Stereoselective Photocatalytic Crossed [2 + 2] Cycloadditions to Enantioenriched Polysubstituted Bicyclo[2.1.1]hexanes

High Resolution Image Download MS PowerPoint Slide Bicyclo[2.1.1]hexanes are highly sought-after as rigid sp 3 -rich building blocks for medicinal chemistry with their twelve substituent positions providing exciting opportunities for molecular design. However, most current synthetic methods to these structures offer no control over substituent stereochemistry and critically, allow for the substitution of only one of the three carbon bridges. We report a diastereoselective photochemical crossed [2 + 2] cycloaddition that enables the stereocontrolled synthesis of polysubstituted bicyclo[2.1.1]hexanes with substituents on all three of the carbon bridges. Both steric and orbital influences could be used to control stereoselectivity. Derivatives with twelve different substitution patterns and up to six substituted positions could be prepared in up to >19:1 dr and importantly, enantioenriched highly substituted bicyclo[2.1.1]hexanes could also be accessed. A comprehensive mechanistic and stereochemical analysis explains all obtained stereoselectivities and will help guide future applications of the reaction.