Substâncias enantiomericamente puras (SEP): a questão dos fármacos quirais

The thalidomide disaster, in the 60,s, is the most painful reminder of the importance of chirality for biological activity. After this episode, much attention has been devoted to study the correlations between toxicological and pharmacological properties and chirality. Actualy, to get a licence for a new chiral drug in EUA, European community and Japan, it is necessary to study the biological properties of each enatiomer independently. This article presents an overview about the importance of the chirality of organic compounds and its relationships with biological activity, asymmetric synthetic methodologies and market.

Determination of Atropine Enantiomers in Ophthalmic Solutions by Liquid Chromatography Using a Chiral AGP (R) Column

Many therapeutic agents are commercialized under their racemic form. The enantiomers can show differences in the pharmacokinetic and pharmacodynamic profile. The use of a pure enantiomer in pharmaceutical formulations may result in a better therapeutic index and fewer adverse effects. Atropine, an alkaloid of Atropa belladonna, is a racemic mixture of l-hyoscyamine and d-hyoscyamine. It is widely used to dilate the pupil. To quantify these enantiomers in ophthalmic solutions, an HPLC method was developed and validated using a Chiral AGP (R) column at 20 degrees C. The mobile phase consisted of a buffered phosphate solution (containing 10 mM 1-octanesulfonic acid sodium salt and 7.5 mM triethylamine, adjusted to pH 7.0 with orthophosphoric acid) and acetonitrile (99 + 1, v/v). The flow rate was 0.6 mL/min, with UV detection at 205 nm. In the concentration range of 14.0-26.0 mu g/mL, the method was found to be linear (r > 0.9999), accurate (with recovery of 100.1-100.5%), and precise (RSD system: <= 0.6%; RSD intraday: <= 1.1%; RSD interday: <= 0.9%). The method was specific, and the standard and sample solutions were stable for up to 72 h. The factorial design assures robustness with a variation of +/-10% in the mobile phase components and 2 degrees C of column temperature. The complete validation, including stress testing and factorial design, was studied and is presented in this research.

Development and validation of sensitive methods for determination of sibutramine hydrochloride monohydrate and direct enantiomeric separation on a protein-based chiral stationary phase

Sibutramine hydrochloride monohydrate, chemically 1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl) hydrochloride monohydrate (SB center dot HCl center dot H2O), was approved by the U.S. Food and Drug Administration for the treatment of obesity. The objective of this study was to develop, validate, and compare methods using UV-derivative spectrophotometry (UVDS) and reversed-phase high-performance liquid chromatography (HPLC) for the determination of SB center dot HCl center dot H2O in pharmaceutical drug products. The UVDS and HPLC methods were found to be rapid, precise, and accurate. Statistically, there was no significant difference between the proposed UVDS and HPLC methods. The enantiomeric separation of SB was obtained on an alpha-1 acid glycoprotein column. The R- and S-sibutramine were eluted in < 5 min with baseline separation of the chromatographic peaks (alpha = 1.9 and resolution = 1.9).

Development of molecularly imprinted polymers using supercritical fluid technology

