Biosynthetically‐Inspired Oxidative Cleavage Platform Enables Rapid Access to Diverse and Architecturally Complex Chemotypes From Indole Alkaloids

High‐throughput screening (HTS) of compound libraries is a primary driver in the discovery of therapeutic leads. HTS libraries are largely composed of structurally simple organic compounds bearing few, if any, complex molecules which limits the kinds of molecular targets that can be drugged. Herein, we describe a biosynthesis‐inspired ring distortion approach involving oxidative ring cleavage, ring rearrangement, and ring expansion reactions from indole alkaloids. A Witkop–Winterfeldt oxidative ring cleavage of 11 indole alkaloids and derivatives provided keto‐lactams in up to 98% yield (47% yield average). Quinolones were formed via Camps cyclization from keto lactams, or following direct exposure of indole to potassium superoxide with yields up to >99% (52% yield average; 14 examples). Select keto lactams and ketone substrates were subjected to Schmidt reactions and urea synthesis to deliver alternative chemotypes. In total, this platform led to the synthesis of >25 distinct chemotypes (molecular architectures) from 14 indole alkaloids. Chemoinformatic analyses were used to quantify chemical diversity, stereochemical complexity, and favorable physiochemical properties of this compound collection. Overall, this oxidative cleavage platform represents a significant expansion of the kinds of complex molecules accessed from indole alkaloids to uncover new biological insights relevant to human health and disease.