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

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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.