Exploring the intricacies of inverse hydride shuttle catalysis in azabicyclic scaffold construction with contiguous stereocenters

Abstract

Asymmetric catalysis is crucial for synthetic organic chemistry, with significant implications in the synthesis of natural products and pharmaceuticals. Despite experimental advancements in the synthesis of chiral azabicyclic scaffolds using achiral organocatalysts and fluoro-aryl boranes, the fundamental mechanistic origins behind the introduction of three contiguous stereocenters remain largely unexplored. This study presents the first computational investigation into the intricacies of inverse hydride shuttle catalysis and the effect of electron-withdrawing groups in the asymmetric synthesis of azabicyclic frameworks. The condensed Fukui function analysis was employed to unravel the structure–activity relationship of five different fluoro-aryl boranes in the asymmetric synthesis of alkaloid scaffolds. The activation strain model analysis provided a quantitative assessment of contributions from interactions and deformations. The insights discovered align with experimental observations and could prove valuable in establishing efficient, selective, and sustainable methods for stereoselective synthesis without the need for any chiral source in the reaction.