Development of chiral nucleophilic pyridine catalysts: applications in asymmetric quaternary carbon synthesis

TADMAP (1a), a new chiral DMAP catalyst, has been designed to place a C(3)-benzylic trityl group over one face of the pyridine ring, while a C(3)-benzylic acetoxy group creates a chirotopic environment on the other face. TADMAP was prepared in four steps (37% overall) from triphenylacetic acid and (dimethylamino)pyridine and was resolved using camphorsulfonic acid. TADMAP catalyzes the enantioselective rearrangement from oxazolyl phenyl carbonates 4 to azlactones 5, from furanyl phenyl carbonate 8 to the furanone 9, from the benzofuranyl carbonates 11a and 11b to benzofuranones 12a and 12b, and from the indolyl carbonates 11c and 11d to oxindoles 12c and 12d. The products are formed in good yield and, in most cases, with practical levels of enantiomer excess at the newly formed quaternary carbon.     

Design and synthesis of a new type of ferrocene-based planar chiral DMAP analogues. A new catalyst system for asymmetric nucleophilic catalysis

A new first-generation catalyst system for nucleophilic catalysis has been developed. It is based on a planar chiral ferrocene skeleton with either the potent nucleophile 4-(dimethylamino)pyridine (DMAP) or the related 4-nitropyridine N-oxide attached in either the 2- or the 3-position. The syntheses are short, efficient, and enantioselective and X-ray crystal structures of both DMAP-derived catalysts are presented. The DMAP-based catalysts were tested in asymmetric reactions and the 3-derivative 14 showed good activity and a moderate level of enantioselectivity. The sense of induction (selectivity) was studied using molecular modeling and the results pointed at new directions for future generations of catalysts based on this design.     

Catalytic enantioselective desymmetrization of meso-diamines: a dual small-molecule catalysis approach

The desymmetrization of meso-diamines was accomplished via enantioselective monobenzoylation facilitated by the cooperative action of two small-molecule catalysts. A chiral acyl-transfer reagent is formed in situ through the interplay of benzoic anhydride, 4-(dimethylamino)pyridine as a nucleophilic catalyst, and a chiral amide-thiourea cocatalyst.     

新轴手性N,N-Dioxide Biscarbolin衍生物催化酮亚胺的不对称硅氢化反应

以L-色氨酸为原料合成了5个伯酰胺结构的轴手性双咔啉N—O催化剂N2,N2'-二氧-9,9'-二甲基-3,3'-取代甲酰胺-β-双咔啉(4A~4E),并用于不对称催化酮亚胺的还原反应.结果表明,催化剂的催化转化率较高(80%~98%),立体选择性(e.e.值)较好,其中催化剂N2,N2'-二氧-9,9'-二甲基-3,3'-环己基甲酰胺-β-双咔啉(4B)的催化转化率达到了98%,e.e.值达68%.     

有机相酶催化转酯化反应拆分西酞普兰中间体

利用脂肪酶催化的不对称转酯反应成功远程拆分具有季碳手性中心的西酞普兰中间体4-[4-(二甲基氨基)-1-(4’-氟苯基)-1-羟基丁基]-3-(羟基甲基)苄腈(1). 以乙酸乙烯酯作为酰基供体, 通过筛选酶和溶剂, 确定最佳脂肪酶及溶剂分别为Candida antarctica lipase B (Novozym 435)和乙腈; 并在该反应体系中考察了反应温度、二醇1与酰基供体的比例、酶浓度和摇床转速等对反应的影响, 确定优化的反应条件为: 温度30 ℃, 二醇1与酰基供体的物质的量比为1∶5, 酶浓度为10 mg/mL, 摇床转速200 r/min. 分别考察二醇1浓度为60和180 mmol/L的反应情况, 均具有较高的选择性和反应速度. 实验结果表明酶能够多次重复利用.     

An effective use of benzoic anhydride and its derivatives for the synthesis of carboxylic esters and lactones: a powerful and convenient mixed anhydride method promoted by basic catalysts

Various carboxylic esters are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine by the promotion of a basic catalyst such as 4-(dimethylamino)pyridine. A variety of lactones are also prepared in high yields at room temperature from the corresponding omega-hydroxycarboxylic acids with use of 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction occurs with triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular condensation reaction. These methods are successfully applied to the synthesis of erythro-aleuritic acid lactone and an eight-membered-ring lactone moiety of octalactins A and B. The efficiency of the cyclizations is compared to those of other reported lactonizations.     

A flexible and versatile strategy for the covalent immobilization of chiral catalysts based on pyridinebis(oxazoline) ligands

[reaction: see text] Flexible and versatile methods have been developed for the immobilization of chiral pyridinebis(oxazoline) ligands by covalent bonding to a solid support, either by grafting or by polymerization. Different spacers can easily be introduced to modulate the support-ligand distance and the electronic properties of the chiral ligand. As an example, 2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine has been immobilized on polystyrene resins, both on a Merrifield-type resin by grafting and on supports prepared by polymerization of 4-vinyl-substituted ligands. The corresponding Ru complexes have been tested as catalysts in the cyclopropanation reaction between styrene and ethyl diazoacetate. The catalytic activity, the enantioselectivity, and the recyclability are strongly dependent on the catalyst preparation method and the total exclusion of oxygen and moisture in the filtration process. Under such optimized conditions, yields over 60% with up to 90% ee can be obtained in four successive reactions-the best cyclopropanation results described to date for a chiral solid ruthenium catalyst.     

