Total Synthesis of Marine-Derived Alkaloids of the Nagelamide Family

Nagelamide 家族海洋生物碱的全合成

• 批准号: 8101666
• 负责人: Carl Lovely
• 金额: $ 24.22万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-13 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101666
• 关键词: Agelas; Alkaloids; Anti-Bacterial Agents; Azides; Biological; Biological Factors; Biological Testing; Chemistry; Collaborations; Complex; Coupled; Coupling; Development; Exhibits; Family; Family member; Generations; Hydantoins; Imidazole; Investigation; Literature; Marines; Methods; Palau' amine; Palladium; Parents; Pattern; Porifera; Positioning Attribute; Preparation; Process; Protocols documentation; Pyrroles; Reaction; Reagent; Reporting; Running; Sampling; Side; Skeleton; Staging; Synthesis Chemistry; System; Therapeutic Agents; United States National Institutes of Health; Work; adduct; analog; dimer; interest; member; novel; novel therapeutics; operation; oroidin; oxidation; programs

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.

描述（由申请人提供）：含有2-氨基咪唑的海洋生物碱不仅为新型合成化学的发展提供了机会，而且为新型治疗剂或生物探针的产生提供了机会。在这项工作中，我们选择专注于海绵代谢物中oroidin家族的几个相关天然产物，这些产物的复杂性范围广泛，并为开发新的合成方法和策略提供了一个论坛。具体地说，我们建议开发几种抗菌生物碱的合成方法，这些生物碱被称为nagelamide。我们的策略集中于简单咪唑的细化，特别是4,5-二碘咪唑衍生物的功能化，这为构建有用的含咪唑构建块提供了一种直接的方法。在第一个特定目标中，我们建议通过片段偶联策略开发两种密切相关的oroidin二聚体nagelamide B和C的全合成。具体来说，我们将使用格氏试剂对4,5-二碘咪唑进行顺序和位置选择性精化，以制备两种功能化的乙烯基咪唑，它们将偶联以提供目标纳基酰胺的基本框架。我们实验室的初步研究已经证明了这种方法的总体可行性。在第二个特定目标中，我们建议完成nagelamide R和t的全合成。这些邻避蛋白二聚体在吡咯-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例子。为了接近这些分子，我们计划研究钯催化的串联氧芳基化反应来构建恶唑啉

项目成果

Thio acid-mediated conversion of azides to amides - exploratory studies en route to oroidin alkaloids.

硫代酸介导的叠氮化物向酰胺的转化——在制备蝴蝶苷生物碱的过程中的探索性研究。

• DOI: 10.1016/j.tetlet.2017.08.050
• 发表时间: 2017
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Herath,ApsaraK;Bhandari,ManojR;Gout,Delphine;Yousufuddin,Muhammed;Lovely,CarlJ
• 通讯作者: Lovely,CarlJ