Theoretical Studieson the Competing Mechanism andOrigin of Diastereoselectivity of NHC-Catalyzed Intramolecular [3+ 2] Annulations of Ynals

Chiral tricyclic 6,5,5-fused rings exhibit structural diversity and possess important biological activities in the synthesis of natural products. However, predicting the possible mechanism and origin of stereoselectivity in these reactions remains a challenge. In this article, we conducted a theoretical investigation into the NHC-catalyzed intramolecular [3 + 2] annulations of ynals to generate tricyclic 6,5,5-fused rings. Our calculations revealed that NHC could nucleophilically attack the carbonyl group of the ynal reactant, leading to the formation of a Breslow intermediate via a 1,2-proton transfer. Subsequently, an intramolecular Michael addition takes place, resulting in a 6–5 bicyclic intermediate. We then compared the competitive processes involving proton transfer and the Mannich reaction. The more energetically favorable process involves an HOAc-assisted proton transfer process, followed by the Mannich reaction. To ascertain the origin of the diastereoselectivity, we performed noncovalent interaction (NCI) and atom-in-molecule (AIM) analyses. This work is useful for understanding the general principles and detailed mechanisms of the synthesis of chiral 6,5,5-fused tricyclic scaffolds with unique diastereoselectivity.