【作者】 徐彬；

【导师】 周其林；

【作者基本信息】 南开大学 ， 有机化学， 2015， 博士

【摘要】 氢迁移过程广泛存在于有机反应中。由于氢原子体积小、反应速度快、迁移途径多等特点,实现氢迁移过程的有效手性控制一直是具有挑战性的课题。目前使用人工合成的手性催化剂仍然难以实现对高活性反应中间体质子迁移过程的直接立体控制。金属卡宾对含有孤对电子X?H键（X=O,N,S,P等）的不对称插入反应是高效构筑碳?杂原子键的方法,具有重要的应用价值。该反应的立体化学决定步骤就是叶立德中间体的不对称质子迁移过程。由于叶立德中间体稳定性差,反应活性高,使用传统的手性金属络合物催化剂很难实现对其质子迁移过程的有效手性控制,因此严重限制了该反应的不对称催化研究进展。本论文以不对称插入反应为切入点,设计了一种结构新颖的手性质子梭催化剂,首次实现了对叶立德中间体质子迁移过程的直接立体控制,进而完成了几类挑战性不对称插入反应,为质子迁移过程的直接立体控制提供了新的思路。具体研究工作如下:我们首先研究了手性螺环双噁唑啉配体和铜的络合物催化的N?H键不对称插入反应,实现了一系列α-烷基-α-重氮酯对苯胺N–H键的不对称插入反应,获得了高达98%ee的对映选择性。机理研究表明该反应经历了氮叶立德中间体,通过分步过程完成了插入反应,反应决速步骤是产生新手性中心的1,2-质子迁移步骤。根据上述机理研究的关键信息,我们提出了新颖的手性质子梭催化剂概念,即通过具有接收质子和释放质子功能的质子梭催化剂直接介入反应活性中间体的质子迁移过程,从而实现反应的手性诱导。为此,我们设计并合成了一系列手性螺环磷酸作为质子梭催化剂。手性螺环磷酸的羟基部分可以作为质子给体,而磷酰基可以作为质子的受体,从而实现对质子迁移过程的催化。而在螺环磷酸骨架的6,6’-位可以方便地引入各种取代基,因而有可能对质子迁移过程实现有效的手性控制。我们将手性螺环磷酸作为质子梭催化剂,应用于铑催化α-重氮酯对酰胺N?H键的不对称插入反应中,获得了很高的活性（催化剂用量可以降低至0.1%,反应在1 min内结束,收率最高达97%）和对映选择性（90?95%ee）。在该反应中,非手性的双铑催化剂分解重氮生成金属卡宾,产生相应的氮叶立德中间体,手性螺环磷酸则催化该氮叶立德中间体的1,2-质子迁移过程,进而高效地实现了反应的手性诱导。在此基础上,我们研究了手性质子梭催化剂和非手性双铑络合物协同催化α-重氮酮化合物对酰胺N?H键的不对称插入反应,获得了高达95%ee的对映选择性,合成了一系列具有重要合成价值的手性α-氨基酮化合物。这是首例α-重氮酮化合物对含有孤对电子X?H键的不对称插入反应报道。随后,我们研究了手性质子梭催化剂和非手性双铑络合物协同催化α-重氮酯对S?H键的不对称插入反应,获得了高达98%ee的对映选择性,这代表了目前S?H键不对称插入反应的最好结果。我们通过该反应合成了一系列具有重要生物活性和合成价值的手性α-巯基酯化合物,并高效合成了重要的含硫手性化合物（S）-Thiomandelate和手性药物（S）-Efucimibe。此外,我们运用在线红外监测、核磁³¹P NMR等方法,证实了手性螺环磷酸是独立发挥手性催化诱导作用的。然后,我们通过密度泛函理论计算方法（DFT Calculations）,获得了协同催化X?H键插入反应的机理历程、关键活性中间体以及不对称质子迁移过渡态等重要反应信息,合理解释了反应的高活性、高对映选择性以及手性产物的绝对构型等实验现象。机理研究表明,手性螺环磷酸在反应过程中确实可以有效降低质子迁移过程中的能垒,并通过催化剂周围的手性环境,实现了反应的高效手性控制。这些结论都为手性质子梭催化剂的进一步发展和应用提供了理论依据。除了卡宾对X?H键的不对称插入反应,我们还成功将手性质子梭催化剂应用于卡宾对苯环C（sp²）?H键的不对称插入反应中,以高达97%ee的对映选择性实现了非手性双铑络合物催化α-重氮酯对取代苯环C（sp²）?H键的不对称插入反应。这是分子间金属卡宾对苯环C（sp²）?H键不对称插入反应的首例成功报道。该反应的成功实现说明手性质子梭催化剂能够很好地诱导偶极子中间体等其它活性中间体的不对称质子迁移过程,在不对称质子转移控制方面有着广阔的应用前景。通过上述研究,我们成功发展了手性质子梭催化剂,并使用该催化剂实现了一系列挑战性卡宾插入反应,为多种重要手性砌块提供了新的高效合成方法。这些研究成果拓展了人们对质子转移过程的认识,表明使用合理设计的催化剂,可以实现对活性中间体质子转移过程的有效立体控制。手性质子梭催化剂有望在不对称质子迁移反应中得到更广泛的应用,并将对发展新的不对称诱导模式及手性催化剂产生重要的启发和推动作用。更多还原

