Asymmetric conjugate reduction of alpha,beta-unsaturated ketones and esters with chiral rhodium(2,6-bisoxazolinylphenyl) catalysts

New asymmetric conjugate reduction of beta,beta-disubstituted alpha,beta-unsaturated ketones and esters was accomplished with alkoxylhydrosilanes in the presence of chiral rhodium(2,6-bisoxazolinylphenyl) complexes in high yields and high enantioselectivity. (E)-4-Phenyl-3-penten-2-one and (E)-4-phenyl-4-isopropyl-3-penten-2-one were readily reduced at 60 degrees C in 95 % ee and 98 % ee, respectively, by 1 mol % of catalyst loading. (EtO)2MeSiH proved to be the best hydrogen donor of choice. tert-Butyl (E)-beta-methylcinnamate and beta-isopropylcinnamate could also be reduced to the corresponding dihydrocinnamate derivatives up to 98 % ee.     

Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.     

An efficient route for synthesis of 5,6‐diphenylimidazo‐[2,1‐b]thiazoles as antibacterial agents

The reaction of 4,5‐diphenylimidazol‐2‐thione ( 1 ) with aromatic ketones 2a‐i using the acidified acetic acid method afforded the 4,5‐diphenyl(2‐imidazolylthio)acetophenones 3a‐h in good yields. While, the cyclized product 4i was obtained directly upon reaction of 1 with α‐acetyl naphthalene. Compounds 3a‐h were cyclized directly to the corresponding 3‐aryl‐5,6‐diphenylimidazo[2,1‐b]thiazoles (4a‐c) and ( 4e‐h ). In the same manner the reaction of 1 with aliphatic and/or alicyclic ketones gave the 3‐(4,5‐diphenyl‐2‐imidazolylthio)acetone derivatives 5a‐d , 2‐(4,5‐diphenylimidazolylthio)cycloalkanones 8a,d and the tricyclic compounds 9b‐c respectively. The cyclized compounds 6a‐d and 9a,d were obtained by cyclization of 5a‐d and 8a,b respectively. Oxidation of 1 gives the corresponding bis(4,5‐diphenyl‐2‐imidazolyl)‐disulfide ( 10 ) in 90% yield. Some of the synthesized compounds were tested for antifungal and antibacterial activity.     

Highly enantioselective conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones catalyzed by 9-amino-9-deoxyepiquinine

Asymmetric conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones was studied using chiral primary amines as the catalysts. 9-Amino-9-deoxyepiquinine was found to be highly efficient catalyst for the transformation. 4-Bromo-4-nitroketones were obtained with excellent enantioselectivities (97-99% ee) and good yields (61-99%) for a variety of alkyl vinyl ketones. The product could be further debrominated with Bu₃SnH/AIBN to provide chiral 4-nitroketones in good yield and without loss of the optical purity.     

Catalytic enantioselective amination of enolsilanes using C2-symmetric copper(II) complexes as chiral Lewis acids

[formula: see text] [Cu(S,S)-t-Bu-box](OTf)2 (1) catalyzes the enantioselective amination of enolsilanes with azodicarboxylate derivatives. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters added to the azo-imide in greater than 95% ee. The use of an alcohol additive was critical to achieving catalyst turnover.     

Enantioselective synthesis of optically active secondary amines via asymmetric reduction

The enantioselective synthesis of optically active secondary amines via the asymmetric reduction of N-substituted ketimines with various chiral hydride reagents, such as Itsuno's reagent (1), Corey's reagent (2), K glucoride (3), Sharpless' reagent (4), and Mosher's reagent (5) has been investigated. Among the hydride reagents examined, 1 gave the best results in terms of asymmetric induction. Thus, the reduction of N-phenylimine derivatives of aromatic ketones with 1 provided the corresponding amines in 96–98% yields with high optical induction, such as 73 % ee for acetophenone N-phenylimine (6a), 87 % ee for propiophenone N-phenylimine (6b), 88 % ee for bulyrophenone N-phenylimine (6c), and 71 % ee for isobutyrophenone N-phenylimine (6d). In the case of N-alkyl ketimine derivatives, the reduction afforded somewhat lower optical inductions as compared to those of N-phenyl derivatives, giving 46 % ee for acetophenone N-benzylimine (6f), 52 % ee for acetophnone N-ⁿ-heptylimine (6g) and 43 % ee for acetophenone N-cyclohexylimine (6h). However, the substitution of a bulky alkyl group on nitrogen of the ketimines increases remarkably the optical induction of product amine, such as 80 % ee for acetophenone N-tert-butylimine (6e). The reduction of N-substituted aliphatic ketimines gave very low optical inductions (7.4 – 24 % ee). The catalytic effects of oxazaborolidines (1a and 2a) in the reduction of ketimines with 1 and 2 were also examined.     

