Chemical Synthesis of Chiral Bioactive Molecules

手性生物活性分子的化学合成

• 批准号: 10400902
• 负责人: Sarah Elizabeth Reisman
• 金额: $ 59.46万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400902
• 关键词: Academia; Address; Adopted; Alkenes; Area; Biological; Carbon; Carboxylic Acids; Chemicals; Chemistry; Complex; Coupling; Development; Diterpenes; Lead; Logic; Medicine; Methods; Natural Products; Organic Chemistry; Outcomes Research; Oxides; Pharmaceutical Chemistry; Pharmacologic Substance; Preparation; Reaction; Research; Research Personnel; Training; catalyst; chemical reaction; chemical synthesis; design; graduate student; human disease; invention; programs; small molecule; theories; tool

Project Summary To enable the preparation of bioactive molecules with increased complexity, it is imperative to develop both the synthetic logic (the design concepts) and the synthetic tools (the chemical reactions) to assemble molecules with chiral centers and polycyclic frameworks. The proposed research program seeks to address this need through chemical research in two general areas. The first research area will focus on the synthesis of complex, highly oxidized, biologically active diterpenes. These total synthesis efforts inspire the invention of new reactions and investigate the ability of existing reactions to solve strategic bond constructions in complex settings. Synthetic access to these natural products will transform our ability to use them and their synthetic derivatives as biological probes or as lead compounds for the development of new medicines. The second research area will focus on the development of new Ni-catalyzed cross-electrophile coupling reactions. These reactions have emerged as versatile methods for carbon–carbon bond formation that are increasingly being adopted by chemists in academia and the pharmaceutical sectors. Despite recent advances, several challenges remain, particularly with respect to the development of catalyst-controlled stereoselective cross-electrophile coupling. To address these challenges, this research seeks to 1) identify new modes of electrophile activation to broaden the scope of products that can be prepared by Ni-catalyzed cross-electrophile coupling; 2) develop stereoselective cross-electrophile coupling reactions of small rings for medicinal chemistry and natural product synthesis; and 3) develop enantioselective CEC reactions of feedstock building blocks such as carboxylic acids and olefins. The expected outcomes of this research program are two-fold: it will provide new reactions and strategies for preparing complex polycyclic molecules, and it will provide access to medicinally relevant natural products and their derivatives. This research will be carried out by a team composed of the PI, four chemistry graduate students and one postdoctoral researcher. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.

项目摘要 为了使生物活性分子的复杂性增加，必须发展 合成逻辑（设计概念）和合成工具（化学反应）都需要组装 具有手性中心和多环形框架的分子。拟议的研究计划旨在解决 通过在两个一般领域进行化学研究的需求。第一个研究领域将重点放在合成上 复杂，高度氧化的生物活性二萜。这些全面的综合努力激发了 发明新反应并研究现有反应解决战略键结构的能力 在复杂的设置中。综合使用这些天然产品将改变我们使用它们及其使用的能力 合成衍生物作为生物学问题或新药物开发的铅化合物。这 第二研究领域将重点介绍新的NI催化跨电动耦合的发展 反应。这些反应已成为碳 - 碳键形成的多功能方法 越来越多地被学术界和药品领域的化学家采用。尽管最近 进步，仍然存在一些挑战，特别是关于催化剂控制的发展 立体选择性跨电动耦合。为了应对这些挑战，本研究试图1）确定 新型的电生物激活模式以扩大可以通过Ni催化制备的产品范围 交叉噬菌体耦合； 2）开发小环的立体选择性跨电动耦合反应 药物化学和天然产物合成； 3）开发对映选择性CEC的反应 原料构建块，例如羧酸和烯烃。这项研究的预期结果 程序是两个方面：它将提供新的反应和策略来制备复杂的多环分子，即 它将提供获得与药物相关的天然产品及其衍生产品的访问权限。这项研究将是 由由PI组成的团队，四个化学研究生和一名博士后研究员组成的团队。 作为该项目的一部分，研究生和博士后研究人员将接受严格的培训 有机化学的理论，方法和策略。这项研究的成功执行将提供 新工具可以使小分子合成人类疾病的研究和治疗。