Primary Amines as Versatile Precursors for the Synthesis of Bioactive Molecules and Macromolecular Drug Carriers
Project Summary/Abstract The invention of new therapeutics is a multidisciplinary endeavor in which chemistry plays a crucial role. Following the discovery of a target responsible for a disease?generally a protein?chemists are tasked to provide small-molecule inhibitors or agonists that will selectively bind to the target receptor and induce a cascade of molecular events responsible for improving the patient?s condition. Identification of a drug candidate combining potency, efficacy, low toxicity, and desirable pharmacokinetics requires an intense synthetic effort during which thousands of molecules are created by diversification of a bioactive scaffold. In order to support these drug discovery campaigns, there is a constant need to invent new methods allowing for selective modifications of complex molecules including peptides, carbohydrates, and other natural products. Once a drug candidate is nominated, chemists need to devise a scalable process route that meets cost, safety, and FDA requirements, which is another opportunity for chemical innovation. Some pharmaceuticals might have poor physical properties and/or stability, which might necessitate the development of polymeric drug-delivery systems to fully achieve their potential. These intricate macromolecules represent another type of synthetic challenge since they are designed to release their cargo upon external stimulation, for example, via a subtle pH or temperature change. This research program seeks to deliver new methods of widespread interest and to illustrate their relevance to pharmaceutical research by delineating efficient syntheses of challenging small molecules and stimuli-responsive polymers. The overarching theme of this proposal is the transformation of primary amines?one of the most ubiquitous groups in natural and synthetic molecules?into a variety of linkages including C?C, C?H, C?F, and C?B bonds via C?N activation. In the first section, a click reaction will be developed to transform primary amines into sulfamides. These rather exotic groups will be investigated as hydrogen-bond donors in polymeric and bioactive molecules, as well as precursors for a C?N activation platform. Furthermore, as a click linker, sulfamides will serve to selectively functionalize peptides and aminoglycosides. A collaboration will also be launched to develop this reaction as a tool for peptide macrocyclization. The second section explores the potential of sulfamides as progenitors of radical pairs, whose subsequent recombination will afford an array of aliphatic C?C bond formations. The last section hypothesizes that sulfamides can also be transformed via transition-metal catalysis, which would open the door to (hetero)arylation, fluorination, and borylation reactions, among others. These mechanistically distinct C?N activation processes will be applied to the functionalization of bioactive molecules and polymeric architectures for drug delivery.