不对称傅-克反应在构建手性3-取代吲哚中的研究进展

由于手性3-取代吲哚化合物是许多具有生物活性天然产物和药物分子的核心骨架,其合成方法的研究就格外令人注目.尤其是近二十年来,利用手性金属配合物和有机小分子催化剂实现吲哚的C(3)位不对称傅-克烷基化反应已成为有机界广泛研究的热点.按照促进不对称傅-克烷基化反应的手性催化剂进行分类,就近年来其在3-取代吲哚化合物合成中的应用加以综述,并对今后的发展方向进行了展望.     

基于三氟甲基砌块的催化不对称傅-克反应研究进展

引入三氟甲基基团可以显著提高有机分子的化学和代谢稳定性、亲脂性以及在细胞膜中的渗透性,因此发展高效合成三氟甲基化合物,特别是手性三氟甲基化合物的方法具有非常重要的意义.基于三氟甲基砌块的催化不对称傅-克反应可以高效高选择性获得手性三氟甲基芳香化合物,是最近发展起来的一个研究热点.自从日本Mikami小组采用手性钛络合物研究了首例基于三氟甲基砌块的催化不对称傅-克反应,不同种类的手性有机金属催化剂(如手性钛,铜,锌,锆,钯,镱,钇,镍,钙等金属络合物)和手性有机小分子催化剂(如金鸡纳碱,手性脯氨醇硅醚,手性磷酸等)都在这类不对称催化反应中得到应用.作者主要对反应组分(特别是不同类型的三氟甲基砌块)、反应条件、反应机理和合成应用等方面的研究进行了综述.最后,对这类反应所存在的问题和局限性进行了总结,并对今后发展方向作了展望.     

催化不对称Friedel-Crafts反应

傅-克反应是有机化学中最基本的反应之一,但是对于催化的不对称傅-克反应的研究则处于起步阶段。最近这方面的研究获得了突破,本文简要介绍了催化不对称傅-克反应的最新动态,包括各种手性Lewis酸催化体系的开发及其在不对称合成中的应用。     

手性有机分子催化剂在不对称催化中的应用

近三十年来,不对称催化研究获得了迅猛发展[1].按手性催化剂的种类分,一般可分为手性有机金属配合物催化以及路易斯酸、碱等手性有机分子催化.手性有机金属配合物催化剂在不对称还原、不对称氧化等官能团转化反应中的应用,已达到实用阶段;不使用金属的有机分子催化剂由于其对环境友好,也日益被重视,有机合成化学中十分重要的碳-碳键形成反应,如Aldol反应、Diels-Alder反应等,近年来发表了很多使用手性有机分子催化剂的成功的实例.早在1971年Wiechert[2]等人曾以脯氨酸为催化剂,用于分子内不对称醇醛缩合(Aldol)反应,1974年Hajos[3]等…     

Diels-Alder反应在不对称合成中的研究进展

狄尔斯-阿尔德（DA）反应自被发现以来，在有机经学中占有重要地位。对近 年来DA反应不对称合成催化剂（尤其是手性Lewis酸化合物）、手性助剂和手性双 烯三个主要方面的研究进展进行了讨论。     

手性金属配合物应用于不对称Henry反应研究进展

手性β-硝基醇化合物是一类用途广泛的双官能团化合物，不对称Henry加成反应是制备手性β-硝基醇化合物最有效的方法之一，同时该反应在构建碳-碳键的过程中具有优异的原子经济性。在不对称Henry加成反应中，手性催化剂起到至关重要的作用，近年来围绕这一课题取得了许多重要进展。本文将从手性金属配合物中的铜配合物、锌配合物、稀土金属配合物、锰配合物以及钴配合物等多方面综述金属配位型催化剂在不对称催化Henry反应中的研究进展，并对其未来的发展前景进行了展望。      

双锌催化剂催化的吡咯与查尔酮类化合物的不对称傅-克烷基化反应（英文）

报道了分子内双锌催化剂催化的吡咯和查尔酮类化合物的不对称傅-克烷基化反应,分子内双锌催化剂由手性配体(S,S)-1和2 equiv.的二乙基锌原位反应生成.温和条件下,在15 mol%的催化剂作用下,反应以优秀的产率(高达99%)和优秀的对映选择性(对映体过量值高达99%)生成一系列β-吡咯二氢查尔酮化合物.并提出了一个可能的反应机理来解释反应的手性诱导过程.     

