Studies in Amide and Peptide Synthesis

描述（由申请人提供）：本提案寻求支持开发一种全新的酰胺和肽化学合成方法，补充现有的基于羧酸和胺的脱水酰胺合成方法。溴代烷在利用胺受体和活化剂（卤代离子）的直接酰胺合成中充当羧酸替代物。从非天然氨基酸（从天然来源分离的具有生物活性的线性和环状肽的常见成分）中提取酰胺的简明制备是一个中心主题。如果没有这种新的范例，替代化学方法将以大量步骤为代价获得所需的酰胺，并且难以去除中间体和产物的立体异构体污染。实用化学合成具有生物活性

DESCRIPTION (provided by applicant): 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.