Multidimensional steric parameters in the analysis of asymmetric catalytic reactions

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.

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Figure 1: Visualization of the experimental basis of several steric parameters and comparison of their determined values.
Figure 2: NHK allylations of benzaldehyde and acetophenone using standard conditions.
Figure 3: The Charton steric parameter is experimentally based and has inherent limitations.
Figure 4: Reanalysis of the data shown in Fig. 2 using Sterimol parameters.
Figure 5: Examination of substrate effects in the desymmetrization of bisphenols.
Figure 6: Propargylation of acetophenone re-analysed using Sterimol parameters in place of Charton parameters.

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Acknowledgements

The authors thank Joel Harris for critical discussions on data analysis and Scott Miller for access to data and insightful discussions regarding this work. Thanks also go to Marisa Kozlowski for introducing us to Sterimol parameters. This work was supported by the National Science Foundation (CHE-0749506 and CHE-1110599).

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All authors discussed the results and commented on the manuscript.

Correspondence to Matthew S. Sigman.

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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

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