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: 10540398
• 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/10540398
• 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; TP53 gene; Technology; Terpenes; Textiles; Therapeutic; Vertebral column; Vision; chemical synthesis; clinically relevant; cycloaddition; design; forging; inhibitor; innovation; interest; lupeol; natural product inspired; 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。项目摘要/摘要： 研究概述 - 研究的重点是有机综合，对开发特别感兴趣 有机化学中的合成策略和反应性模式，促进 具有潜在有价值的医学和/或生物学特性的复杂分子。我们已经发展了 三十多个立体选择性C – C键形成反应基于反应性区域，包括 金属囊肿介导的交叉偶联，[3+2]环载条，乙烯基环丙烷的重排和自由基 级联化学。尽管其中一些是在旨在实现A的计划中开发的 反应性的基础，适合实现各种独特的“收敛” C – C键 在自然产品合成的广泛领域的计划中，其他过程中出现了。这些 合并活动，旨在通过创新来推动有机化学的基本骨干 在立体选择性合成领域内，通常将其视为使技术加油 医学相关科学的探索。例如，我们发现：（1）非阿片类镇痛药 （2）独特的旁系同源物选择性HSP90抑制剂（2） 探索苯喹酮Ansamycins的合成，（3）靶向细胞毒性剂 来自与lehaliDE b的合成有关的活性的多发性骨髓瘤，（4）第一个非肽 具有自然产品启发的寡聚的p53 DBD的选择性配体，（5）最有效的 来自针对萜类化合物的最新研究的雌激素受体β（ERβ）的选择性激动剂。 该程序的总体视野 - 这种反应发展的无缝整合，天然产品 综合，并努力利用我们的技术作为发现新颖作品的能力工具 具有独特生物学特性的物质定义了科学的基本结构，并且将 继续成为Micalizio实验室科学的重点，几十年来。 未来五年的目标 - 努力将集中于自然产品全合成，新反应 开发并建立了概念统一的对四环和五半的不对称进入 萜类化合物。这些活动包括面向目标的综合运动，围绕Ryanodol，Corialactone D， Azadiradione（柠檬酸脂），samandarin（类固醇生物碱），Oleandrin（Cardenolide），Euphol（Euphane）和 Lupeol（五半三萜）。这些活动的核心是建立和 在广泛的复杂范围的背景下展示新的合成设计和反应方法 天然产品。新兴的兴趣是建立一个普遍的“常见”不对称和步骤经济 合成策略，能够锻造潜水员类的萜类骨骼。该领域的贡献将 显然指导我们的自然产品追求，但在设计/发现自然的努力方面也起着核心作用 针对一系列药物相关生物学的产品启发的代理。