Dissertação para obtenção do Grau de Doutor em Química Sustentável

Novel technology for preparation of optically active chemicals

Asymmetric synthesis using modified heterogeneous catalysts has gained lots of interest in the production of optically pure chemicals, such as pharmaceuticals, nutraceuticals, fragrances and agrochemicals. Heterogeneous modified catalysts capable of inducing high enantioselectivities are preferred in industrial scale due to their superior separation and handling properties. The topic has been intensively investigated both in industry and academia. The enantioselective hydrogenation of ethyl benzoylformate (EBF) to (R)-ethyl mandelate over (-)-cinchonidine (CD)-modified Pt/Al2O3 catalyst in a laboratory-scale semi-batch reactor was studied as a function of modifier concentration, reaction temperature, stirring rate and catalyst particle size. The main product was always (R)-ethyl mandelate while small amounts of (S)-ethyl mandelate were obtained as by product. The kinetic results showed higher enantioselectivity and lower initial rates approaching asymptotically to a constant value as the amount of modifier was increased. Additionally, catalyst deactivation due to presence of impurities in the feed was prominent in some cases; therefore activated carbon was used as a cleaning agent of the raw material to remove impurities prior to catalyst addition. Detailed characterizations methods (SEM, EDX, TPR, BET, chemisorption, particle size distribution) of the catalysts were carried out. Solvent effects were also studied in the semi-batch reactor. Solvents with dielectric constant (e) between 2 and 25 were applied. The enantiomeric excess (ee) increased with an increase of the dielectric coefficient up to a maximum followed by a nonlinear decrease. A kinetic model was proposed for the enantioselectivity dependence on the dielectric constant based on the Kirkwood treatment. The non-linear dependence of ee on (e) successfully described the variation of ee in different solvents. Systematic kinetic experiments were carried out in the semi-batch reactor. Toluene was used as a solvent. Based on these results, a kinetic model based on the assumption of different number of sites was developed. Density functional theory calculations were applied to study the energetics of the EBF adsorption on pure Pt(1 1 1). The hydrogenation rate constants were determined along with the adsorption parameters by non-linear regression analysis. A comparison between the model and the experimental data revealed a very good correspondence. Transient experiments in a fixed-bed reactor were also carried out in this work. The results demonstrated that continuous enantioselective hydrogenation of EBF in hexane/2-propanol 90/10 (v/v) is possible and that continuous feeding of (-)-cinchonidine is needed to maintain a high steady-state enantioselectivity. The catalyst showed a good stability and high enantioselectivity was achieved in the fixed-bed reactor. Chromatographic separation of (R)- and (S)-ethyl mandelate originating from the continuous reactor was investigated. A commercial column filled with a chiral resin was chosen as a perspective preparative-scale adsorbent. Since the adsorption equilibrium isotherms were linear within the entire investigated range of concentrations, they were determined by pulse experiments for the isomers present in a post-reaction mixture. Breakthrough curves were measured and described successfully by the dispersive plug flow model with a linear driving force approximation. The focus of this research project was the development of a new integrated production concept of optically active chemicals by combining heterogeneous catalysis and chromatographic separation technology. The proposed work is fundamental research in advanced process technology aiming to improve efficiency and enable clean and environmentally benign production of enantiomeric pure chemicals.

”Nonlinear optical properties of polymers containing azomesogens and chiral molecules: theoretical and experimental evaluations."

The present work emphasizes the use of chirality as an efficient tool to synthesize new types of second order nonlinear materials. Second harmonic generation efficiency (SHG) is used as a measure of second order nonlinear response. Nonlinear optical properties of polymers have been studied theoretically and experimentally. Polymers were designed theoretically by ab initio and semiempirical calculations. All the polymeric systems have been synthesized by condensation polymerization. Second harmonic generation efficiency of the synthesized systems has been measured experimentally by Kurtz and Perry powder method

Optical and Thermal Properties of Diethyl-(2R, 3R) (1)-tartrate Based Chiral Polyurethanes with Main Chain Amido Chromophores

The toluene diisocyanate based optically active chiral polyurethanes were synthesized according to the symmetry conditions. The noncentrosymmetric (both charge asymmetry and spatial asymmetry) environment were attained by the incorporation of the chiral units (diethyl-(2R,3R)(þ)-tartrate) and donor-acceptor building blocks in the main chain which induce a helical conformation in the macromolecular chain. A series of optically active polyurethanes containing chiral linkages in the polymer back bone have been synthesized by using DBTDL catalyst by incorporating the amido diols which were obtained by the aminolysis of e-caprolactone by using the diamines, diaminoethane, diaminobutane, and diaminohexane respectively. The effect of incorporation of the chiral molecule diethyl-(2R,3R)(þ)-tartrate on the properties of polyurethanes was studied by changing the chromophores and also by varying the chiral-chromophore composition. Various properties of polyurethanes were investigated by UV, Fluorescence, TG/DTA, XRD, polarimetric techniques, Kurtz-Perry powder techniques, etc.

Isosorbide based chiral polyurethanes: optical and thermal studies

A new class of chiral polyurethanes containing amido linkages in the polymer backbone have been synthesized by reacting toluene diisocyanate with isosorbide (IS) chiral moiety and the chromophores [N,N0-ethane- 1,2-diyl bis(6-hydroxy hexanamide), N,N0-butane-1,4-diyl bis(6-hydroxy hexanamide) and N,N0-hexane-1,6-diyl bis (6-hydroxy hexanamide)]. The corresponding chromophores were obtained by the aminolysis of e-caprolactone by using the diamines, diaminoethane, diaminobutane and diaminohexane, respectively. All the polymers were synthesized according to the symmetry conditions so as to obtain the non-centrosymmetric environment. A series of polyurethanes were synthesized by varying the chiral– chromophore composition. The polyurethanes developed were characterized by optical and thermal methods.

