Oxazolone Cycloadducts as Heterocyclic Scaffolds for Decahydroquinoline Alkaloid

恶唑酮环导管作为十氢喹啉生物碱的杂环支架

• 批准号: 8475110
• 负责人: Stephen Philip Fearnley
• 金额: $ 12.24万
• 依托单位: YORK COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475110
• 关键词: Address; Alder plant; Alkaloids; Antimalarials; Area; Award; Beryllium; Biological; Biological Factors; Biological Testing; Collaborations; Complex; Cyclization; Development; Discipline; Educational process of instructing; Electrons; Evaluation; Excision; Face; Funding; Goals; Hand; Investigation; Laboratories; Malonates; Marines; Metabolic Pathway; Methodology; Modeling; Nature; Neurologic; Oxazolidinones; Oxazolone; Poison; Process; Property; Protocols documentation; Publications; Pyrrolidines; Rana; Reaction; Role; Route; Rupture; Scientist; Series; Side; Solutions; Source; Specialist; Structure; Study models; System; Therapeutic; Toxin; Work; analog; base; carbene; career development; cycloaddition; diene; gephyrotoxin; improved; innovation; novel; pharmacophore; public health relevance; pyrrolidine; scaffold

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.

描述（由申请人提供）：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，它可以为生物测试提供足够的材料，并允许获得结构类似物， 可能反过来揭示了关键药效团。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都是广泛和支持。我们选择的目标是：（i）gephyrotoxin 287 C，具有有趣和特定神经兴奋特性的许多箭毒蛙生物碱之一，和（ii）lepadins F和G，具有显著抗疟疾活性的相似但不同的海洋代谢物。对于gephyrotoxi，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。这个框架已经在手，现在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路径的具体性质，就可以确定一条通往目标的直接路线。对lepadin核心的类似方法略有不同，因为它具有缺电子2 取代的二烯，在恶唑酮Diels-Alders中尚未尝试的系统。一系列简单的模型研究将揭示这种环加成的特征[整体模式;取代基的作用/作用] 然后预期的环加合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的全合成的新合成方法，并且这样做将为生物学评价提供许多结构相关的类似物。