双功能有机小分子催化不对称合成反应的理论研究

【作者】 卢楠；

【导师】 陈德展；

【作者基本信息】 山东师范大学 ， 物理化学， 2012， 博士

【摘要】 有机催化，作为和金属催化及酶催化具有同等地位的催化方法，因其高效性和高选择性，成为构建分子骨架的重要工具。目前有机合成化学的重点在于不对称合成方面，主要用于制药、材料和生物学等领域。近年来，新的不对称催化反应不断被发现，高效、高选择性和高普适性的有机催化剂不断被研发，不对称有机催化处于蓬勃发展的黄金时期。从分子水平上研究各类不对称有机催化反应的机理，各种有机催化剂的活化机制，有助于了解催化反应历程，解释实验现象，揭示催化剂结构与活性的关系，进而为新型、高效催化剂的研发与修饰提供关键的理论指导。本文用理论计算方法详细研究了双手性类、手性双磷化物、硫脲类双官能团、仲胺类双官能团和胍类双官能团五个系列有机催化剂驱动的八种不对称合成反应，探讨了反应机理以及催化剂的各官能团在催化过程中的作用机制。提出了诸多创新性观点。具体研究内容和结论如下：首先应用密度泛函方法对含中央手性和轴手性元素的两种新型催化剂在催化2, 4-戊二酮与硝基烯烃的不对称Michael加成反应时的对映选择性控制进行了详细地研究。表征了产生（S）和（R）型Michael加合物的两条对映选择性反应通道。反应的对映选择性由第一步碳-碳键形成决定，第二步质子迁移是反应的决速步。对对映选择性起源的初步分析表明：含有中央手性与轴手性元素的催化剂的对映选择性水平取决于两种不对称元素在几何结构上的匹配与否。若催化剂呈现一种“闭合”的几何构型，则中央手性与轴手性元素的合作成为可能，共同起作用以提高催化剂的对映选择性控制能力。如果催化剂呈现一种“敞开”的几何结构，则两不对称元素之间不可能有合作关系，所以仅由一种手性元素控制的对映选择性最终降低。研究了硫脲-叔胺催化的硝基烯烃与氮-甲苯磺酰基亚胺的对映选择性aza-Morita Baylis Hillman型反应的机理。根据计算结果，反应过程包括两个基元步骤：（1）作为路易斯碱，催化剂和硝基烯烃形成的二元复合物前躯体对氮-甲苯磺酰基亚胺的亲核加成；（2）质子从硝基烯烃的甲基转移到氮-甲苯磺酰基亚胺的负电性氮上。最后是产物β-硝基-γ-烯胺的释放和催化剂再生，第二步的质子转移为决速步。对映选择性由催化剂的三种官能团与底物互动所产生的两种非共价相互作用和一种弱共价相互作用的合作效应来控制：作为路易斯碱，叔胺官能团通过弱的共价键来活化硝基烯烃，这种弱共价相互作用引导反应按照这条共价键变化较小的取向作为主要路径来进行；芳环官能团通过π-π堆积相互作用来活化氮-甲苯磺酰基亚胺，这种非共价相互作用选择芳环之间的有效重叠面积改变较少的取向作为反应的主要路径；硫脲官能团为主要路径的驻点提供更加紧凑的氢键网。计算得到的非极性环境的二甲苯溶剂条件下ee值（97.6%）远高于二甲基甲酰胺极性溶剂环境中的ee值（27.2%），这一事实可充分证明我们的结论。研究了羟基-硫脲催化邻-苄基羟胺与吡唑丁烯酸酯共轭胺基加成反应的氢键活化机理和对映选择性控制。对于催化剂对亲电试剂和亲核试剂的作用，我们提出“氢键活化”机理，包括可行的单活化和双活化模型，两种竞争模式下反应过程均是分步的。单活化模型是一种对亲电试剂增强的活化，通过亲电试剂与催化剂的羟基和硫脲基团同时相互作用实现。双活化模型中，亲电试剂被催化剂的硫脲基团活化，同时亲核试剂绑定到羟基上而实现活化，在能量上双活化模型比单活化模型更优越。对映选择性起源于si面的进攻比re面更占优势，这应该归因于决速步的C-N键形成时，催化剂的羟基和硫脲基团对底物产生的氢键网作用。ONIOM计算所预测的ee值与实验数据的一致性很好的支持了这种“氢键活化”机理。对TangPhos催化的联二烯酯和硫醇不对称γ加成反应机理的研究发现，没有TangPhos，未催化的加成反应发生在β-碳上，反应过程包括碳-硫键形成和从硫原子到γ-碳的质子转移，生成β-硫酯。TangPhos催化的不对称γ加成反应分三步：TangPhos加成到联二烯酯的β-碳上产生一个二元复合物，硫醇亲核进攻该二元复合物的γ-碳；质子从TangPhos的磷原子转移到联二烯酯的的羰基氧上；再从羰基氧转移到β-碳上，得到产物γ-硫酯，第一步为决速步。TangPhos的两个磷原子位点对于两底物的活化至关重要。作为亲核催化剂，P2原子与联二烯酯的β-碳形成介于单双键之间的强共价键P2 C2，极大地转移了C2上的正电荷，相对增加了C3原子的亲电性，使其成为γ加成反应的亲电中心，反应的区域选择性随之改变。作为路易斯碱，P1原子去质子化硫醇以提高硫原子的亲核性，同时还作为中介利于向β-碳的质子转移。反应的对映选择性主要由TangPhos的两手性五元环控制，同时叔丁基官能团与之配合起辅助作用。ER路径是连接两手性环的单键转动最小的取向，叔丁基施加的空间阻力也最小，该路径在四条竞争路径中最优势。NBO分析从电子分布的角度也证实ER路径是最稳定的反应通道。我们为主要产物（R）型γ-硫酯预测的ee值也在实验数据范围。研究了O-TMS-保护的二苯基吡咯催化级联双Michael加成反应的机理。计算结果表明反应先后包括分子间亲核加成和分子内环化。两个步骤涉及四个连续立体中心的形成，第二步为决速步。仲胺基团的亚胺离子–烯胺活化模式使得级联双Michael加成反应能够连续地进行。作为电子传送带，亚胺离子吸引电子流以促进反应第一步的亲核加成。第二步烯胺推动电子流来催化环化反应。作为氢键供体，催化剂可以与底物形成三种类型的C–H···O氢键，对反应过程中的驻点提供不同程度的稳定化作用。反应的对映选择性和非对映选择性由催化剂骨架产生的手性环境控制。两种官能团链接吡咯–苯基和吡咯–甲硅烷基醚使反应优先按照连接两基团的单键转动较小的取向来进行。NBO分析、与实验数据吻合的产物ee值和dr值都能够有力的支持我们的结论。对酒石酸催化的醛、β-酮酯与脲的对映选择性Biginelli反应进行了第一次理论探索，考虑了三种情况分别是水、乙醇作溶剂和无溶剂的条件。结果显示三条可能的竞争反应路径共同倾向生成（R）-型二氢嘧啶酮DHPMs。酸催化条件下Biginelli反应的第一步，主要是醛与脲经环化脱水产生一种质子化亚胺的过程。这条途径预测的ee值高达93.2%。另外，由醛与β-酮酯经羟醛缩合反应产生的活泼烯酮也可作为反应的前驱体。然而当中性亚胺作为前驱体时，相应的协同路径因势垒太高而不可能发生。作为催化剂，酒石酸与底物形成氢键网来实现活化，提高质子化亚胺的亲电性和β-酮酯的亲核性。我们的理论研究提供了一种预测，酒石酸可以在乙醇溶剂中有效催化对映选择性Biginelli反应。拥有酸性和中央手性的双重特征，酒石酸这样的天然有机小分子是一类很有潜力的不对称合成反应的催化剂。最后一部分研究了双环手性胍催化5氢-唑（1,3-氧氮杂茂）-4-酮与炔羰基化合物不对称1,4-加成反应的机理，重点分析高立体选择性的起源问题。反应包括5氢-唑（1,3-氧氮杂茂）-4-酮的去质子化、碳-碳键形成和质子转移三个步骤，第一步为决速步。手性胍两个可能的氮原子位点和羟基官能团对底物的活化至关重要。在催化循环中，N1在酸和碱之间变换角色以活化5氢-唑（1,3-氧氮杂茂）-4-酮和促进产物的形成，N2 H2键不仅是5氢-唑（1,3-氧氮杂茂）-4-酮的氢键供体，而且是N1上电子的临时受体。与第一步相关的对映选择性和第二步决定的Z/E选择性由手性胍的骨架控制，五元环–六元环链接起主导作用，引导反应以连接两基团的单键转动较小的取向为优势路径来进行。