Catalyst-Controlled Site-Selective and Epimer-Selective Hydrogenations of Thiostrepton

The hydrogenation of the antibiotic thiostrepton with control over the site- and stereoselectivity of reduction is reported. Studies on model substrates designed to mimic aspects of the consecutive dimeric dehydroalanine (Dha) tail of thiostrepton first culminate in the development of an asymmetric hydrogenation method for a diverse set of bis(Dha) compounds. Monodentate phosphoramidite ligands (e.g., MonoPhos) are optimal and allow for selectivity of up to a 96:2:2:<1 ratio for doubly hydrogenated products. Subsequently, the protecting-group free, diastereomer-selective hydrogenation of the tail fragment of thiostrepton (Dha16 and Dha17) under mild conditions is presented with >80% selectivity for a single stereoisomer, relative to the sum of other detectable products. Opposite MonoPhos chirality results in alternative selectivity for the hydrogenated tail product, establishing ligand-controlled hydrogenation. The further study of ligands enabled hydrogenation of the internal dehydroalanine residue (Dha3), using sterically attenuated phosphoramidite ligands. Strikingly, ligand chirality dictates the stereochemical outcome at the sterically occluded Dha3, allowing for the synthesis of distinct stereoisomers, culminating in two distinct bis-hydrogenated isomers and two distinct tris-hydrogenated stereoisomers. Finally, hydrogenation with yet another phosphine ligand scaffold, a bidentate bisphosphine, results in the controlled formation of a single tetra-hydrogenated product. The structures and stereochemistry of the products are identified using multidimensional nuclear magnetic resonance methods, X-ray crystallography, and comparison to model substrates with confirmed absolute stereochemistry. The new thiostrepton derivatives are benchmarked for their antibiotic activity against representative antibiotic-resistant bacterial strains, revealing significant effects of Dha hydrogenation, and a number of new insights, most notably about the significance of Dha3 for antibiotic activity.