Total Synthesis of Isopalhinine A

异蝶胆碱A的全合成

• 批准号: 9190145
• 负责人: Samantha Elizabeth Shockley
• 金额: $ 4.36万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190145
• 关键词: 3-hydroxybutanal; Acrolein; Alder plant; Alkylation; Amides; Anions; Breathing; Carbon; Carbonates; Catalysis; Chemistry; Complex; Development; Diels Alder reaction; Excision; Family member; Future; Human; Human Biology; Iridium; Ketones; Laboratories; Lead; Ligands; Medicine; Methodology; Methods; Modification; Molecular; Natural Products; Organic Synthesis; Palladium; Pathway interactions; Pharmaceutical Chemistry; Physical condensation; Problem Solving; Process; Reaction; Reporting; Research; Route; Scheme; Series; Structure; base; career; drug discovery; improved; innovation; lycopodium alkaloid; member; novel; novel strategies; novel therapeutics; phosphoramidite; programs; research and development; skills

PROJECT SUMMARY/ABSTRACT The use of target-directed synthesis as inspiration for the discovery of novel reactions gives access to new, medicinally relevant structures and general methods for their synthesis, as well as new synthetic methodologies that will benefit an array of diverse applications. Ultimately, any development that enhances our ability to assemble compounds more efficiently will have a profound impact upon biology and human medicine through medicinal chemistry and process research and development. This application describes the development of a novel reaction methodology for the enantioselective formation of vicinal quaternary and tertiary stereocenters. Specifically, the research strategy exploits this methodology to outline a synthetic route to the natural product isopalhinine A. Isopalhinine A is a Lycopodium alkaloid with the most sterically congested and structurally complex framework of all the members of the family. Since its isolation in 2013, no completed synthesis has been reported to date. In this multifaceted and integrated program, we hypothesize that expanding the scope of our laboratory's recently developed iridium-catalyzed allylic alkylation chemistry from aryl- and alkenyl-substituted allyl carbonates to include alkyl-substituted electrophiles will facilitate a concise, enantioselective synthesis of isopalhinine A. The specific aims of this application are: 1) the expansion of iridium-catalyzed asymmetric allylic alkylation chemistry with prochiral carbon nucleophiles to include alkyl-substituted electrophiles, 2) total synthesis of isopalhinine A: construction of the spirocyclic intermediate, and 3) total synthesis of isopalhinine A: intramolecular Diels-Alder reaction and final modifications. The described expansion in the field of iridium-catalyzed allylic alkylation chemistry as well as the additional innovation embedded within the strategies and tactics employed in the total synthesis will ultimately lead to the more efficient assembly of other complex bioactive targets and, broadly, the discovery of new therapeutics.

项目摘要/摘要 使用目标定向的合成作为发现新反应的灵感，可访问新的， 与药物相关的结构和合成的一般方法以及新的合成 将有益于各种应用程序的方法。最终，任何增强我们的发展 更有效地组装化合物的能力将对生物学和人类医学产生深远的影响 通过药物化学和过程研发。 该应用描述了对映选择性形成的新反应方法的发展 典型季前和第三级立体中心的具体而言，研究策略利用了这种方法 概述到天然产品异丙胺A的合成途径A.异巴氨酸A是一种番茄生物碱的生物碱 家庭所有成员中最具空间充血且结构上复杂的框架。自从它 隔离在2013年，迄今为止尚未据报道完整的合成。在这个多方面和整合 程序，我们假设扩大了实验室最近开发的虹膜催化的范围 来自芳基和烷基取代的烯丙基碳酸盐的烯丙基烷基化化学，包括烷基取代的 电力物将促进异丙胺A的简洁，对映选择性合成。 应用是：1）虹膜催化的不对称烯丙基烷基化化学的扩展 碳亲核试剂包括烷基取代的电力，2）异巴氨酸的总合成：结构 螺旋细胞中间体和3）异甲氨酸的总合成：分子内代尔斯 - alder反应和 最终修改。 所描述的虹膜催化烯丙基烷基化化学领域的扩张以及附加的 嵌入在整个综合中采用的策略和策略中的创新最终将导致 更有效地组装了其他复杂的生物活性靶标，并广泛地发现了新的治疗剂。