Total Synthesis of Isopalhinine A

项目摘要/摘要 使用靶向合成作为发现新反应的灵感提供了新的， 与药物相关的结构及其合成的一般方法，以及新的合成方法 这些方法将使一系列不同的应用程序受益。归根结底，任何能够增强我们的 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影响 通过药物化学和工艺研发。 本申请描述了一种用于对映体选择性形成的新的反应方法学的发展 邻近的第四级和第三级立体中心。具体地说，研究战略利用这种方法论来 概述一条合成天然产物异苯丙氨酸A的合成路线。异苯丙氨酸A是一种石松生物碱，具有 最拥挤和结构复杂的家庭所有成员的框架。因为它的 自2013年分离以来，到目前为止还没有完成合成的报道。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Ir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烷基化化学 亲电性有助于简明、对映体选择性地合成异苯丙氨酸A。 其应用主要有：1)前手性Ir催化不对称烯丙基烷基化反应的拓展 碳亲核试剂包括烷基取代的亲电试剂，2)异苯丙氨酸A的全合成：结构 3)异苯丙氨酸A的全合成：分子内Diels-Alder反应和 最后的修改。 所描述的铱催化的烯丙基烷基化化学领域的扩展以及其他 在全面综合中采用的战略和战术中嵌入的创新最终将导致 更有效地组装其他复杂的生物活性靶点，以及广泛地说，新疗法的发现。

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.