Chiral Dihydropyridines Research Articles

Enhanced Chiral Recognition Abilities of Cyclodextrin Covalent Organic Frameworks via Chiral/Achiral Functional Modification.

β-Cyclodextrin covalent organic frameworks (β-CD COFs) show great potential in enantioseparation due to their uniformly distributed chiral recognition sites and good chemical stability. The hydroxyl and amino groups of β-CD COFs enable facile post-modification to introduce the desired functionality into the frameworks. In this study, we perform post-modification of β-CD COFBPDA with 1,4-butane sultone and [(3R,4R)-4-acetyloxy-2,5-dioxooxolan-3-yl] acetate to construct two kinds of novel functional β-CD COFs. The capillary columns prepared with these two functional β-CD COFs separated chiral dihydropyridines and fluoroquinolones with excellent selectivity and repeatability in capillary electrochromatography, while β-CD COFBPDA-modified capillary columns did not present the chiral recognition ability for these drugs. The mechanism of chiral recognition and the enhanced enantioselectivity of functional β-CD COFs were further demonstrated by molecular docking simulation. The divergent chiral separation performances of β-CD COFs suggest that the introduction of functional groups enables the modification of β-CD COF properties and tuning of its chiral recognition abilities for the diversity of enantioseparation.

Recent Approaches to Chiral 1,4-Dihydropyridines and their Fused Analogues

The purpose of this review is to highlight recent developments in the synthesis of chiral 1,4-dihydropyridines and their fused analogues. 1,4-Dihydropyridines are among the most active calcium antagonists that are used for the treatment of hypertension. Enantiomers of unsymmetrical 1,4-dihydropyridines often show different biological activities and may have even an opposite action profile. Hantzsch synthesis usually produces racemic mixtures of unsymmetrical 1,4-dihydropyridines. Therefore, the development of stereoselective synthesis of 1,4-dihydropyridines is one of the priorities of medicinal chemistry. Over the years, numerous methodologies have been developed for the production of enantiopure 1,4-dihydropyridines, such as stereoselective synthesis using chiral auxiliaries and chiral cyclocondensation partners, chromatographical methods, resolution of diastereomeric 1,4-dihydropyridine salts, enzyme catalysed kinetic resolution, or asymmetrisation of ester groups of 1,4-dihydropyridines. These approaches have been studied in detail and are relatively well established. The catalytic asymmetric approach holds the greatest promise in delivering the most practical and widely applicable methods. Substantial progress has been made toward the development of enantioselective organocatalytic methods for the construction of the chiral dihydropyridines. However, most of them do not provide a convenient way to pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates. Organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes also has great promise in the synthesis of pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates.

HPLC separation of dihydropyridine derivatives enantiomers with emphasis on elution order using polysaccharide‐based chiral columns

The separation of enantiomers of five chiral dihydropyridine derivatives was studied on five different polysaccharide-based chiral HPLC columns with various normal-phase (NP), polar organic, and reversed-phase eluents. Along with the successful separation of analyte enantiomers, the emphasis of this study was on enantiomer elution order (EEO) with various columns and mobile phase composition. The interesting phenomenon of reversal of EEO, recently reported in the case of amlodipine (AML) depending on the concentration of formic acid in acetonitrile, was also confirmed with NP eluents. Under RP conditions at relatively low water content, the EEO of AML could also be reverted by varying the concentration of formic acid in the mobile phase. However, at higher water content the same parameter did not affect the EEO, but only induced gradual decrease in resolution up to complete co-elution of enantiomers. Additionally, in organic-aqueous mobile phases retention factors decreased with increasing water content but only up to 20% (v/v), while above this concentration the expected typical RP behavior was observed. The presence of the commonly used additive diethylamine in the mobile phase seems important for observing a reversal in EEO with increasing concentration of formic acid. The reversal of the EEO was characteristic of AML only and was not observed for any of other dihydropyridines included in this study.

