New methods to prepare 1,4-oxazin-2-ones and applications in the construction of polysubstituted pyridines

项目摘要 本提案描述了制备1，4-恶嗪酮的新方法的开发 前体，并寻求将这些中间体应用于高度取代的结构 通过合并的环加成/环逆转过程得到吡啶产物。恶嗪酮是 环加成/环还原反应中最活跃的前体的计算和实验 导致吡啶的序列，但仍未得到充分的研究和利用。新的合成方法 所提出的恶嗪酮类化合物的构建方法是直接的，使用普通的开始 材料，并有初步数据支持。恶唑烷酮类药物的计划应用 多取代吡啶的构建将增加我们对基本结构的理解。 这一杂环体系的反应性，并试图揭示一些潜在的 与用于合成吡啶的其他[4+2]/反[4+2]杂环相对的恶嗪酮。吡啶类化合物 是嵌入生物活性分子中最普遍的结构之一。因此， 构建吡啶基序的新方法(特别是那些不易获得的基序 通过其他方法)是值得的，并且对生物医学科学具有极其重要的意义。 除了基础研究外，应用还指向潜在的合成 该提案包括了与生物相关的结构。其中包括(1)统一的 麦角生物碱家族中独有的成员--木犀草酮A和B的合成策略 展示了吡啶和哌啶的结构以及(2)针对转化率的研究 B-氨基醇在含N-末端丝氨酸和苏氨酸残基的多肽中的作用 活性恶嗪酮中间体。我们建议通过计算来比较多肽-- 以这种方式制备的恶嗪酮类化合物与其他Diels-Alder反应底物相比，是一个前奏 到可能的下游生物结合应用。 William&Mary不提供化学博士学位(仅限理科/理科)；因此，我的 研究组由本科生(和一名硕士研究生)组成。我的 当前的研究计划为学习创造了严格的环境，并加强了教学 和培训一对一的研究体验。拟议的研究将继续进行 在这样的环境下，并设计在适当的水平上，让学生取得进步。 NIH的支持将使3-4名本科生和1名硕士的研究成为可能 该奖项每一年的候选人。

Project Summary This proposal describes the development of new methods for the preparation of 1,4-oxazinone precursors and seeks to apply these intermediates to the construction of highly substituted pyridine products through a merged cycloaddition/cycloreversion process. Oxazinones are computationally and experimentally the most reactive precursor in cycloaddition/cycloreversion sequences leading to pyridines, yet remain understudied and underutilized. The new synthesis methods proposed for construction of oxazinones are direct, employ common starting materials, and are supported by preliminary data. The planned applications of oxazinones for the construction of polysubstituted pyridines will increase our understanding of the fundamental reactivity of this heterocyclic ring system and seek to reveal some of the potential of oxazinones relative to other [4+2]/retro[4+2] heterocycles used in pyridine synthesis. 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 accessed through other methods) is merited and is acutely significant to the biomedical sciences. In addition to foundational research, applications directed toward the synthesis of potentially biologically relevant structures are included in the proposal. These include (1) a unified synthesis strategy toward xylanigripone A and B, unique members of the ergot alkaloid family that display pyridine and piperidine structures and (2) studies directed to the conversion of the b-amino alcohol function in peptides bearing N-terminal serine and threonine residues into reactive oxazinone intermediates. Computational efforts are proposed to compare peptide- derived oxazinones prepared in this manner to other Diels-Alder reactive substrates, a prelude to possible downstream bioconjugation applications. 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.