Asymmetric synthesis of DNA-encoded libraries of natural product-like compounds.

Project Summary DNA-encoded library (DEL) technology is a powerful method for the discovery of protein ligands. It is capable of screening millions of small molecules for a fraction of the price required to conduct traditional, function-based high-throughput screens. A current limitation of the technology is that it is difficult to incorporate large numbers of sp3 chiral centers into libraries, since few, if any, asymmetric synthesis methods have been validated for DEL synthesis. This is unfortunate, since there is general agreement that DELs with more natural product-like characteristics would be a highly valuable source of drug leads. Here we will adapt asymmetric organocatalytic aldol reactions for solid-phase synthesis of DELs. This effort will involve the development of a novel proximity catalysis method to drive otherwise recalcitrant reactions. If successful, this work will enable the synthesis of DELs of unprecedented stereochemical complexity.