有机催化吲哚与环状酮亚胺膦酸酯的傅-克反应合成含手性季碳胺基膦酸衍生物

在有机合成中,季碳中心的构建始终是一项充满挑战的课题.含手性季碳中心的胺基膦酸化合物以其多样的生物活性,如酶抑制剂、抗真菌剂、抗菌剂和抗病毒剂等,受到了科研工作者的广泛关注.目前已有许多合成策略报道,其中亲核试剂与α-酮亚胺膦酸酯的不对称加成策略为含手性季碳中心胺基膦酸衍生物的合成提供了一条简洁有效的路径,但是却鲜有报道,已有的报道也仅局限于乙酰氰、丙酮、硝基甲烷和芳基硼酸作亲核试剂.为满足多样的手性胺基膦酸衍生物的合成需求,新的合成策略和亲核源仍有待进一步发展.值得一提的是,不对称傅-克反应是一种非常有效的构建碳-碳键的合成方法,并已有广泛报道.基于吲哚与亚胺底物的傅-克反应经验,我们研究组发展了一种有机催化吲哚与环状酮亚胺膦酸酯傅-克反应合成含手性季碳胺基膦酸衍生物的方法,使用的有机催化剂是手性磷酸.通过对溶剂、催化剂和温度的筛选发现,使用在3,3′-位引入吸电子的3,5-二三氟甲基苯基取代的H8-BINOL衍生的手性磷酸作催化剂,反应温度为30 oC,溶剂为均三甲苯时,最高能以98%对映选择性得到含手性季碳胺基膦酸酯化合物.该反应操作简单,条件温和,不仅适用于吲哚衍生物,对吡咯也能取得较好结果.总之,该方法提供了一条简洁有效的合成手性胺基膦酸衍生物的途径.     

有机催化吲哚与环状酮亚胺膦酸酯的傅-克反应合成含手性季碳胺基膦酸衍生物（英文）

在有机合成中,季碳中心的构建始终是一项充满挑战的课题.含手性季碳中心的胺基膦酸化合物以其多样的生物活性,如酶抑制剂、抗真菌剂、抗菌剂和抗病毒剂等,受到了科研工作者的广泛关注.目前已有许多合成策略报道,其中亲核试剂与α-酮亚胺膦酸酯的不对称加成策略为含手性季碳中心胺基膦酸衍生物的合成提供了一条简洁有效的路径,但是却鲜有报道,已有的报道也仅局限于乙酰氰、丙酮、硝基甲烷和芳基硼酸作亲核试剂.为满足多样的手性胺基膦酸衍生物的合成需求,新的合成策略和亲核源仍有待进一步发展.值得一提的是,不对称傅-克反应是一种非常有效的构建碳-碳键的合成方法,并已有广泛报道.基于吲哚与亚胺底物的傅-克反应经验,我们研究组发展了一种有机催化吲哚与环状酮亚胺膦酸酯傅-克反应合成含手性季碳胺基膦酸衍生物的方法,使用的有机催化剂是手性磷酸.通过对溶剂、催化剂和温度的筛选发现,使用在3,3′-位引入吸电子的3,5-二三氟甲基苯基取代的H8-BINOL衍生的手性磷酸作催化剂,反应温度为30℃,溶剂为均三甲苯时,最高能以98%对映选择性得到含手性季碳胺基膦酸酯化合物.该反应操作简单,条件温和,不仅适用于吲哚衍生物,对吡咯也能取得较好结果.总之,该方法提供了一条简洁有效的合成手性胺基膦酸衍生物的途径.     

手性相转移催化剂及其在不对称合成中的应用

进行不对称合成反应,反应体系中要有手性因素存在。如手性反应物、手性试剂、手性催化剂或手性溶剂等。使用手性相转移催化剂诱导不对称合成是近十年发展起来的一种手段。虽然目前采用这种方法结果还不能令人满意,但由于简易可行,类似于酶催化作用,故被应用于不对称合成反应。     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.     

