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

The 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 Bronsted base, the alpha-functionalization of ketones with tertiary-amine-derived Bronsted 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 : 1 dr and 96 % ee). Furthermore, as a synthetic application, this method provides an alternative pathway to enantioenriched high-value products like gamma-lactones and indan-2-ol derivatives.