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Catalysis-Enabled Access to Cryptic Geldanamycin Oxides

preprint
submitted on 08.01.2020 and posted on 09.01.2020 by Margaret J. Hilton, Christopher Brackett, Brandon Q. Mercado, Brian S. J. Blagg, Scott Miller
Catalytic, selective modifications of natural products can be a fertile platform for unveiling not only new natural product analogs with altered biological activity, but also for revealing new reactivity and selectivity hierarchies for embedded functional groups in complex environments. Motivated by these intersecting aims, we report site and stereoselective oxidation reactions of geldanamycin facilitated by aspartyl-peptide catalysts. Through the isolation and characterization of four new geldanamycin oxides, we discovered a synergistic effect between lead peptide-based catalysts and geldanamycin, resulting in an unexpected reaction pathway. Curiously, it seems unlikely that our discoveries would not have been possible absent the outer sphere interactions intrinsic to both the catalyst and the natural product. The result is a set of new “meta” catalytic reactions that deliver both unknown and previously incompletely characterized geldanamycin analogs. Enabled by the catalytic, site-selective epoxidation of geldanamycin, biological assays were carried out to document the bioactivities of the new compounds.

History

Email Address of Submitting Author

scott.miller@yale.edu

Institution

Yale University

Country

USA

ORCID For Submitting Author

0000-0001-7817-1318

Declaration of Conflict of Interest

The authors declare no competing financial interest.

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in ACS Central Science

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