Griseoviridin (1) is a natural antibiotic of mixed polyketide-non-ribosomal peptide origin that was isolated in 1955 from culture broth filtrates of a strain of Streptomyces griseus by Bartz and co-workers. The compound belongs to the streptogramin class A of antibiotics and features a polyunsaturated 23-membered macrolactone ring contanining a vinyl sulfide motif, a 1,4-disubstituted oxazole heterocycle, a 1,3-diol, and a conjugated (E-E)-dienyl amine. Only one total synthesis of 1 has been reported to date by Meyers and co-workers that is based on formation of the macrocyclic bis-lactam by ring-closing olefin metathesis (RCM). In contrast, a number of studies have described the synthesis of differently protected versions of the 9-membered lactone ring; however, the cyclized products were not further processed towards the total synthesis of 1. So far, no structure-activity relationship studies on 1 have been reported. Based on its intriguing structural architecture and in order to assess its potential as a lead structure for new antibiotics drug discovery, we have embarked on the total synthesis of 1. Our approach towards 1 envisions the assembly of fragments A and B by means of an amide coupling and a Stille cross-coupling (in either order). Three approaches have been pursued for the construction of the lactone core of fragment A (Scheme 1), namely: (1) Mitsunobu lactonization of hydroxy acid 2; (2) RCM of diene 3; and (3) RCM of diene 4a followed by oxidation and double bond shift into the a,b-position. In this contribution we describe the synthesis of 2, 3, and a desmethyl variant of 4a (i. e. 4b) and their cyclization to the corresponding lactones. The Mitsunobu cyclization of 2 and the RCM of 3 proceeded in moderate (ca. 40%) or low (ca. 20%) yield, but the subsequent conversion of the ester products into the free acids could not be accomplished. In contrast, conditions could be established that allowed the RCM-based cyclization of 4b in 60% yield. The conversion of the cyclization product into the corresponding propargyl amide as well as the synthesis of 4a are currently in progress.

Studies towards the total synthesis of griseoviridin: Approaches towards the preparation of the 9-membered lactone core

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