The Total Synthesis of Bioactive Molecules and the Development of the Methodological Underpinning

这项建议描述了新的和有用的化学转化的发展，以及这些转化的应用，以应对通过化学合成制备具有生物或医学意义的目标分子的挑战。我们的研究小组的长期目标是：1)揭示现有官能团的未知反应性，目的是开发新的、有用的合成方法；2)发展供体-受体环丙烷化学；3)探索新的锥烯化学；4)开发制备和功能化杂环基元的新方法；5)将上述合成方法应用于具有重要生物活性的天然和非天然目标分子的简便合成。 在这份提案中，我们将描述我们解决上述长期目标的计划以及详细描述我们计划解决以下更集中的短期目标：1)开发供体受体环丙烷的新反应，包括与氮杂环丙烷、氮杂环丙烷和二氮杂环丙烷的反应，2)探索非传统偶极如酮胺在有用的合成反应中的应用，3)最近开发的吡咯合成的研究，4)串联Conia-Ene/Diels-Alder反应的开发及其在合成中的应用，5)将Diels-Alder/Plieninger吲哚化法应用于天然产物的合成；6)将上述方法应用于杂环天然产物的合成。 上述化学预计将大大增加合成化学家可用的化学方法论的武器库。这些使能技术将允许合成化学家通过化学合成更多地获得复杂分子。我们建议中描述的研究将有助于培训熟练合成复杂分子的化学家。这将为他们在学术和工业领域的职业生涯做好准备，特别是作为药物化学家。

This proposal describes the development of new and useful chemical transformations and the application of those transformations to the challenge of preparing, by chemical synthesis, target molecules of biological or medicinal significance. Our research group has the long term goals of: 1) Uncovering previously unknown reactivity of existing functional groups with the aim of developing new, useful synthetic methods, 2) developing the chemistry of donor-acceptor cyclopropanes, 3) exploring new Conia-ene chemistry, 4) developing new ways to prepare and functionalize heterocyclic motifs, and 5) applying the synthetic methods above to the expedient synthesis of natural and unnatural target molecules possessing important biological activity. In this proposal we will describe our plans to address the above long term objectives as well as describing, in detail, our plans to address the following more focused shorter term objectives: 1) The development of new reactions of donor acceptor cyclopropanes including the reactions with azirines, aziridines, and diazines, 2) the exploration of unconventional dipoles such as keteneamines in useful synthetic reactions, 3) the investigation of a very recently developed pyrrole synthesis, 4) the development of a tandem Conia-ene/Diels-Alder reaction and its application in synthesis, 5) the application our Diels-Alder/ Plieninger indolization strategy to the synthesis of the natural product and 6) we will apply the methods above to the synthesis of heterocylic natural products such as tronocarpine, callosine, halichlorine and actinophyllic acid The above chemistry is anticipated to add significantly to the arsenal of chemical methodology available to the synthetic chemist. These enabling technologies will allow the synthetic chemist greater access to complex molecules by chemical synthesis. The research described in our proposal will aid in the training of chemists skilled in the synthesis of complex molecules. This will prepare them for both academic and industrial careers, particularly as pharmaceutical chemists.