Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products

描述（由申请人提供）：拟议研究的目标是开发新的化学方法，以合成生物活性类黄酮和黄酮衍生的天然产物，从而产生新的抗癌和抗感染药物。将开发的化学方法包括新的[4+2]脱氢环加成用于合成戊烯基类黄酮和相关的Diels-Alder天然产物，使用手性硼配合物对2'-羟基查尔酮和二烯的对映选择性[4+2]环加成，金属催化，3-羟基黄酮的不对称重排，乙烯基将硅氧呋喃加成到5-羟色酮合成四羟基蒽酮。以及间醌类中间体（m-QM）的光环加成以构建双环[3.2.2]体系。Porco教授及其同事将把这些新方法应用于化学合成具有生物活性的天然产物靶点，包括kuwanons G和H、sangennol F、sangennol C、sorocenol B、secalonic acid A和D、microsphaerin B和acremoxanthone A。合作将在生物测定中评估化合物，包括它们作为人胃泌素释放肽受体（GRP-R）拮抗剂的功效，以及它们作为E3泛素连接酶gp78抑制剂的功效。以及疟疾寄生虫恶性疟原虫的地理分离株。拟议项目的目的是：实现了GRP-R拮抗剂kuwanons G和H的全合成以及sorcenol B， sanggenol F，完成四羟基蒽酮双烯内酯A和B的不对称合成，完成二聚体天然产物二氯酸A和D和微球素B的全合成，完成抗感染药物阿克莫胺素A和阿克莫山酮A的合成。该项目将为Porco教授及其合作者提供新的研究方向，包括纳米颗粒在有机反应中的应用，不对称催化，新的环加成策略，目前的拨款计划是不可能的。

DESCRIPTION (provided by applicant): The goal of the proposed research is develop new chemical methodologies to enable the synthesis of bioactive flavonoid and xanthone-derived natural products that could lead to novel, anti-cancer and anti-infective agents. Chemical methodologies that will be developed include novel [4+2] dehydrogenative cycloadditions for the synthesis of prenylflavonoid and related Diels-Alder natural products, enantioselective [4+2] cycloadditions of 2'-hydroxychalcones and dienes using chiral boron complexes, metal-catalyzed, asymmetric rearrangement of 3-alloxyflavones, vinylogous addition of siloxyfurans to 5-hydroxychromones to synthesize tetrahydroxanthones, and photocycloaddition of m-quinone methide (m-QM) intermediates to construct bicyclo[3.2.2] ring systems. Professor Porco and colleagues will apply these new methodologies to the chemical synthesis of bioactive natural product targets including kuwanons G and H, sangennol F, sangennon C, sorocenol B, secalonic acids A and D, microsphaerin B, and acremoxanthone A. Collaborations are in place to evaluate compounds in biological assays, including their efficacy as human gastrin-releasing peptide receptor (GRP-R) antagonists, as inhibitors of the E3 ubiquitin ligase gp78, and against geographic isolates of the malarial parasite P. falciparum. The aims of the proposed project are to: Achieve total syntheses of the GRP-R antagonists kuwanons G and H and the asymmetric syntheses of sorocenol B, sanggenol F, and sanggenons A and C. Develop asymmetric syntheses of the tetrahydroxanthones blennolides A and B and accomplish total syntheses of the dimeric natural products secalonic acids A and D and microsphaerin B. Achieve syntheses of the anti-infective agents acremodinin A and acremoxanthone A. The proposed project will enable new research directions for Professor Porco and his collaborators involving the use of nanoparticles in organic reactions, asymmetric catalysis, and novel cycloaddition strategies that are not possible with current grant programs.