Stereocontrolled synthesis of quinine and quinidine

Disubstituted cyclopentene was prepared from cyclopentene monoacetate and transferred into disubstituted piperidine via oxidative cleavage of the olefin moiety followed by piperidine ring formation. The piperidine was then condensed at the side chain with a quinoline part to afford the olefin precursor of quinine. Finally, the olefin was converted into quinine through the corresponding epoxide. Quinidine was synthesized in a similar way.     

Chiral discrimination of quinine and quinidine based on notable room temperature phosphorescence lifetime differences with γ-cyclodextrin as chiral selector

Upon addition of small amount of bromocyclohexane (BrCH), quinine (QN) and quinidine (QD) display strong room temperature phosphorescence (RTP) in γ-cyclodextrin (γ-CD) solution without deoxygenation. The associated phosphorescence decay curves can be best fitted to biexponential patterns and quite different RTP lifetimes are obtained for QN (86.9 and 12.5 ms) and QD (12.1 and 4.17 ms), indicating a distinct chiral discrimination of γ-CD toward this pair of pseudo-enantiomers. The corresponding association constants evaluated for QN/γ-CD/BrCH and QD/γ-CD/BrCH are 3.47 × 10⁵ and 4.67 × 10⁴ L mol⁻¹, respectively. It can be inferred that their different ability to form complexes with the chiral γ-CD is accounted for the notable difference in RTP lifetimes between QN and QD.     

Improved synthesis of quinine alkaloids with the Teoc protective group

TeocCl (Teoc: C(O)O(CH₂)₂TMS) generated in situ was conveniently used for trans-protection of the N-Bn piperidine intermediate to N-Teoc piperidine. Later, deprotection of the Teoc group and the subsequent quinuclidine ring formation was achieved with CsF in a domino fashion to afford the quinine alkaloids.     

Determination of tannic acid by direct chemiluminescence in a FIA assembly

The determination of tannic acid is performed in a FIA assembly on the basis of the analytical output obtained by oxidation of the acid. The analyte solution was daily prepared in a mixture of quinine as sensitiser and perchloric acid and it was injected into a pure water stream acting as a carrier. This solution merges with the mixture potassium permanganate in perchloric medium and the resulting chemiluminescence is monitored. The method was applied over the range 0.5–20 mg l⁻¹ of tannic acid with a LOD 100 μg l⁻¹. The reproducibility was 2.1% and the sample throughput 54 h⁻¹. The influence of foreign substances was studied and the new method is applied to the determination of tannic acid in pharmaceutical and galenic formulations in human urine and surface waters.     

Organocatalytic asymmetric synthesis of quinine and quinidine

Quinine and quinidine were synthesized by a highly enantio- and stereoselective approach starting from a proline-catalyzed asymmetric cycloaldolization of benzyl bis(2-formylethyl)carbamate which gave a 70:30 mixture of (3R,4R)-N-Cbz-3-hydroxymethyl-4-hydroxypiperidine (96% ee) and its 4S-epimer (92% ee) in 94% yield after in situ NaBH₄ reduction.     

Determination of penicillin V potassium in pharmaceuticals and spiked human urine by chemiluminescence

A simple and selective method for penicillin V potassium (PVK) determination by chemiluminescence (CL) was developed. Oxidation of PVK by alkaline hydrogen peroxide produces CL, which is greatly enhanced by N, N-dimethyl formamide (DMF) and N-cetyl-N,N,N-trimethylammonium bromide (CTMAB). Optimum conditions were established using luminometry. There is a linear relationship between the chemiluminescent peak height and the amount of PVK within the range 0.5–129.5 mg L⁻¹, with a detection limit of 0.2 mg L⁻¹. The coefficient of variation was 1.2% for 40 mg L⁻¹ PVK solution (n = 7). The method is very simple, has high sensitivity and good selectivity, and is usable for process control. It was successfully utilized for the determination of PVK in pharmaceuticals and spiked human urine.      

Determination of phenols by flow injection and liquid chromatography with on-line quinine-sensitized photo-oxidation and quenched luminol chemiluminescence detection

