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

Ni 影响恶唑烷酮的 C-O 活化以构建小的手性杂环

• 批准号: 8588792
• 负责人: Matthew Steven Winston
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-11-16 至 2015-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588792
• 关键词: Alkenes; Amino Alcohols; Aziridines; Biological Factors; Carbon Dioxide; Carbon Monoxide; Catalysis; Complex; Decarboxylation; Development; Electron Spin Resonance Spectroscopy; Evaluation; Exhibits; Industry; Lactams; Libraries; Ligands; Magnetic Resonance; Mediating; Methods; Modeling; Nickel; Nitrogen; Nuclear; Oxazolidinones; Pathway interactions; Pharmacologic Substance; Phase; Property; Pyrrolidines; Reaction; Solvents; Therapeutic; Transition Elements; Work; antineoplastic antibiotics; carbene; catalyst; combinatorial; discount; drug discovery; insight; large scale production; molecular recognition; novel; pharmacophore; planetary Atmosphere; public health relevance; pyrrolidine; pyrroline; research study; screening; synthetic drug

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.

描述(申请人提供)：鉴于手性恶唑烷酮的广泛可获得性，手性恶唑烷酮类化合物是潜在有用的但被忽视的催化底物。利用过渡金属催化剂，从恶唑烷酮中挤出二氧化碳可以得到活性氮杂金属环丁烷中间体，这些中间体可以被带到各种复杂的含氮产品中。在镍的催化下，手性恶唑烷酮类化合物将转化为小的手性杂环，如氮杂环类和内酰胺类。在镍介导的烷基C-O插入手性恶唑烷酮后，脱羧基将得到氮杂金属环丁烷中间体。还原消除将得到手性氮杂环丙烷。或者，在一氧化碳气氛下，可以构建高度取代的手性内酰胺类化合物。许多含有手性氮杂环或β-内酰胺官能团的天然产物具有重要的医药性质，如抗癌和抗菌活性；然而，由于缺乏合成这些手性杂环的方法，它们提出了巨大的合成挑战。这项建议中概述的镍催化方法将提供一种从现成的手性前体中提取这些药效团的方便、简便和不同的方法。重要的是，这种方法可以组合使用来构建潜在生物活性分子的文库。反应筛选将在简单、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。然后在这种转化中对高取代度的底物进行评估。建议进行机理和光谱研究，包括自由基陷阱实验，以确定Ni0/NiII或NiII/NiIII循环是否运行，以及立体化学信息的有害损失是否通过自由基中间体发生。此外，假想的中间体将被合成，并受到反应条件的影响，以确定它们是否位于催化循环中。通过深入了解所提出的转换的机制，可以使进一步的优化合理化，并使方法变得通用。