Synthetic Studies of Nocardia Derived Metallophores and Rare Bacterial Amino Sugars

Abstract

Transvalencin A and uniformides A and B are structurally-related zinc-binding small molecules isolated from the Nocardia genus in 2004 and 2022, respectively. In contrast to the closely related siderophores, these compounds display antimicrobe and anti-immune activity as metal complexes. This suggests a mechanism beyond the metal sequestration usually attributed to the bioactivity of metallophores. This unique property in conjunction with the structural novelty of these natural products led us to target them for total synthesis. In our efforts, we utilized Davis oxidation and photooxidation to install the key peripheral oxidations in a stereoselective manner. We found assembly of the central heterocycle inhibited by the adjacent oxa-quaternary center. Nocobactin NA-a and -b are siderophores produced by Nocardia farcinica and are structurally related to the mycobactins produced by several species of Mycobacterium. It has been previously demonstrated that xenosiderophores exhibit bacteriostatic effects on Mycobacterium tuberculosis and inhibit the growth of tumor cells. Our syntheses of nocobactin NA-a and -b feature a key reductive alkylation sequence to obtain both hydroxamate residues and a Yamaguchi esterification to forge the central ester linkage. Lastly, AAT is a rare deoxy amino sugar found on the cell surface of several pathogens. Specifically, AAT has been incorporated into zwitterionic polysaccharides (ZPS) which elicit a T-cell dependent immune response. For this reason, ZPS units are of interest as components of carbohydrate-based vaccines. However, AAT is not isolable from natural sources in tractable quantities. We detail our efforts to access this desirable material from L-threonine.