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Abstract
Although asymmetric catalysis is universally dependent on spatial interactions to impart specific chirality on a given substrate, examination of steric effects in these catalytic systems remains empirical. Previous efforts by our group and others have seen correlation between steric parameters developed by Charton and simple substituents in both substrate and ligand; however, more complex substituents were not found to be correlative. Here, we review and compare the steric parameters common in quantitative structure activity relationships (QSAR), a common method for pharmaceutical function optimization, and how they might be applied in asymmetric catalysis, as the two fields are undeniably similar. We re-evaluate steric/enantioselection relationships, which we previously analysed with Charton steric parameters, using the more sophisticated Sterimol parameters developed by Verloop and co-workers in a QSAR context. Use of these Sterimol parameters led to strong correlations in numerous processes where Charton parameters had previously failed. Sterimol parameterization also allows for greater mechanistic insight into the key elements of asymmetric induction within these systems. Many parameters have been designed to describe steric size, but few have been able to explain consistently the selectivity of asymmetric catalytic reactions. Here, Sterimol parameters — originally used to develop quantitative structure–activity relationships in medicinal chemistry — have been used to quantify enantioselectivity in a diverse collection of asymmetric catalytic reactions. Cite this article
Harper, K., Bess, E. & Sigman, M. Multidimensional steric parameters in the analysis of asymmetric catalytic reactions. Nature Chem 4, 366–374 (2012). https://doi.org/10.1038/nchem.1297 