Stereoselective Methods Research Articles

Establishing bioequivalence of racemic venlafaxine formulations using stereoselective assay method: Is it necessary?

A bioequivalence study for venlafaxine generic formulation was conducted as an open label, balanced, randomized, two-way crossover, single-dose study. In this study, a comparison of various pharmacokinetic parameters of venlafaxine hydrochloride 150 mg modified release capsules of Ranbaxy and EFEXOR®-XR 150 mg capsules of Wyeth, in healthy, adult, male, human subjects under fasting condition was performed to conclude bioequivalence. Venlafaxine and its major active metabolite O-desmethylvenlafaxine (ODV) are racemates. The "(S)-(+)" and "(R)-(-)" enantiomers of venlafaxine and ODV are established as being active. Hence, subject samples were analyzed using nonstereoselective and stereoselective assay methods. Both (S)-(+) and (R)-(-) enantiomers of venlafaxine and ODV showed similar absorption and disposition. The 90% confidence intervals for venlafaxine, (R)-(-)-venlafaxine as well as (S)-(+)-venlafaxine were within acceptance range concluding bioequivalence. The results obtained by stereoselective assay were comparable to the nonstereoselective analysis, as sum of concentrations of (S)-(+)- and (R)-(-)-enantiomers of venlafaxine and ODV. The mean (S)-(+)/(R)-(-) ratios of the enantiomers of venlafaxine and ODV at various time points were consistent in the study subjects. Therefore, the estimation of venlafaxine and ODV using nonstereoselective assay method is effective in distinguishing formulation differences (if any) in bioequivalence studies in a cost-effective manner.

Stereoselective determination of the epimer mixtures of itraconazole in human blood plasma using HPLC and fluorescence detection

Itraconazole is an antifungal drug widely used in a variety of fungal infections, which have become a significant public-health problem in recent decades. Itraconazole is a chiral drug consisting of two diastereoisomeric racemates, i.e., four stereoisomers. Data in the literature suggests that stereochemistry may play a significant role in the action and disposition of the drug and therefore stereoselective analytical methods for the determination of the drug in biological fluids are needed for the elucidation of that role. We report a stereoselective HPLC method that incorporates solvent extraction, the use of an internal standard, two chiral stationary phases in series, and fluorescence detection. The procedure is enantioselective and partially diastereoselective and provides the concentrations in blood plasma of the two epimer mixtures 2R,4S,2'R/2R,4S2'S and 2S,4R,2'R/2S,4R,2'S, respectively, each of which is a combination of the two epimers that differ in the configuration at the sec-butyl group. The analytical method has suitable sensitivity, recovery, precision, and accuracy. Analysis of the plasma of a human subject six hours after the oral administration of a single 200-mg dose of itraconazole showed a 3.4-fold difference between the concentrations of the epimer mixtures. The method has certain advantages over the published alternative procedure that uses LC-MS.

ChemInform Abstract: Stereoselective Heterocycle Synthesis Through Oxidative Carbon—Hydrogen Bond Activation

AbstractReview: 74 refs.

Stereoselective method development and validation for determination of concentrations of amphetamine-type stimulants and metabolites in human urine using a simultaneous extraction–chiral derivatization approach

