Effecting C-O activation of oxazolidinones by Ni to construct small, chiral heter

描述（由申请人提供）：鉴于其广泛的可用性，手性恶唑烷酮是潜在的有用的，但被忽视的催化底物。利用过渡金属催化剂，从恶唑烷酮中挤出CO2可以得到反应性氮杂-金属环丁烷中间体，该中间体可用于各种复杂的含氮产品。ni催化手性恶唑烷酮转化为小手性杂环化合物，如叠氮嘧啶和内酰胺。在ni介导的烷基C-O插入手性恶唑烷酮后，脱羧作用将得到氮杂金属环丁烷中间体。还原消除得到手性叠氮醚。或者，在一氧化碳气氛下，可以构建高取代的手性¿-内酰胺。许多含有手性叠氮或内酰胺功能的天然产物具有重要的医学特性，如抗癌和抗生素活性；然而，由于这些手性杂环化合物合成方法的缺乏，给它们的合成带来了巨大的挑战。本提案中概述的镍催化方法将为从现成的手性前体中获得这些药效团提供一种方便、简单和不同的方法。重要的是，这种方法可以组合使用，以建立潜在的生物活性分子文库。反应筛选将在一个简单的，未取代的恶唑烷酮模型底物上进行，以优化反应条件，包括配体和溶剂。高取代的底物将在这个转化中被评估。机制和光谱研究，包括自由基陷阱实验，建议确定Ni0/NiII或NiI/NiIII循环是否起作用，以及是否通过自由基中间体发生有害的立体化学信息损失。此外，假设的中间体将被合成并经受反应条件，以确定它们是否位于催化循环。通过深入了解所提出的转换的机制，可以对进一步的优化进行合理化，并使该方法具有通用性。

DESCRIPTION (provided by applicant): Given their wide availability, chiral oxazolidinones are potentially useful but ignored substrates for catalysis. Using transition metal catalysts, CO2 extrusion from oxazolidinones could be envisioned to afford reactive aza-metallacyclobutane intermediates that can be taken to a variety of complex nitrogenous products. The Ni-catalyzed transformation of chiral oxazolidinones to small chiral heterocycles, such as aziridines and ¿-lactams, will be developed. Following Ni-mediated alkyl C-O insertion into a chiral oxazolidinone, decarboxylation will afford the aza-metallacyclobutane intermediate. Reductive elimination will afford chiral aziridines. Alternatively, under a carbon monoxide atmosphere, highly substituted chiral ¿-lactams can be constructed. Many natural products containing chiral aziridine or ¿-lactam functionality exhibit medicinally important properties, such as anticancer and antibiotic activity; however, due to the scarcity of methods toward the synthesis of these chiral heterocycles, they present formidable synthetic challenges. The Ni-catalyzed method outlined in this proposal would offer a convenient, facile, and divergent approach to these pharmacophores from readily available chiral precursors. Importantly, this method can be used combinatorially to construct libraries of potentially bioactive molecules. Reaction screening will be carried out on a simple, unsubstituted oxazolidinone model substrate to optimize reaction conditions, including ligands and solvent. Substrates of higher-substitution will then be evaluated in this transformation. Mechanistic and spectroscopic studies, including radical trap experiments, are proposed to determine whether a Ni0/NiII or NiI/NiIII cycle operates, and whether deleterious loss of stereochemical information occurs via a radical intermediate. In addition, hypothesized intermediates will be synthesized and subjected to reaction conditions to determine whether or not they lie along the catalytic cycle. By gaining insight into the mechanism of the proposed transformation, further optimization can be rationalized, and the method made general. PUBLIC HEALTH RELEVANCE: Synthetically-challenging nitrogen-containing rings are found in countless medicinally-active molecules. In this proposal, a novel nickel-catalyzed reaction will be developed to allow the fast, convenient construction of these functionalities from readily available starting material. This approach uses cheap, abundant catalysts and precursor, and may potentially be amenable to the large-scale production of pharmaceuticals in industry.