Theoretical Study and Rational Design of Noncovalent Interactions Enable Organocatalytic Divergent [2+2] and [4+2] Annulations

Organocatalytic regiodivergent annulations represent a challenging yet powerful strategy for the rapid construction of structurally distinct products. Herein, we employ theoretical studies to reveal how noncovalent interactions govern divergent [2+2] and [4+2] annulation pathways catalyzed by N-heterocyclic carbene (NHC) and isothiourea. Guided by computational insights, the NHC structure was strategically redesigned to modulate its noncovalent interaction profile, thereby switching its original regioselectivity. Experimental validation confirmed the predictions, underscoring the pivotal role of noncovalent interactions in controlling the regioselectivity.