Exploring phase-transfer catalysis with molecular dynamics and 3D/4D quantitative structure -- Selectivity relationships

Citation

Melville JL, Lovelock KRJ, Wilson C, Allbutt B, Burke E, Lygo B & Hirst JD (2005) Exploring phase-transfer catalysis with molecular dynamics and 3D/4D quantitative structure -- Selectivity relationships. Journal of Chemical Information and Modeling, 45 (4), pp. 971-981. https://doi.org/10.1021/ci050051l

Abstract
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.

Journal
Journal of Chemical Information and Modeling: Volume 45, Issue 4