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium: Diastereo‐ and Enantioselective Synthesis of Polycyclic Butenolides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium: Diastereo‐ and Enantioselective Synthesis of Polycyclic Butenolides

AbstractThe interaction of N‐methyldihydropyridine with carbene complexes of chromium promotes their spontaneous homologation upon addition of a hydride to the carbene carbon and an insertion of CO. This is followed in the case of complexes tethered to a triple bond by cascade insertions of the triple bond and of a CO ligand giving finally butenolides. The scope of the reaction has been established with its limitations, together with the stereochemical outcome, which is discussed. [5.5], [5.6], [5.7] bicyclic and tricyclic systems have been synthesised together with chiral butenolides starting from chiral carbene complexes. Most of the new structures have been assessed by X‐ray crystallography. This transformation was first extended to dihydronicotinamides, to chiral dihydropyridines such as dihydronicotines which led to the butenolides in an enantioselective way, and to other sources of hydrides. Second, a series of nucleophiles such as alkoxides, alkyllithium and alkylmagnesium compounds led also to polycyclic, substituted butenolides. Moreover, the final lactone enolates could be trapped with oxygen and gave unsaturated lactonols. The key point in all of these reactions is the formation of tetrahedral intermediates upon interaction of the nucleophiles with the carbene carbon. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

ChemInform Abstract: Enantioselective Approach to Butenolides upon Reduction of Alkoxycarbene Complexes of Chromium with Chiral Dihydropyridines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

An enantioselective synthesis of isoquinuclidines from 3-substituted chiral pyridinium salts

A new enantioselective approach to chiral isoquinuclidines, such as 15 , 18 and 21 , is reported. The key step of these syntheses is a cycloaddition between chiral dihydropyridines 14 or 20 , now readily available from tetrahydropyridinium salts 6 or 11 , and achiral dienophiles. The reaction proceeds with a very good endo-selectivity and moderate d.e.

Enantioselective approach to butenolides upon reduction of alkoxycarbene complexes of chromium with chiral dihydropyridines

Chromium alkoxycarbene complexes tethered to a triple bond react with a series of chiral dihydropyridines, among which is N-methyl-1,2-dihydronicotine, to give enantioselectively, upon cascade insertion reactions, polycyclic butenolides.

Enantiomeric separation of a group of chiral dihydropyridines by electrokinetic chromatography.

Electrokinetic chromatography (EKC) was employed to achieve the enantiomeric separation of a group of chiral 1,4-dihydropyridines (DHPs) with pharmacological activity. Micelles of bile salts alone or mixed with neutral cyclodextrins, micelles of sodium dodecyl sulfate (SDS) mixed with neutral cyclodextrins, and anionic cyclodextrin derivatives, i.e., carboxymethyl-gamma-cyclodextrin (CM-gamma-CD), carboxymethyl-beta-cyclodextrin (CM-beta-CD), and succinylated beta-cyclodextrin (Succ-beta-CD), were employed as pseudostationary phases. The enantiomeric separation ability of these chiral selectors with respect to DHPs was studied in different experimental conditions. CM-beta-CD was shown to be the best chiral selector to perform the enantiomeric separation of DHPs by EKC. Next, the influence of the CM-beta-CD concentration, the pH and nature of the buffer, the temperature, and the applied voltage on the enantiomeric resolution of DHPs was studied. The use of a 50 mM ammonium acetate buffer, pH 6.7, 25 mM in CM-beta-CD together with an applied voltage of 15 or 20 kV, and a temperature of 15 degrees C enabled the individual enantiomeric separation of twelve DHPs, each one into its two enantiomers, and their separation in multicomponent mixtures of up to six DHPs into all their enantiomers.

IMDA/retro-Mannich approach to cis-perhydroquinoline Lycopodium alkaloids: asymmetric synthesis of (+)-luciduline.

[formula: see text] The first chiral auxiliary mediated asymmetric synthesis of the naturally occurring Lycopodium alkaloid (+)-luciduline has been accomplished. Key steps include an IMDA reaction of a chiral dihydropyridine, a subsequent retro-Mannich ring opening, and a novel cationic reductive cyclization reaction.

Lipase-Catalyzed Enantioselective Hydrolysis of Bis(acyloxymethyl) 1,4-Dihydro-3,5-pyridinedicarboxylates Leading to Optically Active Medicines.

Chiral 4-aryl-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylates and 1, 4-dihydro-2, 4, 6-trimethyl-3, 5-pyridinedicarboxylate have been obtained in 80-99%ee by lipase-catalyzed hydrolysis of bis(acyloxymethyl) 1, 4-dihydro-3, 5-pyridinedicarboxylate in an H2O/organic solvent system. These chiral dihydropyridines were readily converted into chiral drugs, such as nicardipine, felodipine and PCA 4248.

