This proposal seeks support to develop a fundamentally new approach to amide and peptide chemical synthesis, one that complements existing methods based on dehydrative amide synthesis using carboxylic acids and amines. Bromonitroalkanes serve as carboxylic acid surrogates in a direct amide synthesis that utilizes an amine acceptor and an activating agent (a halonium ion). The concise preparation of amides derived from nonnatural amino acids, common constituents of biologically active linear and cyclic peptides that have been isolated from natural sources, is a central theme. Without this new paradigm, alternative chemical methods would provide access to the desired amides at the cost of a large number of steps, and the contamination of intermediates and products by stereoisomers that are difficult to remove. The practical chemical synthesis of biologically active peptides is an immediate goal. In the short term, peptides of modest size (~10 residues) will be prepared and diversified using the principles of medicinal chemistry. In the long term, use of this novel amide synthesis will be used in combination with conventional methods to provide access to large peptides (e.g. biologics) modified site-specifically with nonnatural amino acids. PUBLIC HEALTH RELEVANCE: This proposal describes the development of new synthetic methods to prepare amide and peptide (polyamide) small molecules. Peptides have increasingly impacted human health through their use as therapeutics (so-called biologics) and the development of innovative new methods for their synthesis stands to further accelerate the discovery and development of peptide therapeutics.