Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space.

Saturated bridged-bicyclic compounds are currently under intense investigation as building blocks for pharmaceutical drug design. However, the most common methods for their preparation only provide access to bridgehead-substituted structures. The synthesis of bridge-functionalised species is highly challenging but would open up many new opportunities for molecular design. We describe a photocatalytic cycloaddition reaction that provides unified access to bicyclo[2.1.1]hexanes with 11 distinct substitution patterns. Bridge-substituted structures that represent ortho-, meta-, and polysubstituted benzene bioisosteres, as well as those that enable the investigation of chemical space inaccessible to aromatic motifs can all be prepared using this operationally simple protocol. Proof-of-concept examples of the application of the method to the synthesis of saturated analogues of biorelevant trisubstituted benzenes are also presented.