Propellane Alkaloid Biosynthesis and Total Synthesis via Interrupted Reaction Pathways

Interrupted reactions, in which an intermediate is redirected from its conventional mechanistic pathway, offer a unique approach to the assembly of complex natural products. This study details the biosynthesis of a newly discovered family of alkaloids named the subrubines alongside the total synthesis of the penultimate member, pensubrubine, featuring distinct interrupted reaction pathways. These natural products, identified using high-resolution genome mining of an active site mutation, represent the only reported microbial diaza[3.3.3]-propellane pyrrolidinoindolines. We demonstrate through complete pathway reconstitution that the putatively annotated ene-reductase SubF functions as the propellane synthase that directs an enolate intermediate toward an intramolecular Mannich cyclization. Concurrently, a concise 7-step total synthesis of pensubrubine was developed, employing a diastereoselective interrupted Fischer indolization reaction to rapidly construct the diaza[3.3.3]-propellane core and establish the absolute configuration of pensubrubine. The reported bio- and total syntheses of subrubines showcase the value of interrupted pathways in assembling complex scaffolds.