Asymmetric [2,3]-Wittig rearrangement induced by a chiral carbanion whose chirality was transferred from an epoxide

[reaction: see text] The enantioselective [2,3]-Wittig rearrangement of 1-allyloxy-1-(naphthalen-2-yl)-4-siloxy-2,4-pentadienyl anion, derived from optically enriched 4,5-epoxy-1-(naphthalen-2-yl)-5-silyl-2-pentenyl allyl ether via a base-induced ring opening of the epoxide followed by Brook rearrangement, has been studied. The chirality of the epoxide was transferred to the alcohols in up to 97% ee, depending on the solvent used. The best result was obtained in 1,4-dioxane at a temperature above room temperature.     

A Novel Approach to 2,2-Disubstituted 1,2-Dihydro-4-phenylquinolines

The reaction of 2-(1-phenylvinyl)aniline and 4-chloro-2-(1-phenylvinyl)aniline with acetophenone derivatives, 1-(naphthalen-1-yl)ethanone and 1-(furan-2-yl)ethanone in toluene at 110–115° with toluene-4-sulfonic acid as a catalyst leads in good-to-excellent yields to the 2,2-disubstituted 1,2-dihydro-4-phenyl-quinolines 1–18 (Scheme 1, Table). The structure of the new racemic 1,2-dihydroquinolines 1–18 is determined by NMR spectroscopy. A reaction mechanism proceeding via a 6π-electrocyclic rearrangement of 2-(1-phenylvinyl)anils 19 as the key step is proposed for the formation of these compounds (Scheme 1). The scope and limitations of the novel methods are discussed (Scheme 2).     

Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide).

The enantiomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid [(+/-)-1, rebamipide, OPC-12759], a new antiulcer agent that enhances mucosal resistance, were synthesized from optically active alpha-amino acid derivatives of 2(1H)-quinolinone. The key intermediates, alpha-amino acid derivatives, were prepared by asymmetric synthesis and optical resolution. The (+)-1 was about 1.7 times as potent as the (-)-isomer in antiulcer activity against ethanol-induced gastric ulcers.     

Discovery of New Pyrazolopyridine,Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design,Synthesis, Docking Studies,and Anti-Proliferative Activity

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-⁻C² functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C²-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC₅₀ values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC₅₀ 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC₅₀ ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC₅₀ 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.     

A facile preparation of 1-(6-hydroxyindol-1-yl)-2,2-dimethylpropan-1-one

An effective synthesis of 1-(6-hydroxyindol-1-yl)-2,2-dimethylpropan-1-one (4) was developed starting from 1H-indole (2). The key step involved suitable utilization of 4-(1-pyrrolidino)pyridine for the removal of the chloroacetyl moiety from chloroacetic acid 1-(2,2-dimethylpropionyl)-1H-indol-6-yl ester (3); a possible mechanism is, also, presented. Compound 4 might lead to selectively substituted derivatives, either on the phenolic-OH or the indolyl-NH, with putative biological interest. In this respect, we found that the core structure of 1H-indol-6-ol (1) possesses a degree of aldose reductase inhibitory potential, at a concentration of 100 microM.     

Axially chiral tridentate isoquinoline derived ligands for diethylzinc addition to aldehydes

The synthesis and resolution of new tridentate isoquinoline-derived ligands has been developed. The key steps in the synthetic sequence include successive, chemo-selective Suzuki-Miyaura cross-couplings of 1,3-dichloroisoquinoline with suitable arylboronic acids. The new ligands prepared in this manner were resolved either via molecular complexation with N-benzylcinchonidinium chloride as with 1-[3-(2-hydroxyphenyl)isoquinolin-1-yl]naphthalen-2-ol or via chromatographic separation of its epimeric camphorsulfonates as for 1,3-bis-(2-hydroxynaphthalen-1-yl)isoquinoline. 4-tert-Butyl-2-chloro-6-[1-(2-hydroxymethylnaphthalen-1-yl)isoquinolin-3-yl]phenol was resolved by chiral semi-preparative HPLC. The application of these ligands in the diethylzinc addition to aldehydes was investigated. In certain cases, the desired secondary alcohols were obtained in high yield with excellent enantiomeric excess (ee?>?99%) at low catalyst loading (1?mol%).     

Synthesis of some tolperisone metabolites in racemic and optically active form

1-(4′-Carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-one M3, erythro-1-(4′-carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-ol M4 and threo-1-(4′-carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-ol M5, metabolites of the muscle relaxant tolperisone were synthesized in racemic and optically active forms.     

