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Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation

An Erratum to this article was published on 18 December 2012

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Abstract

Selectivity in the catalytic functionalization of complex molecules is a major challenge in chemical synthesis. The problem is magnified when there are several possible stereochemical outcomes and when similar functional groups occur repeatedly within the same molecule. Selective polyene oxidation provides an archetypical example of this challenge. Historically, enzymatic catalysis has provided the only precedents. Although non-enzymatic catalysts that meet some of these challenges became known, a comprehensive solution has remained elusive. Here, we describe low molecular weight peptide-based catalysts, discovered through a combinatorial synthesis and screening protocol, that exhibit site- and enantioselective oxidation of certain positions of various isoprenols. This diversity-based approach, which exhibits features reminiscent of the directed evolution of enzymes, delivers catalysts that compare favourably to the state-of-the-art for the asymmetric oxidation of these compounds. Moreover, the approach culminated in catalysts that exhibit alternative-site selectivity in comparison to oxidation catalysts previously described.

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Figure 1: Precedent and goal of catalytic oxidation of farnesol.
Figure 2: Catalyst library design by split-and-pool synthesis via the OBOC library method.
Figure 3: Results and raw data for the site-selective oxidation of farnesol and geranylgeraniol with m-CPBA, 2,3-selective catalyst 9b and 6,7-selective catalyst 12d.

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  • 20 November 2012

    In the version of this Article originally published, the bottom right-hand structure of Table 1 appeared incorrectly. This has now been corrected in the HTML and PDF versions.

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Acknowledgements

This work is supported by National Institutes of Health (NIH R01-GM096403) to S.J.M., and P.A.L. was partially supported by NIH CBI-TG-GM-067543. P.A.L. thanks B. Fowler for collaborating to build the library that resulted in catalyst 6, and S. Alexander and the Schepartz laboratory for assistance.

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P.A.L. designed and performed the experiments and S.J.M. oversaw the project. Both authors analysed data and co-wrote the manuscript.

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Correspondence to Scott J. Miller.

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The authors declare no competing financial interests.

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Lichtor, P., Miller, S. Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation. Nature Chem 4, 990–995 (2012). https://doi.org/10.1038/nchem.1469

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