Atropisomers are molecules whose chirality is brought about through a hindered bond rotation, typically an sp2-sp2 axis. Often one atropisomeric conformation is biologically active for a given target, while the other may have off-target effects. It was shown that one could increase the selectivity of promiscuous rapidly interconverting inhibitors by rigidifying the atropisomeric bond through introduction of bulky substituents ortho to the atropisomeric axis, with the less sterically hindered scaffold inhibiting more of the kinome. Relaxed scans of the torsion angle revealed a quadruple- well potential energy surface. It was hypothesized that the higher second derivative of the R-chirality well in the sterically hindered atropisomer led to a higher selectivity. To computationally evaluate this hypothesis, the transition states geometries and energies for the bond rotation were optimized using B3LYP/6-31G(d) density functional methods, and Intrinsic Reaction Coordinate calculations were carried out to confirm these transition states. The surface was then fit to an analytical function. Variational wavefunctions and energies were optimized on this surface by diagonalization of the Hamiltonian matrix using a harmonic oscillator basis. These results were then used to calculate the vibrational entropy along this coordinate for comparison to experiment.<br/>

Computational analysis of a hindered bond rotation in atropisomers

2019 Fall National Meeting

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