Samarium(II) iodide mediated radical/polar crossover reactions of cyclobutenes. An efficient approach to the BCD ring system of the penitrems

[reaction: see text] Radical/polar crossover reactions of derivatives of 1-(2-cyclobutenyl)-2-(2-iodoaryl)ethanones with acetone promoted by samarium diiodide and HMPA provide 1-(1-hydroxy-1-methylethyl)-2,2a,4,8b-tetrahydro-1H-cyclobuta[a]naphthalen-3-one derivatives in about 50% isolated yield. This reaction shows promise for construction of the BCD ring fragment of the penitrems.     

Stereoselective synthesis of optically active disilanes and selective functionalization by the cleavage of silicon-naphthyl bonds with bromine

Optically active disilanes with one chiral silicon center, (R)-1,2-dimethyl-1-(naphth-1-yl)-1,2,2-triphenyldisilane and (R)-1,2,2-trimethyl-2-(4-methoxynaphth-1-yl)-1-(naphth-1-yl)-1-phenyldisilane, were obtained by the reaction of (S)-methyl(naphth-1-yl)phenylchlorosilane (> 99% ee) with methyldiphenylsilyllithium or by the reaction of methyldiphenylchlorosilane with optically active (S)-methyl(naphth-1-yl)phenylsilyllithium and by the reaction of (S)-methyl(naphth-1-yl)phenylchlorosilane (> 99% ee) with dimethyl(4-methoxynaphth-1-yl)silyllithium. Under the optimized conditions, the reactions proceeded with almost complete inversion for the cholorosilanes and retention for the silyl anions. Optically active disilanes with two chiral centers, (1R,2R)-1,2-dimethyl-1,2-di(naphth-1-yl)-1,2-diphenyldisilane and (1S,2S)-1,2-di(4-methoxynaphth-1-yl)-1,2-dimethyl-1,2-diphenyldisilane, were obtained in high optical purity by the reactions of corresponding optically active halogenosilanes (Cl or F) with optically active silyllithiums. The silicon-silicon bond and the silicon-naphthyl bond of (R)-1,1,2-trimethyl-1,2-di(naphth-1-yl)-2-phenyldisilane and (1R,2R)-1,2-dimethyl-1,2-di(naphth-1-yl)-1,2-diphenyldisilane were cleaved without selectivity on bromination. The silicon-(4-methoxynaphth-1-yl) bond of (R)-1,2,2-trimethyl-2-(4-methoxynaphth-1-yl)-1-(naphth-1-yl)-1-phenyldisilane was regiospecifically cleaved, followed by the stereoselective cleavage of the remaining chiral silicon-naphthyl bond (94% inversion). Although the silicon-(4-methoxynaphth-1-yl) bonds of (1S,2S)-1,2-di(4-methoxynaphth-1-yl)-1,2-dimethyl-1,2-diphenyldisilane (> 99% ee) were regioselectively cleaved without silicon-silicon bond scission, remarkable racemization could not be avoided during the one-pot reaction.     

含金刚烷基团的新型手性单齿亚磷酸酯配体的合成及其在不对称1,4-共轭加成反应中的应用

以轴手性的BINOL/H8-BINOL(BINOL为联苯酚)和大位阻的金刚烷酰氯为原料,合成了系列新型手性单齿亚磷酸酯配体,并应用于Cu催化的二乙基锌对环烯酮的不对称1,4.共轭加成反应中.结果表明,配体结构中部分氢化的2,2'-(1,1'-联萘基)亚磷酸酯单元和金刚烷基团,有助于改善反应的对映选择性,对映选择性最高可...     

Synthesis of Phosphate Esters by Using Diphenyl Ditelluride as Organocatalyst

We report a protocol for the synthesis of new dialkyl(1-(organolthio)naphthalen-2-yl)phosphates and derivatives via a dehydrogenative phosphorylation reaction between functionalized naphthols and H-phosphonates. Diphenyl ditelluride was employed as an organocatalyst and sonochemistry as an alternative energy source. The reaction conditions were defined through a factorial design approach, and the best condition provided the synthesis of dialkyl(1-(organolthio)naphthalen-2-yl)phosphates in yields that varied from 51–98 % under ultrasound irradiation after 2 h of sonication. The synthetic protocol was also effective for phenol and thiophenol starting materials. All products were characterized by state-of-the-art spectroscopic and spectrometric techniques.     

