Site-Selective C-H Borylation Directed by Noncovalent Interactions - PROJECT SUMMMARY Almost all new drugs on the market emerged from the synthesis of thousands of structurally similar molecules. Once a compound is identified to possess targeted therapeutic activity, medicinal chemists generate an extensive array of derivative compounds with numerous modifications in structure to tune key properties, such as potency, selectivity, stability and solubility. The ability to structurally edit a single compound at multiple sites would circumvent the need for lengthy de novo syntheses of each derivative, exponentially improving the efficiency of the drug discovery process. Transition metal-catalyzed functionalization of C–H bonds has emerged as a powerful tool for late-stage derivatization of complex molecules. However, selectivity between multiple C– H bonds in similar structural environments remains a challenge. Current methods to control site selectivity suffer from various shortcomings, including the need to install and remove directing groups, limitation to simple structures, and inability to overcome large differences in the reactivity of C–H bonds. The proposed research focuses on the development of a systematic and tunable strategy to control site selectivity of iridium-catalyzed C–H borylation that is capable of overcoming inherent substrate preferences and that can target specific C–H bonds. The proposed approach leverages a variety of common functionalities in bioactive molecules as recognition sites, conferring generalizability while avoiding the need for directing groups. In addition, the proposed approach is informed by a recent breakthrough by the sponsor’s laboratory showing a dramatic activating effect of 2-aminophenanthroline ligands on the borylation of C–H bonds. The impact of this research is a flexible tool for precise structural editing of bioactive compounds. Specifically, the proposed research will include the synthesis of a suite of ligands derived from 2-aminophenanthroline, bearing interaction sites that are connected to the backbone with a sidearm linker and that are capable of attractive noncovalent interactions with common Lewis-basic functionalities. A modular synthetic approach is described, enabling the assessment of various interaction sites as well as structure and connectivity of the sidearm linker. Iridium catalysts generated from the ligands will be tested for their ability to overcome the inherent selectivity of substrates toward undirected borylation. Upon success, a series of sites will be targeted for functionalization by adjustment of the linker structure. Subsequent functionalization of complex, biologically active compounds will demonstrate generality of the method and applicability to lead optimization. Mechanistic studies will be integrated in each step of the proposed research to guide catalyst design and improve reaction efficiency and site-selectivity. Achieving the specific aims of the proposed research will provide chemists with a powerful strategy for precise, targeted, late- stage diversification of complex organic molecules, thereby accelerating the generation of biologically active compounds.