Designing the "search pathway" in the development of a new class of highly efficient stereoselective hydrosilylation catalysts

The direct coupling of oxazolines and N-heterocyclic carbenes leads to chelating C,N ancillary ligands for asymmetric catalysis that combine both an "anchor" unit and a stereodirecting element. Reacting various N-substituted imidazoles with 2-bromo-4(S)-tert-butyl- and 2-bromo-4(S)-isopropyloxazoline gave the imidazolium precursors of the stereodirecting ancillary ligands. A library of ten different ligand precursors was obtained by using this simple procedure (65-97 % yield). These protioligands were metalated in a subsequent step by reaction with [{Rh(mu-OtBu)(nbd)}2] (nbd=norbornadiene), generated in situ from KOtBu and [{RhCl(nbd)}2] giving the corresponding N-heterocyclic carbene complexes [RhBr(nbd)(oxazolinyl-carbene)] 4 a-j in good yields. X-ray diffraction studies of two of the rhodium complexes, 4 d and 4 j, established a distorted square-pyramidal coordination geometry with the bromo ligand occupying the apical position. The rhodium-carbene bond length was found to be 2.070(4) A (4 d) and 2.012(3) A (4 j). Complexes 4 a-j were treated with AgBF4 in dichloromethane, giving the active cationic square-planar catalysts for the hydrosilylation of ketones. As a reference reaction for the catalyst optimisation, the hydrosilylation of acetophenone with diphenylsilane was studied and the system optimised with respect to the counterion (BF(4) (-)), solvent (THF) and the silane reducing agent (diphenylsilane). The reaction product (1-phenylethanol) was obtained with the highest enantiomeric excess (ee) by carrying out the reaction at -60 degrees C, whilst the enantioselectivity drops upon going both to lower and higher temperatures. The observation that the temperature dependence of the ee values goes through a maximum indicated a change in the rate-determining step as the temperature is varied. The determination of the initial reaction rate in the hydrosilylation of acetophenone upon varying the catalyst (4 d) and substrate concentrations at -55 degrees C established a rate law for the initial conversion which is first-order in both substrates as well as the catalyst (Vi = k[4][PhCOMe][Ph2SiH2]). The catalytic system derived from complex 4 d was found to afford high yields and good enantioselectivities in the reduction of various aryl alkyl ketones (acetophenone: 92 % isolated yield and 90 % ee, 2-naphtyl methyl ketone: 99 % yield, 91 % ee). The selectivity for the reduction of prochiral dialkyl ketones is comparable or even superior to the best previously reported for prochiral nonaromatic ketones; whereas cyclopropyl methyl ketone is hydrosilylated with an enantioselectivity of 81 % ee, the increase of the steric demand of one of the alkyl groups leads to improved ee's, reaching 95 % ee in the case of tert-butyl methyl ketone. Linear chain n-alkyl methyl ketones, which are particularly challenging substrates, are reduced in good asymmetric induction, such as 2-octanone (79 % ee) and even 2-butanone (65 % ee).     

Asymmetric transfer hydrogenation of aryl ketones catalyzed by salt-free two samarium centers supported by a chiral multidentate alkoxy ligand

[reaction: see text] We synthesized a chiral multidentate ligand, (R,R,R,R)-N,N,N',N'-tetra(2-hydroxy-2-phenylethyl)-1,3-xylylene diamine [(R)-2], which can support two metals at adjacent positions. Asymmetric transfer hydrogenation of acetophenone and its derivatives was conducted by using salt-free bimetallic lanthanoid complexes of (R)-2, and the combination of two samarium atoms and (R)-2 was found to be the best catalyst system for asymmetric transfer hydrogenation of aryl ketones in high enantioselectivity (up to >99% ee).     

Enantioselective synthesis of 2,2-disubstituted terminal epoxides via catalytic asymmetric Corey-Chaykovsky epoxidation of ketones

Catalytic asymmetric Corey-Chaykovsky epoxidation of various ketones with dimethyloxosulfonium methylide using a heterobimetallic La-Li(3)-BINOL complex (LLB) is described. The reaction proceeded smoothly at room temperature in the presence of achiral phosphine oxide additives, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (97%-91% ee) and yield ( > 99%-88%) from a broad range of methyl ketones with 1-5 mol% catalyst loading. Enantioselectivity was strongly dependent on the steric hindrance, and other ketones, such as ethyl ketones and propyl ketones resulted in slightly lower enantioselectivity (88%-67% ee).     

