Total Synthesis of Marine-Derived Alkaloids of the Nagelamide Family

描述（由申请人提供）：含有2-氨基咪唑的海洋生物碱不仅为开发新的合成化学，而且为产生新的治疗剂或生物探针提供了机会靶点。在这项工作中，我们选择专注于海绵代谢物的oroidin家族的几种相关天然产物，这些天然产物具有复杂性，并为开发新的合成方法和策略提供了论坛。具体而言，我们建议开发几种被称为nagelamides的抗菌生物碱的合成方法。我们的策略是集中在简单的咪唑的阐述，特别是4，5-二碘咪唑衍生物的官能化，这提供了一个简单的方法，用于建设有用的咪唑含积木。在第一个具体目标中，我们建议通过片段偶联策略开发两个密切相关的oroidin二聚体，nagelamide B和C的全合成。具体地说，我们将采用顺序和位置选择性的4，5-二碘咪唑与格氏试剂制备两个官能化的乙烯基咪唑，这将被耦合，以提供目标nagelamides的基本框架。我们实验室的初步研究已经证明了这种方法的普遍可行性。在第二个具体目标中，我们建议完成nagelamide R和T的全合成。这些oroidin二聚体在吡咯-咪唑家族中是独特的，因为它们是唯一报道的含有恶唑啉部分的实例。为了接近这些分子，我们计划研究串联钯催化的氧芳基化反应来构建恶唑啉 杂环并引入第二咪唑部分。在第三个具体目标中，我们建议审查6？4，5-二乙烯基咪唑的电环化反应构建了几种玉簪素衍生天然产物中发现的四氢苯并咪唑骨架。我们计划利用这种化学方法，使用nagelamide C作为前体来进行ageliferin和nagelamide E的全合成。本研究过程中制备的样品将提供给NIH（NCI-DTP和MLSCN）运行的项目，以确定合成天然产物和高级合成中间体的生物活性。 公共卫生相关性：衍生自海绵的化合物通常具有广泛的生物活性，在本发明的情况下，感兴趣的化合物表现出抗菌活性。此外，它们经常需要开发新的合成方法和组装策略。本提案所述工作旨在确定和开发方法，以提供合成途径，获取合理数量的最初在Agelas sp.海绵中发现的几种天然材料。一旦获得，这些材料的生物活性将通过NIH赞助的项目进行评价。

DESCRIPTION (provided by applicant): Marine alkaloids containing 2-aminoamidazoles provide targets of opportunity for not only the development of novel synthetic chemistry, but also for the generation of novel therapeutic agents or biological probes. In this effort, we have chosen to focus on several related natural products from the oroidin family of sponge metabolites that range in complexity and provide a forum to develop new synthetic methods and strategies. Specifically, we propose to develop synthetic approaches to several of anti-bacterial alkaloids known as the nagelamides. Our strategy is centered on the elaboration of simple imidazoles, specifically the functionalization of 4,5-diiodoimidazole derivatives, which provides a straightforward approach for the construction of useful imidazole-containing building blocks. In the first Specific Aim we propose to develop total syntheses of two closely related oroidin dimers, nagelamide B, and C through a fragment coupling strategy. Specifically, we will employ the sequential and position selective elaboration of 4,5-diiodoimidazoles with Grignard reagents to prepare two functionalized vinylimidazoles, which will be coupled to provide the basic frameworks of the target nagelamides. Preliminary studies from our lab have demonstrated the general feasibility of the approach. In the second Specific Aim we propose to complete the total syntheses of nagelamide R and T. These oroidin dimers are unique within the pyrrole-imidazole family as they are the only reported examples to contain an oxazoline moiety. To approach these molecules, we plan on investigating a tandem palladium-catalyzed oxy-arylation reaction to construct the oxazoline heterocycle and incorporate the second imidazole moiety. In the third Specific Aim we propose to examine a 6?-electrocyclization reaction of 4,5-divinylimidazoles to construct the tetrahydrobenzimidazole skeleton found in several oroidin-derived natural products. We plan on utilizing this chemistry to perform total syntheses of ageliferin and nagelamide E using nagelamide C as a precursor. Samples prepared in the course of this investigation will be offered to programs run by the NIH (NCI-DTP and MLSCN) to determine the bioactivities of synthetic natural products and advanced synthetic intermediates. PUBLIC HEALTH RELEVANCE: Compounds derived from marine sponges typically possess a broad range of biological activities, in the present cases the compounds of interest exhibit anti-bacterial activity. In addition, they frequently demand the development of new synthetic methods and strategies for their assembly. The work described in this proposal aims to define and develop methods to provide synthetic access to reasonable quantities of several of these naturally occurring materials originally found in Agelas sp. marine sponges. Once obtained, the biological activity of these materials will be evaluated through NIH-sponsored programs.