Synthesis of Heterocyclic Natural Products

本研究计划的主要目标是继续开发新的合成方法和新策略，以合成生物活性杂环化合物和生物碱天然产物。在宾夕法尼亚州立大学化学系化学合成项目的支持下，Weinreb教授将进行一些结构独特和复杂的含氮天然产物的靶向全合成。此外，将探索新的合成方法，包括分子间和分子内共轭加成亚硝基烯烃，包括描述该过程的立体化学特征。还将研究影响碳和异亲核试剂对亚硝基盐的催化对映选择性共轭加成的方法。这项工作旨在通过“Umpolung”过程为醛和酮的α -烷基化提供广泛有用的新方法。碳亲核试剂与亚硝基烯烃的分子间共轭加成将构成一些缬沙胺类吲哚生物碱的全合成的关键步骤。研究将在独特的吲哚生物碱放线树酸（一种有效的羧肽酶u抑制剂）的对映选择性全合成中使用分子内添加亚硝基烯烃，重点将放在生产和精炼方法上，该方法对参与化学药物合成的有机和药物化学家具有潜在的广泛适用性和实用价值。药物研究和药物开发每年对美国经济产生数十亿美元的影响，其成功在很大程度上依赖于学术实验室提供的合成方法。PI将继续通过在美国和国外的制药公司和会议上举办研讨会来传播在这笔资助下进行的研究成果。此外，这项资助将为硕士和博士学生提供复杂合成有机和杂环化学的实践培训。在NSF资助下接受培训的年轻科学家最终将在化学工业中担任研究职位，通常是在制药或其他与健康相关的公司，从而具有重要的经济影响，并为美国和世界人口提供重大的健康益处。

The primary objective of this research program is to continue to develop a combination of novel synthetic methods and new strategies for the synthesis of bioactive heterocycles and alkaloid natural products. Under the support of the Chemical Synthesis Program of the Chemistry Division, Prof. Weinreb at Pennsylvania State University will conduct target oriented total syntheses of a number of structurally unique and complex nitrogen-containing natural products. Moreover, new synthetic methodology involving inter- and intramolecular conjugate additions to nitrosoalkenes will be explored including delineating stereochemical features of the process. Methodology will also be investigated for effecting catalytic enantioselective conjugate additions of carbon and heteronucleophiles to nitrososalkenes. This work aims to provide widely useful new methodology for alpha-alkylation of aldehydes and ketones via an "Umpolung" process. Intermolecular versions of conjugate additions of carbon nucleophiles to nitrosoalkenes will constitute key steps in total syntheses of some of the vallesamine class of indole alkaloids. Studies will be conducted on the use of an intramolecular Michael addition of a nitrosoalkene in an enantioselective total synthesis of the unique indole alkaloid actinophyllic acid, a potent inhibitor of the enzyme carboxypeptidase U. Emphasis will be placed upon producing and refining methodology having potentially broad applicability and practical value to organic and medicinal chemists involved in synthesis of chemotherapeutic agents. Pharmaceutical research and drug development has a multibillion dollar annual impact on the US economy, and its success is heavily dependent on synthetic methodology provided by academic laboratories. The PI will continue to disseminate the results of the research conducted under this grant by presenting seminars at pharmaceutical companies and conferences in both the US and abroad. In addition, this grant will provide practical training for M.S. and Ph.D. students in sophisticated synthetic organic and heterocyclic chemistry. The young scientists to be trained under this NSF grant will eventually take research positions in the chemical industry, most often in pharmaceutical or other health-related corporations, thereby having an important economic impact as well as providing significant health benefits to the populations of the US and the world.