当胍含有缺电子和大的取代基时，反应的对映选择性提高。如果胍的结构中羟基被甲基醚屏蔽，则其催化能力和对映选择性控制就大大降低，且得到相反构型的对映体作为主要产物。所研究的三种手性胍都支持Z式异构体且Z/E选择性都很好。从电子分布的角度，NBO分析可证实我们的结论，且计算的ee值和Z/E比率也与实验数据吻合。对具有相反中央手性的两种金鸡纳碱盐催化的2-环己烯-1-酮与H2O2的不对称环氧化反应的理论研究显示：催化反应包括第一步，伴随催化剂的叔胺对H₂O₂的去质子化而协同进行的过氧羟基与烯酮β–碳的亲核加成。第二步，关环即O-O键断裂，C-O键形成同时发生羟基质子化作用。第一步决定反应的对映选择性，第二步是决速步。第一步可以通过轴向和面向两条可能的路径进行。催化剂的伯胺盐通过形成亚铵离子来活化烯酮，选择环的扭转张力较小的取向作为主要反应路径。叔胺作为一般的碱来实现对H₂O₂的活化，倾向于H₂O₂去质子化和羟基质子化程度较大的路径。（S）-型催化剂j参与的反应，轴向路径比面向路径更有利，产生主要的环氧化物[2S,3S]-3。（R）-型催化剂k的结果刚好相反，优势的面向路径生成的主要产物是异构体[2R,3R]-3。为实验现象提供了有力的理论支持。该催化环氧化反应的对映选择性是在烯酮和H₂O₂被活化的过程中，由双官能团催化剂的中央手性元素控制的。对产物er值的定量预测与实验值接近，对取代基效应的研究表明了一种实验观察到的重要趋势，即反应的对映选择性随着β–位置取代基和环状烯酮环的增大而提高。更多还原

【Abstract】 As a catalytic method with the same status of enzyme catalysis and metalcatalysis, organocatalysis has been an important tool for building the molecularscaffold owing to the high efficiency and selectivity. At present, the focus of organicsynthetic chemistry is asymmetric synthesis which is mainly used in the fields ofpharmacy, materials, biology and so on. Recently, new asymmetric catalytic reactionshave been discovered continuously. The organocatalysts have been developed withhigh efficiency, high selectivity and high universality. Thereby the asymmetricorganocatalysis is in the golden period of vigorous development. The investigation onthe mechanism of various asymmetric reactions and the activation of differentorganocatalysts could facilitate understanding of catalytic reaction process, explainingthe experimental results, revealing the catalyst structure-activity relationship and thenproviding theoretical guidance for the development of new high-efficiency catalysts.In this dissertation, five series of typical organocatalysts were selected for study. Theyare dual chiral, bisphosphine, thiourea, secondary amine and chiral guanidinederivated bifunctional catalysts. Eight catalytic asymmetric reactions wereinvestigated and discussed in detail by using theoretical calculation methods. In theprocess of exploring the reactive mechanism of different units in catalysts, weproposed many innovative ideas.The specific research and conclusions are as following:The mechanism of enantioselectivie control of organocatalyst with central andaxial chiral elements in Michael addition of 2,4-pentandione to nitroalkene isinvestigated using density functional theory （DFT） calculation. Two enantioselectivechannels are characterized in detail. Enantioselectivity is determined in the C-C bondformation and the proton transfer is identified as the energetic bottleneck. Generally,the level of enantioselectivity of catalysts depends on geometrical match or mismatchof two asymmetric elements. The“closed”geometry of catalyst makes thecooperation of two chiralities possible, so that the central and axial chirality work together to enhance the enantioselective control. The“open”structure of catalystmakes the cooperation of two asymmetric elements impossible, so that itsenantioselectivity dominated only by one type of chirality is decreased.Thiourea-tertiary amine-catalyzed enantioselective aza-Morita Baylis Hillmanreaction of nitroalkene and N-tosylimine has been investigated using DFT