Enantioselective synthesis of 1,3-bicyclo[2.1.1]hexanes as meta-benzene bioisosteres

Bicyclo[2.1.1]hexanes are rigid bridged scaffolds with well-defined exit vectors that have been proposed as appropriate bioisosteres of phenyl rings. Although many racemic syntheses have recently emerged, access to single enantiomers of these skeletons remains a major challenge. To provide a solution to that, we have developed an enantioselective copper-catalyzed protoborylation to obtain 1,3-disubstituted bicyclo[2.1.1]hexanes as suitable mimics of meta-benzenes. The stereocontrolled formation of these bicyclic frameworks, which present an unprecedented substitution pattern, was achieved through a desymmetrization of bicyclo[2.1.1]hex-2-enes. Remarkably, the employment of such strained alkenes had no precedent in catalysis, providing a novel platform for the functionalization of the bicyclo[2.1.1]hexane core. The obtained versatile enantioenriched building blocks have been incorporated into the structure of different drug analogues, leading to an improvement of solubility, metabolic stability and permeability in comparison with the parent drugs. Moreover, the drug analogues showed a retention of biological activity by targeting the same molecular receptors, which unambiguously validated them as suitable meta-benzene bioisosteres.