Amphetamine-type stimulants (ATS) are a group of chiral amine drugs which are commonly abused for their sympathomimetic and stimulant properties. ATS are extensively metabolised by hepatic cytochrome P450 enzymes. As metabolism of ATS has been shown to be highly stereospecific, stereoselective analytical methods are essential for the quantitative determination of ATS concentrations for both in vivo and in vitro studies of ATS metabolism. This paper describes a new stereoselective method for the simultaneous determination of amphetamine (AM), methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-hydroxymethamphetamine (HHMA) and 3,4-hydroxyamphetamine (HHA) in human urine samples validated according to the United States Food and Drug Administration guidelines. In this method, analytes are simultaneously extracted and derivatized with R-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (R-MTPCl) as the chiral derivatization reagent. Following this, the analytes were subjected to a second derivatization with N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) which targets the hydroxyl groups present in HMMA, HMA, HHMA and HHA. The derivatized analytes were separated and quantified using gas chromatography–mass spectrometry (GC–MS). The method was evaluated according to the established guidelines for specificity, linearity, precision, accuracy, recovery and stability using a five-day protocol. Intra-day precision ranged from 0.89 to 11.23% RSD whereas inter-day precision was between 1.03 and 12.95% RSD. Accuracy values for the analytes ranged from −5.29% to 13.75%. Limits of quantitation were 10μg/L for AM, MA, MDMA, HMA and HMMA and 2μg/L for MDA, HMA and HHA. Recoveries and stability values were also within accepted values. The method was applied to authentic ATS-positive samples.

Analytical procedures for the determination of the selective serotonin reuptake inhibitor antidepressant citalopram and its metabolites

The antidepressant citalopram (CIT) is a potent and highly selective serotonin reuptake inhibitor (SSRI) which has been introduced in therapy as a racemic drug. CIT has been used to treat central nervous system affective disorders such as depression, anxiety, obsessive-compulsive disorders, various phobias, borderline personality disorders, bipolar disorders as well as indications wherein inhibition of serotonin reuptake is desired. CIT is demethylated to demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), which retain considerable activity as SSRIs. Therefore, in recent years, the monitoring of the levels of these analytes in biological fluids for toxicological and therapeutic purposes has been a target worthy of interest. In addition, the differences in activity between CIT enantiomers established the need to assess its behaviour in the field of pharmacological research. It is also necessary to develop analytical methodologies that make it possible to determine the levels of enantiomer concentrations. This review includes most of the published analytical methods for achiral assay of racemic CIT and its metabolites based on high-performance liquid chromatography coupled with UV, fluorescence and mass spectrometry detectors, capillary electrophoresis and gas chromatography with mass spectrometry detectors among others. With regard to the monitoring of enantiomers of CIT and of its metabolites, stereoselective methods based on chiral chromatographic columns, chiral additives in mobile phases and on the derivatization with a chiral reagent are also collected. In addition, different procedures of extraction are mentioned as well as liquid-liquid extraction, solid-phase extraction, solid-phase microextraction, automated online extraction or liquid-phase microextraction in different biological and environmental samples.

Stereoselective Construction of an Asymmetric Carbon Center Possessing a Trifluoromethyl Group

Stereoselective synthetic methods for the construction of the tertiary or quaternary asymmetric carbon centers having a trifluoromethyl group and carbon substituent(s) or hydrogen atom, not heteroatom substituent(s), are described. Keywords: A direct stereoselective trifluoromethylation, building block methodology, diastereoselective, enantioselective, chiral, photochemical, organocatalyst

Chiral phosphoric acid catalyzed peroxidation of imines.

Chiral phosphoric acid catalyzed peroxidation of imines.

Biocatalytic asymmetric formation of tetrahydro-β-carbolines

Strictosidine synthase triggers the formation of strictosidine from tryptamine and secologanin, thereby generating a carbon–carbon bond and a new stereogenic center. Strictosidine contains a tetrahydro-β-carboline moiety—an important N-heterocyclic framework found in a range of natural products and synthetic pharmaceuticals. Stereoselective methods to produce tetrahydro-β-carboline enantiomers are greatly valued. We report that strictosidine synthase from Ophiorrhiza pumila utilizes a range of simple achiral aldehydes and substituted tryptamines to form highly enantioenriched (ee >98%) tetrahydro-β-carbolines via a Pictet–Spengler reaction. This is the first example of aldehyde substrate promiscuity in the strictosidine synthase family of enzymes and represents a first step toward developing a general biocatalytic strategy to access chiral tetrahydro-β-carbolines.

