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

容易获得的七元环系统将有助于合成 具有这种环系统的生物学重要化合物。三碳环核 三个目标，毒胡萝卜素，grayanotoxin III和guanacastepene J，将被 合成的，以证明合成的效用，效率，和灵活性的丙二酸 环羰基化反应实现这项建议的目标将提供一个更 联烯与过渡金属催化环羰基化反应 反应.此外，该项目的长期目标是应用这一点， 毒胡萝卜素、guanacastepene J和grayanotoxin III的全合成策略 这将有助于获得新的中间体和类似物， 问题研究长期目标不在本建议的范围内。具体目标 包括： 1)将Allenic Pauson-Khand反应的范围扩展到更密集的 官能化前体，包括但不限于联烯醇酯。环羰基化 联烯醇酯的合成提供了快速获得<$-乙酰氧基环己烯酮的途径。快速 在Rh（I）催化条件下，联烯醇乙酸酯的异构化将被探索， 动态动力学法合成<$-乙酰氧基环烯酮 不对称转化（DYKAT）。 2)利用Pauson-Khand法合成毒胡萝卜素的碳环骨架 联烯醇酯的反应。毒胡萝卜素是一种高度氧化的碳环， 特别适合于这种以适时引入氧气为特征的方法 限制保护和去保护步骤的数量的功能。而且 在目标1中开发的DYKAT协议将被利用作为实现 非对映选择性联烯Pauson-Khand反应。Thapsigargin拥有有趣的 作为亚纳摩尔的肌浆抑制剂的生物活性， 内质网Ca+2 ATP酶（SERCA）。 3)合成胍那卡斯烯J的碳环核心，胍那卡斯烯J是一个具有碳环核心的化合物， guanacastepene家族，但其生物活性尚未被证实的化合物。 由于数量非常有限而建立。该合成的特征在于一个Allenic Pauson- 使用不寻常的戊烯叉丁烯二酸的Khand反应。 4)经由以高度生物降解为特征的路线合成灰斑蛙毒素III的碳环核心 官能化的丙二烯-炔前体以产生分子复合物骨架。 灰蝶毒素是破译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.