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

项目摘要 该提案描述了制备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构建高度取代的 吡啶产物通过合并的环加成/环逆转过程。恶嗪酮类是 在计算和实验上，环加成/环逆转中最具反应性的前体 导致吡啶的序列，但仍然研究不足和利用不足。合成新 所提出的用于构建恶嗪酮的方法是直接的，采用共同的起始原料， 材料，并得到初步数据的支持。恶嗪酮类药物在 多取代吡啶的构建将增加我们对基础的理解， 这种杂环系统的反应性，并试图揭示一些潜在的 恶嗪酮相对于吡啶合成中使用的其它[4+2]/逆[4+2]杂环。吡啶 是嵌入生物活性分子中最普遍的结构之一。因此，在本发明中， 构建吡啶基序的新方法（特别是那些不容易获得的 通过其他方法）是值得的，对生物医学科学具有重大意义。 除了基础研究之外，应用程序还指向潜在的合成 生物相关结构包含在提案中。其中包括：（1）统一 麦角生物碱家族中独特成员木尼曲酮A和B的合成策略 显示吡啶和哌啶结构的化合物，和（2）针对 b-氨基醇在含有N-末端丝氨酸和苏氨酸残基的肽中的功能， 反应性恶嗪酮中间体。计算的努力，提出了比较肽- 衍生的恶嗪酮以这种方式制备到其他Diels-Alder反应底物， 可能的下游生物缀合应用。 William &玛丽不提供化学博士学位（仅限BS/MS）;因此，我的 研究小组由本科研究人员（和一名MS候选人）组成。我 目前的研究计划创造了一个严格的学习环境，并加强教学 和一对一研究经验的培训。拟议的研究将继续进行。 在这种氛围下，并在适当的水平，为学生取得进展。 美国国立卫生研究院的支持将使3-4名本科生和一名硕士生能够进行研究 候选人每年获奖。

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.