Year: 2026
Type: article
Abstract: 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.
Source: ACS Central Science
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Awards: Acquisition of Upgraded NMR Instrumentation for Chemistry Research, Education and Training, G1661892572, G2923451624, NMR Console and Prodigy CryoProbe, G4305609567, Graduate Research Fellowship Program (GRFP), Time-of-Flight Mass Spectrometer for Synthesis Supporting Biomedical Research, Total Synthesis of Complex Molecules, G8316310998, G863947390, G895126265, G9000243959, G910930967
OpenAlex ID: W7148894962