Enantioselective and Diastereoselective Synthesis of Spiroazabicyclo[2.n]alkanes by Rhodium-Catalyzed Cyclopropanations

Spirocyclopropanes have become a prevalent structural motif in drug discovery campaigns. However, methods to generate these spirocyclopropanes stereoselectively are scarce, highlighting the need for novel synthetic methods. In this report we describe the synthesis of various spiroazabicyclo[2.n]alkanes by means of a dirhodium tetracarboxylate catalyzed cyclopropanation of exocyclic olefins using do-nor/acceptor carbenes. The optimum chiral dirhodium tetracarboxylate catalyst, Rh2(p-PhTPCP)4 results in highly enantioselective cyclopropanation of symmetrical azacyclomethylidenes, highly enantioselective and diastereoselective cyclopropanation of non-symmetrical azacyclomethylidenes, and can achieve up to 83,000 turnovers. Computational studies reveal that the cyclopropanation is occurring under non Curtin-Hammett conditions and the stereoselectivity is controlled by the way the substrate can fit into the chiral pocket generated by the ligands.