Development of New Strategies for Chemical Synthesis and Study of Complex Natural Products

化学合成新策略的开发和复杂天然产物的研究

• 批准号: 10627743
• 负责人: Mohammad Movassaghi
• 金额: $ 73.74万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627743
• 关键词: Alkaloids; Amides; Architecture; Biochemical; Biological; Biology; Chemicals; Chemistry; Collection; Complement; Complex; Derivation procedure; Development; Evaluation; Family; Future; Generations; Human; Hydroxylation; Indole Alkaloids; Interdisciplinary Study; Investigation; Methodology; Methods; Molecular; Monoterpenes; Natural Products; Preparation; Property; Reaction; Reagent; Research; Sampling; Secure; Structure; Therapeutic; Validation; chemical synthesis; design; diketopiperazine; insight; interest; novel therapeutic intervention; programs; rational design; tool

Project Summary/Abstract The detailed study of the fundamental chemistry and biological properties of complex natural products provides critical insight toward understanding their mode of action and enables development of new approaches for treatment of various human ailments. This research program focuses on the development of efficient and concise strategies for the total chemical syntheses of structurally complex and biologically active natural products. The target compounds are selected based on novelty of molecular architecture and associated challenges, paucity of prior synthetic studies, abundance of opportunities for development of new synthetic strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological studies. The systematic discovery, development, and application of new synthetic strategies and methodologies explored in this program continue to provide synthetic samples of rare and precious compounds for structure validation and detailed examination of their chemistry and biology. This program focuses on synthetic studies of the rich families of complex natural products including cyclotryptamine, diketopiperazine, and monoterpene indole alkaloids. A central interest is the development of generalizable directed, regioselective, stereoselective, and efficient union of complex fragments providing late-stage couplings to secure challenging linkages, including complete stereocontrol at quaternary stereogenic centers. Convergent and guided assembly of advanced fragments is complemented by development and application of new highly selective chemical transformations for the rapid generation of molecular complexity. These transformations include new methods for amide derivatization, azaheterocycle syntheses, cascade bond–forming reactions involving enamines, stereoretentive hydroxylation of complex substrates, and stereocontrolled sulfidation made possible through employing new reagents and conditions developed in this program. This program’s access to potently bioactive collection of families of complex alkaloids and related derivatives continues to enables exciting biochemical collaborative investigations. The array of synthetic molecules accessed through this program behold great promise as new bioactive compounds and mechanistic tools, and these compounds are continually evaluated and examined through multidisciplinary collaborations.

项目摘要/摘要 对复杂天然产物的基本化学和生物学性质的详细研究 Products为了解其行动模式提供关键洞察力，并支持 开发治疗各种人类疾病的新方法。这项研究 该计划的重点是开发高效和简明的总化学品战略 合成结构复杂且具有生物活性的天然产物。目标是 化合物是根据分子结构的新颖性来选择的，并与 挑战、缺乏先前的综合研究、丰富的发展机遇 新的合成战略和方法，拥有重要的生物活性，以及 未来化学和生物学研究的潜力。系统的发现， 探索的新的综合战略和方法的开发和应用 计划继续为结构提供稀有和贵重化合物的合成样品 对他们的化学和生物学进行验证和详细检查。本节目的重点是 包括环色胺在内的丰富复杂天然产物家族的合成研究， 二酮并哌嗪和单萜吲哚生物碱。一个主要的兴趣是发展 复数的广义定向、区域选择性、立体选择性和有效并 提供后期连接以确保具有挑战性的连接的碎片，包括完整的 第四纪立体发生中心的立体控制。汇聚的和导向的组件 先进的片段得到了新的高度选择性的开发和应用的补充 快速产生分子复杂性的化学转化。这些 转化包括酰胺衍生化的新方法，氮杂环的合成， 涉及烯胺的级联成键反应，络合物的立体保留羟基化 底物，以及通过使用新试剂实现的立体控制硫化 以及在这个项目中开发的条件。这个项目可以获得潜在的生物活性 一系列复杂生物碱和相关衍生物的收集继续使人兴奋 生物化学合作研究。通过访问的合成分子阵列 这一计划作为新的生物活性化合物和机械工具前景看好，而且 这些化合物不断地通过多学科进行评估和检查 合作。