Development of Metallopeptides for Site-Selective Transformations of the Antibiotic Thiostrepton - Project Summary Catalysis is an enabling technology for selective synthesis in organic chemistry. In the majority of transformations, catalysts are based on distinct homogeneous, heterogeneous, or enzymatic platforms, enabling high chemo- and site-selectivity for a particular transformation. However, when substrates become more complex, including for the functionalization of natural products, traditional catalytic methods can become incompatible with the functional group complexity of these molecules. Therefore, there is motivation to develop site-selective catalysts that are compatible with the molecules at the frontier of human health efforts. One approach to achieving enzyme-like selectivity is the use of synthetic peptide catalysts. Similar to enzymes, synthetic peptides have chirality, can participate in a variety of covalent or non-covalent interactions, and can also have a secondary structure to create an active site for catalysis. To date, peptide catalysts have been developed for organo-catalyzed transformations but are in the early stages of potential application in transition metal catalyzed reactions. This proposal will develop peptide-containing transition metal catalysts for the site- selective transformations of complex targets. In particular, due to the rapid development of antibiotic resistance, the late-stage functionalization of antibiotics is of particular relevance to human health efforts. To begin our efforts, the potent, structurally complex antibiotic thiostrepton has been selected for this purpose. Thiostrepton is not currently used in the clinic due to poor pharmacokinetic properties; therefore, modification of thiostrepton using these catalysis offers the exciting potential to develop new, more potent antibiotics. We will specifically develop site- selective hydrogenation and additional transition metal catalyzed reactions for the synthesis of derivatives and development of structure-activity relationships that could be used to design new thiopeptide antibiotics. Towards these goals, the following aims have been developed: 1) Identification of Transition Metal Catalysts for the Enantioselective Functionalization of Thiostrepton 2) Development of Peptide-Containing Catalysts for Site-Selective Hydrogenation 3) Expansion of Methods for Site-Selective Modification of Thiostrepton With these Aims, design principles for site-selective catalysis will be uncovered, significantly contributing to known methods for the synthesis of molecules with potentially improved bioactivity. 1
