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

描述（由申请人提供）：通过催化不对称C-C键与氟烯醇酯、炔烃和酰胺形成手性有机氟化合物的合成对手性化合物的需求不断增加以及含氟有机药物的快速增长要求开发新的合成方法，以提供各种氟化手性构建块的实际途径。采用新的战略，可以控制氟化亲核试剂和亲电试剂独特的稳定性和反应模式，这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。我们将开发一种不对称催化的方法，在原位和温和的条件下，由现成的三氟乙酰基衍生的前体生成的氟化亲核试剂。用脂肪醛和芳香族醛催化铜-双恶唑啉反应获得了丰富的初步结果，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制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。利用我们实验室最近开发的双恶唑烷配体，我们发现了一种实用的催化三氟甲基酮不对称烷基化的入口。进一步的配体和方法开发将与机制研究和有希望的反应参数筛选携手并进。我们已经在这个重要的反应上取得了实质性的进展，这一经验为将酰胺和磺酰胺引入催化C-C键的形成提供了一个独特的机会。我们的初步研究提供了有希望的概念验证结果，并表明这一研究方向将为各种新的多功能手性构建块提供前所未有的途径。计划的催化剂和反应发展将以详细的机理研究为指导，并导致对所提议方法的范围和应用的深入调查。我们多方面的努力将引入原位生成的氟烯醇酯用于不对称催化（目标1），一种实用的三氟甲基酮烷基化方法（目标2），以及与酰胺及其衍生物的催化对映选择性加成反应（目标3）。额外的重点将放在新的构建单元的合成使用和反应，这些构建单元将由在这项工作中提供的广泛的亲电和亲核物质产生。

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.