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.     

Application of multivariate methods to the simultaneous Fourier Transform Infrared (FT-IR) spectrometric determination of stereo-isomers; quinine and quinidine

The two stereo-isomers; quinine and quinidine have been determined in their mixtures in the IR region using chemometric multivariate methods, principal component regression (PCR) and partial least squares (PLS). A training set of thirty synthetic binary mixture solutions in the possible combinations containing 0.0 - 4.0 and 4.0 - 0.0% w/v quinine and quinidine, respectively in chloroform was used to develop the multivariate calibrations. A validation set containing thirty synthetic binary mixtures of variable ratios in the range of 0.2 - 4.0 and 4.0 - 0.2% w/v for quinine and quinidine, respectively in chloroform was used to validate the developed calibrations. The results of analysis of the validation synthetic mixtures were found to be 100.5+/-0.44% (R.S.D.%=0.44) and 100.5+/-0.38% (R.S.D.%=0.38) for quinine and 100.1+/-0.67% (R.S.D.%=0.67) and 100.1+/-0.68% (R.S.D.%=0.68) for quinidine using PCR and PLS models, respectively.     

Non-aqueous capillary electrophoretic enantioseparation of N-derivatized amino acids using cinchona alkaloids and derivatives as chiral counter-ions

A non-aqueous capillary electrophoretic method developed with quinine and tert.-butyl carbamoylated quinine as chiral selectors for the enantioseparation of N-protected amino acids was applied to the investigation of other quinine derivatives as chiral additives. The optimum composition of the background electrolyte was found to be 12.5 mM ammonia, 100 mM octanoic acid and 10 mM chiral selector in an ethanol-methanol (60:40, v/v) mixture. Under these conditions, a series of chiral acids, as various benzoyl, 3,5-dinitrobenzoyl and 3,5-dinitrobenzyloxycarbonyl amino acid derivatives were investigated with regards to selectand-selector relationships and enantioselectivity employing quinine, quinidine, cinchonine, cinchonidine, tert.-butyl carbamoylated quinine, tert.-butyl carbamoylated quinidine, dinitrophenyl carbamoylated quinine and cyclohexyl carbamoylated quinine as chiral selector.     

Factors controlling adsorption equilibria from solution onto solid surfaces: the uptake of cinchona alkaloids on platinum surfaces

The room-temperature adsorption of four closely related cinchona alkaloids and three reference quinoline-based compounds from CCl4 solutions onto a polycrystalline platinum surface was characterized by in situ reflection-absorption infrared spectroscopy (RAIRS). The adsorption equilibrium constants (Kads) were found to follow the sequence cinchonine > quinidine > cinchonidine > quinine > 6-methoxyquinoline > lepidine > quinoline. Some of this ordering can be explained by differences in solubility, but quinidine displays a much larger Kads than expected on the basis of its large relative solubility; bonding to the surface must also play a role in determining its behavior. It was determined that each alkaloid binds differently on Pt at saturation coverages. While the quinoline ring of cinchonidine tilts along its long axis to optimize pi-pi intermolecular interactions, in cinchonine it tilts along the short axis and bonds through the lone electron pair of the nitrogen atom instead, and both quinine and quinidine exhibit additional bonding via the methoxy oxygen atom at intermediate concentrations. Perhaps a more surprising result from this work is the fact that cinchonine displays a higher Kads than cinchonidine, quinine, or quinidine even though, according to previous work, it can be easily displaced from the surface by any of those other cinchona alkaloids. A full explanation of these observations requires consideration of the solvent above the adsorbed species.     

