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

描述（由申请人提供）：通过与氟烯醇化物、炔和酰胺的催化不对称C-C键形成合成手性有机氟对手性化合物的不断增长的需求和含氟有机药物的快速增长要求开发新的合成方法，该方法提供对各种氟化手性结构单元的实际使用。引入允许控制氟化亲核试剂和亲电试剂的独特稳定性和反应性模式的新策略为简化当前和未来的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，在温和的条件下，从容易获得的三氟乙酰基衍生的前体原位生成的氟化亲核试剂。该方法的可行性和实用性得到了充分的初步结果，通过铜双恶唑啉催化反应，使用脂肪族和芳香族醛。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，并将该方法扩展到目前难以捉摸的氟化亲核试剂的范围。 使用我们实验室最近开发的双恶唑烷配体，我们发现了一个实用的三氟甲基酮的催化不对称炔基化反应的入口。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。我们已经取得了实质性的进展，这一重要的反应，这方面的经验提供了一个独特的机会，介绍了苯磺酰胺和炔磺酰胺催化C-C键的形成。我们的初步研究提供了有希望的概念验证结果与甲苯磺酰化的crosside获得，并表明，这一研究方向将提供前所未有的访问各种各样的新的多功能手性积木。 计划中的催化剂和反应开发将以详细的机理研究为指导，并导致对拟议方法的范围和应用进行深入调查。我们多方面的努力将引入原位生成的氟烯醇化物的不对称催化（目标1），一个实用的方法炔基化的三氟甲基酮（目标2），和催化对映选择性加成反应与酰亚胺及其衍生物（目标3）。额外的重点将给予新的积木，将产生广泛的亲电和亲核物种在这项工作中提供的合成使用和反应。

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.