Synthesis of Bioactive Marine Natural Products

天然产物代表了新药开发的一个非常重要的平台，并为包括化学，生物学和医学在内的所有科学领域的研究提供了持续的刺激。拟议的研究的目的是研究方法和开发的合成策略，这将允许一个有效的和立体控制的化学合成的代表性成员从两个家庭的生物活性的天然产物：zoanthamine生物碱和cembranolides。目标天然产物具有不寻常的化学结构，强大的生物活性和未探索的生物作用模式，这证明了它们作为新的生物工具和药物开发的潜力。所提出的方法源于未开发的反应性的电子丰富的物种，如二烯和呋喃，在环加成反应，并强调这些反应的潜力，用于建设高度官能化的杂环。所提出的策略将测试上述方法的范围和局限性，并评估其在天然产物合成中的适用性。该策略还被设计为通过在一个步骤中并入多个碳-碳键形成事件来从相对未官能化的起始材料产生结构复杂性。这些策略将为天然产物的简化类似物的合成铺平道路，这些天然产物与母体结构相结合，将用于询问新化学结构的生物学，并将其化学反应性转化为生物学作用模式。 公共卫生相关性：本文介绍了两类具有生物活性的海洋天然产物的合成研究计划：虫黄胺生物碱和西松烷内酯。所选择的靶点具有有趣的化学结构和非常有效的生物活性，可作为开发新药的先导结构。我们建议探索一种策略，对zoanthamines的合成是由生物合成假说的启发。我们的初步研究结果表明，它是可能的合成这些复杂的天然产物从一个无环前体通过调整多环化反应级联。我们计划探索这一反应级联的新的多环图案的合成，并将其应用于合成zoanthenol。除了合成方面的成就外，我们的研究结果预计将在合成方法学领域，特别是2-氨基二烯的反应性方面产生重大影响。我们还建议开发一种统一的方法，对选定的西松烷内酯的合成是基于未开发的1-环氧呋喃的反应性。这些化合物的合成将为评价其生物学和药理学特征铺平道路，这将与该领域的专家合作进行。

DESCRIPTION (provided by applicant): Natural products represent a very significant platform for the development of new drugs and provide a continuous stimulus for research in all areas of science, including chemistry, biology and medicine. The objective of the proposed research is to study methods and develop synthetic strategies that would permit an efficient and stereocontrolled chemical synthesis of representative members from two families of bioactive natural products: the zoanthamine alkaloids and the cembranolides. The targeted natural products have uncommon chemical structures, potent biological activities and unexplored biological modes of action, which attest to their potential as new biological tools and leads for drug development. The proposed methods stem from the unexplored reactivity of electronically rich species, such as dienes and furans, during cycloaddition reactions and highlight the potential of these reactions for the construction of highly functionalized heterocycles. The proposed strategies will test the scope and limitations of the above methods and evaluate their applicability in natural product synthesis. The strategies are also designed to create structural complexity from relatively unfunctionalized starting materials by incorporating multiple carbon-carbon bond forming events in one step. These strategies will pave the way for the synthesis of simplified analogues of the natural products that, in combination with the parent structures, will be used to interrogate the biology of the new chemical structures and translate their chemical reactivity to biological mode of action. PUBLIC HEALTH RELEVANCE: We describe a research program toward the synthesis on two classes of bioactive marine natural products: the zoanthamine alkaloids and the cembranolides. The selected targets have interesting chemical structures and very potent bioactivities as lead structures for the development of new pharmaceuticals. We propose to explore a strategy toward the synthesis of zoanthamines that is inspired by a biosynthesis hypothesis. Our preliminary results suggest that it is possible to synthesize these complex natural products starting from an acyclic precursor by tuning a polycyclization reaction cascade. We plan to explore this reaction cascade for the synthesis of new polycyclic motifs and apply it to the synthesis of zoanthenol. In addition to the synthetic achievements, the results of our study are expected to have great impact in the areas of synthetic methodology, in particular to the reactivity of 2-aminodienes. We also propose to develop a unified approach toward the synthesis of selected cembranolides that is based upon the unexplored reactivity of 1-epoxyfurans. The synthesis of these compounds will pave the way for evaluation of their biological and pharmacological profile that will be pursued in collaboration with experts in the field.