Rotational Motion in Bispidines: A Conformational Study

Bispidines (namely 3,7-diazabicyclo[3.3.1]nonanes) are a class of bicyclic diamines characterized by two fused piperidine rings. Found predominantly in natural products, bispidines exhibit a range of pharmacological effects, making them of significant interest in drug design1. Beyond their medicinal uses, bispidine structures have emerged as promising scaffolds in the fields of organocatalysis or molecular motors2-3. This is the case of bispidine diamides where the relative position of the two carbonyl groups is reminiscent of molecular machine with stops at the syn/anti position, thus allowing chiral−achiral switching (Scheme 1A)4-5. While various studies have investigated the relative positioning of the two amide groups, a detailed conformational analysis of rotameric bispidines beyond diamides has not yet been fully explored. In our work, a series of rotameric bispidines have been examined experimentally and computationally, revealing how intramolecular stabilizing effects play an essential role in determining observable rotational motion with particular attention given to the factors influencing the rate and direction of rotation for different classes of bispidinic rotamers (Scheme 1B). This research could have important implications in molecular design since restricted amide bond rotations are key not only in motor motion, but also in foldamers6-7. Particular attention has been given to the factors influencing the rate and direction of rotation for different classes of bispidinic rotamers. The insights gained from this work aim to provide valuable guidance for the design of new molecular motors or organocatalysts, where the ability to control rotational movement is crucial to the function of the system.