亮点介绍

正三烯胺催化2,5-二烯酮的不对称反电子需求氮杂Diels-Alder反应Angew.Chem.Int.Ed.2013,52,14173~14176远端手性控制一直是不对称催化领域的一个重大挑战,而以前的研究主要依靠酶催化和分子内手性信息的传递.四川大学华西药学院陈应春课题组近年来发展了三烯胺催化模式,能够实现2,4-烯醛、酮类化合物远端ε-位活化,在三烯胺中间体β,ε-位发生高立体选择性环加成反应.鉴于含有α'-CH的2,4-二烯酮1a易形成交叉共轭的三烯胺,不能实现远端ε-位活化,该课题组采用打断的2,5-二烯酮1b,通过远端δ,ε-C=C的诱导效应产生     

不对称三烯胺催化的发展

手性胺可以与多不饱和羰基化合物原位生成三烯胺中间体,其给电子效应根据插烯规则可通过共轭不饱和体系传递,进而提高三烯胺体系的HOMO能量,并能够在远端β,ε-或δ,ε-位与多种缺电子烯烃发生Diels-Alder环加成反应。采用这种合成策略,可以制备许多结构多样和复杂的环状手性化合物。这种策略除了能够高效地在羰基化合物远端直接实现官能团化,更重要的是ε-反应位点即使距离催化剂手性中心达七个键之远,仍能获得优秀的立体选择性控制,这在不对称合成中具有重要的研究价值。本文将总结近年来不对称三烯胺催化机制的发现及发展,重点介绍2,4-二烯醛、多种二烯酮、含羰基芳香化合物经由三烯胺、交叉共轭三烯胺或形式三烯胺进行的不对称反应,并对手性胺催化的进一步应用进行展望。     

HOMO活化的2-吡喃酮与2,5-二烯酮反电子需求的不对称Diels-Alder反应

2-吡喃酮的不对称Diels-Alder（DA）反应可以高效、高立体选择性地构建多官能团化的双环内酯手性骨架.目前贫电子的2-吡喃酮多依赖于手性Lewis酸通过降低LUMO能量与富电子烯烃发生反电子需求环加成反应,活化机制相对单一,因此发展新的活化模式合成此类骨架尤为重要.报道了在金鸡纳碱衍生的伯胺作用下,环状2,5-二烯酮能形成延伸型三烯胺中间体,从而活化远端δ,e-双键,与3-甲氧羰基-2-吡喃酮发生反电子需求不对称DA反应.该方法能够以中等到良好的收率（46%～82%）、优异立体选择性（93%～99%ee,>19∶1 dr）高效构建含有多个连续手性中心的双环内酯化合物.通过内酯醇解开环,能高收率进一步转化为手性环己烯醇化合物.我们发展的经HOMO活化的不对称反电子需求DA反应可以为构建手性双环内酯骨架提供一种较为实用的新方法.     

绣线菊碱C、D关键BCD三环中间体的不对称合成

从易于制备的非手性烯丙醇化合物出发,以经典的的Sharpless不对称环氧化为关键反应构建烯丙仲醇手性中心,共经10步线性步骤以28.6%的总收率首次实现了绣线菊碱C、D全合成路线中BCD三环中间体(-)-4的不对称合成,该合成路线中涉及3个新化合物,其结构经¹H NMR, ¹³C NMR和HR-MS(ESI)表征。     

左旋薄荷醇的不对称合成

以4-羟基-2-丁酮和异丙叉丙酮为起始原料,经羟醛缩合、不对称氢化、羰基还原、钌催化氢化等4步反应制得左旋薄荷醇。总产率为33%,非对映体过量de值达到93%。详细探讨了铜催化剂及其用量、手性配体的选择、反应溶剂和时间等因素对胡薄荷烯酮不对称氢化反应的影响。中间体及目标化合物均通过了¹H NMR、¹³C NMR和HRMS等技术手段的分析测定及结构表征。     

手性方酰胺催化巴比妥酸和硝基烯的不对称Michael加成反应

用手性环己二胺衍生的方酰胺催化1,3-二甲基巴比妥酸和硝基烯的不对称Michael加成反应,合成了一系列新型巴比妥衍生物,其结构经¹H NMR和¹³C NMR表征。并考察了底物结构对反应收率和立体选择性的影响。结果表明：该反应可获得较高的收率(80%~100%)和中等至良好的对映选择性(ee 43%~90%)。     

2,5-二芳基-1,4-苯醌类化合物的合成

以1,4-苯醌和芳基硼酸为原料,通过溴代和Suzuki偶联反应合成了8种2,5-二芳基-1,4-苯醌类化合物,收率74%～84%,其结构经¹H NMR、¹³C NMR和HR-MS(ESI-TOF)表征。     

手性特窗酸类化合物的合成

考察了一系列手性吡咯烷叔胺硫脲催化剂对4 氯代乙酰乙酸乙酯与亚胺的不对称Mannich/Cyclization串联反应的催化性能，合成了一系列具有潜在生物活性的手性特窗酸类衍生物，产率62%～92%，对映选择性68%～96%，产物结构经¹H NMR, ¹³C NMR, IR和HR-MS确证。并对反应条件进行了优化，对反应机理进行了推测。     

亮点介绍

通过三烯胺机制催化2,4-二烯酮的不对称Diels-Alder反应Angew.Chem.Int.Ed.2012,51,4401～4404三烯胺(trienamine)机制作为新发展的一种有机胺催化模式,已经成功应用于通过HOMO-活化的不对称Diels-Alder反应中,然而仅有的几篇报道都局限于2,4-二烯醛底物.四川大学华西药学院     

