Studies in Amide and Peptide Synthesis

描述（由申请人提供）：该提案寻求支持，以开发酰胺和肽化学合成的全新方法，该方法补充了基于使用羧酸和胺的脱水酰胺合成的现有方法。溴硝基烷烃在利用胺受体和活化剂（卤离子）的直接酰胺合成中用作羧酸替代物。非天然氨基酸是从天然来源中分离出的具有生物活性的线性和环状肽的常见成分，其酰胺的简明制备是一个中心主题。如果没有这种新的范例，替代的化学方法将以大量的步骤为代价提供所需的酰胺，以及难以去除的立体异构体对中间体和产物的污染。生物活性物质的实用化学合成 肽是一个直接的目标。在短期内，将使用药物化学原理制备中等大小（约10个残基）的肽并使其多样化。从长远来看，使用这种 新的酰胺合成将与常规方法结合使用，以提供用非天然氨基酸进行位点特异性修饰的大肽（例如生物制剂）的途径。

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.