Highly enantioselective hydrogenation of aromatic-heteroaromatic ketones

Asymmetric hydrogenation of ketone 1 using trans-RuCl(2)[(R)-xylbinap][(R)-daipen] (3) as a catalyst afforded secondary alcohol 2 quantitatively and in 99.4% ee. Further exploration of the effect of the thiazole ring substitution revealed that the catalyst was highly effective for the enantioselective hydrogenation of 5-benzoyl thiazoles, which afforded corresponding alcohols in 92-99% ee. The same protocol was applicable to a variety of aromatic-heteroaromatic ketones to generate secondary alcohols in excellent enantioselectivities. [reaction: see text]     

(1S,2S)-1,2-二苯基乙二胺修饰Ir/HAP催化苯乙酮及其衍生物的不对称加氢反应

采用浸渍法在温和条件下制备了羟基磷灰石负载的铱催化剂(Ir/HAP), 并以X射线衍射(XRD), 透射电子显微镜(TEM), X射线光电子能谱(XPS), 比表面积测定(BET)以及附带能量散射X射线谱的扫描电子显微镜(SEM-EDS)等手段对载体和催化剂进行了表征. 以(1S,2S)-1,2-二苯基乙二胺((1S,2S)-DPEN)为手性修饰剂时, 该催化剂对苯乙酮及其衍生物不对称加氢反应表现出较高活性和对映选择性(ee). 在氢气压力为3.0 MPa、303 K条件下反应3 h, 苯乙酮及其衍生物的加氢转化率在94.7%以上, 其中生成2'-(三氟甲基)苯乙醇的对映选择性高达81.5%. 在不使用其它配体作稳定剂的情况下, 该结果比目前文献报道值高. 通过对比研究发现, 羟基磷灰石作为载体优于二氧化硅等其它无机载体. 催化剂通过简单离心分离可循环使用多次, 无明显的金属铱流失.     

Asymmetric cross-aldol reaction of isatin and ketones catalyzed by crude earthworm extract as efficient biocatalyst

ABSTRACT

The asymmetric cross-aldol reaction of simple ketones (acetone, cyclohexanone) with isatin derivatives in the presence of crude extract from earthworms as green and effective biocatalyst proceeds easily in MeCN/H₂O (1:1) as solvent to afford 3-hydroxy-2-oxindoles derivatives. Ten compounds were synthesized in high yields (62–88%) and moderate ee (29–42%). Structure of the synthesized compounds has been characterized on the basis of NMR spectra and CHN analysis. The ee of the obtained compounds was determined by chiral phase HPLC analysis.     

Catalyst development for organocatalytic hydrosilylation of aromatic ketones and ketimines

A new family of Lewis basic 2-pyridyl oxazolines have been developed, which can act as efficient organocatalysts for the enantioselective reduction of prochiral aromatic ketones and ketimines with trichlorosilane, a readily available and inexpensive reagent. 1-Isoquinolyl oxazoline, derived from mandelic acid, was identified as the most efficient catalyst of the series, capable of delivering high enantioselectivities in the reduction of both ketones (up to 94% ee) and ketimines (up to 89% ee).     

Chiral pyrrolidine quaternary derivatives as organocatalysts for asymmetric Michael additions

A series of chiral pyrrolidine quaternary derivatives were designed and synthesized. It was found that these derivatives are highly efficient organocatalysts for the asymmetric Michael addition reactions of aldehydes and ketones to nitroolefins with high yields (up to 96%), high enantioselectivities (up to 99% ee), and high diastereoselectivities (up to 97:3 dr). Furthermore, catalyst 7a could be recycled without remarkable loss of catalytic activity and stereoselectivity.     

Enantioselective organocatalyzed Henry reaction with fluoromethyl ketones

Remarkable generality in scope of new C9-benzoylcupreines bearing electron-withdrawing substituents for the nitroaldol condensation with fluoromethyl ketones is presented. Both tri- and difluoromethyl ketones provided excellent levels of stereoinduction (ee 76-99%) under mild reaction conditions and low loading of catalyst (1-5 mol%).     

Asymmetric hydrogenation of aromatic ketones catalyzed by the TolBINAP/DMAPEN-ruthenium(II) complex: a significant effect of N-substituents of chiral 1,2-diamine ligands on enantioselectivity

Asymmetric hydrogenation of acetophenone in the presence of Ru(II) catalysts coordinated by TolBINAP and a series of chiral 1,2-diamines was studied. The sense and degree of enantioselectivity were highly dependent on the N-substituents of the diamine ligands. The N-substituent effect was discussed in detail. Among these catalysts, the (S)-TolBINAP/(R)-DMAPEN-Ru(II) complex showed the highest enantioselectivity. The mode of enantioface selection was interpreted by using transition state models based on the X-ray structure of the catalyst precursor. The chiral catalyst effected the hydrogenation of alkyl aryl ketones and arylglyoxal dialkyl acetals to afford the chiral alcohol in >99% ee in the best cases. Hydrogenation of racemic benzoin methyl ether with the chiral catalyst through dynamic kinetic resolution gave the anti-alcohol (syn:anti = 3:97) in 98% ee, while the reaction of alpha-amidopropiophenones resulted in the syn-alcohols (syn:anti = 96:4 to >99:1) in >98% ee.     

