Synthesis of Chiral Organofluorines via Catalytic Asymmetric C-C Bond Formation w

通过催化不对称 C-C 键形成合成手性有机氟化合物

• 批准号: 8495556
• 负责人: Christian Wolf
• 金额: $ 33.73万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495556
• 关键词: Alcohols; Aldehydes; Alkynes; Attention; Biological Availability; Carbon; Catalysis; Chemicals; Chemistry; Copper; Data; Development; Development Plans; Exhibits; Family; Fluorine; Future; Future Generations; Goals; Hydration status; Imines; In Situ; Investigation; Ketones; Laboratories; Lead; Ligands; Metabolic; Methodology; Methods; Nitrogen; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Production; Property; Protocols documentation; Reaction; Reagent; Research; Resistance; Role; Route; Scientist; Structure; Students; System; Time; Training; Work; Zinc; analog; catalyst; chemical synthesis; design; dipole moment; drug discovery; experience; graduate student; high school; improved; insight; lipophilicity; method development; public health relevance; screening; stem; undergraduate student

DESCRIPTION (provided by applicant): Synthesis of Chiral Organofluorines via Catalytic Asymmetric C-C Bond Formation with Fluoroenolates, Alkynes and Ynamides The ever-increasing demand for chiral compounds and the rapid rise of fluoroorganic pharmaceuticals call for the development of new synthetic methods that provide practical access to a wide variety of fluorinated chiral building blocks. The introduction of new strategies that allow control of the unique stability and reactivity patterns of fluorinated nucleophiles and electrophiles offers invaluable opportunities to streamline chemical syntheses of current and future fluoroorganic drugs. We will develop a method for asymmetric catalysis with fluorinated nucleophiles generated in-situ and under mild conditions from readily available trifluoroacetyl derived precursors. The feasibility and practicality of this approach are demonstrated with ample preliminary results obtained by a copper-bisoxazoline catalyzed reaction using aliphatic and aromatic aldehydes. Continued ligand development and the planned mechanistic investigations will further improve the enantioselectivity of this reaction and extend this methodology to a range of currently elusive fluorinated nucleophiles. Using bisoxazolidine ligands recently developed in our laboratories we have found an entry towards a practical catalytic asymmetric alkynylation of trifluoromethyl ketones. Further ligand and method development will go hand-in-hand with mechanistic studies and screening of promising reaction parameters. We have made substantial progress with this important reaction and this experience provides a unique opportunity to introduce ynamides and ynesulfonamides to catalytic C-C bond formation. Our preliminary investigations provide promising proof-of-concept results obtained with a tosylated ynamide and show that this research direction will provide unprecedented access to a diverse range of new versatile chiral building blocks. The planned catalyst and reaction developments will be guided by detailed mechanistic studies and lead to in-depth investigations of the scope and applications of the proposed methods. Our multifaceted efforts will introduce in-situ generated fluoroenolates to asymmetric catalysis (Aim 1), a practical method for the alkynylation of trifluoromethyl ketones (Aim 2), and catalytic enantioselective addition reactions with ynamides and derivatives thereof (Aim 3). Additional emphasis will be given to the synthetic use and reactions of the new building blocks that will be generated by the wide range of electrophiles and nucleophilic species made available during this work.

描述（由申请人提供）：通过催化不对称的C-C键与荧光素，炔烃和Ynamides合成手性有机氟，对手性化合物的需求不断增长，并迅速增加了氟机药物的迅速升高到各种氟化的手性构件。引入了新策略，以控制氟接亲和电力的独特稳定性和反应性模式，这为简化当前和未来氟有机药物的化学合成提供了宝贵的机会。 我们将开发一种方法，用于与易于使用的三氟乙酰基衍生前体的氟接亲核者的不对称催化方法。通过使用脂族和芳族醛的铜 - 三唑啉催化反应获得的充足的初步结果证明了这种方法的可行性和实用性。持续的配体发育和计划的机械研究将进一步改善该反应的对映选择性，并将该方法扩展到一系列目前难以置信的氟接核菌。 使用最近在我们的实验室中开发的双沙戈唑胺配体，我们发现了三氟甲基酮的实用催化不对称酸性化。进一步的配体和方法开发将与机械研究和筛查有希望的反应参数并驾齐驱。我们对这一重要反应取得了长足的进步，这种经验为将YNAGIDES和YNESULFONAMIDES引入催化C-C键形成提供了独特的机会。我们的初步调查提供了通过tosylated Ynamide获得的有希望的概念验证结果，并表明该研究方向将提供前所未有的访问，以访问各种新的多功能性手性构建块。 计划的催化剂和反应发展将以详细的机械研究为指导，并导致对所提出方法的范围和应用进行深入研究。我们的多方面努力将引入原位产生的氟烯酸酯进行非对称催化（AIM 1），这是三氟甲基酮的藻类化的实用方法（AIM 2），以及与Ynamide和衍生物的催化对映射的添加反应（AIM 3）。这项工作中提供的多种电力和亲核种类将产生的新构建块的合成使用和反应将给予其他重点。