Chiral molecules on surfaces

chiral molecules can modify surfaces in many ways. Long-range chiral structures can be induced by local chirality, which can act as templates stereo-directing other molecules. Such templates are either based on the arrangement of molecules alone or involve reconstruction of the substrate suface. Stereo-direction can also be achieved buy direct local interaction between chiral moleculesx. Even the adsorption of achiral molecules onto achiral surfaces can induce local chirality due to a reduction ofsymmetry in the presence of the surface. Intrinsically chiral metal and oxide surfaces can act as templates for enantioselective adsorption and surface reactions without any surface modification.

Preparation of Achiral and Chiral (E)-Enaminopyran-2,4-diones and Their Phytotoxic Activity

A short and efficient approach to a range of new chiral and achiral functionalized (E)-enaminopyran-2,4-diones starting with commercially available dehydroacetic acid is described. The phytotoxic properties of these (E)-enaminopyran-2,4-diones were evaluated by their ability to interfere with the growth of Sorghum bicolor and Cucumis sativus seedlings. A different sensitivity of the two crops was evident with the (E)-enaminopyran-2,4-diones. The most active compounds were also tested against two weeds, Ipomoea grandifolia and Brachiaria decumbens. To the best of our knowledge, this is the first report describing enaminopyran-2,4-diones as potential plant growth regulators.

Probing chiral interfaces by infrared spectroscopic methods

Biological homochirality on earth and its tremendous consequences for pharmaceutical science and technology has led to an ever increasing interest in the selective production, the resolution and the detection of enantiomers of a chiral compound. Chiral surfaces and interfaces that can distinguish between enantiomers play a key role in this respect as enantioselective catalysts as well as for separation purposes. Despite the impressive progress in these areas in the last decade, molecular-level understanding of the interactions that are at the origin of enantiodiscrimination are lagging behind due to the lack of powerful experimental techniques to spot these interactions selectively with high sensitivity. In this article, techniques based on infrared spectroscopy are highlighted that are able to selectively target the chiral properties of interfaces. In particular, these methods are the combination of Attenuated Total Reflection InfraRed (ATR-IR) with Modulation Excitation Spectroscopy (MES) to probe enantiodiscriminating interactions at chiral solid-liquid interfaces and Vibrational Circular Dichroism (VCD), which is used to probe the structure of chirally-modified metal nanoparticles. The former technique aims at suppressing signals arising from non-selective interactions, which may completely hide the signals of interest due to enantiodiscriminating interactions. Recently, this method was successfully applied to investigate enantiodiscrimination at self-assembled monolayers of chiral thiols on gold surfaces. The nanometer size analogues of the latter--gold nanoparticles protected by a monolayer of a chiral thiol--are amenable to VCD spectroscopy. It is shown that this technique yields detailed structural information on the adsorption mode and the conformation of the adsorbed thiol. This may also turn out to be useful to clarify how chirality can be bestowed onto the metal core itself and the nature of the chirality of the latter, which is manifested in the metal-based circular dichroism activity of these nanoparticles.

Biotransformations of Substituted Phenylethanols and Acetophenones by Environmental Bacteria

Whole cells of hydrocarbon-degrading bacteria, isolated from polluted sediments in the Santos Estuary (Baixada Santista, Sao Paulo, Brazil), were able to catalyse oxidoreduction reactions with various substituted phenylethanols and acetophenones as substrates. A number of substituted phenylethanols were formed with high (>99 %) enantiomeric excess. The results of microbial oxidation of phenylethanols 2, 3, 5-7 by Acinetobacter sp. 6.4T and the reduction of acetophenones 1a-6a by Serratia marcescens 5.4T showed that the bacteria used as biocatalysts in this study present significant potential for exploitation in biotechnological processes. The reduction of prochiral acetophenones by Serratia marcescens 3.5T yielded optically active alcohols with 90-99 % enantiomeric excess, and Acinetobacter sp. 6.4T is a potential biocatalyst for the oxidation of alcohols.

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.

omega-Transaminases as efficient biocatalysts to obtain novel chiral selenium-amine ligands for Pd-catalysis

omega-Transaminases have been evaluated as biocatalysts in the reductive amination of organoselenium acetophenones to the corresponding amines, and in the kinetic resolution of racemic organoselenium amines. Kinetic resolution proved to be more efficient than the asymmetric reductive amination. By using these methodologies we were able to obtain both amine enantiomers in high enantiomeric excess (up to 99%). Derivatives of the obtained optically pure o-selenium 1-phenylethyl amine were evaluated as ligands in the palladium-catalyzed asymmetric alkylation, giving the alkylated product in up to 99% ee.