Enantioselective Synthesis of Tetrahydro-1H-1,3-methanocarbazoles by Formal (3 + 3)-Cycloaddition Using Bicyclo[1.1.0]butanes

Abstract

Asymmetric synthesis presents many challenges, with the selective formation of chiral bridged polyheterocycles being a notable example. Cycloadditions using bicyclo[1.1.0]butanes (BCB) offer a promising solution along those lines, yet, despite significant advances in that emerging area, asymmetric control has remained limited thus far. Here, we describe an organocatalytic, enantioselective formal (3 + 3)-cycloaddition of BCBs with 1H-indol-3-yl((hetero)aryl)methanol derivatives. This approach enables the rapid and efficient synthesis of chiral tetrahydro-1H-1,3-methanocarbazole derivatives (34 examples) from readily available starting materials, with very good stereochemical control (up to 98:2 er). Successful scale-up experiments and product modification demonstrated the potential of this methodology. Control experiments and DFT calculations provide insights into the mechanistic pathway.