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: 10206350
• 负责人: Mohammad Movassaghi
• 金额: $ 47.09万
• 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/10206350
• 关键词: Alkaloids; Amides; Architecture; Biochemical; Biological; Biology; Chemicals; Chemistry; Collection; Complement; Complex; 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; Sulfides; Therapeutic; Validation; base; chemical synthesis; design; diketopiperazine; insight; interest; novel strategies; programs; 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.

项目概要/摘要 复杂天然物质的基本化学和生物特性的详细研究 产品为理解其作用模式提供了重要的见解，并使得 开发治疗各种人类疾病的新方法。这项研究 计划的重点是为整个化学品制定高效、简洁的战略 结构复杂且具有生物活性的天然产物的合成。目标 根据分子结构和相关的新颖性来选择化合物 挑战、缺乏先前的综合研究、丰富的发展机会 新的合成策略和方法，拥有显着的生物活性，以及 未来化学和生物学研究的潜力。系统的发现， 本研究探索的新合成策略和方法的开发和应用 计划继续提供稀有和珍贵化合物的合成样品用于结构 对其化学和生物学进行验证和详细检查。该计划重点关注 丰富的复杂天然产物家族的合成研究，包括环色胺， 二酮哌嗪和单萜吲哚生物碱。核心利益是发展 复杂的可概括的定向、区域选择性、立体选择性和高效联合 片段提供后期耦合以确保具有挑战性的连接，包括完整的 四元立体中心的立体控制。收敛和引导组装 先进片段辅以新的高选择性的开发和应用 快速生成分子复杂性的化学转化。这些 转化包括酰胺衍生化、氮杂环合成的新方法， 涉及烯胺的级联成键反应、络合物的立体保留羟基化 通过使用新试剂使底物和立体控制硫化成为可能 以及该计划中制定的条件。该计划可以获得有效的生物活性 复杂生物碱和相关衍生物家族的收集继续使令人兴奋的 生化协作研究。通过访问的合成分子阵列 该计划作为新的生物活性化合物和机械工具具有巨大的前景，并且 这些化合物通过多学科不断评估和检查 合作。