Facile access to bicyclo[2.1.1]hexanes by Lewis acid-catalyzed formal cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes

Abstract

AbstractSaturated three-dimensional carbocycles have gained increasing prominence in synthetic and medicinal chemistry. In particular, bicyclo[2.1.1]hexanes (BCHs) have been identified as the molecular replacement for benzenes. Here, we present facile access to a variety of BCHs via a stepwise two-electron formal (3 + 2) cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes (BCBs) under Lewis acid catalysis. The reaction features wide functional group tolerance for silyl enol ethers, allowing the efficient construction of two vicinal quaternary carbon centers and a silyl-protected tertiary alcohol unit in a streamlined fashion. Interestingly, the reaction with conjugated silyl dienol ethers can provide access to bicyclo[4.1.1]octanes (BCOs) equipped with silyl enol ethers that facilitate further transformation. The utilities of this methodology are demonstrated by the late-stage modification of natural products, transformations of tertiary alcohol units on bicyclo[2.1.1]hexane frameworks, and derivatization of silyl enol ethers on bicyclo[4.1.1]octanes, delivering functionalized bicycles that are traditionally inaccessible.