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.

项目总结/摘要 使用靶向合成作为发现新反应的灵感， 本发明还涉及它们的药用相关结构和合成的一般方法，以及新的合成方法。 这些方法将有利于各种不同的应用程序。最终，任何能够增强我们 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 通过药物化学和工艺研究和开发。 本申请描述了一种新的反应方法的发展， 第四和第三立构中心。具体而言，研究战略利用这种方法， 概述了天然产物异松碱A的合成路线。Isopalhinine A是石松属生物碱， 是该家族所有成员中空间上最拥挤和结构上最复杂的框架。以来 2013年分离，迄今为止尚未报告完成的合成。在这个多方面和综合的 计划，我们假设，扩大我们实验室最近开发的铱催化的范围， 从芳基-和烯基-取代的烯丙基碳酸酯到包括烷基-取代的烯丙基碳酸酯的烯丙基烷基化化学 亲电试剂将促进异大黄素A的简明的、对映选择性的合成。具体目标是 应用领域有：1）拓展了铱催化的不对称烯丙基烷基化反应， 碳亲核试剂，包括烷基取代的亲电试剂，2）异松宁A的全合成： 3）异巴戟碱A的全合成：分子内Diels-Alder反应和 最后的修改。 所描述的铱催化烯丙基烷基化化学领域的扩展以及另外的 在全面综合中采用的战略和战术中所包含的创新将最终导致 更有效地组装其他复杂的生物活性靶点，并广泛地发现新的治疗方法。