Organocatalytic Desymmetric Conjugate Addition to Cyclobutanone: An Enantio‐ and Diastereoselective Synthesis of [6,5,4]‐Fused Carbocycles

Abstract

AbstractThe first organocatalytic, non‐destructive desymmetrisation of 3‐substituted cyclobutanone followed by intramolecular cyclisation is described. Owing to the slow activation of the pronucleophile by the weak Brønsted base, the α‐functionalization of ketones with tertiary‐amine‐derived Brønsted base catalysis has been chemically challenging in asymmetric transformations. Herein, we demonstrate that the cinchona‐derived squaramide catalyst works effectively for the intramolecular Michael addition of cyclobutanone to enones and affords the architecturally fascinating [6,5,4]‐fused carbocyclic skeleton in good yields and excellent diastereo‐ and enantioselectivities (up to >20 : 1drand 96 %ee). Furthermore, as a synthetic application, this method provides an alternative pathway to enantioenriched high‐value products like γ‐lactones and indan‐2‐ol derivatives.