ChemInform Abstract: Novel and Stereoselective Methods for the Preparation of Aromatic Lactams via Reductive Coupling Reactions Mediated by SmI2.

Abstract Samarium(II) diiodide-mediated reductive cross-coupling of N -alkylated phthalimides with carbonyl compounds is shown to afford hydroxylated α-hydroxylactams. Ketoamides obtained by dehydration of these compounds through keto-enol tautomer isomerization were reduced with NaBH 4 in a completely stereoselective manner in the presence of CeCl 3 to give threo -aromatic lactams as the sole product. Direct reductive deoxygenation of these α-hydroxylactam intermediates with Et 3 SiH in the presence of Lewis acid also displayed high stereoselectivity to afford the same threo -lactams exclusively. The mechanistic origins of this stereoselectivity are briefly documented.

Stereoselective Metabolic and Pharmacokinetic Analysis of the Chiral Active Components from Herbal Medicines

The discrimination and evaluation of stereoselective metabolism of enantiomers are of paramount significance for developing effective and safe chiral drugs. However, there is still a lack of comprehensive and in-depth understanding of stereospecific disposition of chiral components in Herbal Medicines. In this article, stereoselective methods including capillary electrophoresis, high-performance liquid chromatography, gas chromatography, supercritical fluid chromatography and hyphenation techniques for chiral drug metabolism studies are reviewed. Furthermore, applications of modern analytical techniques to study enantioselective metabolic profiling of the active components from Herbal Medicines in vitro and in vivo in recent years are also presented and the representative examples are enumerated. Keywords: Chiral analysis, Drug metabolism, Pharmacokinetics, Herbal medicines

Borane‐mediated asymmetric reduction of acetophenone by enantiopure aminonaphthols and aminoalcohols as catalytic source

Practical, cheap, and stereoselective synthetic methods were applied to the preparation of novel 1-(aminoalkyl)naphthol and gamma-aminoalcohol tridentate ligands. The ligands obtained were conveniently applied with good results as catalytic sources in the borane-mediated enantioselective reduction of acetophenone with borane dimethylsulfide. Conformational analysis through molecular modeling allows the rationalization of observed stereochemical outcomes.

Dynamic Kinetic Asymmetric Allylation of Hydrazines and Hydroxylamines

Due to the importance of hydrazines and hydroxylamines as biologically active compounds, the development of stereoselective methods for their preparation constitutes an important task in asymmetric synthesis. However, a limited number of general synthetic protocols have been developed thus far. The authors report the efficient preparation of chiral hydrazines and hydroxylamines via palladium-catalyzed amination of vinyl epoxide in the presence of the Trost biphosphine ligand 1. Reactions generally proceed regioselectively, furnishing the corresponding branched products with high yields and enantio-selectivities up to 97% ee. Synthetic power of this protocol has been demonstrated via a concise synthesis of (R)-piperazic acid accomplished in five steps in 41% overall yield.

Brønsted Acid Catalyzed Formation of Enynes

Conjugated enynes are useful building blocks in organic synthesis, thus regio- and stereoselective methods for their formation are of interest. Ring opening of 1-cyclopropyl-2-propyn-1-ols (1) with heteroatom nucleophiles to provide conjugated enynes has been previously reported with gold, ruthenium, and ytterbium catalysts. The authors report an efficient protocol for the ring opening of 1 employing a Brønsted acid catalyst.

Copper-catalyzed asymmetric conjugate addition of Grignard reagents to 1-( N,N-diisopropylcarbamoyloxy)-1-tosyl- 1-alkenes

A copper-catalyzed conjugate addition of Grignard reagents to 1-( N,N-diisopropylcarbamoyloxy)-1-tosyl-1-alkenes led to 1-( N,N-diisopropylcarbamoyloxy)-1-tosyl-2-branched alkanes. Various copper ligands were screened for this reaction. From certain substrates and allylmagnesium bromide, several Josiphos ligands gave low to moderate asymmetric inductions, along with good diastereoselectivity. The stereochemistry of the 1-( N,N-diisopropylcarbamoyloxy)-1-tosyl-2-branched alkanes from this reaction was assigned by comparison with the same products from another synthetic route using chiral pool synthesis and stereoselective lithiation methods.

