手性有机小分子催化烯胺不对称还原

手性胺是合成天然产物和手性药物的重要中间体，亚胺和烯胺的不对称催化还原是制备手性胺最直接有效的方式之一。手性有机小分子催化的亚胺不对称还原已取得了可喜的进展，但到目前为止，有机小分子催化的烯胺不对称还原，尤其是环状烯胺的不对称还原还少有报道。 本研究从手性叔丁基亚磺酰胺出发，设计并合成了一系列含有叔丁基亚磺酰基的新型脲类及硫脲类催化剂，并将其用于催化三氯硅烷对烯胺的不对称还原，尤其是1, 4-二氢吡啶酯类环状烯胺的不对称还原。通过对催化反应条件的优化，发现当添加1eq H2O时，反应收率和对映选择性明显提高，获得高达99% 的收率和88% ee，同时也取得了很好的非对映选择性（dr = 8:92）。首次实现了三氯硅烷对1, 4-二氢吡啶酯类环状烯胺的高立体选择性还原。 通过机理方面的研究，我们推测反应过程中可能是：首先，底物1, 4-二氢吡啶酯与催化剂形成氢键而被活化，当加入添加剂后，添加剂与三氯硅烷反应释放出一个质子，然后受活化的1, 4-二氢吡啶酯捕获该质子转变成更活泼的亚胺正离子的中间体。随后，在催化剂上的手性硫氧的活化下，三氯硅烷的负氢加成到受活化的亚胺正离子的中间体上，最后生成比较有利的反式产物1, 4, 5, 6-四氢吡啶乙酯。 Calalytic enantioselective reduction of imines and enamines represents one of the most straightforward and efficient methods for the preparation of chiral amines, which is an important class of intermediates for the synthesis of natural products and chiral drugs. Significant progresses have been made in organocatalytic enantioselective reduction of imines. However, asymmetric reduction of enamines, especially of cyclic enamines catalyzed by small organocatalysts has scarcely been reported. In this study, starting from chiral tert-butanesulfinamide, a series of structurally simple tert-butanesulfinyl urea and thiourea organocatalysts were developed and employed in asymmetric reduction of enamines by triclorosilane, particularly in the reduction of cyclic enamines such as Hantzsch 1, 4-dihydropyridines. During the optimization of reaction condictions, we found that the addition of one equivalent of H2O could significantly improve the yields and enatioselectivities. Under optimal condictions, 99% yield, up to 88% ee, and 8:92 diastereomeric ratio were obtained. Thus, we have for the first time realized the highly stereoselective reduction of Hantzsch 1, 4-dihydropyridines catalyzed by triclorosilane. As for the mechanism, we speculate that the Hantzsch 1, 4-dihydropyridine was firstly engaged with the catalyst through hydrogen bond. The proton released from the reaction of the additive and triclorosilane next added to one of the C=C bond to make an active iminium intermediate, which was then attacked by the nucleophlic hydrogen of HSiCl3 activated by the Lewis basic sulfinyl function of the catalyst to provide superior trans-1, 4, 5, 6-tetrahydropyridine products.

路易斯碱催化还原胺化反应研究

胺及其衍生物是很多重要生物活性分子的结构单元，是合成天然产物和手性药物的重要中间体。 直接还原胺化由于其合成步骤简单而成为制备二级胺和三级胺的简便方法。为了发展一种较为简便的直接还原胺化反应，我们把研究的重点放在开发一种简便实用的有机小分子催化方法上。由文献调研可知，现已报道的直接还原胺化方法大多是催化醛或酮与一级胺或者脂肪二级胺的直接还原胺化，而醛或酮与芳香二级胺的直接还原胺化却尚无报道。在本文中，我们发现用简单的四甲基乙二胺(TEMED)在室温下以二氯甲烷为溶剂即可催化三氯氢硅对酮和芳香二级胺之间的直接还原胺化反应，并取得了高达92%的收率。该反应条件温和，底物普适性广，各种类型的酮均可以与芳香二级胺进行直接还原胺化，并且得到比较满意的收率。 同时，我们从手性Sulfoximine出发，设计和合成了一系列的Sulfoximine类新衍生物，并将其应用于间接还原胺化反应中。遗憾的是我们并没有得到预期的不对称催化效果。 Amines and their derivatives are basic structural motifs in natural products and pharmaceuticals and highly versatile building blocks for various organic substrates. Direct reductive amination (DRA) is a convenient method for the preparation of secondary and tertiary amines owing to its operational simplicity. In an effort to develop a simple and convenient procedure for direct reductive amination reaction, we focused our study on search for a mild and efficient organocatalytic system. In the literature, there are many reports concerning DRA between aldehydes or ketones and either primary amines or secondary aliphatic amines. But there are no reports concerning DRA between aldehydes or ketones and secondary aromatic amines. In this study, we have developed a highly practical method for the synthesis of tertiary amines by the direct reductive amination of ketones and secondary aromatic amines with tetramethylethylenediamine (TEMED) as the catalyst using HSiCl3 as the reducing agent in dichloromethane (affording up to 92% yield). This method can be carried out under mild conditions and is compatible with many functional groups. A variety of ketones were efficiently aminated with secondary aromatic amines to afford the corresponding amines in good to excellent yields. Starting from chiral sulfoximine, we designed and synthesized a series of new sulfoximine derivatives and tested their efficiencies as asymmetric organocatalysts for the reduction of imines, which, unfortunately, only exhibited low catalytic activity and enantioselectivity.

