Synthetic Studies on Rare and Novel Marine Alkaloids

通过这一奖项，化学系化学合成计划资助范德比尔特大学化学系的Gary Sulikowski教授开发从海绵中分离出的结构新颖和稀有的海洋生物碱的合成路线。该工作为生物医学研究提供了获取海洋天然产物的有效方法。在这些研究过程中开发的化学在从制药、化学和生物技术行业到基础生物和化学研究努力的领域具有广泛的相关性。感兴趣的海洋天然产物具有独特的分子结构，关于它们的生物学特性和作为治疗先导的潜力的信息很少。研究内容包括甲苯酰胺、卤代环胺、单环胺和野茉莉素A海洋生物碱的合成。这些天然产物的化学合成使人们能够更深入地研究它们的生物学特性，并为用作治疗癌症和微生物感染的治疗剂奠定了基础。此外，该项目还为进入制药和化学工业的研究生和本科生提供了极好的培训。在每个拟议的化学合成中，新的转化都被纳入多步合成方案中，使得不仅可以组装感兴趣的海洋生物碱，而且可以广泛地推进氮杂环合成。在每一种建议的全合成中，使用溴顺丁烯二酸酐作为双烯亲和剂在立体选择性的Diels-Alder反应中都有特色。通过利用初始Diels-Alder反应中出现的关键立体化学和官能团的反应，关键的环加成反应的产物被推进到复杂的多环结构。

ABSTRACTWith this award, the Chemical Synthesis Program of the Chemistry Division is funding Professor Gary Sulikowski of the Department of Chemistry at Vanderbilt University to develop synthetic routes to structurally novel and rare marine alkaloids isolated from marine sponges. This work provides efficient methods to access marine natural products for biomedical study. The chemistry developed during the course of these studies has a broad relevance in areas ranging from the pharmaceutical, chemical, and biotechnology industries to basic biological and chemical research endeavors. The marine natural products of interest possess unique molecular structures with minimal information on their biological properties and potential as therapeutic leads. Studies include the synthesis of upenamide, halicyclamines, xestocyclamine and haliclonin A marine alkaloids. The chemical synthesis of these natural products enables deeper investigation into their biological properties and a foundation for use as therapeutic agents for the treatment of cancer and microbial infections. In addition, the project provides excellent training of graduate and undergraduate students for entry into the pharmaceutical and chemical industry.In each proposed chemical synthesis, new transformations are incorporated into multi-step synthetic schemes enabling the assembly of not only the marine alkaloids of interest but advance nitrogen heterocycle synthesis broadly. The use of bromomaleic anhydride as a dienophile in stereoselective Diels-Alder reactions is featured in each proposed total synthesis. The products of the key cycloaddition reaction are advanced to complex polycyclic structures by employing reactions that take advantage of key stereochemistry and functionality emerging from the initial Diels-Alder reaction.