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.项目摘要/摘要： 研究概述-研究的重点是有机合成，特别是开发 有机化学中促进构筑的合成策略和反应模式 具有潜在有价值的药用和/或生物特性的复杂分子。我们已经开发出 30多个基于反应性区域的立体选择性C-C键形成反应，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计划内开发的，旨在实现 适合实现多种独特的“收敛”碳-碳键形成的反应性基础 在天然产物合成这一广泛领域的项目中，也出现了一些新的过程。这些 综合活动，旨在通过创新推动有机化学的基本支柱 在立体选择性合成领域，通常被认为是使技术成为燃料 在与医学相关的科学方面的探索。例如，我们发现：(1)一种非阿片类止痛药 从针对刀豆碱的生物碱的努力中，(2)独特的准对数选择性Hsp90抑制剂源于 苯醌阿霉素类药物的合成探索(3)选择性靶向细胞毒药物 多发性骨髓瘤与合成活动相关的乐华内酯B，(4)第一个非肽类 具有天然产物启发的寡聚作用的P53的DBD的选择性配体，以及(5)最有效的 以及最近针对萜类化合物的雌激素受体β(ERβ)的选择性激动剂。 该计划的总体愿景-反应开发、天然产品的无缝集成 合成，以及努力利用我们的技术作为发现新组合物的使能工具 具有独特生物性质的物质定义了科学的基本结构，这种结构已经并将 继续是Micalizio实验室未来几十年的科学重点。 未来五年的目标-努力将重点放在天然产物全合成，新反应 发展，并建立了概念上统一的四环和五环不对称进入 萜类化合物。这些活动包括以目标为导向的围绕兰诺醇，科里拉内酯D， 氮杂二酮(柠檬苦素)、萨芒达林(类固醇生物碱)、齐墩果苷(卡地奈德)、安息香酚(安非他明)和 羽扇豆醇(五环三萜)。这些活动的核心是建立和建立 在广泛的复杂背景下展示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种普遍的“共同”不对称和步步经济 能够锻造不同类别的萜类骨架的合成策略。在这一领域的贡献将 清楚地指导我们对自然产品的追求，但也在设计/发现自然产品的努力中发挥核心作用 以产品为灵感的药物，目标是一系列与医学相关的生物学。