Practical synthesis of (E)- and (Z)-2-silyl-3-penten-1-ols with high enantiopurity

Practical methods for the synthesis of the optically active (E)- and (Z)-2-silyl-3-pentene-1-ols are described. The optically pure (E)-allylsilane was synthesized from commercially available (R)-3-butyn-2-ol in five steps involving hydrozirconation followed by alkylation of the resulting alkenylmetal with BnOCH₂Cl. On the other hand, both enantiomers of the corresponding (Z)-allylsilane were prepared from commercially available dimethylphenylvinylsilane through epoxidation, the regioselective epoxide-opening reaction with 1-propynylmagnesium bromide, and the subsequent optical resolution using a lipase.     

An efficient synthesis of optically active five- and six-membered cyclic compounds with selectable stereo-controls by a Ti(II)-mediated cyclization of chiral secondary 2,7- and 2,8-enyn-1-ol derivatives

Ti(II)-mediated cyclization of readily accessible optically active secondary 2,7- and 2,8-enyn-1-ol derivatives enables the selective preparation of any one of the four possible stereoisomers of the cyclized product with high optical purity.     

Novel chemoenzymatic strategy for the synthesis of enantiomerically pure secondary alcohols with sterically similar substituents

A novel chemoenzymatic strategy for the synthesis of enantiomerically pure secondary alcohols with sterically similar substituents is described. The key step is the kinetic lipase-catalyzed resolution of racemic mixtures of substituted propargylic alcohols. The efficiency of this new approach was tested in the preparation of the corresponding enantiomers of 1,11-hexadecandiol derivatives ((R)-5 and (S)-5). Two strategies were tested. In the first one, the racemic intermediate 1-octyn-3-ol (1) was resolved enzymatically and then elongated with 1-bromo-9,11-dioxadodecane. Alternatively, the racemic 1 can be elongated to the corresponding racemic 17,19-dioxa-7-eicosyn-6-ol (3) first and then resolved biocatalytically. Twelve commercially available lipases were screened for the kinetic resolution of these intermediates. Among them, Candida antarctica lipase (CAL-B) and Humicola lanuginosa lipase (HLL) were the best biocatalysts for the resolution of 1 (S enantiomer 90% ee, E = 35), and 3 (R enantiomer 90% ee, E = 34), respectively.     

Synthesis,characterization and anticancer evaluation of 2-(naphthalen-1-ylmethyl/naphthalen-2-yloxymethyl)-1-[5-(substituted phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-1H-benzimidazole

In the present study o-phenylenediamine and naphtene-1-acetic acid/2-naphthoxyacetic acid were used as a starting material through a series of steps and 2-(naphthalen-1-ylmethyl/Naphthalen-2-yloxymethyl)-1H-benzimidazol-1-yl]acetohydrazide 5a, 5b were obtained. In the first series 1,3,4-oxadiazole derivatives have been synthesized from Schiff base of the corresponding hydrazide i.e. 2-[2-(naphthalen-1-ylmethyl)-1H-benzimidazol-1-yl]acetohydrazide 5a by using Chloramin-T. In the second series 1,3,4-oxadiazole has been synthesized from 2-{2-[(naphthalen-2-yloxy)methyl]-1Hbenzimidazol-1-yl}acetohydrazide 5b by using phosphorous oxychloride and aromatic acid. These compounds were evaluated by IR, NMR, Mass spectrometry, elemental analysis and finally in vitro anticancer evaluation was carried out by NCI 60 Cell screen at a single high dose (10–5 M) on various panel/cell lines. One compound 7c was found to be the most active on breast cancer cell line and compounds 4b and 7d were moderately active.     

Enzymatic kinetic resolution of tert-butyl 2-(1-hydroxyethyl)phenylcarbamate, a key intermediate to chiral organoselenanes and organotelluranes

The enzymatic kinetic resolution of tert-butyl 2-(1-hydroxyethyl)?phenylcarbamate via lipase-catalyzed transesterification reaction was studied. We investigated several reaction conditions and the carbamate was resolved by Candida antarctica lipase B (CAL-B), leading to the optically pure (R)- and (S)-enantiomers. The enzymatic process showed excellent enantioselectivity (E > 200). (R)- and (S)-tert-butyl 2-(1-hydroxyethyl)phenylcarbamate were easily transformed into the corresponding (R)- and (S)-1-(2-aminophenyl)ethanols.     

