[原创]游书力 [复制链接]

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　　游书力 中国科学院上海有机化学研究所博士生导师。 1975年出生，1996年于南开大学化学系获学士学位，2001年于上海有机所获博士学位，2001-2004年在The Scripps Research Institute从事博士后研究，2004-2006年任Genomics Institute of the Novartis Research Foundation研究员，2006年4月任上海有机所研究员 研究领域金属有机化学、不对称合成 主要学术成就已发表论文23篇，申请专利6项，曾获中科院院长奖学金特别奖 (2001) 及全国百篇优秀博士论文 （2003） ")T\_ME  

论文题目：二茂铁配体在不对称烯丙基取代反应中的应用 ")T\_ME  
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作者简介：游书力，男，1975年04月出生，1996年09月师从于中国科学院上海有机化学研究所戴立信教授，于2001年06月获博士学位。 ")T\_ME  
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     本论文主要是研究二茂铁平面手性在不对称催化反应中的作用，设计合成新型二茂铁配体及其在钯催化烯丙基取代反应中的应用。 ")T\_ME  
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            平面手性二茂铁化合物作为配体在不对称催化反应中有着广泛的应用，,然而对于平面手性作用的研究却并不太多.钯催化烯丙基取代反应是一类重要的有机反应，关于其不对称的研究主要集中在1,3-二苯基体系中，而在合成中非常重要的反应，如利用前手性亲核试剂及非对称烯丙基体系的钯催化烯丙基取代反应，成功的例子很少。因而我们选用反应机理相对比较清楚的钯催化烯丙基取代反应来研究平面手性的作用。在前项工作基础上合成一类有效的手性二茂铁配体，拓宽烯丙基化反应的底物或反应类型，为解决这些问题做出我们的一些贡献。 ")T\_ME  
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1. 二茂铁平面手性作用的研究 ")T\_ME  
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            以恶唑啉为导向基团，通过邻位锂化方便地合成了一系列二茂铁硫恶唑啉配体，d.e.值都可>99/1，我们选择钯催化烯丙基取代反应中较为成熟的1, 3-二苯基烯丙基醋酸酯作为底物进行考察，结果发现所合成二茂铁硫恶唑啉配体非常有效，ee值可高达98%。而且和苯环衍生的硫恶唑啉相比反应活性相对较高。通过设计合成一些配体的非对映体及仅具有平面手性的配体，将它们应用于反应中考察平面手性的作用，发现中心手性起到了决定产物ee值和绝对构型的作用，但在配体中，平面手性和中心手性的匹配在取得高对映选择性上也是重要的。通过对烯丙基钯络合物研究来模拟反应的过渡态，在我们的配体催化体系中产物对映选择性是热力学及动力学共同控制的结果，结合碳谱也解释了配体中的手性匹配问题。 对于只有平面手性的二茂铁硫氮配体，由于本身硫醚取代基在和钯配位时有一个新的手性生成，对于平面手性的研究造成一定的干扰，其催化产物对映选择性结果都比较差，只有当恶唑啉上有两个苄基时，有效地卡住了二苯基p-烯丙基底物，固定了硫苯基朝向，取得了较高的ee值(71.8%)。 ")T\_ME  
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            平面手性二茂铁硒恶唑啉配体可以从二茂铁恶唑啉高非对映选择性地合成，这些配体在钯催化烯丙基取代反应中显示很高的对映选择性(99.3% ee)，平面手性对对映选择性没起到决定作用。在该反应中配体的活性比较低，但作为含硒配体在不对称催化中的应用来讲，我们所合成的二茂铁硒氮配体取得的对映选择性结果是文献中报道的最高的一例。 ")T\_ME  
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为了解决硫及硒和钯配位时产生新手性及配体活性较低的问题，我们合成了平面手性二茂铁膦氮配体。这类配体在钯催化烯丙基烷基化(94.6% ee)和烯丙基胺化反应(97.2% ee)中都表现出了高的对映选择性。对于烯丙基胺化反应，我们研究了外加添加剂对对映选择性的影响，我们发现四丁基氟化铵的加入可以大大提高反应速度及对映选择性。令人鼓舞的是设计合成的只具有平面手性的膦氮配体，也可以取得中等到良好的对映选择性。我们发现当恶唑啉上取代基立体位阻减小时我们发现当恶唑啉上取代基立体位阻减小时，产物的对映选择性就会相对较高，因而平面手性的影响很可能就是通过二茂铁非取代茂环和底物及亲核试剂之间的相互作用而产生的。恶唑啉上取代基空间位阻减小时，钯及p-烯丙基底物离二茂铁骨架比较近，因而所受影响就比较大，其产物ee值就会比较高。 ")T\_ME  
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在1, 2-二取代的平面手性二茂铁配体中，对于烯丙基取代反应，平面手性没有起到主导作用，但是当中心手性存在时，平面手性的引入，可以加强已有的中心手性的诱导作用，以达到较高的对映选择性。 ")T\_ME  
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2. 平面手性二茂铁修饰的手性口袋型双膦配体的合成及应用 ")T\_ME  
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            通过设计合成了一类平面手性二茂铁修饰的手性口袋型双膦配体，由于有平面手性的辅助而具有更强的口袋效应。这类配体在前手性亲核试剂的不对称烯丙基化构筑手性季碳中心的反应中，显示了较好的反应活性及对映选择性。当利用亚胺的氨基酸酯衍生物时，可以得到一些非天然的季碳氨基酸衍生物，ee值最高可以达到75.3%。一些简单的酮的烯醇负离子也可用作亲核试剂，产物为a-位双取代的具有季碳中心的酮，ee值可高达95%。在一些底物中结果优于文献中苯环衍生的手性口袋配体。在这里所得的产物都是在有机合成中非常有用但又难以制备手性化合物。 ")T\_ME  
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            此外合成了平面手性口袋膦氮配体并应用在模型的烯丙基取代反应中，在烷基化和胺化反应中都有中等到良好的对映选择性(85% ee)。单一平面手性二茂铁羧酸膦应用在环状烯丙基醋酸酯的烷基化反应中也取得了中等到良好的对映选择性(61.8% ee)。 ")T\_ME  
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3. 1, 1'-二茂铁膦氮配体的合成及其在不对称区域选择性钯催化烯丙基取代反应中的应用 ")T\_ME  
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            针对钯催化区域选择性烯丙基取代反应特点，设计合成了1, 1'-二茂铁膦氮配体，配体合成相对简单而且比较稳定。配体在合成时生成一个手性膦，导致了非对映异构体的生成，但可以用柱层析方便地分开，通过测定其单晶结构结合核磁以及产物的极性特点对手性膦的绝对构型给予了确定。 ")T\_ME  
