Stereoselective polysubstituted bicyclo[1.1.0]butane synthesis by rhodium-catalyzed kinetic resolution.

Abstract

Bicyclo[1.1.0]butanes (BCBs) are a distinctive class of strained small-ring carbocycles of growing importance in synthetic and medicinal chemistry. However, the enantioselective synthesis of polysubstituted BCBs remains a largely unsolved challenge. Herein, we report a general chemical platform for the stereoselective assembly of chiral or meso 1,2,3,4-tetrasubstituted BCBs from internal alkynes and carbenes via stepwise [2+1+1'] or one-pot [2+1+1] cycloaddition reactions, respectively. Successful execution of these transformations exploits the combination of triftosylhydrazones (carbene precursors) and chiral dirhodium catalysts. The sterically hindered catalyst Rh₂(<i>R</i>-3,5-<i>di</i>PheTPCP)₄ features a confined chiral microenvironment that enables exquisite discrimination between cyclopropene enantiomers, affording highly enantioenriched polysubstituted BCBs through kinetic resolution upon reaction with chiral rhodium carbenes. This chemistry operates under mild reaction conditions, employs readily available starting materials, and exhibits broad substrate scope.