Revised Assignment of Absolute Configuration of the cis- and trans-N6-Deoxyadenosine Adducts at C14 of (±)-11β,12α-Dihydroxy-13α,14α-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene by Stereoselective Synthesis

We have reassigned relative and absolute configurations by unambiguous stereoselective syntheses of the cis- (13s and 13R) and trans-N6-deoxyadenosine (dAdo) adduct diastereomers (14S and 14R) derived from (+/-)-11beta,12alpha-dihydroxy-13alpha,14alpha-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]P DE-2), previously reported by Li et al. [(1999) Chem. Res. Toxicol. 12, 758-767]. Two stereoselective methods, asymmetric aminohydroxylation of the (+/-)-trans-11,12-dihydrodiol (3) with 3',5'-di-O-(tert -butyldimethylsilyl)-2'-deoxyadenosine (4) and the highly stereoselective cis addition of 4 to (+/-)-DB[a,l]P DE-2 in hexafluoropropan-2-ol (HFP), were employed. Both afforded a 1:1 mixture of the cis-N6-dAdo adduct diastereomers, which were separated as triacetates (5S and 5R) in comparable yields (approximately 80%). The corresponding trans adduct diastereomers (10S and 10R) were obtained by coupling the aminotriol derived from trans opening of (+/-)-DB[a,l]P DE-2 with 6-fluoro-(2'-deoxy-3,5-di-tert-butyldimethylsilyloxy-beta-D-erythro-pentafuranosyl)purine (9) and subsequent acetylation in approximately 70% yield. The cis-5S and -5R and trans-10S and -10R were separately treated with 7% HF-pyridine followed by ammonolysis in NH3-saturated MeOH to give the dAdo adducts with all hydroxyl groups free (13S, 13R, 14S, and 14R). Comparison of the 1H NMR and CD spectra of these presently synthesized dAdo adducts with spectra of the previously reported compounds revealed that the interpretation of the 1H NMR and CD spectra and assignment of the relative stereochemistry (cis/trans) and absolute configuration made by Li et al. were at variance with our results. The above highly stereoselective syntheses of (+/-)-DB[a,l]P DE-2 adducted dAdo derivatives enabled efficient preparation of each of the four possible stereoisomeric 5'-dimethoxytrityl-3'-phosphoramidites for use in oligonucleotide synthesis.

Enzyme-assisted physicochemical enantioseparation processes: Part I. Production and characterization of a recombinant amino acid racemase

The demand for enantiopure substances, e.g. for pharmaceutical applications or fine chemical production, continues to increase. This has led to the development of numerous stereoselective synthesis methods. Nevertheless a large number of chemical syntheses still result in racemic mixtures making a subsequent enantioseparation step necessary and thus are restricted to a maximum yield of 50%. Our work focuses on strategies to overcome this limitation by combining physicochemical separation processes with enzymatic racemization of the unwanted enantiomer in order to produce enantiopure amino acids. This paper deals with the production and characterization of a suitable amino acid racemase with broad substrate specificity (EC 5.1.1.10) from Pseudomonas putida which we cloned into Escherichia coli. Two enzyme lyophilizates of different purity were obtained from which the crude ( CL) was sufficient for the racemization of methionine (Met) and the pure ( PL) was used for asparagine (Asn). Racemization reactions of D-/ L-Asn in H 2O and D-/ L-Met in 95 vol.% 100 mM KP i-buffer, 5 vol.% methanol (MeOH) at different pH values and temperatures were characterized. The studied range of reaction parameters was chosen in dependency on planned enantioseparation processes. We found increasing V max values when temperature was risen stepwise from 20 to 40 °C for both systems and when pH was shifted from 6 to 8 for the Met system. The presented results provide the basis for engineering enzyme-assisted physicochemical enantioseparation processes.

