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：
10436386
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.

项目概要/摘要化学合成长期以来通过发现和制备而造福于公众健康药物、天然产物的合成与研究、药物新方法的开发继续并加速此类贡献需要开发新的化学方法，重点是提高选择性、效率、实用性和可扩展性以及访问多样化和新颖的化学空间的能力我们的实验室专注于创造。化学新方法、新试剂、生物活性天然产物的全合成等各个项目。专注于填补文献中的关键空白，同时提供即时且实用的最终产品在基础化学和转化药物发现的背景下用于科学界。该提案结合了两个不同但主题相关的计划，它们具有共同的总体目标开发新方法和试剂以实现新的化学转化并探索新的化学品空间直接应用于药物化学、天然产物合成和药物发现。拟议工作的一部分将开发新方法，以便有效安装磺酰亚胺基将部分固定到简单和复杂的支架上，以及使用含有磺酰亚氨基的试剂合成其他难以进入的化学空间，包括药学相关的螺环和该提案中的方法包括亚砜亚胺的合成和应用。不对称分子转移试剂，使用亚砜亚胺作为阴离子的手性阴离子稳定基团继电器化学，磺酰亚胺酰氟和手性双功能模块合成的发展在第二部分中，开发了二氮丙啶作为独特的氮转移试剂。试剂，可与多种化学手柄发生反应，包括羧酸、未活化的 C–H 这些反应的产物二氮丙啶是多用途的杂环。很容易一步转化为高价值的胺、肼和含氮杂环。该化学将应用于肼、酰肼和哌嗪酸的靶向合成含有天然产物、不对称转化以及蛋白质组学新型探针的合成。整个提案中开发的化学将促进新的小型材料的发现和开发学术界和工业界跨疾病状态的分子疗法。