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Bacterial natural product biosynthetic genes, canonically clustered, have been increasingly found to rely on hidden enzymes encoded elsewhere in the genome for completion of biosynthesis. The study and application of lanthipeptides are frequently hindered by unclustered protease genes required for final maturation. Here, we establish a global correlation network bridging the gap between lanthipeptide precursors and hidden proteases. Applying our analysis to 161,954 bacterial genomes, we establish 5209 correlations between precursors and hidden proteases, with 91 prioritized. We use network predictions and co-expression analysis to reveal a previously missing protease for the maturation of class I lanthipeptide paenilan. We further discover widely distributed bacterial M16B metallopeptidases of previously unclear biological function as a new family of lanthipeptide proteases. We show the involvement of a pair of bifunctional M16B proteases in the production of previously unreported class III lanthipeptides with high substrate specificity. Together, these results demonstrate the strength of our correlational networking approach to the discovery of hidden lanthipeptide proteases and potentially other missing enzymes for natural products biosynthesis.

 

Axially chiral enamides bearing a N–C axis have been recently studied and were proposed to be valuable chiral building blocks, but a stereoselective synthesis has not been achieved. Here, we report the first enantioselective synthesis of axially chiral enamides via a highly efficient, catalytic approach. In this approach, C(sp 2 )–N bond formation is achieved through an iridium-catalyzed asymmetric allylation, and then in situ isomerization of the initial products through an organic base promoted 1,3-H transfer, leading to the enamide products with excellent central-to-axial transfer of chirality. Computational and experimental studies revealed that the 1,3-H transfer occurs via a stepwise deprotonation/re-protonation pathway with a chiral ion-pair intermediate. Hydrogen bonding interactions with the enamide carbonyl play a significant role in promoting both the reactivity and stereospecificity of the stepwise 1,3-H transfer. The mild and operationally simple formal N -vinylation reaction delivered a series of configurationally stable axially chiral enamides with good to excellent yields and enantioselectivities.