α-Amino acid derived enaminones and their application in the synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates and other heterocycles

A new and simple synthesis of novel N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps starting from N-protected α-amino acids. The key intermediates are enaminones, which can also be isolated, characterized, and used for the construction of other functionalized heterocycles, before they spontaneously decompose to pyrrole products. 4-Hydroxypyrroles are prone to partial aerial oxidation but can be efficiently alkylated or reduced to stable polysubstituted pyrrolidine derivatives.     

Specific intramolecular aromatic CH insertion of diazosulfonamides

The chemoselectivity in the intramolecular CH insertion of various diazosulfonamides has been experimentally studied. The results reveal that the aliphatic 1,4-, 1,5-, or 1,6-C(sp³)?H insertions of diazosulfonamides are not accessible, while the aromatic 1,5-C(sp²)?H insertion can be realized specifically by adjusting the diazo-adjacent group. In addition, the general chemoselectivities in the intramolecular CH insertions of diazosulfonyl compounds are summarized. Generally, diazosulfones undergo both aromatic 1,5-C(sp²)?H and aliphatic 1,5- and 1,6-C(sp³)?H insertions, while diazosulfonates undergo aliphatic 1,5- and 1,6-C(sp³)?H insertions. However, diazosulfonamides only undergo aromatic 1,5-C(sp²)?H insertion.     

A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen,heteroatom, and carbon nucleophiles

A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.     

Synthesis of novel chiral bidentate hydroxyalkyl-N-heterocyclic carbene ligands and their application in palladium-catalyzed Mizoroki–Heck couplings and asymmetric addition of diethylzinc to benzaldehyde

A small library of new chiral bidentate hydroxyalkyl-imidazolium salts 1 is conveniently synthesized on multi-gram scale from inexpensive and commercially available chiral pool amino acids. The corresponding carbenes, generated by deprotonation of imidazolium salts 1, in combination with palladium(II) chloride were tested in the Mizoroki–Heck coupling reaction. The most significant results in terms of yields and reactivities were achieved with low catalyst loading. The catalytic activities of these imidazolium salts were also investigated in the asymmetric addition of diethylzinc to benzaldehyde. The use of MgO nanoparticles as an additive in conjunction with these ligands played a crucial role in increasing the efficiency of these reactions.     

Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in Friedländer reaction

In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key keto-precursors and their use in Friedländer condensation are described. This paper also focuses on the stability of these keto intermediates and emphasizes the major differences between indolizinones and pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-products of some experiments.     

N-Heterocyclic carbene-palladacyclic complexes: synthesis,characterization and their applications in the C-N coupling and α-arylation of ketones using aryl chlorides

N-Heterocyclic carbene-palladacyclic complexes 3 were successfully achieved in a one-pot procedure under mild conditions. The structure of 3a was unambiguously confirmed by X-ray single crystal diffraction and it was an active catalyst in the Buchwald-Hartwig amination and α-arylation of ketones even at very low catalyst loadings (0.01?mol%).     

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

An efficient iodine-mediated oxidative Pictet-Spengler reaction in dimethyl sulphoxide (DMSO) using terminal alkynes as the 2-oxoaldehyde surrogate for the synthesis of aryl (9H-pyrido[3,4-b]indol-1-yl)methanones is described. The scope of the protocol includes the total synthesis of Fascaplysin, Eudistomins Y₁ and Y₂. The methodology is extended for preparing pyrrolo[1,2-a]-quinoxaline and indolo[1,5-a]quinoxaline derivatives. The utility of 1-aroyl-β-carbolines was demonstrated by performing palladium-catalyzed β-carboline directed ortho-C(sp2)-H functionalization of the phenyl ring with thiomethyl (SMe) group using DMSO as source and for accessing 4-aryl-canthin-6-ones.     

Facile synthesis of bicyclic 1-arylpyrazol-5-ones

In this Letter, we described a facile method for constructing fused bicyclic 1-arylpyrazol-5-one ring system. We employed various methylene-containing carboxylic acids as the substrates and proved that the pyrazolone ring closure requires activated methylene group in intermediate II. Accordingly, a series of structurally diversified, fused bicyclic 1-arylpyrazol-5-ones was prepared in moderate to high yields using the requisite substrates.