有机催化(E)-4-巯基丁-2-烯酸乙酯与4-亚胺基吡唑啉-5-酮的不对称Mannich反应

以金鸡纳碱衍生的手性双功能方酰胺为催化剂,实现了(E)-4-巯基丁-2-烯酸乙酯与4-亚胺基吡唑啉-5-酮的不对称Mannich反应,高效构建了一系列含有四取代的氨基立体中心及N,S-缩醛结构的手性吡唑啉-5-酮类化合物,收率90%,对映选择性95/5 er,其结构经¹H NMR, ¹³C NMR和HR-MS(ESI-TOF)表征。     

A convenient route to enantiopure 3-aryl-2,3-diaminopropanoic acids by diastereoselective Mannich reaction of camphor-based tricyclic iminolactone with imines

A novel and convenient route to the asymmetric synthesis of 2,3-diamino acids via Mannich reaction of iminolactones 1a and 1b with N-protected imines has been achieved in good yields (up to 95%) and high diastereoselectivity (dr: >99:1). Hydrolysis of the Mannich adducts under acidic conditions furnished the desired 3-aryl-2,3-diaminopropanoic acids in good yields (up to 85%) with excellent enantiomeric excesses (99% ee).     

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)‐Sitagliptin

In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona‐based‐squaramide‐catalyzed enantioselective Mannich reactions of diverse imines or α‐amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α‐amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling‐reagent‐free synthesis of the antidiabetic drug (?)‐(R)‐sitagliptin.     

3-苯基异香豆冉酮衍生物的不对称Mannich反应研究

研究了双功能手性硫脲-叔胺催化剂催化的3-苯基异香豆冉酮衍生物与N-保护亚胺的不对称Mannich反应,高收率、高对映选择性(88%~98%)地合成了一系列具有连续季碳叔碳手性中心的新化合物,其结构经1HNMR和13C NMR表征。     

Thermal effects in the organocatalytic asymmetric Mannich reaction

The proline-catalyzed direct asymmetric Mannich reaction between cyclohexanone, formaldehyde, and various anilines is thermally accelerated. With only 0.5 mol % of catalyst, Mannich products with up to 98% ee have been obtained after a short period of time in reactions performed under microwave irradiation. In situ reduction of the resulting ketones affords N-aryl amino alcohols in up to 86% yield.     

含三氟甲基均三唑环的Mannich碱的合成

以3-三氟甲基-4-氨基-5-巯基-1,2,4-三唑(1)为原料,与芳醛在冰醋酸中缩合得相应Schiff碱(2～5),(2～5)与各种仲胺和芳胺在室温下反应,制得24个新的Mannich碱(6～9),利用IR,^1HNMR、MS和元素分析确定了这些化合物的结构。     

β-羰基酸与N-Boc靛红亚胺的脱羧Mannich反应合成3-氨基-3,3'-二取代氧化吲哚衍生物

以5 mol%辛克宁衍生的手性双功能硫脲叔胺为催化剂,β-羰基酸和N-Boc靛红亚胺为原料,经脱羧Mannich反应合成了14个3-氨基-3,3'-二取代氧化吲哚衍生物,收率73%~99%,其结构经1H NMR,13C NMR和HR-MS(ESI)确证。     

Iridium‐Catalyzed Reductive Nitro‐Mannich Cyclization

A new chemoselective reductive nitro‐Mannich cyclization reaction sequence of nitroalkyl‐tethered lactams has been developed. Relying on the rapid and chemoselective iridium(I)‐catalyzed reduction of lactams to the corresponding enamine, subsequent nitro‐Mannich cyclization of tethered nitroalkyl functionality provides direct access to important alkaloid natural‐product‐like structures in yields up to 81 % and in diastereoselectivities that are typically good to excellent. An in‐depth understanding of the reaction mechanism has been gained through NMR studies and characterization of reaction intermediates. The new methodology has been applied to the total synthesis of (±)‐epi‐epiquinamide in four steps.     

间硝基苯甲醛或间氯苯甲醛与芳香胺和芳香酮的Mannich反应

间硝基苯甲醛或间氯苯甲醛与芳香胺和芳香酮在20~25℃和催化量的浓盐酸催化下能直接进行Mannich反应, 用一步合成法合成15个1-芳基-3-芳胺基(3-硝基苯基)丙酮。产率为68~87%。产物结构经元素分析, IR, ^1H NMR, MS鉴定。本文还讨论了反应的适宜条件。     

Direct catalytic asymmetric mannich reactions of malonates and beta-keto esters

The first catalytic asymmetric direct Mannich reaction of malonates and beta-keto esters has been developed. Malonates react with an activated N-tosyl-alpha-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)(2) to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active beta-carboxylic ester alpha-amino acid derivatives. A series of different beta-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of beta-keto esters were used as the substrate. The reaction of different beta-keto tert-butyl esters with the N-tosyl-alpha-imino ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)(2) as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active beta-keto alpha-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-alpha-imino ester to the chiral bisoxazoline/Cu(II)-substrate intermediate are discussed.     

A facile direct anti-selective catalytic asymmetric Mannich reaction of aldehydes with preformed N-Boc and N-Cbz imines

Anti-selective Mannich reactions of N-Boc and N-Cbz protected imines with unmodified aldehydes proceeded smoothly under the catalysis of a secondary amine-thiourea catalyst, which led to high yields (70%-95%) and excellent enantioselectivity (up to 96 : 4 dr and >99% ee) under conventional organic synthetic operations.