Oxazolone Cycloadducts as Heterocyclic Scaffolds for Decahydroquinoline Alkaloid

描述(申请人提供)：本提案的中心主题是几种十氢喹啉生物碱的全合成。这类广泛的天然产物结构多样且复杂，其中许多生物碱具有强大而高度特异的生物活性，对其进行详细研究具有相当大的治疗意义。然而，由于它们通常是从自然来源分离出来的，数量很少，实验室合成被证明是可取的，并提供了许多额外的好处，如确认结构和阐明生物合成/代谢途径。更重要的是，它可以为生物测试提供足够的材料，并允许获得 可能进而揭示关键的药效团。因此，继续开发新的和多样化的方法学以帮助生物碱天然产物的全合成仍然是至关重要的。这里提出的具体方法涉及一种这样的新方法-利用N-取代恶唑酮作为新的分子内Diels-Alder环加成中的亲双烯组分。由于这是一种最初在P.I.S实验室发展起来的反应，拟议的研究有足够的先例，初步结果既广泛又支持。我们选择的目标是：(I)地理毒素287C，具有耐人寻味和特殊的神经兴奋特性的许多有毒飞镖生物碱之一，以及(Ii)瘦素F和G，类似但不同的海洋代谢物，具有显著的抗疟疾活性。对于地卟啉，计划的路线取决于快速构建一个稠密功能化的顺式融合十氢喹啉核心，该核心包含5个所需立体中心中的3个。这一框架已经到位，现在将作为所有进一步阐述最终目标本身的关键杂环脚手架。将采用一些创新的策略来实现这一点，包括两步环丙化-环裂解方法以区域和立体选择性地安装所需的C6取代基，以及通过切割恶唑烷酮部分然后进行Michael环化来串联关闭吡咯烷环。这些研究将同时进行调查，将采用新方法和既定先例相结合。一旦确定了这些反应路径的具体性质，将最终确定通往目标的直接路线。对瘦素核心的类似方法略有不同，因为它的特征是缺乏电子的2 取代二烯，这是一种尚未在恶唑酮Diels-Alders中尝试的系统。一系列简单的模型研究将揭示这种环加成反应的特征[总体模式；取代基的影响/作用] 然后，预期的环加成物将进一步转化为目标化合物。因此，这些努力将直接有助于继续开发用于生物活性生物碱全合成的新的合成方法，这样做将为生物评价提供许多结构上相关的类似物。

DESCRIPTION (provided by applicant): The central theme of this proposal is the total synthesis of several decahydroquinoline alkaloids. This broad class of natural products is structurally diverse and complex, and many of these alkaloids possess powerful yet highly specific biological activity, the detailed investigation of which has considerable therapeutic implications. However, as they are often isolated from natural sources in meager quantities, a laboratory synthesis proves desirable and provides many additional benefits, such as confirmation of structure and elucidation of biosynthetic/metabolic pathways. More importantly, it can supply sufficient material for biological testing, and allows access to structural analogs that may in turn reveal the key pharmacophore. Therefore, continued development of new and varied methodology to aid in the total synthesis of alkaloid natural products remains of the utmost importance. The specific approach proposed herein involves one such nascent methodology - the utilization of N-substituted oxazolones as the dienophilic component in a novel intramolecular Diels-Alder cycloaddition. As this is a reaction originally developed in the P.I.'s laboratories, the proposed studies have ample precedent and preliminary results are both extensive and supportive. Our chosen targets are: (i) gephyrotoxin 287C, one of many poison dart frog alkaloids with intriguing and specific neuroexcitatory properties, and (ii) lepadins F an G, similar yet distinct marine metabolites with significant anti-malarial activity. For gephyrotoxi, the planned route hinges upon rapid construction of a densely functionalized cis-fused decahydroquinoline core containing 3 of the 5 required stereocenters. Already in hand, this framework will now serve as the key heterocyclic scaffold for all further elaboration to the final target itself. A number of innovative strategies will be employed to achieve this, including a 2-step cyclopropanation-ring scission approach to regio- and stereoselective installation of a required C6 substituent, and the tandem closure of a pyrrolidine ring by E2 excision of an oxazolidinone moiety followed by Michael cyclization. These studies, to be investigated in parallel, will employ a combination of new methodology and established precedent. Once the specific nature of these reaction paths is established, a direct route to the target will be finalied. A similar approach to the lepadin core differs slightly in that it features an electron-deficient 2 substituted diene, a system as yet untried in oxazolone Diels-Alders. A series of simple model studies will reveal the character of this cycloaddition [overall mode; effect/role of substituents] and the expected cycloadducts will then undergo further transformation to the target compounds. These efforts will therefore aid directly in the continued development of novel synthetic methodology for the total synthesis of bioactive alkaloids, and in doing so will provide numerous structurally related analogs for biological evaluation.