An on-line quinine-sensitized photo-oxidation with quenched chemiluminescence (CL) detection method is developed for phenols using flow injection (FI) and liquid chromatography (LC). This detection method is based on the decrease of light emission from the luminol CL reaction due to the photo-oxidation of phenols that scavenge the photogenerated reactive oxygen species (e.g. singlet oxygen () and superoxide (O₂⁻)). On-line photo-oxidation is achieved using a coil photo-reactor made from fluoroethylene-propylene copolymer tubing ( mm i.d.) coiled around a mercury UV lamp. A buffer of pH 7 and a concentration of 350 μM for quinine sulfate are determined optimum for the sensitized photo-oxidation. Using a carrier system flow rate of 60 μl/min, calibration curves taken by FI for 10 phenolic compounds in aqueous solutions showed this decreasing sensitivity order: 4-chlorophenol, phenol, 4-nitrophenol, 3-hydroxy-l-kynurenine, 2-nitrophenol, salicylate, 3-nitrophenol, catechol, 2,4-dinitrophenol, and 2,4-dichlorophenol. This detection method using two tandem coil photo-reactors is also applied for the LC separation of phenol, 4-nitrophenol and 4-chlorophenol on an octadecyl (C18) silica LC column using acetonitrile-H₂O (40:60, v/v) as a mobile phase. The quenched CL detection limits (about 1 μM or 20 pmol) for phenol and 4-chlorophenol are comparable to those for UV detection at 254 nm. Some selectivity in the quenched CL detection is evident by no interference in the FI phenol response even when benzaldehyde and phenethanol concentrations are 8 and 15 times that of phenol.     

金鸡纳生物碱电喷雾质谱裂解规律研究

利用电喷雾离子阱质谱（ES-ITMS）技术进行了金鸡纳中4种喹啉类生物碱（奎宁、奎尼定、辛可宁和辛可尼定）的电喷雾质谱研究。在优化的质谱条件下,正离子全扫描时,4种生物碱都易形成带一个质子的分子离子;进一步碰撞诱导解离四种母离子,二级质谱表明羟基丢失、奎宁环断裂及重排为其主要裂解方式。     

测定金鸡纳碱的流动注射化学发光新体系

过氧化氢和高碘酸钠溶液混合能产生弱化学发光,在这一体系中,金鸡纳碱的加入能极大地增强这一化学发光强度,该文对这一化学发光进行了初步的探讨,提出了可能的发光机理,并据此建立了测定金鸡纳碱(奎宁、奎尼丁和辛可宁)的高灵敏度化学发光法;测定奎宁、奎尼丁和辛可宁的线性范围分别为6.0×10-5～1.0×10-2g/L、4.0×10-5～1.0×10-2g/L和1.0×10-3～1.0×10-1g/L,检出限分别为2.1×10-5g/L,1.4×10-5g/L,3.5×10-4g/L;该法适用于奎宁药物的测定.     

Asymmetric sulfenylation of 3-CF3-Oxindoles through organocatalysis with a quinidine derivative

An asymmetric sulfenylation of 3-CF₃-oxindoles catalyzed by a quinidine derivative was described. 3-CF₃-oxindoles with electro-donating groups led to corresponding products in good yield and with good enantioselectivity while 3-CF₃-oxindoles bearing electro-withdrawing groups were not competent substrates due to its significant decomposition at the optimal reaction conditions. As for the sulfenylation reagents based on thiophenol, both electro-donating groups and electro-withdrawing groups were well tolerated.     

Catalytic asymmetric total syntheses of quinine and quinidine

The catalytic, asymmetric syntheses of quinine and quinidine were achieved in 16 steps. The recently developed salen(Al)-catalyzed enantioselective Michael addition of methyl cyanoacetate served to set the crucial C4 stereocenter in 92% ee, and a late-stage asymmetric dihydroxylation was used to differentiate the common intermediate and access the two desired diastereomeric products with high selectivity.     

Determination of quinine in beverages by online coupling capillary isotachophoresis to capillary zone electrophoresis with UV spectrophotometric detection

The present study illustrates the possibilities of capillary isotachophoresis (CITP) online coupled with capillary zone electrophoresis (CZE) and hyphenated with fiber-based spectrophotometric diode array detection (DAD) for the direct, highly reliable, and ultrasensitive determination of quinine (QUI) in real multicomponent ionic matrices (beverages). Here, the CITP provided an effective online sample pretreatment (preseparation and preconcentration) prior to the CZE separation. Due to the CITP sample preconcentration, a simple UV-visible absorbance spectrophotometric detection was sufficient for obtaining very low concentration limits of detection (~2.3 ng/mL). Enhanced separation selectivity due to the combination of different separation mechanisms (CITP vs. CZE) enabled to obtain a pure analyte zone, suitable for its detection and quantitation in the directly injected real samples. The spectrophotometric DAD, unlike single wavelength UV detection, enabled to characterize the purity (i.e. spectral homogeneity) of the analyte zone and preliminary data indicate structurally related compounds via characteristic spectra recorded in the interval of 200-600 nm. The proposed CITP-CZE-DAD method was characterized by favorable performance parameters (sensitivity, linearity, precision, recovery, accuracy, robustness, and selectivity) and successfully applied to the control of QUI and potential QUI impurities in commercial beverages. This method is proposed as a routine automatized method for the highly reliable quality food control.     

