Deoxyenterocin

The type II polyketide synthase (PKS) natural product enterocin (1) was isolated from a mangrove-derived novel species Streptomyces qinglanensis 172205 guided by genome sequence, and its putative biosynthetic gene cluster was revealed. Its natural analogues 5-deoxyenterocin (2) and wailupemycin A-C (3-5) were also identified by tandem mass spectrometry. By feeding experiments with aryl acids, strain 172205 was proved to incorporate partial exogenous starter units into enterocin- and wailupemycin-based analogues, thus being a new and suitable microorganism for engineering unnatural enc-derived polyketide metabolites. In addition, biological assays indicated that enterocin showed obvious inhibitory activity against β-amyloid protein (Aβ1-42) fibrillation and moderate cytotoxicity against HeLa and HepG2 for the first time.

Nature has evolved finely tuned strategies to synthesize rare and complex natural products such as the enterocin family of polyketides from the marine bacterium Streptomyces maritimus. Herein we report the directed ex vivo multienzyme syntheses of 24 unnatural 5-deoxyenterocin and wailupemycin F and G analogues, 18 of which are new. We have generated molecular diversity by priming the enterocin biosynthesis enzymes with unnatural substrates and have illustrated further the uniqueness of this type II polyketide synthase by way of exploiting its unusual starter unit biosynthesis pathways.

Enterocin (vulgamycin) is a structurally remarkable natural product with significant antibiotic activity. The synthesis of a linear polyketide resembling a biosynthetic precursor was achieved using an unusual acyloin reaction. A diazo group was introduced as a protecting group for an enolizable ketone. We were unable to bring about the envisioned biomimetic aldol addition cascade and gained insights into the feasibility of this process by DFT calculations. As an alternative approach to enterocin, we developed a Cu-catalyzed intramolecular cyclopropanation followed by a MgI2-induced fragmentation to install the 2-oxabicyclo[3.3.1]nonane core of the natural product.