Studies in Amide and Peptide Synthesis

描述(由申请人提供)：本提案寻求支持，以开发一种全新的酰胺和多肽化学合成方法，该方法是对现有方法的补充，该方法基于使用羧酸和胺的脱水酰胺合成。在直接的酰胺合成中，溴代烷作为羧酸的替代物，利用胺受体和活化剂(卤离子)。由非天然氨基酸衍生的酰胺的简明制备是一个中心主题，非天然氨基酸是从自然来源中分离出来的具有生物活性的线状和环状多肽的共同成分。如果没有这一新模式，替代化学方法将提供获得所需酰胺的途径，但代价是大量步骤，以及难以去除的立体异构体对中间体和产品的污染。生物活性物质的实用化学合成 多肽是一个直接的目标。在短期内，将利用药物化学的原理制备中等大小(~10个残基)的多肽并使其多样化。从长远来看，使用这一技术 新的酰胺合成将与传统方法结合使用，以提供获得大肽(例如生物制品)的途径，这些大肽是由非天然氨基酸定点修饰的。

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.