REIMAGINING MOLECULAR DISCONNECTIONS: PERSPECTIVES ON TOTAL SYNTHESIS AND SKELETAL EDITING

Abstract

The natural product estate harbors a multitude of structurally diverse scaffolds that challenge the limits of modern synthetic methods. This has motivated the development of new strategies to effect challenging bond constructions and expand the scope of feasible retrosynthetic connections. Site-selective C–H functionalization has emerged as a powerful tactic for circumventing traditional obstacles in complex molecule synthesis. The first section of this work describes our efforts towards the synthesis of maoecrystal V, a historically formidable natural product with an unprecedented molecular framework. An intramolecular rhodium catalyzed C–H insertion facilitates the construction of an advanced tetracyclic intermediate, and we implement a topology-guided approach to establish an elusive quaternary center at the heart of the molecule. The second section describes an enantioselective synthesis of (–)-aflatoxin B2 that produces a key carbon−carbon bond, a benzylic stereocenter, and two arene carbon−oxygen bonds in the course of three C−H functionalizations—an asymmetric rhodium carbene C–H insertion and a palladium catalyzed bis-C(sp2)–H oxidation. Inspired by the diverse frameworks of natural products and the enabling potential of the site-selective peripheral functionalizations, we were drawn to the idea of editing the core skeletons of biologically and pharmaceutically relevant scaffolds, which culminated in a reaction capable of achieving N-to-C point mutations of azaarene N-oxides.