Enantioselective photocatalytic synthesis of bicyclo[2.1.1]hexanes as orthodisubstituted benzene bioisosteres with improved biological activity

1,5-Disubstituted bicyclo[2.1.1]hexanes are bridged scaffolds with well-defined exit vectors that are becoming increasingly popular building blocks in medicinal chemistry since they are saturated bioisosteres of orthosubstituted phenyl rings. Here we have developed the first enantioselective catalytic strategy based on a Lewis acid-catalyzed [2+2] photocycloaddition to obtain these motifs as enantioenriched scaffolds, providing an efficient approach for their incorporation in a variety of drug analogues. The bioisostere-containing drugs have been evaluated in cancer cell viability studies, observing that in some cases the biological activity of the two enantiomers is highly different. This showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its bioactivity, highlighting the need for stereoselective methods towards the construction of the bicyclo[2.1.1]hexane core.