具有环氧化酶-2选择性抑制活性的多取代蒽醌的合成

1-甲基-2-甲氧羰基-3, 6, 8-三羟基-7-甲氧基蒽醌是从唐菖蒲干球茎中分离到的具有环氧化酶-2选择性抑制活性的多取代蒽醌类化合物。本文试图合成该化合物，实现了其类似物的合成，同时发现了几个未见报道的反应。 1．通过Diels-Alder 反应合成了关键中间体——3-甲基-5-羟基-1, 2, 4-苯三甲酸三甲酯，1-COOMe选择性水解产物与1, 2, 3-三甲氧基苯进行分子间Friedel-Crafts反应的产物再进行分子内Friedel-Crafts反应得到了目标产物的类似物1-甲基-2-甲氧羰基-3-羟基-6，7，8-三甲氧基蒽醌（路线1）。目标产物及其它类似物的合成正在进行中。 2．以乙酰乙酸甲酯和巴豆醛为原料，经过Michael加成、分子内的Aldol反应、芳香化、选择性甲酰化和还原反应，得到关键中间体2-甲基-3-羟甲基-6-甲氧基苯甲酸甲酯及其衍生物。通过该化合物与3，4，5-三甲氧基苯甲酸甲酯进行Friedel-Crafts烷基化反应得到了多取代的二苯基甲烷衍生物，拟进一步关环合成目标化合物（路线2）。 3．发现邻甲氧基苯甲酸甲酯中酯甲基可以被正丁基锂和仲丁基锂中烷基交换生成相应的酯，反应的机理不明确。当使用叔丁基锂时，得到的是邻甲氧基苯基叔丁酮，这个方法可以用来合成芳基叔丁酮类化合物。 4．以2-苄氧基-6-甲基苯甲酸甲酯为原料进行氯甲基化反应时，以苯和二氯乙烷作溶剂，发生了苄基的迁移和芳环的偶联，分别得到2，2'-二甲基-3，3'-二甲氧羰基-4，4'-二羟基联苯和2，2'-二甲基-3，3'-二甲氧羰基-4，4'-二羟基-5，5'-二苄基联苯。这是对称联苯合成的新方法。 5．水杨酸羟基邻对位的选择性甲酰化可以分别通过水杨酸和水杨酸甲酯用HMTA/CF3COOH来实现。 6．Lewis酸催化3，4，5-三甲氧基苄醇环化成1, 2, 3, 6, 7, 8, 11, 12, 13-nonamethoxyl-10,15-dihydro-5H-trbibenzo [a, d, g] cyclononene (NDTC)，产率(54%)高于已有方法（12%）。 Methyl 3,6,8-trihydroxy-7-methoxy-1-methylanthraquinone-2-carboxylate is a new COX-2 selective inhibitor isolated from Gladiolus gandavensis. Two strategies were investigated to synthesis this compound, in which some important reactions were discovered. 1. The key intermediate 5-hydroxy-3-methylbenzene-1,2,4-tricarboxylic acid 2,4-dimethyl ester was prepared via Diels-Alder reaction followed by selective hydrolysis of 1-COOMe. This compound was coupled with 1,2,3-trimethoxybenzene and the product undergo intramolecular Friedel-Crafts reaction to give methyl 3-hydroxy-5,6,7-trimethoxy-1-methylanthraquinone-2-carboxylate (1st route). The target compound and other analogues are being prepared with the same procedure. 2. The key intermediates methyl 3-hydroxymethyl-6-methoxy-2-methylbenzoate and its derivatives were prepared starting from crotonaldehyde and methyl acetoacetate via Michael addition, intramolecular aldol reaction, aromatization, formylation and reduction. The intermediates were coupled respectively with derivatives of gallic acid to give polysubstituted diphenylmethane. However, attempts to cyclize these compounds to the target compounds and analogues were not successful (2nd route). 3. In the process for ortho-lithiation of methyl 2-methoxybenzoate, the substrate converted respectively to n-butyl 2-methoxybenzoate and sec-butyl 2-methoxybenzoate when n-BuLi and sec-BuLi were used. However, tert-BuLi reacted with methyl 2-methoxybenzoate afford 2-methoxyphenyl tert-butyl ketone, which could be used to synthesize aryl tert-butyl ketones. 4. The transformtion of methyl 2-benzoxy-6-methylbenzoate to dimethyl 4,4'-dihydroxy-2,2'-dimethylbiphenyl-3,3'-dicarboxylate in benzene, and dimethyl 5,5'-dibenzyl-4,4'-dihydroxy-2,2'-dimethylbiphenyl-3,3'-dicarboxylate in 1,2-dichloroethane in the presence of ZnCl2 provides a new method for the synthesis of symmetric biphenyl. 5. The formylation of salicylic acid at C-5 and methyl 2-hydroxybenzoate at C-3 could be regioselectively realized by using HMTA/CF3COOH. 6. Racemic 1, 2, 3, 6, 7, 8, 11, 12, 13-nonamethoxyl-10, 15-dihydro-5H-trbibenzo [a, d, g] cyclononene was prepared via Lewis acids catalyzed trimerization of 3, 4, 5-trimethoxylbenzyl alcohol with yield (54%) higher than the reported procesure (12%).