method.Enantioselectivity is dominated by the cooperative effect of non-covalent and weakcovalent interactions imposed by different units of catalyst. As Lewis base, the tertiaryamine unit activates nitroalkene via weak covalent bond. The weak covalentinteraction orients the reaction in a major path with smaller variations of this bond.The aromatic ring unit activates N-tosylimine viaπ-πstacking. The non-covalentinteraction selects the major path with smaller changes of the efficient packing areas.Thiourea unit donates more compact H-bonded network in species of the major path.Our conclusion is supported by ee value in solution phase of xylene （97.6%） muchhigher than DMF （27.2%）.The H-bond activation mechanism and enantioselectivity of hydroxyl-thioureacatalyst in conjugate amine addition of O-benzyl hydroxylamine to pyrazole crotonate,is investigated using density functional theory （DFT） calculations. Two competingactivation models are explored in detail. C-N bond formation is stepwise in both ofthe two models. The enantioselective （S）-channel is more favorable than （R）-channelvia the calculated barriers. The enantioselectivity originated from si face preferablethan re face can be attributed to the H-bonded network provided by thiourea andhydroxyl groups in rate-determining step. The enantiomeric excess （ee） valuespredicted through ONIOM calculations are in line with the experiment.TangPhos-catalyzed asymmetricγaddition of thiols to allenoates has beeninvestigated according to density functional theory. The uncatalyzed addition occursatβ-carbon via a process which involves C-S bond formation and proton transfer fromS toγ-carbon. Theβ-thioester is generated. In TangPhos-catalyzed case, thenucleophilic thiol attacksγ-carbon after the addition of TangPhos toβ-carbon. Theproton transfers firstly from P of TangPhos to carbonyl O and then toβ-carbon. Theγ-thioester is obtained. Step1 is rate-limiting. As nucleophilic catalyst, P2 forms strong covalent bond withβ-carbon which shifts the positive charge of C2, leaving C3as the electrophilic center forγaddition. The regioselectivity is consequently altered.As Lewis base, P1 deprotonates thiol enhancing the nucleophility of S and facilitatesthe proton transfer toβ-carbon as a medium. Among four competitive pathways, ERpath is the most favorable one with smallest rotation of the single bond linking twochiral rings in TangPhos. The primary domination on enantioselectivity of chiral ringsis assisted by t-butyl group, which also prefers ER path with the least steric hindrance.Our conclusion is supported by NBO analysis and the predicted ee values according tothe experiment.In next work, we investigated important intermediates and key transition states ofthe organocatalyzed cascade double Michael addition using DFT method. Thecalculated results suggest that the reaction contains intermolecular nucleophilicaddition and intramolecular cyclization, both involving the formation of twostereocenters. The iminium–enamine catalysis of secondary amine unit enables thecascade addition to proceed consecutively. As an electron transport, the iminiumattracts the electron stream to promote the nucleophilic