Oxazolone Cycloadducts as Heterocyclic Scaffolds for Alkaloid Synthesis: Gephyrot

描述(由申请人提供)：这项提案的中心主题是全合成地黄毒素287C，这是许多毒镖蛙生物碱之一，具有耐人寻味的和特定的神经兴奋特性。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ACE获得结构类似物，进而可能揭示关键的药效团。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实验室开发的反应，拟议的研究有足够的先例，初步结果也是支持的。计划中的路线取决于快速建造一个密集功能化的顺式融合十氢喹啉核心，该核心包含所需的5个地质藻毒素立体中心中的3个。一旦完成，这一框架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。虽然早期的模型研究将以外消旋的方式进行，但也提出了使用不对称诱导技术的对映选择性合成。最后，随后计划对进一步的2-环氧氯丙烷-顺式-十氢喹啉目标进行外推。因此，这些针对地藻毒素的努力将有助于继续开发用于全合成生物活性生物碱的新的合成方法，并通过这样做将为生物评价提供许多结构相关的类似物。 与公共卫生相关：这项提案涉及生物碱Gephrotox287C的全合成，这是一种毒镖蛙毒素，具有耐人寻味的神经活性，从而具有治疗潜力。所描述的路线基于新的合成方法，该方法既是通用的，又将导致提供许多结构类似物。这反过来将使我们能够与天然产物进行详细的比较，特别是在结构和与几种神经疾病状态相关的特定生物活性方面。

DESCRIPTION (provided by applicant): The central theme of this proposal is the total synthesis of Gephyrotoxin 287C, one of many poison dart frog alkaloids with intriguing and specific neuroexcitatory properties. 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 aces 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 supportive. The planned route hinges upon rapid construction of a densely functionalized cis-fused decahydroquinoline core containing 3 of the 5 required stereocenters of gephyrotoxin. Once in hand, this framework will 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 finalized. Although early model studies will be pursued in racemic fashion, an enantioselective synthesis using an asymmetric induction technique is also presented. Finally, extrapolation to further 2- epi-cis-fused decahydroquinoline targets is subsequently planned. These efforts toward gephyrotoxin will therefore aid 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. PUBLIC HEALTH RELEVANCE: This proposal addresses the total synthesis of the alkaloid Gephrotoxin 287C, a poison dart frog toxin with intriguing neurological activity and thus therapeutic potential. The described route is based on novel synthetic methodology that is both versatile and will result in the provision of numerous structural analogs. This in turn will enable a detailed comparison with the natural product, particularly in terms of structure and the specific bioactivity associated with several neurological disease states.