Non-aqueous titration of quinine and quinidine sulphates by use of barium perchlorate

A simple non-aqueous titration method has been devised for determining the sulphates of quinine and quinidine. The sulphate is precipitated by addition of excess of barium perchlorate solution in acetic and the liberated alkaloid is then titrated in 1:2 anhydrous acetic-dioxan mixture, with an acetic acid solution of perchloric acid. The end-point is determined either visually with Crystal Violet as indicator or potentiometrically with a glass-Ag/AgCl combination electrode. The method is accurate, precise and suitable for routine analysis of pure materials and tablets.     

Highly effective and enantioselective Phospho-Aldol reaction of diphenyl phosphite with N-alkylated isatins catalyzed by quinine

Cinchona alkaloids were first successfully reported to promote enantioselective Phospho-Aldol reaction of diphenyl phosphite to a variety of N-alkylated isatin derivatives in good to excellent yields (up to 99%) and moderate to good enantioselectivities (up to 73% ee) almost in no time.     

Highly enantioselective aza-henry reaction of ketimines catalyzed by a chiral bifunctional thiourea-tertiary amine derived from quinine

We have developed a highly enantioselective aza-Henry reaction of aryl α-ketoester-derived N-Ts ketimines with a wide range of substrate scope by a simpler bifunctional thiourea-tertiary amine catalyst derived from quinine. A variety of ketimines were investigated and corresponding products were obtained in excellent yields (up to 99% yield) with excellent enatioselectivities (up to 99% ee).     

Rapid quantification of quinine by multi‐stacking in a portable microchip electrophoresis system

A new multi‐stacking pre‐concentration procedure based on field‐enhanced sample injection (FESI), field‐amplified sample stacking, and transient isotachophoresis was developed and implemented in a compact microchip electrophoresis (MCE) with a double T‐junction glass chip, coupled with an on‐chip capacitively coupled contactless conductivity detection (C⁴D) system. A mixture of the cationic target analyte and the terminating electrolyte (TE) from the two sample reservoirs was injected under FESI conditions within the two sample‐loading channels. At the double T‐junction, the stacked analyte zones were further concentrated under field‐amplified stacking conditions and then subsequently focused by transient‐isotachophoresis and separated along the separation channels. The proposed multi‐stacking strategy was verified under a Universal Serial Bus (USB) fluorescence microscope employing Rhodamine 6G as the model analyte. This developed approach was subsequently used to monitor the target quinine present in human plasma samples. The total analysis time for quinine was approximately 200 s with a sensitivity enhancement factor of approximately 61 when compared to the typical gated injection. The detection and quantification limits of the developed approach for quinine were 3.0 μg/mL and 10 μg/mL, respectively, with intraday and interday repeatability (%RSDs, n = 5) of 3.6 and 4.4%. Recoveries in spiked human plasma were 98.1–99.8%.     

Reaction of quinidine acetate, epiquinidine and its acetate in superacid: formation of gem-difluoro derivatives with or without rearrangement

In HF-SbF₅, quinidine 1a or its dihydrochloride cyclises previously obtained with usual acids. A similar reaction is observed in the presence of CCl₄. Under similar conditions quinidine acetate 1b and epiquinidine acetate 2b dihydrochlorides both yield 10,10-difluoro derivatives epimeric at C-3, 6 and 7, and 9c and 10b, and a rearranged difluoro derivative 8b and 11b, respectively. Epiquinidine 2a leads to the expected analogues 10a and 11a and to a ketone 9a. Formation of gem-difluoro compounds implies chloro intermediates at C-10, precursors of α-chlorocarbenium ions, which are trapped by a fluoride ion and which lead by halogen exchange to the products.     

Synthesis and computation of diastereomeric phenanthroline–quinine ligands and their application in asymmetric Henry reaction

A class of chiral ligands has been developed by combining phenanthroline with quinine in a one-step method that does not require resolution. The synthesized three ligands were then coordinated with Cu^(II) and the performance of the resultant chiral catalysts in the asymmetric Henry reaction was evaluated. Moderate to good yields (up to 86%) with high enantioselectivities (up to 99% ee) were observed in the reactions catalyzed by one of the three catalysts. Theoretical calculations were performed to analyze the catalytic activities of the different Cu^(II)-ligand catalysts. Three different ligands were investigated and one ligand was found to adopt an unexpected five-coordinated mode; the second coordinated with two nitrogen atoms of phenanthroline to give a complex, which activated both substrates of Henry reaction; the third was unable to form a complex with Cu^(II).