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: 8398979
• 负责人: Matthew Steven Winston
• 金额: $ 4.71万
• 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/8398979
• 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; Screening procedure; Solvents; Therapeutic; Transition Elements; Work; antineoplastic antibiotics; carbene; catalyst; combinatorial; discount; drug discovery; insight; large scale production; molecular recognition; novel; pharmacophore; planetary Atmosphere; pyrrolidine; pyrroline; research study

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.

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有用但被忽视的催化底物。使用过渡金属催化剂，可以设想从恶唑烷酮中挤出CO2以提供反应性氮杂-金属环丁烷中间体，其可以用于各种复杂的含氮产物。镍催化的手性恶唑烷酮转化为小的手性杂环，如氮杂环丙烷和<$-内酰胺，将被开发。在Ni介导的烷基C-O插入手性恶唑烷酮后，脱羧将得到氮杂-金属环丁烷中间体。还原消除将提供手性氮丙啶。或者，在一氧化碳气氛下，可以构建高度取代的手性内酰胺。许多含有手性氮丙啶或<$-内酰胺官能团的天然产物表现出重要的药用性质，如抗癌和抗生素活性;然而，由于缺乏合成这些手性杂环的方法，它们提出了艰巨的合成挑战。镍催化的方法概述了这一建议将提供一个方便的，容易的，和发散的方法，这些药效团从现成的手性前体。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。然后在该转化中评估较高取代度的底物。机制和光谱研究，包括自由基陷阱实验，提出了确定是否一个镍0/镍II或镍I/镍III循环操作，以及是否有害的立体化学信息的损失发生通过自由基中间体。此外，将合成假设的中间体并使其经受反应条件以确定它们是否沿着催化循环。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，并使该方法具有通用性。 公共卫生相关性：在无数的医学活性分子中发现了具有合成挑战性的含氮环。在这个提议中，一种新的镍催化反应将 可以开发出允许从容易获得的起始材料快速、方便地构建这些官能团的方法。这种方法使用廉价、丰富的催化剂和前体，并且可能适合于工业上大规模生产药物。