addition. Then enamineimpulses the electron stream to catalyze the cyclization. As H bond donor, the catalystforms three types of C–H···O H bond with substrates. The enantioselectivity anddiastereoselectivity are dominated by the catalyst backbone. Two group links ofpyrrole–phenyl and pyrrole–silyl ether orient the reaction in paths with smallerrotations of the linked single bonds. Our conclusion is supported by NBO analysis andthe predicted ee, dr values according to the experiment.Enantioselective Biginelli reaction of aldehyde,β-ketoester, and urea catalyzedby natural （2R, 3R）-tartaric acid has been investigated using density functional theory（DFT） calculations. The results indicate that the most favorable pathway involves aprotonated imine from aldehyde and urea in the first step. Tartaric acid forms H bondsnetwork with substrates enhancing the electrophilicity of protonated imine and thenucleophilicity ofβ-ketoester. （R）-3, 4-dihydropyrimidin-2-（1H）-ones （DHPMs） ispreferable in the reaction. The solvent effect is discussed in the prediction ofenantiomeric excess （ee） values in ethanol and in water. Density functional theory calculations are used to study the reaction mechanismand origins of high stereoselectivity in chiral guanidine-catalyzed asymmetric1,4-addition of 5H-oxazol-4-ones. The reaction involves proton abstraction of5H-oxazol-4-one, C-C bond formation and proton transfer. N1 atom of chiralguanidine exchanges its character as base and acid to activate 5H-oxazol-4-one and tofacilitate the product formation. The role of N2 H2 is not only H bond donor for5H-oxazol-4-one but also electron accepter for N1. The enantioselectivity related withrate-limiting step1 and Z/E selectivity determined in step2 are primarily influenced byfive–six-membered ring link in the backbone of chiral guanidine. The reactionproceeds along the favorable path with smaller rotations of the linked bonds. Theenantioselectivity is improved with guanidine involving electron-deficient and bulkysubstituent. With methyl ether-protected hydroxy in structure, the catalytic ability andenantioselective control of guanidine are extraordinarily low affording oppositeenantiomer as major product. Z-isomers are preferred all the while.Chiral cinchona alkaloid salts-catalyzed asymmetric epoxidation of2-cyclohexen-1-one with hydrogen peroxide （H₂O₂） has been investigated usingdensity functional theory （DFT）. The ring-closure step is rate-limiting in the catalyticreaction. The enantioselectivity-determining step is initial nucleophilic additioninvolving two orientations of axial and equatorial. In （S）-catalyst j-mediated processaxial pathway is favored over equatorial leading to the major epoxide [2S,3S]-3. Anopposite enantiomer [2R,3R]-3 is primarily generated in （R）-catalyst k-assisted casepreferring equatorial pathway. The results indicate that the enantioselectivity ofepoxidation is dominated by central chirality of the bifunctional catalysts in theactivation of enone by primary amine salt via iminium formation and of H₂O₂bytertiary amine reacting as a general base. The substituent effect is also discussed toclarify a tendency existing in experiment.更多还原