Paul Peterson, PhD
Yale University
Catalyst-Controlled Site-Selective and Epimer-Selective Tailoring of Thiostrepton
In the context of late-stage diversification of natural products, two methods for the site-selective tailoring of the antibiotic thiostrepton have been developed. First, hydrogenation of thiostrepton with control over both site- and epimer-selectivity was established. Monodentate phosphoramidite ligands (e.g., MonoPhos) proved optimal, enabling protecting-group-free, diastereoselective hydrogenation of the tail dehydroalanine residues (Dha16 and Dha17) under mild conditions with >80% selectivity for a single stereoisomer. Further ligand optimization enabled selective hydrogenation of the internal dehydroalanine residue (Dha3) using less sterically demanding phosphoramidites. The resulting thiostrepton derivatives were evaluated for antibiotic activity against representative antibiotic-resistant bacterial strains, revealing pronounced effects of Dha hydrogenation and providing new insight into the importance of Dha3 for activity. Second, to introduce C(sp³) functionality, a nickel-catalyzed method for the conjugate alkylation of thiostrepton was developed with >4:1 site-selectivity for the Dha16 position over other possible sites of reactivity and >5:1 diastereoselectivity. Optimization revealed the critical role of an acid additive for observable diastereoselectivity, plausibly due to in situ secondary amine protection. Ongoing efforts are focused on the synthesis of thiostrepton derivatives with improved solubility profiles.
In the context of late-stage diversification of natural products, two methods for the site-selective tailoring of the antibiotic thiostrepton have been developed. First, hydrogenation of thiostrepton with control over both site- and epimer-selectivity was established. Monodentate phosphoramidite ligands (e.g., MonoPhos) proved optimal, enabling protecting-group-free, diastereoselective hydrogenation of the tail dehydroalanine residues (Dha16 and Dha17) under mild conditions with >80% selectivity for a single stereoisomer. Further ligand optimization enabled selective hydrogenation of the internal dehydroalanine residue (Dha3) using less sterically demanding phosphoramidites. The resulting thiostrepton derivatives were evaluated for antibiotic activity against representative antibiotic-resistant bacterial strains, revealing pronounced effects of Dha hydrogenation and providing new insight into the importance of Dha3 for activity. Second, to introduce C(sp³) functionality, a nickel-catalyzed method for the conjugate alkylation of thiostrepton was developed with >4:1 site-selectivity for the Dha16 position over other possible sites of reactivity and >5:1 diastereoselectivity. Optimization revealed the critical role of an acid additive for observable diastereoselectivity, plausibly due to in situ secondary amine protection. Ongoing efforts are focused on the synthesis of thiostrepton derivatives with improved solubility profiles.
