Extending the synthetic utility of 1,4-oxazin-2-ones and 2,5-diketopiperazines

项目摘要 该提案描述了制备1，4-恶嗪-2-酮的新方法的开发。 一种前体，并试图将这些中间体应用于构建高度取代的 吡啶产物通过合并的环加成/环逆转过程。调查 恶嗪酮类将增加我们对这种未充分利用的基本反应性的理解， 杂环系统。此外，吡啶是最常见的结构之一， 嵌入在生物活性分子中因此，新方法的建设， 吡啶基序（特别是那些不容易通过缩合方法制备的基序）是值得的 对生物医学科学有着重大意义。在可能的情况下，多米诺骨牌反应 所包括的工艺在时间方面是经济的，是资源和成本有效的， 并用于快速产生分子复杂性。拟议的基础实验 探索恶嗪酮类相对于其他[4+2]/反式[4+2]的一些潜在上级特征 用于吡啶合成的杂环。针对合成的应用 生物学相关的吡啶被列入提案，以展示 恶嗪酮支架：（1）影响神经突的化合物的一步多组分合成 分化和（2）一个统一的合成策略对愈创木吡啶生物碱（包括 抗癌化合物cananodine和rupestines）。 该提案的第二个目标是促进有用的合成转化， 由亚烷基2，5-二酮哌嗪制得。特别是，这项建议旨在建立可靠的 合成1，2-羰基产物和吡咯-和二氢吡咯-稠合物的方法 二酮哌嗪结构。这些产物作为生物活性化合物或可 成为更复杂结构的重要前体。 威廉和玛丽学院不提供化学博士学位（仅限BS/MS）; 因此，我的研究小组是由本科研究人员（和一个MS 候选人）。我目前的研究计划创造了一个严格的学习环境， 在一对一的研究经验中加强教学和培训。拟议研究 将继续在这种气候下，并在适当的水平，为学生设计， 中求进工作总NIH的支持将使3-4名本科生和1名 每年的硕士候选人奖。

Project Summary This proposal describes the development of new methods for the preparation of 1,4-oxazin-2- one precursors and seeks to apply these intermediates to the construction of highly substituted pyridine products through a merged cycloaddition/cycloreversion process. The investigation of oxazinones will increase our understanding of the fundamental reactivity of this underutilized heterocyclic ring system. Additionally, pyridines are one of the most prevalent structures imbedded within biologically active molecules. Thus, new methods for the construction of pyridine motifs (especially those not easily prepared through condensation methods) is merited and is acutely significant to the biomedical sciences. Where possible, domino reaction processes are included that are economical with regard to time, are resource and cost efficient, and serve to rapidly generate molecular complexity. The proposed foundational experiments probe some of the potentially superior features of oxazinones relative to other [4+2]/retro[4+2] heterocycles used in pyridine synthesis. Applications directed toward the synthesis of biologically relevant pyridines are included in the proposal to showcase enabling features of the oxazinone scaffold: (1) a one-step multi component synthesis of a compound effecting neurite differentiation and (2) a unified synthesis strategy toward the guaipyridine alkaloids (including the anticancer compound cananodine and rupestines). A second objective of the proposal seeks to advance useful synthetic transformations starting from alkylidene 2,5-diketopiperazines. In particular, this proposal seeks to establish reliable methods for the synthesis of 1,2-carbonyl products and pyrrole- and dihydropyrrole-fused diketopiperazine structures. These products are valuable both as bioactive compounds or can be important precursors for the elaboration to more complex structures. The College of William & Mary does not offer a doctoral degree in chemistry (BS/MS only); accordingly, my research group is composed of undergraduate researchers (and one MS candidate). My current research program creates a rigorous environment for learning and enforces teaching and training in the one-on-one research experience. The proposed research would continue within this climate and is designed at an appropriate level for students to make progress. Support from the NIH would enable the research of 3-4 undergraduates and one Master's candidate for each year of the award.