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

Abstract

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.

Synthesis and Characterisation of 1,1′-{[3,5-Bis(dodecyloxy-carbonyl)-4-(thiophen-3-yl)-1,4-dihydropyridine-2,6-diyl]bis-(methylene)}bis(pyridin-1-ium) Dibromide

“…The next step was two-component Hantzsch type cyclisation of dodecyl 3-aminobut-2-enoate [21] (4) and dodecyl (E/Z)-oxo-2-(thiophen-3ylmethylene)butanoate (3) according to previously described methodology in the presence of 10 mol% of 1-butyl-3-methylimidazolium chloride as catalyst [21] providing 1,4-DHP 5 in 49% yield. Various catalysts were used in the synthesis of 1,4-DHP derivatives [26]. During the last few decades, ionic liquids as green catalysts were used for different reactions, including Hantzsch reaction.…”

“…For example, betainium-based ionic liquids were used for the one-pot production of acridinediones through Hantzsch reactions under mild conditions [27], β-cyclodextrin/imidazolium based dicationic ionic liquid in the one-pot, three-component Hantzsch reaction [28], 3-methyl-1-sulfonic acid imidazolium chloride as an acidic ionic liquid in four-component Hantzsch reaction leading to a simple synthetic procedure, short reaction times, less pollution and high yields of the products [29]. Bromination of 2,6-methyl groups of the 3,5-bis(dodecyloxycarbonyl)-2,6-dimethyl-4-(thiophen-3-yl)-1,4-dihydropyridine (5) was performed with NBS according to the previously described procedure [26]. To a solution of 2,6-dimethyl-1,4-DHP 5 in methanol a solution of NBS in methanol was added dropwise, after which the reaction mixture was stirred at r.t. for 3 h. The desired 2,6-bis(bromomethyl)-1,4-DHP 6 was obtained in 68% yield.…”

1,1′-{[3,5-Bis(dodecyloxycarbonyl)-4-(naphthalen-2-yl)-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis{4-[(E)-2-(naphthalen-2-yl)vinyl]pyridin-1-ium}dibromide

“…Taking into account the fact that the introduction of a styrylpyridinium group in a 1,4-DHP scaffold may form hybrid structures possessing more pronounced biological properties, synthesis of cationic amphiphilic 1,4-DHP 4 was performed. The construction of double-charged cationic 1,4-DHPs is a multistep synthesis, where the first step is the preparation of the 1,4-DHP core by Hantzsch synthesis or its variations [17,18]. Insertion of cationic groups at positions 2 and 6 of the 1,4-DHP ring is usually performed via bromination of methyl groups at these positions followed by nucleophilic substitution of bromide with an appropriate heterocyclic or aliphatic amine [4,7].…”

Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts

“…Therefore, several strategies were developed for the enantioselective synthesis of these scaffolds based upon two major approaches (Figure 1b). The first one involving the construction of the dihydroazaarenes, a strategy that will not be covered in this review [3][4][5][6]. The second one involves the dearomatization of azaarenes by nucleophilic addition or reduction (addition of hydride) to the corresponding azaarenium salt.…”