Biomedical subjects
Publications and source records attributed to Barry Lygo.
A catalyst design methodology, utilizing combinatorial synthesis in parallel with chemometric analysis, is presented, which considers the 3D steric and electrostatic properties of substituents about a constant core structure.
O-Alkyl N-anthracenylmethyl derivatives of Cinchona alkaloids can function as enantioselective phase-transfer catalysts. By employing these catalysts in the asymmetric alkylation of glycine imines, one can generate a range of alpha-amino acid derivatives with high levels of enantiomeric excess. It is also possible to generate the catalysts in situ from commercially available chiral amines, which offers the opportunity to evaluate libraries of related structures. This latter approach has been successfully applied to a series of biphenyl quaternary ammonium salts resulting in the development of a new highly selective catalyst and opening up the potential of further expanding the range of alpha-amino acid derivatives that can be prepared.
Studies into the use of a chiral phase-transfer catalyst in conjunction with sodium hypochlorite to effect the enantio-selective formation of alpha,beta-epoxyketones from allylic alcohols are described.
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 q(2) = 0.78) compared to a random choice of low-energy conformations for each catalyst (average q(2) = 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 q(2) = 0.83), as confirmed by repeated training/test splits.