Synthesis of Bioactive Marine Natural Products

描述（由申请人提供）：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。拟议研究的目的是研究方法和制定合成策略，以允许有效和立体控制的化学合成来自两个生物活性天然产物家族的代表性成员：虫胺生物碱和樟脑内酯。目标天然产物具有不寻常的化学结构，强大的生物活性和尚未开发的生物作用模式，这证明了它们作为新的生物工具和药物开发的潜力。所提出的方法源于在环加成反应中未开发的电子丰富物质（如二烯和呋喃）的反应性，并强调了这些反应在构建高官能化杂环方面的潜力。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。该策略还旨在通过在一个步骤中合并多个碳-碳键形成事件，从相对非功能化的起始材料中创建结构复杂性。这些策略将为合成天然产物的简化类似物铺平道路，这些类似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作用模式。

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.