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.
Highlights
Introduction1,4-Dihydropyridines (1,4-DHP) belong to the most beneficial scaffolds with unprecedented biological properties that are investigated by pharmaceutical research providing medicines for the treatment of various diseases [1,2]
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
The intensive investigations of 1,4-DHPs encouraged by successful introduction of nifedipine in early 1970s [5] by Bayer AG led to the development of several generations of calcium antagonists, possessing longer lasting antihypertensive activity, better tissue selectivity, Catalysts 2020, 10, 1019; doi:10.3390/catal10091019
Summary
1,4-Dihydropyridines (1,4-DHP) belong to the most beneficial scaffolds with unprecedented biological properties that are investigated by pharmaceutical research providing medicines for the treatment of various diseases [1,2]. 4-Aryl-1,4-DHP derivatives are among the most active calcium antagonists [4]. The intensive investigations of 1,4-DHPs encouraged by successful introduction of nifedipine in early 1970s [5] by Bayer AG led to the development of several generations of calcium antagonists, possessing longer lasting antihypertensive activity, better tissue selectivity, Catalysts 2020, 10, 1019; doi:10.3390/catal10091019 www.mdpi.com/journal/catalysts. Some representatives of the class are isradipine, felodipine,nicardipine isradipine, and gradualand onset of activity. Representatives of the class are felodipine, nicardipine (second generation), and lercanidipine (third generation), and (second generation), amlodipine,amlodipine, barnidipine,barnidipine, and lercanidipine (third generation), and cilnidipine cilnidipine (fourth generation).
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