路易斯碱催化的烯胺不对称还原研究

手性胺不仅是许多天然产物和手性药物的重要结构单元，而且也是非常有用的拆分试剂、手性配体和手性催化剂。亚胺和烯胺的不对称催化还原是制备手性胺的最直接有效的方式之一，手性有机小分子催化的亚胺不对称还原已取得了很大的进展，但到目前为止，有机小分子催化的烯胺不对称还原极少见文献报道。 本研究以廉价的三氯氢硅为氢源、DMF 等路易斯碱为催化剂实现了烯胺的高效还原。通过反应条件的优化，各种烯胺底物在0.1 eq. DMF 催化下、12 个小时内可以获得非常高的收率（>93%）。 在本课题组前期研究的基础上，我们筛选并设计了一系列以手性哌啶酸和叔丁基亚磺酰胺为母体的有机小分子路易斯碱催化剂，它们能催化三氯氢硅对(Z)-N-苄氧羰基-1-苯基丙烯胺的不对称还原，获得很高的收率和中等的对映选择性，并且具有很好的底物普适性。另外，通过机理方面的研究，我们推测在反应过程中一分子烯胺先捕获一个质子而转变为亚胺正离子，然后受到路易斯碱活化的三氯氢硅中的富电氢原子进攻该亚胺正离子得到还原产物。 另外，本文列出了在此课题进展中所发现的一些新反应，并且试图去阐释这些反应的作用机理。 Catalytic enantioselective reduction of imines and enamines represents one of the most straightforward and efficient methods for the preparation of chiral amines, which are not only important building blocks of many natrural products and chiral drugs, but also can serve as useful resolution reagents, chiral ligands and chiral catalysts. By now, asymmetric reduction of enamines catalyzed by organocatalysts has scarcely been reported, although organocatalyzed enantioselective reduction of imines has already gained great progress. In this study, we report the DMF-catalyzed reduction of enamines with high yields using HSiCl3 as the reducing agent. Under the optimized reaction conditions, various enamines can be reduced in the presence of 0.1 eq. DMF with high yields (>93%) in 12 hours. We screened a set of Lewis base organocatalysts derived from chiral pipecolinic acid and tert-butanesulfinamide for the reduction of (Z)-N-Cbz-1- phenylpropenamine, including newly designed ones and some of those previously developed in our lab. However, only moderate stereoselectivities, albeit high yields were obtained. As for the mechanism, we speculate that the enamine firstly engages a proton to form an iminium species, which is then attacked by the nucleophlic hydrogen of HSiCl3 activated by Leiws base. During the above studies, we have also discovered some new reactions, for which feasible mechanisms were proposed.