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所合成的配体在钯催化区域选择性及对映选择性的烯丙基烷基化反应中显示了非常高的反应活性，区域选择性最高可以达到99%以上(以支链产物为主)，支链产物ee值最高可以达到97%。综合区域选择性和对映选择性的结果，我们发展的这类新型配体催化体系是已有的各种金属催化区域选择性不对称烯丙基烷基化反应中最为成功的一个。而且值得一提的是，烯丙基醋酸酯范围较广，文献中结果很差的含拉电子基取代的芳基以及甲基取代的端基烯丙基醋酸酯也可以有较高的区域选择性和对映选择性(例如对于对腈基苯基取代的烯丙基醋酸酯底物，支链进攻和端基进攻产物比例仍高达 90/10，支链产物ee: 95%；对于甲基取代的烯丙基醋酸酯底物，支链进攻和端基进攻产物比例仍高达97/3以上，支链产物ee: 94% )。 ")T\_ME  
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            此外在钯催化区域选择性不对称烯丙基胺化反应中所合成的配体也显示了很高的活性及选择性，区域选择性最高可以达到97%以上(以支链产物为主)，支链产物ee值最高可以达到98.2%。该方法是合成手性烯丙基胺类化合物的一个非常适用方法。对于烯丙基烷基化和烯丙基胺化反应中对于配体要求的不同，我们也给予了合理的解释。主要原因是配体中BINOL羟基由于会和苄胺形成分子内氢键而对反应的选择性起到了关键作用。我们也通过设计配体和反应给予了证明。 ")T\_ME  
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            对其他亲核试剂如硫、氧作了一些试探工作，和文献工作相比，我们合成的配体初步显示较为有效，具有良好的发展前景。 ")T\_ME  
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            所合成的配体除了适合于非对称底物的烯丙基取代反应外，对于对称的烯丙基醋酸酯也有非常好的结果。对于1, 3-二苯基烯丙基醋酸酯的烷基化和胺化反应，ee值最高分别为93% 和98%，此外，在对1, 3-二甲基烯丙基醋酸酯的烷基化反应中ee值最高也可达65%。而且，值得注意的是这类配体的反应活性都非常高，对于由于催化剂活性低难以在工业上应用的钯催化烯丙基取代反应来说，这无疑是一大喜讯。 ")T\_ME  
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4. 1, 1'-平面手性二茂铁膦氮配体在钯催化烯丙基取代反应中的应用 ")T\_ME  
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对于1, 1'-二茂铁膦氮配体，在我们小组工作的基础上，首先通过对两对只具有平面手性的配体之间的催化结果比较，证明了平面手性的确可以作为一种独立手性诱导；其次通过对p-烯丙基钯络合物动力学研究，发现在反应过程中除了组分之间热力学因素导致的比例问题外，各个组分反应活性差别也是决定产物ee值高低的一个重要因素。 ")T\_ME  
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This thesis focused mainly on studying the role of planar chirality in asymmetric catalysis, synthesizing novel ferrocene ligands and applying them to palladium-catalyzed allylic substitution reactions. ")T\_ME  
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            Planar chiral ferrocene compounds have been extensively used as ligands in asymmetric catalysis. The role of planar chirality has, however, been more or less neglected. The palladium-catalyzed allylic substitution reaction is one of the most important reactions in constructing C-C and C-hetero atom bonds. The asymmetric study was limited to the symmetrical 1, 3-diphenyl allylic system. There were few successful examples of regioselectivity in reactions of unsymmetrically allylic derivatives, and enantioselectivities obtained with prochiral nucleophiles. In this thesis, it was intended to investigate the role of planar chirality, and to design and synthesize novel ligands. ")T\_ME  
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1. The role of planar chirality ")T\_ME  
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            Thioether deveritives of ferrocenyl oxazolines were synthesized conveniently from ferrocenyl oxazolines with high diasteroselectivities (>99/1). All the ligands were found to be effective in the palladium-catalyzed allylic alkylation with 1, 3-diphenylprop-2-enyl acetate, with the highest ee being 98%. In addition, these ligands showed higher activity than thioether deveritives of phenyl oxazolines. By comparing the results with several pairs of diastereoisomeric ligands or ligands only with planar chirality, the ee and the absolute configuration of the products were found to be determined mainly by the central chirality , however, the matching  of planar chirality with central chirality is very important in obtaining high enantioselectivity. The palladium complexes were synthesized and characterized by X-ray diffraction and solution NMR. The high ee of the products was caused by both kinetic and thermodynamic effects. The ee was low when using ligands with only planar chirality because of low diastereoselectivity during the complexation between sulfur and palladium, with the formation of new chiral center on sulfur. ")T\_ME  
