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

说明书(申请人提供)：通过催化不对称C-C键与氟烯醇酸盐、炔烃和Ynamide形成C-C键合成手性有机氟化合物对手性化合物的需求日益增长，含氟有机药物的迅速崛起要求开发新的合成方法，提供各种氟化手性构建块的实际途径。新策略的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，利用原位生成的氟化亲核试剂，在温和的条件下，从容易获得的三氟乙酰衍生前体中进行不对称催化。用脂肪醛和芳香醛催化的铜-双恶唑啉反应得到了大量的初步结果，证明了该方法的可行性和实用性。继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一系列含氟亲核试剂。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三氟甲基酮的催化不对称炔化反应的方法。进一步的配体和方法开发将与机理研究和筛选有希望的反应参数齐头并进。我们在这一重要反应方面取得了实质性进展，这一经验为我们提供了一个独特的机会，可以将氰胺类化合物和芳磺酰胺类化合物引入催化C-C键的形成。我们的初步研究提供了很有希望的概念验证结果，并表明这一研究方向将提供前所未有的途径，获得一系列新的多功能手性构建块。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。我们的多方面工作将把原位生成的氟烯醇酸盐引入不对称催化(AIM 1)，一种实用的三氟甲基酮的烷基化反应(AIM 2)，以及催化与氰胺及其衍生物的对映选择性加成反应(AIM 3)。将进一步强调在这项工作中提供的各种亲电体和亲核物种将产生的新构造物的合成用途和反应。

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.