Enantioselective Catalysis CXLI [1]. Tridentate Ligands with 1-(Pyridin-2-yl)ethylamine as Chiral Building Block in the Enantioselective Transfer Hydrogenation of Acetophenone

Summary.  A series of novel tridentate ligands with nitrogen and oxygen donor sites was synthesized starting from enantiomerically pure (S)- and (R)-1-(pyridin-2-yl)ethylamine, the preparation and resolution of which was developed. The new optically active ligands were tested as in situ catalysts together with Ru(PPh₃)₃Cl₂ in the enantioselective transfer hydrogenation of acetophenone with isopropanol. The secondary amine ligand (S)-2,4-di-tert-butyl-6-(1-(pyridin-2-yl)ethylamino)methylphenol gave the best results with almost quantitative conversion and 47%ee. Received August 17, 2001. Accepted August 27, 2001     

Self-cyclization of (E)-2-(trimethylsilylmethyl)pentadienol derivative. Synthesis of bicyclo[4.3.0]nonane ring systems

Utility and limitation of the title reaction was studied. When (E)-3-(4-t-butyl- and 4-phenylcyclohex-1-en-1-yl)-2-(trimethylsilylmethyl)prop-2-en-1-ols were treated with Ms₂O or MsCl, 3-t-butyl- and 3-phenyl-8-methylbicyclo[4.3.0]nona-1(6),7-dienes were obtained, respectively. The corresponding (Z)-isomer afforded a complex mixture, among which an elimination product was detected. (E)-4-(4-t-Butylcyclohexylidene)-2-(trimethylsilylmethyl)but-2-en-1-ol afforded only elimination product.     

Synthesis and Characterization of new Monomers and Polymers Containing Hindered Piperidine Groups

Abstract

Two new methacryloyl ureas, 1-(2-methylacryloyl)-3-(2,2,6,6-tetra-methylpiperidin-4-yl)-urea and 1-butyl-3-(2-methylacryloyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)-urea (monomer I and monomer II), were prepared by the addition reaction of 2-methylacryloyl iso-cyanate with 2,2,6,6-tetramethylpiperidin-4-yl-amine or butyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amine in a molar ratio of 1:1 at low or room temperature. In a similar way, the syntheses of two new methacryloyl carbamates, 1-(2,2,6,6-tetra-methylpiperidin-4-yl)-3-(2-methylacryloyl)-carbamate and l-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-3-(2-methylacryloyl)-carbamate (monomer III and monomer IV), were completed by the reaction of 2,2,6,6-tetra-methylpiperidin-4-ol or 1,2,2,6,6-pentamethylpiperidin-4-ol with 2-methylacryloyl isocyanate in the presence of dibutyltin dilaurate as catalyst at 60°C. The four new monomers were homopolymerized, and copolymerized with styrene by AIBN as initiator at 70°C. The structures of the new monomers and their polymers were characterized by FT-IR and NMR spectroscopy and by GPC.     

几种手性原子转移自由基聚合引发剂的合成及其在螺旋选择性聚合中的应用

合成了(S)-2,2'-二(溴甲基)-1,1'-联萘, (S)-2'-甲基-2-溴甲基-1,1'-联萘, α-溴代苯乙酸薄荷酯, N-薄荷基-α-溴代苯乙酰胺和α-溴代苯乙酸胆甾烷醇酯5种旋光的溴代烷并将其用作非手性单体甲基丙烯酸-1-苯基二苯并环庚醇酯 (PDBSMA)的原子转移自由基聚合(ATRP)的手性引发剂. 为了使这些手性引发剂在引发一步生成的初级自由基不发生消旋化, 引发剂中的手性中心都不直接与溴原子相连. 用这5种手性溴代烷做引发剂引发PDBSMA的ATRP所得聚合物可分成四氢呋喃(THF)可溶部分和THF不溶部分. THF可溶部分具有较大的比旋光度. 对THF可溶部分的手性光学性质研究以及比较该部分聚合物和在同样引发条件下得到的甲基丙烯酸甲酯聚合物的比旋光度, 我们得出聚合物大的比旋光度是由聚合物单手性螺旋过量引起的结论, 即合成的手性引发剂对PDBSMA的ATRP均有一定的螺旋选择性, 其中(S)-2,2'-二(溴甲基)-1,1'-联萘、(S)-2'-甲基-2-溴甲基-1,1'-联萘螺旋选择性最好. 引发剂的螺旋诱导能力跟聚合反应的温度有很大关系, 聚合温度上限为70 ℃, 在0～70 ℃之间, 随着温度的升高引发剂的螺旋选择性逐渐增强.