Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products

描述(申请人提供)：拟议研究的目标是开发新的化学方法，以合成具有生物活性的类黄酮类和黄原酮衍生的天然产物，从而产生新型的抗癌和抗感染药物。将开发的化学方法包括用于合成戊基黄酮类化合物和相关Diels-Alder天然产物的新的[4+2]脱氢环加成反应，利用手性硼配合物进行2‘-羟基查尔酮和二烯的不对称[4+2]环加成反应，金属催化的3-异氧基黄酮类化合物的不对称重排反应，硅氧呋喃与5-羟基色酮的乙烯基加成反应合成四羟色酮，以及中间体m-QM的光环加成反应以构建双环[3.2.2]环体系。Porco教授和他的同事将把这些新方法应用于生物活性天然产物靶标的化学合成，包括kuwanons G和H、sangennol F、sangennon C、sorocenol B、secalonic酸A和D、microsphaerin B和acemoxanthone A。目前正在开展合作，以评估化合物在生物检测中的有效性，包括它们作为人类胃泌素释放肽受体(GRP-R)拮抗剂的有效性，作为E3泛素连接酶gp78的抑制剂，以及对抗恶性疟原虫地理分离株的有效性。该项目的目标是：实现GRP-R拮抗剂kuwanons G和H的全合成以及山梨烯醇B、sanggenol F、sanggenone A和sanggenons A和C的不对称合成。开发四氢黄原酮blennolide A和B的不对称合成，并完成二聚体天然产物扇形酸A和D以及微球蛋白B的全合成。实现抗感染药物Acemodinin A和acemoxanthone A的合成。该项目将为Porco教授和他的合作者提供新的研究方向，包括在有机反应中使用纳米粒子、不对称催化和新的环加成策略，这些都是目前的拨款计划无法实现的。

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.