【Abstract】 Hydrogen shift widely exists in organic transformations.Due to the features of small sizes,fast rates and uncertain pathways,asymmetric hydrogen shift is hard to be achieved.Although some asymmetric proton transfers have been realized by enzymes,it is still very difficult to directly induce the asymmetric proton transfers of active intermediates by artificial chiral catalysts nowadays.Transition-metal-catalyzed asymmetric carbene insertion reaction into X?H（X=N,O,S,P,etc.）bonds is an efficient method of constructing C?X bonds.The chirality-determining step of such transformation is an asymmetric proton transfer of highly active and sensitive ylide intermediates,which could rarely be well-catalyzed by traditional chiral metal complexes.Thus,taking asymmetric X?H insertion reactions as a starting point,we tried to clarify the mechanism of asymmetric proton transfers in the insertion reaction.With the insights,we developed a series of novel chiral proton shuttle catalysts,which could directly induce the asymmetric proton transfers of several challenging insertion reactions.We firstly investigated the asymmetric N?H insertion reactions catalyzed by copper complexes of chiral spiro bisoxazolines.The asymmetric N–H insertion reactions of numerousα-alkyl-α-diazoacetates and anilines were achieved with excellent enantioselectivities（up to 98%ee）.The detailed mechanism study supports that asymmetric N–H insertion reaction is a stepwise transformation,and the proton transfer of ylide intermediates is the rate-determining step.We came up a concept of chiral proton shuttle catalysts,and proposed that the asymmetric proton transfers of active intermediates could be directly induced through the proton-trapping and proton-releasing of chiral proton shuttle catalysts.We designed and synthesized a series of spiro phosphoric acids（SPAs）as the first generation of chiral proton shuttle catalysts.The P=O part was proposed as proton-acceptor while the P?OH part can serve as proton-donor.Meanwhile,the6,6’-positions of SPAs could be derived by introducing substituents,which could tune SPAs’chiral inducing abilities.Using SPAs as chiral proton shuttle catalysts,we accomplished the rhodium（II）catalyzed asymmetric N?H insertion reactions ofα-diazoesters and Boc NH₂ with high enantioselectivities（90?95%ee）,high yields（85?97%yield）,fast reaction rate（in 1 min）at low catalyst loading（as low as to 0.1 mol%）.The achiral dirhodium carboxylates is responsible for decomposition of diazo substrates and generation of ammonium ylide intermediates,while the SPAs catalyze the asymmetric 1,2-proton transfer of ylides and afforded high enantioselectivities.Comparing to the tranditional chiral complex catalysts,the cooperative catalysts involving chiral proton shuttles could significantly improve the reactivities and enantioselectivities.We developed the first highly enantioselective N?H insertion reaction ofα-diazoketones by the cooperative catalysis of dirhodium（II）carboxylates and chiral spiro phosphoric acids.The insertion reaction provides a new access to versatile chiralα-aminoketones with fast reaction rates（in 1 min）,good yields（up to 97%yield）and high enantioselectivities（86?95%ee）under mild and neutral conditions.Chiral proton shuttle catalysts significantly expanded the substrate scope of asymmetric insertion reactions.We developed the first highly enantioselective S–H insertion reaction by cooperative catalysis of dirhodium（II）carboxylates and chiral spiro phosphoric acids（SPAs）under mild and neutral reaction conditions with fast reaction rates,high yields（77–97%yields）,and excellent enantioselectivities（up to 98%ee）.The catalytic S–H bond insertion reaction provides a highly efficient method for the synthesis of chiral sulfur-containing compounds and advances the synthesis of sulfur-containing drug（S）-Eflucimibe.Taking the asymmetric S–H inserton as model reaction,we investigated the mechanism of the asymmetric proton transfer catalysed by chiral proton shuttle catalysts.Firstly,a systematical study using ³¹P NMR and in situ FT-IR spectroscopy excluded the possibility of in situ generated chiral dirhodium（II）spiro-phosphates,verified that the SPAs performed as independent chiral proton shuttle catalysts.Secondly,DFT calculations showed that the activation energy of the proton transfer could be remarkably reduced by SPAs,so that the SPAs could catalyze the asymmetric proton transfers efficiently.Besides the asymmetric X?H insertion reactions,we further introduced the chiral proton shuttle catalysts into the rhodium（II）catalyzed intermolecular asymmetric C（sp²）?H insertion reactions ofα-diazoesters and substituted benzene rings.High enantioselectivities（up to 97%ee）were achieved,and a range of chiralα-biarylesters were obtained.更多还原