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Selenide deveritives of ferrocenyl oxazolines were also synthesized from ferrocenyl oxazolines with high diasteroselectivities (>99/1). All the ligands were found to be effective in palladium-catalyzed allylic alkylation and the highest ee was 99.3%. Planar chirality did not play a decisive role in enantioselective control. These ligands are less reactive, but this is the highest enantioselectivity yet reported for selenide-containing  ligands. ")T\_ME  
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In order to avoid the new chiral center during the coordination between palladium and sulfur, phosphino deveritives of ferrocenyl oxazolines were also synthesized. With these ligands, high ee was realized in palladium-catalyzed allylic alkylation  (94.6%) and amination (97.2%). We studied effects of additives in the allylic amination reaction. We found that (n-Bu)_{4NF could improve the reactivity and enantioselectivity. When ligands with only planar chirality were used in the two model reactions (allylic alkylation and amination), comparatively high enantioselectivities were obtained. In addition, higher enantioselectively was obtained when the groups on the oxazoline ring were less sterically demanding. That is, substrate will be closer to the backbone of ferrocene. These results indicated that the planar chirality effected the asymmetric induction by the interaction between the substrate and the backbone of ferrocene, especially the nonsubstituted Cp-ring. ")T\_ME}  
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In conclusion, in the palladium-catalyzed allylic substitution reaction using 1, 2-disubstituted planar chiral ferrocene ligands, planar chirality did not play decisive role in enatioselective control. However, the matching of planar chirlity with central chirality is very important in obtaining high enantioselectivity. ")T\_ME  
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2. Synthesis and application of planar chiral ferrocene modified bisphosphine pocket ligands ")T\_ME  
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            A series of planar chiral ferrocene modified bisphosphine pocket ligands were synthesized, which showed stronger inductive effects with the aid of planar chirality. These ligands were found to be very effective in construction of quaternary carbon centers by using asymmetric allylic alkylation. Some non-coded a,a-disubstituted amino acids could be obtained with up to 75.3% ee by using ketone imino esters as nueclophilles in the allylic alkylation reaction. The enolates of simple ketone could also be used as nueclophilles here, yielding a,a-disubtituted ketones with ee’s up to 95%. In many cases, the results were better than those reported for phenyl-derived ligands. The products here are very useful but difficult to prepare by other methods. ")T\_ME  
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In addition, planar chiral ferrocene modified P, N- pocket ligands were synthesized, which gave good enantioselectivity in palladium-catalyzed allylic substitution of 1, 3-diphenylprop-2-enyl acetate (85% ee).  Phosphino ferrocenyl carboxylic acid with only planar chirality also gave good enantioselectivity in palladium-catalyzed allylic substitution of   cycloalkeny-acetates (61.8% ee). ")T\_ME  
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3. Synthesis and application of 1, 1’-ferrocene P, N-ligands in enatio- and regio-selective palladium-catalyzed allylic substitution reactions ")T\_ME  
