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）：通过与氟烯醇盐、炔烃和酰胺进行催化不对称 C-C 键形成来合成手性有机氟化合物对手性化合物的需求不断增加，以及含氟有机药物的迅速崛起，要求开发新的合成方法，为各种氟化手性结构单元提供切实可行的途径。引入新策略可以控制氟化亲核试剂和亲电子试剂的独特稳定性和反应模式，为简化当前和未来含氟有机药物的化学合成提供了宝贵的机会。 我们将开发一种在温和条件下由容易获得的三氟乙酰基衍生前体原位生成的氟化亲核试剂进行不对称催化的方法。使用脂肪族和芳香族醛进行铜-双恶唑啉催化反应获得的大量初步结果证明了该方法的可行性和实用性。持续的配体开发和计划的机理研究将进一步提高该反应的对映选择性，并将该方法扩展到一系列目前难以捉摸的氟化亲核试剂。 使用我们实验室最近开发的双恶唑烷配体，我们发现了三氟甲基酮的实用催化不对称炔基化的入口。进一步的配体和方法开发将与机理研究和有希望的反应参数的筛选齐头并进。我们在这一重要反应方面取得了实质性进展，这一经验为将炔酰胺和炔磺酰胺引入催化 C-C 键形成提供了独特的机会。我们的初步研究提供了用甲苯磺酰化乙酰胺获得的有希望的概念验证结果，并表明该研究方向将为各种新型多功能手性结构单元提供前所未有的途径。 计划的催化剂和反应开发将以详细的机理研究为指导，并对所提出的方法的范围和应用进行深入研究。我们的多方面努力将原位生成的氟烯醇盐引入不对称催化（目标 1）、三氟甲基酮炔基化的实用方法（目标 2）以及与 ynamides 及其衍生物的催化对映选择性加成反应（目标 3）。将额外强调新结构单元的合成用途和反应，这些新结构单元将由本工作期间提供的各种亲电子试剂和亲核物质产生。