Asymmetric Synthesis with Organofluorines and Terminal Ynamides

对手性化合物不断增长的需求和令人印象深刻的 氟化药物在美国药品市场上的流行引起了人们的关注 开发可实际获得的合成方法的动机 多功能有机氟化合物。战略的引入提供了对 含氟物种独特的稳定性和反应性模式提供了无价的 简化当前和未来药物的化学合成的机会。多用途的 到目前为止很少被研究的末端氰化物的化学和新的C- 我们实验室最近发现的F功能化方法也有类似的前景。 拟议研究的目标是引入非对称方法来 催化与含氟亲核试剂形成碳-碳键 易得前体或多官能团的温和脱酰C-C裂解 亲核前分子，继续我们不对称ynamide加成的带头努力 反应，开发新的C-F官能化化学。从总体上看， 用充分的证据突出了计划中的活动和合成用途的前景- 概念的结果和机械的洞察力。将把相当大的重点放在 例如，目前难以捉摸的反应和新方法的引入 史无前例的不对称Michael加成/Nef反应，选择性的C-F活化 碳-碳和碳-杂原子键的形成以及无碱氰化物 加法。此外，所提出的多官能团手性化合物的总体用途 本课程将探索生物活性化合物全合成的基本要素。 反应发展的努力将由详细的机理研究和 包括各种有机催化剂和手性化合物筛选和系统优化 配体，包括以前在我们的 实验室。总之，这项提案的预期结果很可能负担得起新的 有机氟和末端氰化物不对称催化的工具和方向 以及将感兴趣的一般反应洞察和合成机会 各种各样的合成化学家和药物化学家。

The ever-increasing demand for chiral compounds and the impressive prevalence of fluorinated pharmaceuticals on the US drug market generate compelling motivation for the development of synthetic methods that yield practical access to multifunctional organofluorines. The introduction of strategies that provide control over the unique stability and reactivity patterns of fluorinated species offers invaluable opportunities to streamline chemical synthesis of current and future drugs. The versatile chemistry of terminal ynamides which have been barely investigated to date and new C- F functionalization methodology recently discovered in our lab bear similar promise. The goals of the proposed research are to introduce asymmetric methods for catalytic carbon-carbon bond formation with fluorinated nucleophiles generated either by mild deacylative C-C cleavage of readily available precursors or from multifunctional prenucleophiles, to continue our spearheading efforts with asymmetric ynamide addition reactions, and to develop new C-F functionalization chemistry. The general feasibility of the planned activities and the synthetic utility prospects are highlighted with ample proof- of-concept results and mechanistic insights. Considerable emphasis will be placed on the introduction of currently elusive reactions and new methodologies, for example unprecedented asymmetric Michael addition/Nef reactions, C-F activation for selective carbon-carbon and carbon-heteroatom bond formation, and base-free ynamide additions. In addition, the overall usefulness of the proposed multifunctional chiral building blocks for the total synthesis of biologically active compounds will be explored. The reaction development efforts will be guided by detailed mechanistic studies and include screening and systematic optimization of a variety of organocatalysts and chiral ligands, including bisoxazolidines which have been developed previously in our laboratory. Altogether, the anticipated outcomes of this proposal are likely to afford new tools and directions for asymmetric catalysis with organofluorines and terminal ynamides as well as general reaction insights and synthetic opportunities that will be of interest to a wide range of synthetic and medicinal chemists.