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            A new type of ferrocene based P, N-ligands has been designed and synthesized conveniently with the aim of regio- and enantio-selective control in palladium-catalyzed allylic substitution. A new phosphine chiral center was generated during synthesis leading to two diasteroisomers, which were easily isolated using column chromatography. Structure determination was done using X-ray diffraction and NMR spectroscopy. ")T\_ME  
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All the ligands synthesized here are very effective in regio- and enantio-selective palladium-catalyzed allylic alkylation of mono-substituted allylic acetates. High selectivity could be achieved for a very wide range of substrates (up to branch / linear > 99 / 1 and 97% ee for the branch product). In many cases, our catalyst is the most successful one in terms of substrate scope, activity of the catalyst, yields, regoiselectivity and enantioselectivity. High regio- and enatio-selectivity could be obtained for the electron-withdrawing substituted phenyl or the methyl substituted allylic acetates (for 4-cynophenyl allylic acetate, branch / linear 90 / 10 and 95% ee for the branch product; for methyl allylic acetate, branch / linear > 97 / 3 and 94% ee for the branch product). ")T\_ME  
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            In addition, these ligands were also effective in palladium-catalyzed allylic amination of monosubstituted allylic acetates, with ee up to 98.2% (for branch product) and regioselectivity up to 97 / 3. It afforded a practical method to synthesize chiral allylic amines. We also give an explanation for the different requirements for ligands in these two reactions (alkylation and amination). It was also shown that the free OH in the ligand was very important in selective control by hydrogen bonding to the benzylamine. ='_3qn.  
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In preliminary, these ligands also showed good enantioselective control using other nuclephiles like sulfur or oxygen. ='_3qn.  
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Apart from the unsymmetrical substrates, the symmetrical allylic acetates were also used in allylic alkylation and amination reactions with these ligands, with ee’s up to 93% and 98% respectively for 1, 3-diphenylprop-2-enyl acetate. In addition, 65% ee was obtained for 1, 3-dimethylprop-2-enyl acetate. Interestingly, the reactivities of these ligands are all very high. That is encouraging for palladium-catalyzed allylic substitution reactions which is difficult to use in industry due to the current low reactivity of catalysts. ='_3qn.  
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4. Application of 1, 1'-Planar chiral P, N-ligands into palladium-catalyzed allylic substitution ='_3qn.  
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Based on the work on our group, we synthesized two pairs of 1, 1'- P, N-ligands with only planar chiraltiy. Comparing the results from them, planar chirality was shown to be useful for controling the enantioselectivity by itself. Kinetic study of p-palladium allylic complexes showed that in addition to the ratio of different species in the complexes, the different reactivities of the different species played a key role in enantiocontrol. ='_3qn.  
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