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

用于 C-C 和 C-N 键形成的新试剂

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10436386
• 关键词: Acceleration; Alcohols; Amines; Anions; Carboxylic Acids; Chemicals; Chemistry; Communities; Complex; Development; Diazomethane; Disease; Drug Delivery Systems; Fluorides; Goals; Hydrazines; Hydrogen Bonding; Industrialization; Industry; Laboratories; Link; Literature; Methods; Molecular; Natural Products; Nitrogen; Organic Chemistry; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Preparation; Production; Proteomics; Public Health; Reaction; Reagent; Series; Societies; Work; bioactive natural products; chemical synthesis; direct application; drug discovery; novel; piperazic acid; product development; programs; scaffold; small molecule therapeutics

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.

项目总结/摘要 化学合成长期以来通过发现和制备 药物，天然产物的合成和研究，以及药物新方法的开发 交付等。要继续和加速提供这种捐助， 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 新化学方法、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一个关键空白，同时提供即时实用的最终产品。 在基础化学和转化药物发现的背景下，为科学界所用。 该提案结合了两个不同但主题相关的方案，这些方案的总体目标是 开发新的方法和试剂，使新的化学转化和探索新的化学 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 拟议工作的一部分将开发新的方法，允许有效地安装磺酰亚胺 本发明还涉及含磺酰亚胺基的试剂在简单和复杂支架上的应用，以及含磺酰亚胺基的试剂用于 合成其它难以接近的化学间隔物，包括药学上相关的螺环， 天然产品。在该建议中的方法之一是亚砜亚胺的合成和应用， 不对称分子转移试剂，磺酰亚胺作为阴离子的手性阴离子稳定基团的用途， 接力化学，磺酰亚胺氟和手性双功能的模块化合成的发展 磺酰亚胺基关键试剂。在第二部分中，双氮杂环丙烷被开发为独特的氮转移 试剂，其与各种各样的化学手柄反应，包括羧酸、未活化的C-H 键、醇和α-位。这些反应的产物，二氮杂环丙烷，是通用的杂环， 容易在一个步骤中转化为高价值的胺、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- 包含天然产物、不对称转化和蛋白质组学新探针的合成。 整个提案中开发的化学将促进新的小分子化合物的发现和开发。 在学术界和工业界，分子疗法跨越疾病状态。