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 复杂自然的基本化学和生物学特性的详细研究 产品为理解其行动方式提供了关键的见解，并启用 开发用于治疗各种人类疾病的新方法。这项研究 计划着重于为总化学的高效和简洁策略的发展 结构复杂和生物活性天然产物的合成。目标 基于分子结构和相关的新颖性选择化合物 挑战，先前的合成研究的匮乏，开发机会的抽象 新的合成策略和方法，重要的生物学活性的潜力以及 未来化学和生物学研究的潜力。系统发现， 在此探讨的新合成策略和方法的开发和应用 程序继续为结构提供稀有和珍贵化合物的合成样品 对其化学和生物学的验证和详细检查。该计划重点 复杂天然产物的富裕家族的合成研究，包括环丙胺， 二甲苯吡喃和单苯乙烯吲哚生物碱。核心利益是发展 可概括的，调节性的，立体选择性和有效的复杂结合 提供后期耦合以确保挑战联系的片段，包括完整 季源性中心的立体控制。收敛和指导组装 高级片段是通过开发和应用新的高度选择性完成的 用于快速生成分子复杂性的化学转化。这些 转换包括用于酰胺衍生化的新方法，azaheteroclecle合成， 级联键 - 形成反应，涉及敌人，立体定位羟基化。 底物和立体控制的硫化是通过采用新试剂而成为可能的 和该计划中发展的条件。该计划可以访问潜在的生物活性 复杂的生物碱和相关衍生物的家庭的收集继续使令人兴奋 生化协作研究。通过访问的合成分子阵列 该计划将新的生物活性化合物和机械工具和机械工具和 通过多学科对这些化合物进行连续评估和检查 协作。