Harnessing atropisomerism as a drug discovery tool is an emerging trend in the pharmaceutical industry. In biaryl systems, if the barrier to rotation of a sigma bond is sufficiently high, then the resulting atropisomers can be non-interconverting enantiomers that may have stereospecific binding to their targets. We recently began a program to identify novel heterocyclic biaryl atropisomers and to synthesize them asymmetrically. Our initial studies focused on using computational studies to predict which functional groups would impart stable atropisomerism. Using density functional theory, we calculated the rotational profiles of more than 50 heterocyclic biaryls, from which we were able to derive calculated barriers to rotation. These studies were followed up with synthesis of the most promising candidates and then a determination of the barrier to rotation experimentally. We have identified multiple molecules with barriers of rotation higher than 30 kcal/mol, with the highest barrier to rotation observed to be 39 kcal/mol. Comparisons between the computational and experimental work will be presented. Progress towards the identification of the absolute stereochemistry of the enantiopure atropisomers by electronic circular dichroism will also be presented.

Computational-experimental approach to heterobiaryl atropisomerism

ACS Spring 2022

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