ChemInform Abstract: Preparation of Chiral Hexahydroquinolizinones and Tetrahydroindolizinones by Regio‐ and Diastereoselective Sonochemical Cyclization of Chiral Dihydropyridines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Preparation of chiral hexahydroquinolizinones and tetrahydroindolizinones by regio- and diastereoselective sonochemical cyclization of chiral dihydropyridines

Chiral hexahydroquinolizinones 13 and tetrahydroindolizinones 17 were prepared from functionalized chiral dihydropyridines by regio- and diastereoselective sonochemical cyclization.

Chiral animals: Powerful auxiliaries in asymmetric synthesis

Abstract

ChemInform Abstract: Preparation and Utilization of Chiral Dihydropyridines. Synthesis of Chiral Indoloquinolizines and Benzoquinolizines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Preparation and Utilization of Chiral Dihydropyridines. Synthesis of Chiral Indoloquinolizines and Benzoquinolizines

An asymmetric synthesis of 3-formyl-1,4-dihydropyridines is described that entails the addition of organocopper reagents to activated 3-imidazolidinylpyridine, prepared with chiral diamines. The activator can be a chloroformate or an acid chloride. The methodology was used for the asymmetric syntheses of the indoloquinolizine and benzoquinolizine alkaloid frameworks

Enzyme-catalyzed Synthesis of Biologically Active (S)-Nilvadipine

Optically active 2-hydroxymethyl-1,4-dihydropyridine was obtained by lipase-catalyzed transesterification of isopropyl methyl 1,4-dihydro-2- hydroxymethyl-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate. This chiral dihydropyridine was readly converted into biologically active (S)-nilvadipine

Enantioselective determination of felodipine and other chiral dihydropyridine calcium entry blockers in human plasma

A sensitive method for the enantioselective determination of felodipine in human plasma is described. Following alkaline extraction with dichloromethane—pentane, racemic felodipine and its primary pyridine metabolite are simultaneously assayed using capillary gas chromatography on a DB-1 column, with electron-capture detection. The enantiomers of felodipine are quantitatively separated by high-performance liquid chromatography on a Chiralcel OJ column, containing tris(4-methylbenzoate)-modified cellulose coated on silica, and off-line detection using the same gas chromatographic system is applied. The limits of determination in plasma (and the inter-assay coefficient of variation (C.V.) at levels below 1 ng/ml) were 0.1 ng/ml (C.V. 13%) for felodipine, 0.1 ng/ml (C.V. 15%) for the enantiomers of felodipine and 0.3 ng/ml (C.V. 7%) for its pyridine metabolite. The method has proved to be applicable to several other chiral dihydropyridine calcium entry blockers, including nitrendipine, with comparable sensitivities.

ChemInform Abstract: Stereoselective Reduction of C=X by a Chiral 1,4‐Dihydropyridine (NADH‐Mimic) in a Self‐Immolative Process.

AbstractThe chiral dihydropyridine (+)‐(II) reduces the ketones (I) in the presence of magnesium perchlorate to give the optically active alcohols (S)‐(III).

Qualitative and Quantitative Structure‐Activity Relationships for Calcium Channel Modulating 1,4‐Dihydropyridine Derivatives: A Hypothetical Molecular Receptor Model

AbstractBased on force field methods, quantum chemical calculations and using molecular graphics a hypothetical receptor model for calcium antagonists and agonists from the 1,4‐dihydropyridine (DHP) series has been developed. In a previous study it could be shown, that calcium channel activating DHP's reduced the molecular electrostatic receptor potential, while this is increased by calcium channel blocking DHP's. These effects offer a possible explanation for the opposite behaviour of chiral dihydropyridines. In continuation of this work a quantitative structure‐activity study with a group of calcium channel blockers provided a three binding site model for the drug receptor interaction. Calculated interaction energies correlate well with biological potencies (r = 0.94, s = 0.28). The postulated receptor model shows structural similarities to segments of the very recently published amino acid sequence of the receptor for 1,4‐dihydropyridine calcium channel blockers.