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: 8688278
• 负责人: Stephen Philip Fearnley
• 金额: $ 12.38万
• 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/8688278
• 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）：该提案的中心主题是几种decahydroquinoline生物碱的总合成。这种广泛的天然产品在结构上是多样的和复杂的，其中许多生物碱具有强大而又高度特定的生物学活性，其详细研究具有相当大的治疗意义。但是，由于它们通常从微薄的天然来源中分离出来，因此实验室合成被证明是可取的，并提供了许多额外的好处，例如确认结构和生物合成/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，并允许访问结构类似物 可能反过来揭示了关键的药理。因此，持续开发新的和多样化的方法，以帮助总合成生物碱天然产物的总合成仍然是最重要的。 本文提出的特定方法涉及一种这种新生的方法论 - 在新型分子内二烷 - alder alder Cycloadition中，N-取代的恶唑酮作为二烯酚成分的利用。由于这是最初在P.I.实验室中发展的反应，因此拟议的研究具有足够的先例和初步的结果。我们选择的靶标是：（i）Geyproyotoxin 287c，这是具有吸引人和特定神经兴奋性特性的许多毒龙蛙生物碱之一，以及（ii）Lepadins f an G，类似但相似但独特的海洋代谢产物具有显着的抗卫生活性。对于Gephyrotoxi，计划的路线会在快速构建一个密集官能化的顺式融合的Decahydroquinoline Core时取决于5个所需的立体中心。现在，该框架现在将成为所有进一步阐述最终目标本身的关键杂环脚手架。将采用许多创新的策略来实现这一目标，包括针对所需C6取代基的区域和立体选择性安装的两步环甘油植物的分裂方法，以及通过甲状酸羟基唑酮群体进行E2的E2脱吡咯烷环的串联封闭。这些研究将同时进行研究，将采用新方法和建立先例的结合。一旦建立了这些反应路径的具体性质，将直接终止通往目标的途径。 Lepadin Core的一种类似方法略有不同，因为它具有电子缺陷2 取代的二烯，这是一种尚未在恶唑酮Diels-alders中未经试验的系统。一系列简单的模型研究将揭示此环加成的特征[整体模式；取代基的效果/作用] 然后，预期的环载体将进一步转化为目标化合物。因此，这些努力将直接有助于持续开发新型的合成方法，以完全合成生物活性生物碱，这样做将为生物学评估提供许多与结构相关的类似物。