Novel chiral stationary phases based on peptoid combining a quinine/quinidine moiety through a C9‐position carbamate group

By connecting a quinine or quinidine moiety to the peptoid chain through the C9‐position carbamate group, we synthesized two new chiral selectors. After immobilizing them onto 3‐mercaptopropyl‐modified silica gel, two novel chiral stationary phases were prepared. With neutral, acid, and basic chiral compounds as analytes, we evaluated these two stationary phases and compared their chromatographic performance with chiral columns based on quinine tert‐butyl carbamate and the previous peptoid. From the resolution of neutral and basic analytes under normal‐phase mode, it was found that the new stationary phases exhibited much better enantioselectivity than the quinine tert‐butyl carbamate column; the peptoid moiety played an important role in enantiorecognition, which controlled the elution orders of enantiomers; the assisting role of the cinchona alkaloid moieties was observed in some separations. Under acid polar organic phase mode, it was proved that cinchona alkaloid moieties introduced excellent enantiorecognitions for chiral acid compounds; in some separations, the peptoid moiety affected enantioseparations as well. Overall, chiral moieties with specific enantioselectivity were demonstrated to improve the performance of peptoid chiral stationary phase efficiently.     

Enantioseparation of anionic analytes by non-aqueous capillary electrophoresis using quinine and quinidine derivatives as chiral counter-ions

A non-aqueous capillary electrophoretic method developed for the enantioseparation of N-protected amino acids has been applied to the investigation of five new quinine and quinidine derivatives as chiral selectors: 1-adamantyl carbamoylated quinine, 3,4-dichlorophenyl carbamoylated quinidine, allyl carbamoylated dihydroquinine, allyl carbamoylated dihydroquinidine and 1-methyl quininium iodide. The composition of the background electrolyte was 12.5 mM ammonia, 100 mM octanoic acid in an ethanol-methanol (60:40 v/v) mixture containing a 10 mM concentration of the chiral selector. Under these conditions, the enantioseparation of a series of various benzoyl, 3,5-dinitrobenzoyl and 3,5-dinitrobenzyloxycarbonyl amino acid derivatives was studied with respect to selectand-selector relationship and enantioselectivity.     

In silico and in vitro identification of candidate SIRT1 activators from Indonesian medicinal plants compounds database

Sirtuin 1 (SIRT1) is a class III family of protein histone deacetylases involved in NAD⁺-dependent deacetylation reactions. It has been suggested that SIRT1 activators may have a protective role against type 2 diabetes, the aging process, and inflammation. This study aimed to explore and identify medicinal plant compounds from Indonesian Herbal Database (HerbalDB) that might potentially become a candidate for SIRT1 activators through a combination of in silico and in vitro methods. Two pharmacophore models were developed using co-crystalized ligands that allosterically bind with SIRT1 similar to the putative ligands used by SIRT1 activators. Then, these were used for the virtual screening of HerbalDB. The identified compounds were subjected to molecular docking and 50 ns molecular dynamics simulation. Molecular dynamics simulation was analyzed using MM-GB(PB)SA methods. The compounds identified by these methods were tested in an in vitro study using a SIRT-Glo™ luminescence assay. Virtual screening using structure-based pharmacophores predicted that mulberrin as the best candidate SIRT1 activator. Virtual screening using ligand-based pharmacophores predicted that gartanin, quinidine, and quinine to be the best candidates as SIRT1 activators. The molecular docking studies showed the important residues involved were Ile223 and Ile227 at the allosteric region. The MM-GB(PB)SA calculations confirmed that mulberrin, gartanin, quinidine, quinine showed activity at allosteric region and their EC₅₀ in vitro values are 2.10; 1.79; 1.71; 1.14 μM, respectively. Based on in silico and in vitro study results, mulberin, gartanin, quinidine, and quinine had good activity as SIRT1 activators.     

