Project Summary/Abstract Ansatrienins, including mycotrienin I, are natural products with high activity for the inhibition of eukaryotic protein synthesis that act through the binding of eukaryotic elongation factors. Bacteria rely on homologous elongation factors to synthesize proteins, yet these enzymes have not been the target of clinically useful antibiotics. Here, I propose to develop a concise synthesis of mycotrienin I that would underpin the synthesis of unnatural ansatrienins with novel biological activities. Elongation factors have been the targets of cytotoxic, investigational anticancer treatments, and unnatural ansatrienins could be designed to serve the same role with a greater therapeutic index. I will also aim to design unnatural ansatrienins that inhibit bacterial protein synthesis and do not bind human elongation factors. Existing routes to Ansatrienins are poorly suited to the synthesis of synthetic analogues because they are long or lack modularity, thereby hindering modification of the aromatic structure that drives the selectivity of these natural products. The development of a modular, convergent route to this class of natural products could form the basis of new classes of anticancer and antibiotic drugs and generate useful tool compounds for the investigation of the elongation step in both eukaryotic and prokaryotic protein synthesis. As existing classes of antibiotics face increasing resistance by common bacterial pathogens, the development of new classes of antibiotics based on ansatrienins, to which resistance is unlikely to be widespread, would fill a major unmet medical need.