Enantioselective total synthesis of octalactin a using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.     

Asymmetric hydrogenation of aromatic ketones with MeO-PEG-supported BIPHEP/DPEN ruthenium catalysts

A soluble polymer (MeO-PEG) supported biphenylbisphosphine (BIPHEP)-Ru/chiral diamine (1,2-diphenylethylenediamine) complex, in which the polymer is attached to the two phenyl rings of BIPHEP ligand, has been prepared, and shown to be highly active with good enantioselectivity for the catalyzed asymmetric hydrogenation of unfunctionalized aromatic ketones. The derived chiral ruthenium complex 5 proved to be stable in air allowing facile catalyst recycling. Especially for 4′-tert-butyl-acetophenone and 1-acetonaphthone, excellent ee values up to 96.5% and 95.9% have been obtained which are comparable to or even higher than the enantioselectivity achieved with 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-Ru-DPEN catalyst under similar conditions.     

Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea

We synthesized a new class of bifunctional catalysts bearing a thiourea moiety and an amino group on a chiral scaffold. Among them, thiourea 1e bearing 3,5-bis(trifluoromethyl)benzene and dimethylamino groups was revealed to be highly efficient for the asymmetric Michael reaction of 1,3-dicarbonyl compounds to nitroolefins. Furthermore, we have developed a new synthetic route for (R)-(-)-baclofen and a chiral quaternary carbon center with high enantioselectivity by Michael reaction. In these reactions, we assumed that a thiourea moiety and an amino group of the catalyst activates a nitroolefin and a 1,3-dicarbonyl compound, respectively, to afford the Michael adduct with high enantio- and diastereoselectivity.     

A Mechanistic Investigation of the Kinetic Resolution of Secondary Aromatic Alcohols Using a Ferrocene‐Based Planar Chiral 4‐(Dimethylamino)pyridine Catalyst

A detailed computational and kinetic analysis of the acetylation of 1‐phenylethanol with acetic anhydride catalyzed by planar chiral 4‐(dimethylamino)pyridine (DMAP) catalyst (?)‐ 1 is presented. The study includes a computational investigation of the potential‐energy surface including the acylation and stereoselective transition states at the DFT level of theory. Experimentally, the kinetic study shows that the reaction proceeds in a first‐order manner in catalyst, whereas both substrates, acetic anhydride and 1‐phenylethanol, show fractional order, which is in accordance with steady‐state conditions. The fractional order depends on an equilibrium between the free catalyst and the acetylated catalyst.     

2,3-Dihydroimidazo[1,2-a]pyridines: a new class of enantioselective acyl transfer catalysts and their use in kinetic resolution of alcohols

The long-known, but previously unexplored 2,3-dihydroimidazo[1,2-a]pyridine (DHIP) has been shown to be a competent acyl transfer catalyst. Its chiral 2-phenyl derivatives obtainable in two steps from commercially available starting materials have proved to be effective acylation catalysts, giving high levels of enantioselectivity (s = 20-85) in kinetic resolution of secondary benzylic alcohols. A transition state model explaining the observed selectivity has been proposed.     

A theoretical investigation into chiral phosphoric acid-catalyzed asymmetric Friedel-Crafts reactions of nitroolefins and 4,7-dihydroindoles: reactivity and enantioselectivity

This article mainly focused on high level Density Functional Theory (DFT) studies on the chiral phosphoric acid-catalyzed Friedel-Crafts reactions between 4,7-dihydroindoles and nitroolefins. Firstly, the reactivities of 4,7-dihydroindole and indole in the chiral phosphoric acid-catalyzed Friedel-Crafts reactions with nitroolefin have been compared. The higher reactivity of 4,7-dihydroindole could be attributed to its higher HOMO energy as well as its more suitable trajectory to attack the nitroolefin in the transition state. Secondly, the origin of the enantioselectivity of the chiral phosphoric acid-catalyzed Friedel-Crafts reaction of 4,7-dihydroindole with nitroolefin has been studied using complete models on PBE1PBE/[6-311+G(d,p), 6-31G(d,p)] level. When (S)-1b was used as the catalyst, the enantioselectivity of the reaction is entirely controlled by the steric effect between the catalyst and the substrate. Whereas for catalyst (S)-1c the enantioselectivity is determined by the solvent effect.     

