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

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. In this study, 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 through 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 Rh 2 ( R -3,5- di 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, uses readily available starting materials, and exhibits broad substrate scope.