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 为了能够制备具有更高复杂性的生物活性分子，开发 合成逻辑(设计概念)和合成工具(化学反应)来组装 手性中心和多环骨架的分子。拟议的研究计划旨在解决 这需要通过化学研究在两个大体领域进行。第一个研究领域将集中在合成上 复杂、高度氧化、生物活性的二萜类化合物。这些全面的综合努力激励着 发明新的反应并调查现有反应解决战略纽带构建的能力 在复杂的环境中。对这些天然产品的人工获取将改变我们使用它们和它们的能力 作为生物探针或新药开发的先导化合物的合成衍生物。这个 第二个研究领域将集中在开发新的镍催化的交叉亲电偶联 反应。这些反应已经成为形成碳-碳键的多种方法，它们是 越来越多地被学术界和制药部门的化学家采用。尽管最近 尽管取得了一些进展，但仍然存在一些挑战，特别是在催化剂控制的发展方面 立体选择性交叉亲电偶联。为了应对这些挑战，这项研究试图1)确定 新的亲电活化模式，以拓宽镍催化制备产品的范围 交叉亲电偶联反应；2)发展立体选择性的小环交叉亲电偶联反应 药物化学和天然产物的合成；3)发展不对称的CEC反应。 原料组成块，如羧酸和烯烃。这项研究的预期结果 计划有两个方面：它将为制备复杂多环分子提供新的反应和策略， 它还将提供获得与医学相关的天然产品及其衍生品的途径。这项研究将是 由PI、四名化学研究生和一名博士后研究员组成的团队进行了这项研究。 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 有机化学的理论、方法和策略。这项研究的成功实施将提供 能够合成用于研究和治疗人类疾病的小分子的新工具。