Studies in Amide and Peptide Synthesis

4.2.1项目总结和相关性 该提案寻求支持，以开发一种全新的酰胺和肽化学品的方法， 合成，一种补充现有的方法，基于脱水酰胺合成， 羧酸和胺。溴硝基烷烃在直接酰胺中用作羧酸替代物 利用胺受体和活化剂（卤离子）的合成。简明 由非天然氨基酸衍生的酰胺的制备， 从天然来源中分离的线性和环状肽是一个中心主题。没有这个 一种新的范式，替代化学方法将以不断上升的成本提供所需的酰胺 由于制备复杂肽所需的大量步骤， 中间体和产物的立体异构体，难以除去。 生物活性肽的实际化学合成是一个直接的目标。从短期来看， 将制备中等大小（~10个残基）的肽并使其多样化。从长远来看，这一创新 酰胺合成的方法将与常规方法结合使用， 涉及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）。

4.2.1 Project Summary and Relevance 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 rising cost due to the large number of steps required to prepare complex peptides, 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. In the long term, this innovative approach to 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.