Total Synthesis of (-)-Kaerophyllin,(-)-Hinokinin and (±)-Isohinokinin

Kaerophyllin (1) ,hinokinin (2 )andtheiranalogue isohinokinin (3)belongtothedibenzylbutyrolactone lig nans .Kaerophyllin (1)wasisolatedfromtherootofspot tedcowparsley (ChaerophyllummaculatumWilld .) 1andhinokinin (2 )wasisolatedfromtheheartwoodofLiboce drusformosanaFlorin .2 AccordingtoMacRaeandTow ers ,3afivememberedlactoneringandamethylenedioxylgroupwereimportantstructuralcharacteristicswhichcon tributetotheactivityoflignansasantitumoragents .More over ,anunsaturateddoublebondbetweenC3—…     

Application of site-selective ion–molecule reactions to the analysis of the cinchona alkaloids

Functional group interactions within biologically relevant molecules are among the most influential yet least understood factors in determining their reactive behaviors. Reactions of dimethyl ether ions, which have previously been shown to be site-selective, with four cinchona alkaloids, cinchonine, cinchonidine, quinine and quinidine, have been examined. These reactions are each shown to produce qualitatively similar spectra for the stereoisomeric pairs cinchonidine–cinchonine and quinidine–quinine, but small variations in the relative abundances of the products indicate that some stereoselectivity can be observed. The site selectivity of each of the reagents was investigated by observing the reactions occurring with model subunits of the alkaloids.     

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin,and (−)‐Pavidolide B: A Divergent Approach

A concise and divergent approach for the total syntheses of four cembrane diterpenoids, namely (+)‐sarcophytin, (+)‐chatancin, (?)‐3‐oxochatancin, and (?)‐pavidolide B, has been developed, and it also led to the structural revision of (?)‐isosarcophytin. The key steps of the strategy feature a double Mukaiyama Michael addition/elimination, a Helquist annulation, two substrate‐controlled facial‐selective hydrations, and a pinacol rearrangement. The described syntheses not only achieved these natural products in an efficient manner, but also provided insight into the biosynthetic relationship between the two different skeletons.     

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin,and (−)‐Pavidolide B: A Divergent Approach

A concise and divergent approach for the total syntheses of four cembrane diterpenoids, namely (+)‐sarcophytin, (+)‐chatancin, (?)‐3‐oxochatancin, and (?)‐pavidolide B, has been developed, and it also led to the structural revision of (?)‐isosarcophytin. The key steps of the strategy feature a double Mukaiyama Michael addition/elimination, a Helquist annulation, two substrate‐controlled facial‐selective hydrations, and a pinacol rearrangement. The described syntheses not only achieved these natural products in an efficient manner, but also provided insight into the biosynthetic relationship between the two different skeletons.     

Conformational analysis of quinine and its pseudo enantiomer quinidine: a combined jet-cooled spectroscopy and vibrational circular dichroism study

Laser-desorbed quinine and quinidine have been studied in the gas phase by combining supersonic expansion with laser spectroscopy, namely, laser-induced fluorescence (LIF), resonance-enhanced multiphoton ionization (REMPI), and IR-UV double resonance experiments. Density funtional theory (DFT) calculations have been done in conjunction with the experimental work. The first electronic transition of quinine and quinidine is of π-π* nature, and the studied molecules weakly fluoresce in the gas phase, in contrast to what was observed in solution (Qin, W. W.; et al. J. Phys. Chem. C2009, 113, 11790). The two pseudo enantiomers quinine and quinidine show limited differences in the gas phase; their main conformation is of open type as it is in solution. However, vibrational circular dichroism (VCD) experiments in solution show that additional conformers exist in condensed phase for quinidine, which are not observed for quinine. This difference in behavior between the two pseudo enantiomers is discussed.     

Total Synthesis of (+)‐Rubriflordilactone A

Two enantioselective total syntheses of the nortriterpenoid natural product rubriflordilactone A are described, which use palladium‐ or cobalt‐catalyzed cyclizations to form the CDE rings, and converge on a late‐stage synthetic intermediate. These key processes are set up through the convergent coupling of a common diyne component with appropriate AB‐ring aldehydes, a strategy that sets the stage for the synthetic exploration of other members of this family of natural products.     

