the Reaction of Bicyclo[1.1.0]butyl Boronate Complexes with Electrophiles: Reaction Development, Scope, and Stereochemical Origins

Abstract

Difunctionalization reactions of C-C -bonds have the potential to streamline access to molecules that would otherwise be difficult to prepare.However, the development of such reactions is challenging because C-C -bonds are typically unreactive.Exploiting the high ring-strain energy of polycyclic carbocycles is a common strategy to weaken and facilitate the reaction of C-C -bonds, but there are limited examples of highly strained C-C -bonds being used in difunctionalization reactions.We demonstrate that highly strained bicyclo[1.1.0]butylboronate complexes (strain energy: ca.65 kcal/mol), which were prepared by reacting boronic esters with bicyclo[1.1.0]butyllithium, react with electrophiles to achieve the diastereoselective difunctionalization of the strained central C-C -bond of the bicyclo[1.1.0]butylunit.The reaction shows broad substrate scope, with a range of different electrophiles and boronic esters being successfully employed to form a diverse set of 1,1,3-trisubstituted cyclobutanes (>50 examples) with high diastereoselectivity.The high diastereoselectivity observed has been rationalized based on a combination of experimental data and DFT calculations, which suggests that separate concerted and stepwise reaction mechanisms are operating depending upon the migrating substituent and electrophile used.