新型双功能有机-金属催化剂的设计与合成及其在不对称催化反应中的应用研究

Asymmetric catalysis has grown rapidly and made considerable progress in recent years, but there are still some unachievable reactions by organocatalysis and transition metal catalysis alone. The efficient combination of organocatalysis and transition metal catalysis can dissolve these challenging problems. It became one of the most important research fields and received great attention. At present, the development of combined transition metal and organo-catalyzed transformations usually existed the incompatibility of catalysts, substrates, intermediates and solvents. Therefore, this project is devoted to developing a new catalytic strategy to solve these problems, we will make use of a bifunctional molecule bearing dual activating modes of metal catalysis and organocatalysis. It can demonstrate the advantages of them, efficiently catalyze new and challenging reactions, greatly improve the reactivity, efficiency and selectivity of some known chemical transformations. This project will propose to design and synthesize several kinds of novel ligands by introducing the organocatalysts, such as urea, thiourea, squaramide, chiral amine and phosphoramide etal, to ferrocenyl diphosphine ligand, and will apply the new bifunctional organo-metal catalysts into asymmetric reactions. We will explore the interaction mechanism between catalysts and substrates, and disclose the influencing factors of reactivity and selectivity. It will provide experimental and theoretic basis for design new chiral catalysts, and will further promote the development and application for organo-metal catalysis.

近年来，不对称催化领域发展迅速并取得重大进步，但仍有很多仅使用有机催化和金属催化难以实现的化学反应。将有机催化和金属催化联合起来解决单一催化剂面临的难题，已成为热门的研究领域之一，备受人们的青睐。目前，有机与金属双催化模式之间往往存在催化剂、底物、中间体、溶剂之间的不兼容问题。因而，本项目拟提出新的不对称催化策略，运用单一分子将有机催化和金属催化有效结合起来，同时发挥两类催化模式的优势，发展新型双功能有机-金属催化剂，高效地实现一些新的、具有挑战性的反应，提高一些已知反应的活性、效率和选择性。将脲、硫脲、方酰胺、手性胺、磷酰胺等重要有机催化剂与性能优异的二茂铁双膦配体相结合，合成一系列的新型配体，对其金属配合物催化的不对称反应进行深入研究。探索催化剂与底物之间的相互作用机制，揭示影响反应活性和选择性的因素，为设计新的手性催化剂提供实验与理论依据，进一步推动有机-金属催化的发展和应用。

申请人基于有机-金属催化策略成功地发展了一系列结构新颖、精细可调的双功能手性双膦-硫脲配体，并将其应用于一系列金属催化的不对称氢化反应，形成了特色的有机-金属催化体系，取得了一些重要的研究成果，高效地构建了数目众多的、官能团结构多样化的手性化合物，发展了多种高反应活性、高立体选择性、符合绿色化学要求的不对称催化合成新方法。另外，申请人基于非共价键离子对活化策略发展了一系列拥有自主知识产权的、含次级基团Ugi胺骨架的新型手性双膦配体Wudaphos、含双重次级基团的二级膦氧(SPO)双膦配体SPO-Wudaphos、“鸡爪”型含次级基团Ugi胺骨架的新型手性双膦配体t-Bu-Wudaphos。积极将这些性能优异的新型手性双膦配体应用于金属催化的潜手性不饱和羧酸、磺酸、磷酸及其衍生物中的不对称氢化反应中，取得了非常优异的反应结果，催化效率高，底物适用范围广，合成了一系列的手性酸类化合物。申请人还将发展的这些不对称氢化反应方法学运用到一些生物活性分子的合成中，简便、高效地实现了α-2-肾上腺素受体拮抗剂类似物、姜黄酮turmerone关键中间体、治疗低血糖药物mitiglinide关键中间体、具有潜在抗肿瘤有丝分裂活性的药物Cryptophycin的中间体、抗抑郁剂MKC-242、潜在的α-1D-肾上腺素能拮抗剂WB4101、5-HT1A受体激动剂BSF-190555、抗高血压药物(R)-doxazosin、非甾体抗炎止痛药Naproxen、Ibuprofen、Flurbiprofen等化合物的合成，具有非常大的潜在应用价值。