New efficient enantioselective synthesis of 2-oxopiperazines: a practical access to chiral 3-substituted 2-oxopiperazines

The development of efficient and stereoselective methods to produce 1,4-disubstituted-2-oxopiperazine in enantiomerically pure form, from a readily available starting material is crucial. Herein, we report a reduction modification to our previously described synthesis of 1,4-disubstituted-2-oxopiperazine and also two original shortly accessed pathways. These new pathways can be routinely performed on a multigram scale and should rapidly find a place in the preparation of the 3-substituted-2-oxopiperazine diastereomers. Stereoselective alkylation of 1,4-disubstituted-2-oxopiperazine led to the corresponding (3 S)-diastereomer or (3 R) -diastereomer from the corresponding 2-oxopiperazine enantiomer with the chiral inductor substituted at the N 1 (1 ∗) position, respectively, in good yield.

Recent Advances in Lewis Base-Catalyzed, Stereoselective Tandem Aldol b- and g-Lactonizations

Stereoselective methods for the synthesis of β-lactones involving a Lewis base-promoted (nucleophile-promoted) aldol-lactonization manifold have continued to expand since the initial reports of Bormann and Wegler in the late 1960's and later by Wynberg and Staring in the early 1980's. This review will cover these developments including enantioselective versions of these processes. Cinchona alkaloids and various pyridine derivatives have been used most extensively to expand the repertoire of β-lactones accessible by this process. Furthermore, recent advances in the development of a 3 -d 3 -umpolung pathways using N-heterocyclic carbenes have also enabled access to previously unattainable manifolds for the stereoselective synthesis of both p- and γ-lactones via aldol-lactonization pathways. This review covers literature in this area in the period from 1967- June 2008.

Manganese(III) Acetate: A Versatile Reagent in Organic Chemistry

Free radical reactions have become increasingly important, as well as a very attractive tool, in organic synthesis within the last two decades, due to their powerful, selective, specific, and mild reaction abilities. Mn(OAc)3 mediated oxidative free radical reactions have been extensively developed in the last twenty years. Numerous regio-, chemo-, and stereoselective synthetic methods have been developed in both inter- and intramolecular reactions, and have detailed the progress of Mn(OAc)3 mediated oxidative free radical reactions since the end of the 19th century. The new literature about the new synthetic methods on Mn(OAc)3 mediated carbon-carbon bond formation and carbon-oxygen bond formation reactions has not been extensively reviewed. The present paper summarizes the recent developments in oxidative free radical reactions mediated by Mn(OAc)3. Mn(OAc)3 mediated reactions of conjugated systems (e.g., alkenes, alkynes, 1,3-alkadienes, l,3-alkadiynes, 1-alken-3-ynes) with β-dicarbonyl compounds, Mn(OAc)3 mediated alkylation, such as the oxidative addition of an aldehyde or ketone to alkenes, Mn(OAc)3 mediated free-radical cyclization of alkenes with active methylene compounds in the presence of oxygen to afford the cyclic peroxides; lactone synthesis by the Mn(OAc)3 mediated oxidative addition of carboxylic acids to alkenes, Mn(OAc)3 mediated cyclization of α- (methylthio)acetamides, enamides, and β-keto carboxamides to afford cyclic products. Mn(OAc)3 oxidative free-radical cyclizations of allylic β-dicarbonyl compounds, for example, the cyclization of allylic β-ketoesters to afford the corresponding γ-lactone. The reaction of alkenes with sodium azide in the presence of acetic acid was investigated to Keywords: Free radical reactions, Lactone synthesis, Cycloperoxidation, Oxidative Cyclization, Carbon-Oxygen Bond Formation

Base‐Catalyzed Stereoselective Isomerization of Electron‐Deficient Propargylic Alcohols to (E)‐Enones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.