Exploring Phase-Transfer Catalysis with Molecular Dynamics and 3D/4D Quantitative Structure−Selectivity Relationships

Quantitative Structure−Selectivity Relationships (QSSR) are developed for a library of 40 phase-transfer
asymmetric catalysts, based around quaternary ammonium salts, using Comparative Molecular Field Analysis
(CoMFA) and closely related variants. Due to the flexibility of these catalysts, we use molecular dynamics
(MD) with an implicit Generalized Born solvent model to explore their conformational space. Comparison
with crystal data indicates that relevant conformations are obtained and that, furthermore, the correct biphenyl
twist conformation is predicted, as illustrated by the superiority of the resulting model (leave-one-out q2 =
0.78) compared to a random choice of low-energy conformations for each catalyst (average q2 = 0.22). We
extend this model by incorporating the MD trajectory directly into a 4D QSSR and by Boltzmann-weighting
the contribution of selected minimized conformations, which we refer to as ‘3.5D' QSSR. The latter method
improves on the predictive ability of the 3D QSSR (leave-one-out q2 = 0.83), as confirmed by repeated
training/test splits.