Spontaneous transfer of chirality in an atropisomerically enriched two-axis system

Perhaps the most well-recognized stereogenic elements within chiral molecules are sp(3)-hybridized carbon atoms possessing four different substituents. However, axes of chirality may also exist about bonds with hindered barriers of rotation, leading to stereoisomers known as atropisomers.(1) Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs(2) or molecular switches and motors.(3) For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. We report here a two-axis system in which an enantioselective reaction that produces four stereoisomers (two enantiomeric pairs) displays a more complex scenario. Following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is substantially perturbed from the system’s equilibrium position. Notably, as the system undergoes isomerization, one of the diastereomeric pairs is observed to drift spontaneously to a higher enantiomeric ratio. In a compensatory manner, the other diastereomeric pair also converts to an altered enantiomeric ratio, reduced in magnitude from the initial ratio. These observations occur within a class of unsymmetrical amides that exhibits two asymmetric axes – one defined through a benzamide substructure, and the other implicit with differentially N,N-disubstituted amides. The stereodynamics of these substrates provide an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibration.