Since the isolation and absolute structural assignment of peptide-polyketide secondary metabolites, oxazolomycin A and neooxazolomycin, by Uemura and co-workers in 1985, several other congeners now collectively referred to as ‘oxazolomycins’ have been isolated from terrestrial and marine strains of Streptomyces bacteria. These complex natural products have been the focus of research programs around the world aimed at the study of their bioactivity, biosynthesis, total synthesis, and, notably, the stereoselective synthesis of what we term the oxazolomycin ‘core’ (C1-C17). This core architecture features a densely functionalized pyroglutamate ring furnished with a strained spiro-β-lactone, four contiguous stereogenic centers– two of them being adjacent oxa/aza-quaternary centers– and a pendant amidomethyldiene chain (C8-C12). The bioactivity reported for these natural products includes anticancer, antibacterial, and antiviral. The scope of this activity with regard to the organisms affected may reflect the oxazolomycin structure as a general strategy of Streptomyces bacteria against competing organisms, which can potentially be leveraged in the development of a novel therapeutic chemotype to combat infectious disease. Thus an efficient, modular, and stereoselective synthesis of these natural products and analogues is highly desirable. Herein we report the outcome of our synthetic efforts toward these intriguing spiro-β-lactone natural products, which have culminated in an enantioselective total synthesis of oxazolomycin B and inthomycin C, as well as a concise formal total synthesis of neooxazolomycin. The synthesis commences with our group's nucleophile-catalyzed micheal-proton transfer lactamization to construct a simple γ-lactam in enantiopure form. Expedient functionalization of this ring was carried out with excellent stereocontrol, delivering an α-hydroxyaldehyde to which a key diastereoselective addition of a complex organolithium is mediated by a lanthanide salt. Future synthetic studies target alkyne-bearing molecular probes, predicated on the inherantly reactive oxazolomycin core, to be applied in chemical proteomics investigations.

Enantioselective total synthesis of oxazolomycin B, inthomycin C, and formal synthesis of neooxazolomycin

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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