Metallacycle-mediated coupling in stereoselective synthesis

立体选择性合成中金属环介导的偶联

• 批准号: 10317087
• 负责人: GLENN C MICALIZIO
• 金额: $ 57.4万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317087
• 关键词: Address; Agonist; Alkaloids; Area; Benzoquinones; Biological; Biology; Cardenolides; Chemicals; Chemistry; Complex; Coupling; Cytotoxic agent; Development; Estrogen Receptor beta; Foundations; Goals; Investigation; Laboratories; Ligands; Mediating; Medicine; Methods; Multiple Myeloma; Natural Products; Organic Chemistry; Organic Synthesis; Pharmaceutical Chemistry; Play; Process; Property; Reaction; Research; Role; Scheme; Science; Skeleton; Steroids; TP53 gene; Technology; Terpenes; Textiles; Therapeutic; Vertebral column; Vision; base; chemical synthesis; clinically relevant; cycloaddition; design; forging; inhibitor; innovation; interest; lupeol; non-opioid analgesic; novel; paralogous gene; programs; small molecule; stem; targeted agent; tool

1. Project Summary/Abstract: Research Overview – Research is focused on organic synthesis, with particular interest in developing synthesis strategies and modes of reactivity within organic chemistry that facilitate the construction of complex molecules with potentially valuable medicinal and/or biological properties. We have developed over thirty stereoselective C–C bond-forming reactions based on areas of reactivity that include metallacycle-mediated cross-coupling, [3+2] cycloaddition, vinylcyclopropane rearrangement, and radical cascade chemistry. While some of these have been developed within a program aimed at achieving a foundation of reactivity suitable to realize a wide range of unique “convergent” C–C bond forming processes, others have emerged within programs in the broad area of natural product synthesis. These combined activities, that aim to advance the fundamental backbone of organic chemistry through innovation within the field of stereoselective synthesis, are routinely embraced as enabling technology to fuel exploration in medicinally relevant science. For example, we have discovered: (1) a non-opioid analgesic from efforts targeting the alkaloid conolidine, (2) unique paralog selective Hsp90 inhibitors stemming from explorations into the synthesis of benzoquinone ansamycins, (3) selectively cytotoxic agents targeting multiple myeloma from activities associated with the synthesis of lehualide B, (4) the first non-peptidic selective ligand to the DBD of p53 with a natural product-inspired oligomerization, and (5) the most potent and selective agonist of the estrogen receptor beta (ERβ) from recent investigations targeting terpenoids. Overall Vision of the Program – This seamless integration of reaction development, natural product synthesis, and efforts to employ our technology as an enabling tool for the discovery of novel compositions of matter with unique biological properties defines the basic fabric of science that has been, and will continue to be, the focus of science in the Micalizio laboratory for decades to come. Goals for the Next Five Years – Efforts will focus on natural product total synthesis, new reaction development, and establishing a conceptually unified asymmetric entry to tetracyclic and pentacyclic terpenoids. These activities include target-oriented synthesis campaigns around ryanodol, corialactone D, azadiradione (limonoid), samandarin (steroidal alkaloid), oleandrin (cardenolide), euphol (euphane), and lupeol (pentacyclic triterpenoid). These activites have, at their core, the ambition to establish and demonstrate novel synthesis designs and reaction methods in the context of a wide range of complex natural products. An emerging interest is to establish a general “common” asymmetric and step economical synthetic strategy capable of forging diverse classes of terpenoid skeletons. Contributions in this area will clearly guide our natural product pursuits, but also play a central role in efforts to design/discover natural product-inspired agents targeting a range of medicinally relevant biology.

1.项目概要/摘要： 研究概述-研究重点是有机合成，特别关注开发 有机化学中的合成策略和反应模式，有助于构建 具有潜在有价值的医药和/或生物学特性的复杂分子。我们已经开发 超过30种立体选择性C-C键形成反应，基于反应性区域，包括 金属环介导的交叉偶联、[3+2]环加成、乙烯基环丙烷重排和自由基 级联化学虽然其中一些是在一个旨在实现 适合于实现广泛的独特的“会聚”C-C键形成的反应性基础 在天然产物合成的广泛领域中，已经出现了其他的过程。这些 联合活动，旨在通过创新推进有机化学的基本支柱 在立体选择性合成领域内，通常被认为是能够促进 医学相关科学的探索。例如，我们已经发现：（1）一种非阿片类镇痛药 从针对生物碱conolidine的努力，（2）独特的parallelism选择性Hsp 90抑制剂，源于 苯醌安莎霉素的合成探索;（3）选择性靶向细胞毒药物 多发性骨髓瘤与lehualide B合成相关的活动，（4）第一个非肽 选择性配体的DBD的p53与天然产物启发的寡聚化，和（5）最有效的 和雌激素受体β（ERβ）的选择性激动剂，最近的研究针对萜类化合物。 该计划的总体愿景-这种无缝集成的反应开发，天然产物 合成，并努力利用我们的技术作为发现新组合物的有利工具 具有独特生物特性的物质的基本结构定义了科学的基本结构， 在未来的几十年里，它将继续成为米卡利齐奥实验室的科学焦点。 未来五年的目标-努力将集中在天然产物全合成，新反应 发展，并建立一个概念上统一的不对称进入四环和五环 萜类这些活动包括围绕ryanodol、马桑内酯D、 氮杂二酮（柠檬酸类）、沙曼达林（甾体生物碱）、夹竹桃苷（Cardenoprotein）、大戟酚（Euphol）和 羽扇豆醇（五环三萜）。这些活动的核心目标是建立和 在广泛的复杂背景下展示了新的合成设计和反应方法 天然产品。一个新出现的兴趣是建立一个普遍的“共同的”不对称和步骤经济 合成策略能够锻造不同类别的萜类骨架。这方面的贡献将 明确指导我们对天然产品的追求，但也在设计/发现天然产品的努力中发挥核心作用。 产品启发的代理人针对一系列医学相关的生物学。