Catalysis-Enabled Access to Cryptic Geldanamycin Oxides

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.