Mechanistic Study on the Asymmetric Cascade Michael Addition of Alkynone and Oxindole Catalyzed by Chiral Guanidine

Density functional theory (DFT) calculations with the M06-2X-D3 functional were used to get the mechanistic investigation and stereoselectivity of the cascade Michael addition of alkynone and oxindole, catalyzed by a chiral guanidine-amide compound. The reaction proceeded through a two-step synergistic process involving sequential C-C and C-O bond formation, together with an H-shift. Because of the high energy barriers of 33.5 kcal mol^-1 (for C-C bond construction) and 41.3 kcal mol^-1 (for C-O bond construction), the reaction was difficult to proceed without the catalyst. The guanidine catalyst facilitated the generation of enolized oxindole species with high nucleophilicity, activating both the enolate oxindole and the alkynone via ion-pairing and multiple hydrogen bonding, significantly lowering the activation barriers. The combination of the guanidine unit and the sulfonamide backbone created an excellent semiclosed chiral environment, promoting asymmetric induction. Due to steric effects from the <i>ortho</i>- and <i>para</i>-substituted <i>i</i>Pr groups in SO₂Ar, the bulky Cy group, and the chiral backbone, the <i>SS</i>-configuration spirocyclization product with high enantio- and diastereoselectivity was formed predominantly. The <i>E</i>/<i>Z</i> selectivity in the formation of the key α,β-unsaturated ketone intermediate was influenced by catalyst-substrate interactions. Extension of the alkyl chain at the 3-position in the oxindole substrate led to the C-O bond formation more difficult, hindering the construction of spirooxindoles.