Asymmetric intermolecular C-H functionalization of benzyl silyl ethers mediated by chiral auxiliary-based aryldiazoacetates and chiral dirhodium catalysts

[reaction: see text] C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryldiazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious choice of chiral catalyst or auxiliary. The dirhodium tetraprolinates such as Rh2((S)-DOSP)4 have been widely successful as chiral catalysts in the C-H functionalization chemistry of aryldiazoacetates, but give poor enantioselectivity in the reactions of aryldiazoacetates with benzyl silyl ether derivatives. The use of (S)-lactate as a chiral auxiliary resulted in C-H functionalization with moderately high diastereoselectivity (79-88% de) and enantioselectivity (68-85% ee). The best results (91-95% de, 95-98% ee), however, were achieved using Hashimoto's Rh2((S)-PTTL)4 catalyst.     

Simple and Effective Synthetic Approach to Chiral 2-Amino-4-piperidinyl Pyridine Derivatives

A facile way has been developed to provide a series of novel chiral N-(4-(piperidin-1-yl)pyridin-2-yl)amide derivatives as potential stereoselective catalysts. The key intermediate, 2-amino-4-piperidinyl pyridine, was obtained by nucleophilic substitution of 2-amino-4-chloropyridine with piperidine in good yields (up to 96%). The total control of enantioselectivity was obtained for the synthesis of L-proline and (R)-1,1′-bi(2-naphthol) derivatives.     

Synthesis of new chiral 2,2'-bipyridine ligands and their application in copper-catalyzed asymmetric allylic oxidation and cyclopropanation

A series of modular bipyridine-type ligands 1 and 3-9 has been synthesized via a de novo construction of the pyridine nucleus. The chiral moieties of these ligands originate from the isoprenoid chiral pool, namely, beta-pinene (10 --> 1), 3-carene (14 --> 3 and 5), 2-carene (28 --> 4), alpha-pinene (43 --> 6-8), and dehydropregnenolone acetate (48 --> 9), respectively. Copper(I) complexes, derived from these ligands and (TfO)(2)Cu (1 mol %) upon an in situ reduction with phenylhydrazine, exhibit good enantioselectivity (up to 82% ee) and unusually high reaction rate (typicaly 30 min at room temperature) in allylic oxidation of cyclic olefins (52 --> 53). Copper-catalyzed cyclopropanation proceeded with < or =76% enantioselectivity and approximately 3:1 to 99:1 trans/cis-diastereoselectivity (54 --> 55 + 56). The level of the asymmetric induction is discussed in terms of the ligand architecture that controls the stereochemical environment of the coordinated metal.     

Asymmetric reduction of representative ketones with a bis-chiral oxazaborolidine system

In recent years, many optically active β-amino alcohols, mostly derived from naturally occurring α-amino acids, have been incorporated into the asymmetric synthesis as chiral auxiliaries or ligands.1 An effective asymmetric catalysts, the oxazaborolidine-borane reagents, which were originally pioneered by Itsuno and Corey,2 were generally prepared from chiral β-amino alcohols by the reaction with boric acid or formed in situ in the presence of borane. These reagents provide excellent enanti…     

Enantioselective organocatalytic Friedel-Crafts alkylation reaction of indoles with 5-hydroxyfuran-2(5H)-one: access to chiral γ-lactones and γ-lactams via a Ugi 4-center 3-component reaction

5-Hydroxyfuran-2(5H)-one 1, a readily available renewable resource, was used as an electrophile in the Friedel-Crafts alkylation of indoles catalyzed by a diphenylprolinol silyl ether. Moderate catalyst loading was achieved because of the high reactivity of 5-hydroxyfuran-2(5H)-one 1 in this process. Reduction of the Friedel-Crafts adduct (FC adduct) afforded indoyl lactones in high yield and enantioselectivity. Moreover, the FC adduct was used as a chiral synthon in a diversity-oriented synthesis, as illustrated by its successful engagement in a 4-center 3-component Ugi reaction (U-4C-3CR) to afford chiral five-membered lactams in high yield and enantioselectivity.     

D(-)-二吡啶甲基酒石酸酰胺在不对称氧化合成埃索美拉唑中的应用

D(-)-酒石酸二乙酯(1)分别与2-氨甲基吡啶和4-氨甲基吡啶反应,合成了D(-)-二吡啶甲基酒石酸酰胺2和3.分别以1～3为手性配体与钛酸异丙酯配合,催化过氧化氢异丙苯(CHP)不对称氧化埃索美拉唑前体(Eso-I)合成埃索美拉唑.结果表明,由配体2或3构成的催化体系在埃索美拉唑合成上显示出较高的催化活性和对映选择性.例如,当以2为配体,甲苯为溶剂,在优化的条件下进行反应时,Eso-I的转化率达84.7%,埃索美拉唑的选择性达91.8%,对映体过量值达89.0%.     

N-methyl-(R)-3-(tert-butyl)-sulfinyl-1,4-dihydropyridine: a novel NADH model compound

We have synthesized a novel chiral NADH model compound, N-methyl-(R)-3-(tert-butyl)-sulphinyl-1,4-dihydropyridine with high enantioselectivity and used it in the reduction of methyl benzoylformate, producing (S)-methyl mandelate in 95% ee. The absolute structure of its precursor, 3-(tert-butyl)sulfinyl pyridine, was determined by X-ray analysis.