Catalysts and Reagents for Amide Bond Synthesis

在这个由化学部化学催化项目资助的项目中，纽约大学的Paramjit Arora教授正在开发用于合成酰胺键的新催化剂，酰胺键是肽的关键键，是蛋白质的基本结构组成部分。生物系统在分子水平上大量使用肽和蛋白质来完成复杂的任务，它们是由多个酰胺键亚基连接在一起的长链组成的。多肽和蛋白质作为化学试剂和治疗剂的使用需要大量生产；然而，这些化合物的合成仍然低效和浪费。该项目建立在经典和现代酰胺键形成方法的基础上，使蛋白质和其他含有酰胺键的重要化合物的合成更高效、更环保。这项研究将为研究生物学和药物化学中的化学过程提供有价值的策略和试剂。该项目还包括教学活动，以培养学生在有机化学和化学生物学的界面。从事这项工作的学生将在基础化学和生物化学技术方面获得广泛的经验，并在生物医学技术中具有潜在的应用前景。与诺伊曼大学的Amy Brown教授合作，化学系正在该大学建立一个为期一个学期的研究型顶点课程。Arora教授正在开发新的有机催化剂，用于酰胺键的形成，该催化剂基于化学选择性连接策略，用于合成蛋白质中的天然酰胺键。酰胺键形成的化学选择反应已经改变了通过片段连接获得合成蛋白质和其他生物偶联物的能力。在这些连接中，酰胺键的形成通过两个片段的羧基和胺端之间的瞬时分子内反应而加速。基于这一原理，Arora教授正在开发醛捕获连接，利用醛和胺的高化学选择性反应活性来加强氨基酸残基和肽之间的酰胺键形成，这是现有技术难以连接的。醛捕获连接利用邻苯甲醛硒酸酯来加强羧基和胺伙伴之间的分子内反应。醛捕获连接的关键优势在于，该方法原则上适用于大多数用于酰胺键形成的n端氨基酸残基，因为捕获步骤从硫酯交换（如天然化学连接）变为醛胺缩合。该方法正被应用于小环、环状肽的合成。

In this project funded by the Chemical Catalysis program of the Chemistry Division, Professor Paramjit Arora of New York University is developing new catalysts for the synthesis of the amide bond, the linchpin bond in peptides, which are a basic structural building block of proteins. Biological systems make heavy use of peptides and proteins to carry out complex tasks at the molecular level, and they are composed multiple amide bond subunits linked together in a long chain. The use of peptides and proteins as chemical reagents and therapeutics necessitates their production in large amounts; however, the synthesis of these compounds remains inefficient and wasteful. This project is building upon classical and contemporary methods for amide bond formation to enable a more efficient and greener synthesis of proteins and other important compounds that contain amide bonds. This research should yield valuable strategies and reagents for studying chemical processes in biology and for medicinal chemistry. The project also includes teaching activities to train students at the interface of organic chemistry and chemical biology. Students engaged in this work are gaining a broad experience in fundamental chemical and biochemical techniques with potential future applications in biomedical technologies. A collaboration with Professor Amy Brown of Neumann University, Department of Chemistry is making progress on establishing a one-semester research-oriented capstone course at that university. Professor Arora is developing new organocatalysts for amide bond formation that are based upon a chemoselective ligation strategy for the synthesis of native amide bonds in proteins. Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, Professor Arora is developing aldehyde capture ligation that parlays the high chemoselective reactivity of aldehydes and amines to enforce amide bond formation between amino acid residues and peptides that are difficult to ligate by existing technologies. Aldehyde capture ligation utilizes an o-benzaldehyde selenoester to enforce an intramolecular reaction between the carboxyl and the amine partners. The key advantage of aldehyde capture ligation is that the method is applicable, in principle, to most any N-terminal amino acid residue for amide bond formation, because the capture step is changed from thioester exchange, as in native chemical ligation, to aldehyde-amine condensation. The methodologies are being applied to the synthesis of small ring, cyclic peptides.