Computational Study Focusing on a Comprehensive Conformational Analysis of Transition States for Aza-Spiro Ring Formations with N-Alkoxyamides

An accurate understanding of conformations in transition states is a critical piece in the theoretical analysis of complex molecular reactions. In this study, we investigated conformationally diverse transition states during intramolecular aza-spiro ring formation with an allylsilane moiety and N-alkoxy iminium ion, a key reaction in the synthesis of fasicularin by Sato and Chida et al., and identified the origins of stereoselectivity of the cyclization. A large number of conformational isomers with forming C-C bonds were comprehensively analyzed using Cremer-Pople puckering parameters. It was found that the conformations of the transition states had different puckering preferences depending on the reactant's double-bond geometry and the product's stereochemical configuration. Furthermore, an asymmetric aza-spiro cyclization with a tolyl group as a chiral auxiliary was investigated, showing that conformational anchoring by both a CH-O hydrogen bond and the CH-p interaction was critical for the asymmetric induction.

Automated summary

This study provides important insights into the theoretical analysis of complex molecular reactions by investigating the conformations and stereoselectivity of transition states. The findings reveal that the double-bond geometry and stereochemical configuration influence the conformations of the transition states, and that the CH-O hydrogen bond and CH-p interaction play critical roles in asymmetric induction.