Oxazolone Cycloadducts as Heterocyclic Scaffolds for Alkaloid Synthesis: Gephyrot

恶唑酮环导管作为生物碱合成的杂环支架：Gephyrot

• 批准号: 8078616
• 负责人: Stephen Philip Fearnley
• 金额: $ 12.06万
• 依托单位: YORK COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-27 至 2011-11-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078616
• 关键词: Address; Alder plant; Alkaloids; Antimalarials; Area; Award; Beryllium; Biological; Biological Factors; Biological Testing; Complex; Cyclization; Development; Diels Alder reaction; Discipline; Educational process of instructing; Evaluation; Excision; Face; Funding; Goals; Hand; Investigation; Laboratories; Malonates; Metabolic Pathway; Methodology; Methods; Nature; Neurologic; Oxazolidinones; Oxazolone; Poison; Process; Property; Protocols documentation; Publications; Pyrrolidines; Rana; Reaction; Route; Rupture; Side; Solutions; Source; Structure; Study models; Techniques; Technology; Therapeutic; Toxin; analog; base; carbene; career development; cycloaddition; cytotoxic; gephyrotoxin; improved; innovation; nervous system disorder; novel; pharmacophore; pyrrolidine; scaffold

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.

描述（由申请人提供）：该提案的中心主题是Gephyrotoxin 287 C的全合成，Gephyrotoxin 287 C是具有有趣和特定神经兴奋特性的许多箭毒蛙生物碱之一。这类天然产物结构多样且复杂，其中许多生物碱具有强大但高度特异性的生物活性，对其进行详细研究具有相当大的治疗意义。然而，由于它们通常从天然来源中以微薄的量分离，实验室合成证明是可取的，并提供了许多额外的好处，如结构的确认和生物合成/代谢途径的阐明。更重要的是，它可以为生物学测试提供足够的材料，并允许对结构类似物进行分析，从而揭示关键药效团。因此，不断开发新的和不同的方法来帮助生物碱天然产物的全合成仍然是至关重要的。 本文提出的具体方法涉及一种这样的新生方法-在新的分子内Diels-Alder环加成中利用N-取代的恶唑酮作为亲二烯组分。因为这是最初在P.I.中产生的反应。的实验室，拟议的研究有充分的先例和初步结果是支持的。计划的路线取决于快速建设一个密集的功能化的顺式稠合十氢喹啉核心含有3所需的5个立体中心的gephyrotoxin。一旦掌握，这个框架将作为所有进一步阐述最终目标本身的关键杂环支架。将采用一些创新的策略来实现这一目标，包括2步环丙烷化-环断裂方法，以区域和立体选择性地安装所需的C6取代基，以及通过E2切除恶唑烷酮部分然后进行迈克尔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的方法。一旦确定了这些反应途径的具体性质，就将最终确定一条通往目标的直接路线。虽然早期的模型研究将追求外消旋的方式，使用不对称诱导技术的对映选择性合成也提出。最后，随后计划外推到进一步的2- epi-cis-fused decahydroquinoline目标。因此，这些对gephyrotoxin的努力将有助于继续开发新的合成方法，用于生物活性生物碱的全合成，并在这样做时将提供许多结构相关的类似物用于生物学评价。 公共卫生关系：该提案涉及生物碱Gephrotoxin 287 C的全合成，Gephrotoxin 287 C是一种具有有趣的神经活性并因此具有治疗潜力的箭毒蛙毒素。所描述的路线是基于新颖的合成方法，其既通用又将导致提供许多结构类似物。这反过来将使详细的比较与天然产品，特别是在结构和特定的生物活性与几种神经疾病的状态。