Ruthenium-Lewis acid catalyzed asymmetric Diels-Alder reactions between dienes and alpha,beta-unsaturated ketones

The complex [Ru(Cp)(R,R-BIPHOP-F)(acetone)][SbF(6)], (R,R)-1 a, was used as catalyst for asymmetric Diels-Alder reactions between dienes (cyclopentadiene, methylcyclopentadiene, isoprene, 2,3-dimethylbutadiene) and alpha,beta-unsaturated ketones (methyl vinyl ketone (MVK), ethyl vinyl ketone, divinyl ketone, alpha-bromovinyl methyl ketone and alpha-chlorovinyl methyl ketone). The cycloaddition products were obtained in yields of 50-90 % and with enantioselectivities up to 96 % ee. Ethyl vinyl ketone, divinyl ketone and the halogenated vinyl ketones worked best and their reactions with acyclic dienes consistently provided products with >90 % ee. alpha-Chlorovinyl methyl ketone performed better than alpha-bromovinyl methyl ketone. The reaction also provided a [4.3.1]bicyclic ring system in 95 % ee through an intramolecular cycloaddition reaction. Crystal structure determinations of [Ru(Cp)((S,S)-BIPHOP-F)(mvk)][SbF(6)], (S,S)-1 b, and [Ru(Cp)((R,R)-Me(4)BIPHOP-F)(acrolein)][SbF(6)], (R,R)-2 b, provided the basis for a rationalization of the asymmetric induction.     

Copper-mediated, palladium-catalyzed coupling of thiol esters with aliphatic organoboron reagents

Thiol esters and B-alkyl-9-BBN derivatives couple in the presence of a copper(I) carboxylate mediator and a palladium catalyst. In contrast to copper-mediated, palladium-catalyzed cross-couplings of thioorganics with boronic acids, the current coupling reaction of 9-BBN derivatives is facilitated by the addition of a base such as Cs(2)CO(3). Under optimized conditions, a variety of thiol esters react with different B-alkyl-9-BBN derivatives giving ketones in moderate to excellent yields.     

3-Pyrrolidinecarboxylic acid for direct catalytic asymmetric anti-Mannich-type reactions of unmodified ketones

We report the development of direct catalytic, enantioselective, anti-selective Mannich-type reactions between unmodified ketones and alpha-imino esters under mild conditions. The reactions were performed using 5-10 mol % of (R)-3-pyrrolidinecarboxylic or (R)-beta-proline as catalyst in an environmentally benign solvent, 2-PrOH, at room temperature. The anti-Mannich products were obtained in good yields with high diastereo- and enantioselectivities (up to anti/syn >99:1, 99% ee). While (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid is an excellent catalyst for the anti-Mannich-type reactions of aldehydes, it did not efficiently catalyze the corresponding Mannich-type reactions of ketones; (R)-3-pyrrolidinecarboxylic acid did efficiently catalyze the Mannich-type reactions of ketones. (S)-Proline or (S)-2-pyrrolidinecarboxylic acid has been reported to catalyze the Mannich-type reactions of ketones to afford the syn-products. Thus, the position of the carboxylic acid group on the pyrrolidine ring directs the stereoselection of the catalyzed reaction, providing either syn- or anti-Mannich products.     

Asymmetric baker’s yeast reductions of bridgehead-substituted bicyclo[2.2.2]octane-2,6-dione derivatives followed by conversion into catalytically active BODOLs for the diethylzinc addition to benzaldehyde

4-Substituted bicyclo[2.2.2]octane-2,6-diones have been synthesized and tested as substrates in the enantioselective reduction with baker’s yeast to give the corresponding hydroxy ketones. It was found that the derivative bearing a TIPSO group at the 4-position was not reduced at all while that with a TBDMSO group gave 87% yield and 46% ee. Other 4-oxy functionalized derivatives were reduced with varying yields (36–87%) and ees (10–82%). The best result was obtained for the 4-Oallyl derivative (80% yield, 82% ee). The hydroxy ketones carrying the benzyloxy and allyloxy groups at the 4-position were converted into the corresponding BODOLs, which were tested as catalysts in the diethylzinc addition to benzaldehyde. In this reaction the ees were 90% and 89%, respectively, which showed that BODOLs substituted at the 4-position are essentially as good catalysts in this reaction as those bearing a hydrogen.