Griseoviridin (1) is a natural product of mixed polyketide-non-ribosomal peptide origin which was first isolated from culture broths of Streptomyces griseus in 1955 by Bartz and co-workers. As a member of the streptogramin A class of antibiotics, griseoviridin (1) displays conserved chemical features, such as a polyunsaturated 23-membered macrolactone/macrolactam ring, a 1,4-disubstituted oxazole heterocycle, a 1,3-syn diol motif, a (E,E)-dienyl amine moiety, and an α,β-unsaturated amide group. Of all group A streptogramins, only griseoviridin (1) incorporates an additional thio-vinyl ether containing 9-membered lactone ring, rendering it the most structurally complex A streptogramin. Its challenging chemical structure combined with its antibacterial activity prompted us to embark on the total synthesis of griseoviridin (1). Retrosynthetically, we envision to access the natural product via a late-stage HWE reaction to achieve the critical 9-membered ring closure, while simultaneously installing the required Z-configured thio-vinyl ether moiety. We hypothesize that conducting this key step with the macrolactam system already installed could provide a favorable pre-organization for the closure of the strained 9-membered ring. The macrocycle is traced back to the two major building blocks 3 and 4 via a Stille cross-coupling and amide coupling sequence. Building block 3, which incorporates the thio-ether linkage, is envisioned to be obtained via an electrophilic sulfur transfer reaction with a sulfenyl chloride intermediate. The oxazole-containing fragment 4 should be accessible by means of a diastereoselective Narasaka-Prasad reduction in order to incorporate the 1,3-syn diol motif, a SmI2-mediated Barbier-type coupling and a Zn(OTf)2-mediated enantioselective propargylation as key steps. In this contribution we will present our efforts so far towards the total synthesis of griseoviridin (1), including the successful synthesis of vinyl iodide 3 and the results of model studies investigating the feasibility of the formation of the 9-membered lactone ring by the envisioned intramolecular HWE reaction.

Studies towards the total synthesis of griseoviridin

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