Catalytic, selective modifications of natural products can be a fertile platform for not only unveiling new natural product analogues 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, our discoveries would likely not have been possible absent the attractive noncovalent interactions intrinsic to both the catalysts and the natural product. The result is a set of new "meta" catalytic reactions that deliver both unknown and previously incompletely characterized geldanamycin analogues. Enabled by the catalytic, site-selective epoxidation of geldanamycin, biological assays were carried out to document the bioactivities of the new compounds.
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