Allenic [2 + 2 + 1] Reactions Enabling Syntheses of Natural Products with 7-Membe

易于获得的七元环系统将有助于合成 具有这种环系的生物上重要的化合物。三个碳环核 在三个目标中，thapsigargin，灰色毒素III和鸟粪苷J将是 合成以展示四烯类化合物的合成效用、效率和灵活性 环羰化反应。实现这一建议的目标将提供更多 对烯烃和过渡金属催化的环羰化反应的一般认识 反应。此外，该项目的长期目标是应用这一 山茶素、鸟苷J和灰霉毒素III的全合成策略 这将以获得新的中间体和类似物为特色，使新的生物 学习。长期目标不在这项提议的范围内。具体目标 这项建议的内容包括： 1)扩展了Allen Pauson-Khandd反应的范围，以包括更密集的 官能化的前体包括但不限于烯醇酯。环羰化反应 二烯丙醇酯提供了快速获得-乙酰氧基环戊二烯酮的途径。The Rapid 将探索在Rh(I)催化条件下烯醇醋酸酯的异构化。 动态动力学法对映体选择性制备α-乙酰氧基环戊二酮 不对称变换(DYKAT)。 2)用Pauson-Khand法合成塔普西格尔金的碳环骨架 烯醇酯的反应。Thapsigargin是一种高度含氧的碳环， 特别适合这种适时引入氧气的方法 限制保护和解除保护步骤数量的功能。此外， 在目标1中开发的DYKAT协议将被用作实现以下目标的潜在手段 非对映选择性异体Pauson-Khandd反应。Thapsigargin具有有趣的特性 作为肌浆和肌浆的亚纳米分子抑制物的生物活性 内质网钙ATPase(SERCA)。 3)合成了鸟粪碳环核J。 鸟粪苷类化合物，但其生物活性尚未被 由于数量非常有限而建立的。合成物的特点是有一种别具一格的保森- Khandd反应使用了一种不同寻常的？-烯亚叉丁烯内酯。 4)合成灰色毒素III的碳环核心，路线具有高度的 将烯-炔前驱体功能化以生成分子复杂的骨架。 灰霉毒素是破解门控机制的重要分子工具 钠离子通道的功能。

Ready access to seven-membered rings systems will facilitate the synthesis of biologically important compounds possessing this ring system. Three carbocyclic cores of three targets, thapsigargin, grayanotoxin III and guanacastepene J, will be synthesized to demonstrate the synthetic utility, efficiency, and flexibility of the allenic cyclocarbonylation reaction. Realization of the goals of this proposal will provide a more general understanding of allenes and transition-metal catalyzed cyclocarbonylation reactions. Moreover, the long-term goals of this project are the application of this strategy to the total synthesis of thapsigargin, guanacastepene J and grayanotoxin III that will feature access to novel intermediates and analogs enabling new biological studies. The long-term goals are not within the scope of this proposal. The specific aims of this proposal include: 1) Extending the scope of the allenic Pauson-Khand reaction to include more densely functionalized precursors including, but not limited to allenol esters. Cyclocarbonylation of allenol esters provides rapid access to ¿-acetoxy cyclopentadienones. The rapid isomerization of allenol acetates under the Rh(I)-catalyzed conditions will be explored for the enantioselective preparation of ¿-acetoxy cyclopentadienones using dynamic kinetic asymmetric transformation (DYKAT). 2) Synthesizing the carbocyclic framework of thapsigargin using the Pauson-Khand reaction of an allenol ester. Thapsigargin is a highly oxygenated carbocycle that is particularly well suited for this method that features well-timed introductions of oxygen functionality limiting the number of protection and deprotection steps. Moreover, the DYKAT protocol developed in Aim 1 will be exploited as a potential means of achieving a diastereoselective allenic Pauson-Khand reaction. Thapsigargin posseses interesting biological activity functioning as a subnanomolar inhibitor of sarcoplasmic and endoplasmic reticulum Ca+2 ATPase (SERCA). 3) Synthesizing the carbocyclic core of guanacastepene J, a member of the guanacastepene family, but a compound in which the biological activity has not been established due to very limited quantities. The synthesis features an allenic Pauson- Khand reaction using an unusual ¿-allenylidene butenolide. 4) Synthesizing the carbocyclic core of grayanotoxin III via a route that features a highly functionalized allene-yne precursor to generate a molecularly complex skeleton. Grayanotoxin is an important molecular tool for deciphering the mechanism for gating functions of the sodium ion channels.