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

1,4-恶嗪-2-酮的制备新方法及其在多取代吡啶构建中的应用

基本信息

批准号：
10794499
负责人：
Jonathan R Scheerer
金额：
$ 35.04万
依托单位：
COLLEGE OF WILLIAM AND MARY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2026-08-31
项目状态：
未结题

项目摘要

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.

项目摘要该提案描述了制备1,4-恶狂的新方法的发展前体并试图将这些中间体应用于高度取代的构建通过合并的环加成/环形交换过程的吡啶产物。恶酮是在计算和实验上是环加成/环列中最具反应性的前体导致吡啶的序列，但仍被研究和未充分利用。新的综合提出的用于构建奥恶酮的方法是直接的，采用了共同的开始材料，并由初步数据支持。奥恶酮的计划应用多基型吡啶的构建将增加我们对基本的理解该异环环系的反应性，并试图揭示奥恶酮相对于其他[4+2]/retro [4+2]吡啶合成中的杂环。吡啶是在生物活性分子中嵌入的最普遍的结构之一。因此，吡啶主题构建的新方法（尤其是那些不容易访问的方法通过其他方法）是值得的，并且对生物医学科学非常重要。除了基础研究外，针对综合的应用该提案中包括了与生物学相关的结构。这些包括（1）统一对木裂A和B的合成策略，麦角生物碱家族的独特成员这显示了吡啶和哌啶结构，以及（2）针对转化的研究 B-氨基酒精功能在带有N末端丝氨酸和苏氨酸残基的肽中反应性恶酮中间体。提出了计算工作以比较肽 - 以这种方式制备的阿恶酮，以其他Diels-alder-alder反应性底物为前奏可能的下游生物共轭应用。 William＆Mary不提供化学博士学位（仅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。我的当前的研究计划为学习和执行教学创造了严格的环境和一对一的研究经验中的培训。拟议的研究将继续在这种气候中，并以适当的水平设计为学生取得进步。 NIH的支持将使3-4名本科生的研究和一名大师的研究奖励的每一年候选人。