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New reagents for C-C and C-N bond formation

用于 C-C 和 C-N 键形成的新试剂

基本信息

批准号：
10606594
负责人：
Justin Matthew Lopchuk
金额：
$ 41.18万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Chemical synthesis has long benefited public health through the discovery and preparation of pharmaceuticals, the synthesis and study of natural products, and the development of new methods for drug delivery among many others. The continuation and acceleration of such contributions requires the development of new chemical methods with a focus on increasing selectivity, efficiency, practicality and scalability, and the ability to access diverse and novel chemical space. Our laboratory focuses on the creation of new chemical methods, novel reagents, and the total synthesis of bioactive natural products. Each project focuses on filling a key gap in the literature while delivering end products that will be of immediate and practical use to the scientific community, both in the context of fundamental chemistry and translational drug discovery. This proposal combines two distinct, but thematically linked, programs that share the overarching goal of developing novel methods and reagents to enable new chemical transformations and explore new chemical space with direct applications to medicinal chemistry, natural product synthesis, and drug discovery. The first section of the proposed work will develop new methods that allow for the efficient installation of sulfonimidoyl moieties onto both simple and complex scaffolds and the use of sulfonimidoyl-containing reagents for the syntheses of otherwise difficult-to-access chemical space including pharmaceutically relevant spirocycles and natural products. Among the methods in this proposal are the synthesis and applications of sulfoximines as asymmetric molecular transfer reagents, the use of sulfoximines as chiral anion stabilizing groups for anion relay chemistry, the development of modular syntheses of sulfonimidoyl fluorides and chiral bifunctional sulfonimidoyl linchpin reagents. In the second section, diazirines are developed as unique nitrogen transfer reagents, which react with a wide variety of chemical handles including carboxylic acids, unactivated C–H bonds, alcohols, and α-positions. The products of these reactions, diaziridines, are versatile heterocycles that are easily transformed in one step to high-value amines, hydrazines, and nitrogen-containing heterocycles. This chemistry will be applied in the target-oriented synthesis of hydrazine, hydrazide, and piperazic acid- containing natural products, asymmetric transformations, and the synthesis of novel probes for proteomics. The chemistry developed throughout this proposal will enhance the discovery and development of new small molecule therapeutics across disease states in both academic and industry.

项目摘要/摘要通过发现和制备化学合成，长期以来一直有益于公众健康药物、天然产物的合成和研究以及药物新方法的开发在许多其他服务中，还有递送服务。这种捐助的持续和加速需要开发新的化学方法，重点是提高选择性、效率、实用性和可伸缩性，以及访问不同和新颖的化学空间的能力。我们的实验室专注于创造新的化学方法、新试剂和生物活性天然产物的全合成。每个项目专注于填补文献中的关键空白，同时提供立竿见影且实用的最终产品在基础化学和转化性药物发现的背景下，向科学界使用。这一提议结合了两个截然不同但主题相连的计划，它们有着共同的总体目标开发新的方法和试剂以实现新的化学转化和探索新的化学物质直接应用于药物化学、天然产物合成和药物发现的空间。第一拟议工作的一节将开发新的方法，以便能够有效地安装磺酰亚胺简单和复杂支架上的部分以及含磺酰亚胺基的试剂用于其他难以接近的化学空间的合成，包括与药物相关的螺旋环类和天然产品。该提案中的方法包括亚磺亚胺的合成和应用。不对称分子转移试剂，使用亚磺亚胺作为阴离子的手性稳定基团继电化学，磺酰亚胺基氟化物和手性双官能团的模块化合成进展磺酰亚胺基关键蛋白试剂。在第二部分中，二氮杂环化合物作为一种独特的氮转移被开发。试剂，可与多种化学手柄反应，包括羧酸、未活化的C-H 键、醇和α-位置。这些反应的产物，二氮杂环，是多种杂环，很容易在一步内转化为高价值的胺、肼和含氮杂环。这一化学将应用于肼、肼和哌嗪酸的定向合成。包括天然产物、不对称转化和蛋白质组学新探针的合成。在整个提议中发展的化学将促进新的小的发现和发展学术界和产业界跨疾病状态的分子疗法。