苯乙酮、氨甲酸酯参与的直接Mannich反应

Mannich反应是有机化学中最重要的碳-碳键形成反应，其产物是合成手性胺的通用中间体。间接Mannich反应使用不稳定的预制烯醇等当体，以未修饰的酮为给体的直接方法将增强Mannich反应的效率。针对低活性苯乙酮、氨甲酸酯参与的直接Mannich反应，研究工作将更具挑战性。 在前期实验中，我们发现Lewis酸-NbCl5可高效催化苯乙酮、芳香醛、芳香胺三组分直接Mannich反应，反应在环境温度下进行，高收率获得Mannich碱。这是以苯乙酮参与的Mannich反应中，实现催化量Lewis酸催化的首次报道。该方法高效且操作简单。但就底物而言，对易去保护、低活性的氨甲酸酯类底物收率较低。我们设想Brønst酸可解决此类底物问题。令人高兴的是，杂多酸可高效催化芳香酮、芳香醛、氨甲酸酯三组分直接Mannich反应，反应在环境温度下进行，高收率获得N-保护的β-氨基酮。该方法底物范围广泛，普适性强且催化剂便宜。 基于杂多酸在苯乙酮、氨甲酸酯为底物直接Mannich反应中的高效性，我们设想杂多酸与功能化的手性有机小分子-手性伯胺组装可解决催化剂回收问题，同时实现不对称催化。实验结果表明，非共价键固载手性伯胺不能有效催化苯乙酮为底物的直接Mannich反应，无论是对映选择性还是收率均较低。随后，我们以丙二酸酯及α-氨基砜为底物，以增强底物活性，同时绕开亚胺的不稳定性。辛可宁伯胺以氢键双活化底物，有效催化原位产生氨甲酸酯类亚胺与丙二酸酯的Mannich反应，高收率获得Mannich碱，ee值中等。 我们采用逐步解决问题的策略解决Mannich反应中的部分问题并在Lewis酸催化、Brønst酸催化、非共价键固载手性伯胺催化及手性伯胺氢键催化的直接Mannich反应中做出了有益探索。 The Mannich reactions are among the most fundamental carbon-carbon bond forming reactions in organic chemistry, and the reaction products are versatile intermediates in the synthesis of chiral amines. The indirect Mannich reaction uses preformed enolate equivalents. However the preformed enolates are unstable. Thus, a direct methodology based on unmodified ketone donors would enhance the efficiency of the Mannich reaction. Especially researches for the directed Mannich reactions of acetophenone, carbamate, which own lower activities, will be more challengeable. In the initial experiments, we found an efficient Lewis acid-NbCl5 which could catalyze three-component Mannich-type reaction of acetophenone, aromatic aldehydes and aromatic amines at ambient temperature in high yields. This is the first report that use catalytic amount of Lewis acid in the Mannich reactions of .acetophenone. The method reported is not only simple to operate but also efficient. However, as far as amines are concerned, the substrates of carbamates which can be deprotected more easily and less reactive than amines give low yields. We envisaged that Brønsted acid would resolve this problem. Pleasingly, heteropoly acids (HPA) efficiently catalyzed one-pot three-component Mannich reactions of aryl aldehydes, aryl ketones, and carbamates at ambient temperature and afforded the corresponding N-protected β-amino ketones in good to excellent yields. This method provides a novel and improved modification of three-component Mannich reactions in terms of a wide scope of aldehydes, ketones and carbamates, economic viability. Based on the high efficiency of heteropoly acids in the Mannich reaction of acetophenone and carbamates, we envisaged that if HPA were combined with functionalized chiral organocatalysts–chiral primary amines the assemblies may be able to act as recoverable asymmetric organocatalysts. The results of exprimentals showed that noncovalently supported heterogeneous chiral primary amine couldn’t effectively catalyze the Mannich reactions which own two the substrate of acetophenone regardless of enantioselectivity and yield. Then, we employed malonates and α-amido sulfones as substrates to enhance reactivity of substrates and circumvent the instability of imines. A moderately enantioselective and highly yield Mannich reaction with in situ generation of carbamate-protected imines from stable α-amido sulfones catalyzed by cinchonine primary amine catalyst was developed. It is noteworthy that cinchonine primary amine can dual activate substrates through H-bond activation and thus promote the reaction. We applied step-by-step-strategy to resolve some problems in the Mannich reactions and did some instructive explorations in Lewis acid catalysis, Brønst acid catalysis, noncovalently supported heterogeneous chiral primary amine catalysis and chiral primary amine as hydrogen-bond catalysis.