Synthesis of Heterocyclic Natural Products

该研究计划的主要目标是继续开发新的合成方法和新的策略，用于合成生物活性杂环化合物和生物碱天然产物。在化学部化学合成项目的支持下，宾夕法尼亚州立大学的Weinreb教授将对一些结构独特和复杂的含氮天然产物进行定向全合成。 此外，新的合成方法，包括分子间和分子内共轭加成到亚硝基烯烃将被探索，包括描绘立体化学特征的过程。 方法学也将被研究用于影响碳和heteronucleophiles到亚硝基烯烃的催化对映选择性共轭加成。 本工作的目的是提供广泛有用的新方法，通过“Umpolung”过程的醛和酮的α-烷基化。 碳原子亲核试剂与亚硝基烯烃的分子间共轭加成反应是吲哚生物碱类化合物全合成的关键步骤。 研究将进行对使用的亚硝基烯烃的分子内迈克尔加成的独特的吲哚生物碱放线菌酸，一种有效的抑制剂的酶羧肽酶U的对映选择性的全合成。重点将放在生产和精炼的方法，具有潜在的广泛适用性和实用价值的有机和药物化学家参与合成的化疗药物。 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取决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该资助下进行的研究结果。 此外，这笔赠款将为M.S.提供实际培训。和博士高级合成有机和杂环化学专业的学生。 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，从而产生重要的经济影响，并为美国和世界人口提供显着的健康益处。

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.