Synthetic Studies on Rare and Novel Marine Alkaloids

摘要：化学系的化学合成项目将利用该奖项资助范德比尔特大学化学系的加里·苏利科夫斯基教授开发从海绵中分离出的结构新颖和罕见的海洋生物碱的合成路线。本工作为获取海洋天然产物用于生物医学研究提供了有效的方法。 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工作的领域具有广泛的相关性。感兴趣的海洋天然产品具有独特的分子结构，关于其生物学特性和作为治疗先导的潜力的信息很少。 研究包括乌本酰胺、盐环胺、xestocyclamine和盐环胺A海洋生物碱的合成。这些天然产物的化学合成使得能够更深入地研究其生物学特性，并为用作治疗癌症和微生物感染的治疗剂奠定基础。此外，该项目还为进入制药和化学行业的研究生和本科生提供了良好的培训。在每一个拟议的化学合成中，新的转化都被纳入多步合成方案，不仅能够组装感兴趣的海洋生物碱，还能广泛地推进氮杂环的合成。溴代马来酸酐在立体选择性Diels-Alder反应中作为亲二烯体的使用在每个提议的全合成中具有特征。关键环加成反应的产物通过采用利用来自初始Diels-Alder反应的关键立体化学和官能性的反应而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.