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Siderophores belonging to the ferrichrome family are essential for the viability of fungal species and play a key role for virulence of numerous pathogenic fungi. Despite their biological significance, our understanding of how these iron-chelating cyclic hexapeptides are assembled by non-ribosomal peptide synthetase (NRPS) enzymes remains poorly understood, primarily due to the nonlinearity exhibited by the domain architecture. Herein, we report the biochemical characterization of the SidC NRPS, responsible for construction of the intracellular siderophore ferricrocin. In vitro reconstitution of purified SidC reveals its ability to produce ferricrocin and its structural variant, ferrichrome. Application of intact protein mass spectrometry uncovers several non-canonical events during peptidyl siderophore biosynthesis, including inter-modular loading of amino acid substrates and an adenylation domain capable of poly-amide bond formation. This work expands the scope of NRPS programming, allows biosynthetic assignment of ferrichrome NRPSs, and sets the stage for reprogramming towards novel hydroxamate scaffolds.

We report a means to achieve the addition of two disparate nucleophiles to the amide carbonyl carbon in a single operational step. Our method takes advantage of non‐precious‐metal catalysis and allows for the facile conversion of amides to chiral alcohols via a one‐pot Suzuki–Miyaura cross‐coupling/transfer‐hydrogenation process. This study is anticipated to promote the development of new transformations that allow for the conversion of carboxylic acid derivatives to functional groups bearing stereogenic centers via cascade processes.

We report a means to achieve the addition of two disparate nucleophiles to the amide carbonyl carbon in a single operational step. Our method takes advantage of non‐precious‐metal catalysis and allows for the facile conversion of amides to chiral alcohols via a one‐pot Suzuki–Miyaura cross‐coupling/transfer‐hydrogenation process. This study is anticipated to promote the development of new transformations that allow for the conversion of carboxylic acid derivatives to functional groups bearing stereogenic centers via cascade processes.