METHODOLOGY FOR THE SYNTHESIS OF OXYGEN CONTAINING HETEROCYCLES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个项目的首要目标是开发新的方法，从简单和容易制备的原料中制备复杂的含氮或含氧多环分子。这项工作的重要性在于多环杂环在药物中普遍存在，是许多具有生物活性的天然产物的组成部分。不幸的是，这些有益的化合物往往很难制备。我的团队正在开发的方法将为生物医学研究人员提供新的工具，使他们能够轻松地从琐碎的起始材料中制备用于药物评估的结构复杂的分子。随着研究的进展和我对方法学范围和局限性的更好理解，我将致力于将这些方法应用于与医学相关的天然产品的合成。 这项工作是基于我发现了一种前所未有的反应(如下面的方案1所示)，该反应发生在肼和二亚甲基硫化物之间，该反应提供了一种高活性的1-氮杂-2-偶氮烯盐作为中间体。它与侧链烯烃发生后续反应，同时形成新的碳-碳键和新的碳氮键，最终生成重氮盐。这一点很重要，因为可用于制造碳-碳键的方法有限，而这个过程的产物是具有有趣的三维结构的多环产物。我们用这种方法制作的结构可能会为药物发现提供有用的药效载体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overarching objective of this project is to develop new ways to prepare complex nitrogen or oxygen-containing polycyclic molecules from simple and easy to prepare starting materials. The importance of this work lies in the fact that polycyclic heterocycles are ubiquitous in medicinal agents and are components of many biologically active natural products. Unfortunately, these beneficial compounds are often difficult to prepare. The methods my group is developing will provide biomedical researchers new tools to easily prepare structurally complex molecules for medicinal evaluation from trivial starting materials. As the research progresses and I gain a better understanding of the scope and limitations of the methodology, I will aim to apply these methods to the synthesis of medicinally relevant natural products. This work is based on my discovery of an unprecedented reaction (shown in Scheme 1 below) between a hydrazone and dimethylsulfide ditriflate which provides a highly reactive 1-aza-2-azoniallene salt as an intermediate. This undergoes a subsequent reaction with a pendent alkene to form a new carbon-carbon and a new carbon nitrogen bond at one time ultimately yielding a diazenium salt. This is important because there are limited methods available to make carbon-carbon bonds, and the product of this process is a polycyclic product that has interesting 3-dimentional structure. The structures that we make using this methodology may provide useful pharmacophores for drug discovery.