Monomeric Cinchona Alkaloid‐Based Catalysts for Highly Enantioselective Bromolactonisation of Alkynes

The cinchona alkaloid dimer (DHQD)₂PHAL has been shown to be a broadly applicable catalyst for asymmetric halogenations. However, this catalyst does not have to be dimeric and a class of monomeric quinidine and quinine‐derived catalysts was prepared, often showing superior selectivity in bromolactonisations of terminal alkynoic acids. Mechanistic investigations show that these organocatalysts act as host molecules that can bind carboxylic acid‐based substrates as guests with substantial binding constants. Based on these findings, it is proposed that this class of catalysts is bifunctional in nature activating the halogenating agent as well as the nucleophile in electrophilic halogenation reactions.     

Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (−)‐Lundurine A

The bioactive Kopsia alkaloids lundurines A–D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (?)‐lundurine A has previously been achieved through a Simmons–Smith cyclopropanation strategy. Here, the total synthesis of (?)‐lundurine A was carried out using a metal‐catalyzed diazo cyclopropanation strategy. In order to avoid a carbene C?H insertion side reaction during cyclopropanation of α‐diazo‐ carboxylates or cyanides, a one‐pot, copper‐catalyzed Bamford–Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7.     

New general sulfinylating process for asymmetric synthesis of enantiopure sulfinates and sulfoxides

[reaction: see text] A general process for the efficient synthesis of sulfinyl transfer agents has been developed using cinchona alkaloids quinine and quinidine as chiral auxiliaries. The importance of these new and unique sulfinyl transfer agents is exemplified by the expedient synthesis of several sulfoxides in excellent enantiopurities and high yields.     

The organocatalytic desymmetrization of meso-ferrocene anhydride

A new and unique organocatalytic process for the desymmetrization of meso ferrocene anhydride has been developed. After optimization with a series of quinine, quinidine and squaramide ligands, the method was effective with a 60% isolated yield and 98% ee.     

Short and Divergent Total Synthesis of (+)‐Machaeriol B, (+)‐Machaeriol D, (+)‐Δ8‐THC,and Analogues

Short and highly efficient stereoselective syntheses provide machaeriols and cannabinoids in a divergent approach starting from a common precursor, commercially available (S)‐perillic acid. Key features of the novel strategy are a stereospecific palladium‐catalyzed decarboxylative arylation and a one‐pot sequence comprising a stereoselective hydroboration followed by oxidation or reduction of the corresponding intermediary boranes. The divergent approach is convincingly demonstrated by the five‐step syntheses of (+)‐machaeriol B, (+)‐machaeriol D, and related analogues, and the four‐step synthesis of (+)‐Δ⁸‐THC and an analogue.     

Development and validation of RP‐HPLC‐fluorescence method for quantitative determination of quinidine,a probe substrate for P‐glycoprotein inhibition assay using Caco‐2 cell monolayer

A simple, sensitive and specific reverse‐phase high‐performance liquid chromatographic (RP‐HPLC) method with fluorescence detection was developed for quantitation of quinidine from HBSS buffer. The method was applicable in the bi‐directional transport assay for evaluation of the inhibitory effect of test compounds on P‐glycoprotein‐mediated quinidine transport; quinidine was used as a probe P‐glycoprotein substrate. The calibration curve was linear (correlation coefficient ≥99) in the range 0.30–100.00 nm. The method was validated and is specific and sensitive with limit of quantitation of 300 pm for quinidine. The method was found to be accurate and precise in the working calibration range. Stability studies were carried out at different storage conditions where the analyte was found to be stable. The applicability and reliability of the analytical method was evaluated by successful demonstration of efflux ratio (P_appB → A/P_appA → B) in the Caco‐2 cell monolayer efflux assay. The efflux ratio for quinidine (100 nm) alone was 10.8, which reduced to less than 2 in the presence of the classical P‐gp inhibitors verapamil and ketoconazole (100 μm each). Copyright © 2009 John Wiley & Sons, Ltd.