Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Abstract

Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.

Biosynthesis and Structure–Activity Relationship Investigations of the Diazeniumdiolate Antifungal Agent Fragin

“…Furthermore, preliminary experiments explored the origin of the terminal N atom of the diazeniumdiolate group and chromatographic evidence suggested that it originated from nitrite. Recently, several reports have indicated similar biosynthetic pathways for the diazeniumdiolate alanosine, the diazo compounds cremeomycin and kanamycin, the pyridazine azamerone, the N ‐hydroxytriazenes triacsins and the hydrazide fosfazinomycin …”

Biosynthesis of the N–N‐Bond‐Containing Compound l‐Alanosine

“…Unlike many natural products, the biosynthetic routes to molecules containing N−N bonds remained enigmatic until recently . From a fundamental perspective, the formation of an N−N bond is a challenging transformation because of the intrinsic difficulty of joining two typically nucleophilic atoms . To address this fundamental challenge, diverse biosynthetic pathways have evolved for the activation of a nitrogen as an electrophile.…”

Identifying the Biosynthetic Gene Cluster for Triacsins with an N‐Hydroxytriazene Moiety

“…The N ‐hydroxytriazene moiety, containing three heteroatom‐heteroatom linkages, is rare in nature and has only been identified in the triacsin family of natural products. In view of the prevalence of N−N and N−O linkages in synthetic drug libraries, there is a great interest in their enzyme‐catalyzed formation to complement the challenges in synthetic approaches . To date, multiple classes of enzymes have been characterized as catalyzing N−O linkages; they include cytochrome P450s and N ‐oxygenases that might be flavin‐dependent or metal‐containing …”