Conformational and Electron Density Analysis of Bicyclo[3.1.0] hexanes: All Roads Lead to Boats

Abstract

In view of the existence of an optimal conformation for molecular recognition and bearing in mind that nucleosides exhibit a broad range of pharmaceutical properties, whereby their conformation has a key role in molecular recognition, the tendency of the pseudosugar moiety in carbanucleosides to adopt a boat‐like conformation has been studied on the basis of a bicyclo[3.1.0]hexane system, resulting in versatile druglike scaffolds to increase molecular recognition. It is already known that using this system as a pseudosugar can fix the conformation in the northern or southern geometry required for biological activity, according to the relative position of the three‐membered ring. By mapping their energy potential surface, we investigated the preference for boat‐like conformers in bicyclo[3.1.0]hexanes. DFT was utilized alongside NBO analysis to explore the enhanced stability of boat‐like conformers, also considering the influence of oxygen, sulfur, and selenium heteroatoms. Additionally, charge density distribution analysis using QTAIM identified key atoms contributing to stability changes. These findings will help to comprehend this behavior in the drug discovery process when conformationally restricted nucleosides are involved.