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Discoipyrroles A-D (DPA-DPD) are recently discovered natural products produced by the marine bacterium Bacillus hunanensis that exhibit anticancer properties in vitro. Initial biosynthetic studies demonstrated that DPA is formed in the liquid fermentation medium of B. hunanensis from three secreted metabolites through an unknown but protein-independent mechanism. The increased identification of natural products that depend on non-enzymatic steps creates a significant need to understand how these different reactions can occur. In this work, we utilized (15)N-labeled starting materials and continuous high-sensitivity (1)H-(15)N HMBC NMR spectroscopy to resolve scarce reaction intermediates of the non-enzymatic discoipyrrole reaction as they formed in real time. This information guided supplemental experiments using (13)C- and (18)O-labeled materials to elucidate the details of DPA's non-enzymatic biosynthesis, which features a highly concerted pyrrole formation and necessary O2-mediated oxidation. We have illustrated a novel way of using isotopically enhanced two-dimensional NMR spectroscopy to interrogate reaction mechanisms as they occur. In addition, these findings add to our growing knowledge of how multicomponent non-enzymatic reactions can occur through inherently reactive bacterial metabolites.

Detailed Mechanistic Study of the Non-enzymatic Formation of the Discoipyrrole Family of Natural Products