Asymmetric Reactions of Oxaziridines

描述(申请人提供)：大多数小的，生物活性的有机化合物通过一系列含氧和含氮的“官能团”与特定的酶发生特殊的相互作用。这种相互作用的特异性和强度取决于分子的整体形状和它在空间中的官能团的排列(即它的“立体化学”)。因此，能够抗击疾病或以其他方式调节生物系统行为的新化合物的发现，依赖于合成密集官能化、定义明确的有机分子的方法的存在。在这方面，合成有机化学的一个特别重要的目标是发现新的转化方法，将简单的、广泛可用的碳氢化合物起始材料转化为复杂的、官能化的分子，并对其立体化学进行高度控制。我们正在研究被称为“恶杂环丙烷”的富含氧和氮的小分子化合物在新的有机反应中的应用。我们假设(1)过渡金属催化剂将提高恶氮杂环类化合物的反应活性，(2)使用不同的催化剂将观察到根本不同的反应，以及(3)这些催化剂将具有控制所产生的增值产品的立体化学的能力。这项拟议的研究将在两个具体目标的背景下检验这些假设。首先，我们将开发铜催化的恶氮杂环丙烷的反应，以构建立体化学定义良好的1，2-氨基醇结构(“氨羟化反应”)。其次，我们将开发钛催化的恶氮杂环丙烷反应，用于构建具有类似高立体化学保真度的1，3-氨基醇结构(“硝酮环加成反应”)。我们项目目标的成功实现将对合成有机化学领域做出重大贡献，并为发现新药、新生物探针和新材料提供一套强有力的工具。与公共卫生相关：大多数药物是小的有机分子，通过使用一系列含氧和含氮的“功能基团”与病原体或人体细胞中的酶相互作用来对抗疾病。一种药物识别数千种靶酶中的一种并控制疾病进展的能力，关键取决于分子的整体形状及其功能基团在空间中的排列。我们正在开发新的方法，用于快速、选择性地构建定义明确的富氮富氧分子，这将使发现和制造下一代有效的抗病药物成为可能。

DESCRIPTION (provided by applicant): Most small, bioactive organic compounds interact specifically with a particular enzyme through a series of oxygen- and nitrogen-containing "functional groups." The specificity and strength of this interaction depends on the overall shape of the molecule and on the arrangement of its functional groups in space (i.e., its "stereochemistry"). The discovery of new compounds with the ability to fight disease or otherwise modulate the behavior of a biological system thus relies on the existence of methods for the synthesis of densely functionalized, well-defined organic molecules. In this regard, a particularly important goal of synthetic organic chemistry is the discovery of new transformations that convert simple, widely available hydrocarbon starting materials into complex, functionalized molecules with high levels of control over their stereochemistry. We are investigating the utility of small, oxygen- and nitrogen-rich compounds called "oxaziridines" in new organic reactions. We hypothesize that (1) transition metal catalysts will increase the reactivity of oxaziridines, (2) fundamentally different reactions will be observed using different catalysts, and (3) these catalysts will have the ability to control the stereochemistry of the resulting value-added products. The proposed research will test these hypotheses in the context of two Specific Aims. First, we will develop copper-catalyzed reactions of oxaziridines for the construction of stereochemically well-defined 1,2- aminoalcohol structures ("aminohydroxylation reactions"). Second, we will develop titanium-catalyzed reactions of oxaziridines for the construction of 1,3-aminoalcohol-containing structures with similarly high levels of stereochemical fidelity ("nitrone cycloadditions"). Successful realization of our project goals will constitute a significant contribution to the field of synthetic organic chemistry and provide a set of powerful tools for the discovery of new drugs, new biological probes, and new materials. PUBLIC HEALTH RELEVANCE: Most drugs are small organic molecules that fight disease by using a series of oxygen- and nitrogen- containing "functional groups" to interact with an enzyme in a pathogen or in a human cell. The ability of a drug to specifically recognize one target enzyme out of thousands and control the progress of a disease depends critically on the overall shape of the molecule and the arrangement of its functional groups in space. We are developing new methods for the rapid, shape-selective construction of well-defined nitrogen- and oxygen-rich molecules, which will enable the discovery and manufacture of the next generation of potent disease-fighting drugs.