Next Article in Journal
The Effect of Tourmaline on SCR Denitrification Activity of MnOx/TiO2 at Low Temperature
Next Article in Special Issue
Redox Isomerization of Allylic Alcohols Catalyzed by New Water-Soluble Rh(I)-N-Heterocyclic Carbene Complexes
Previous Article in Journal
Monolith Metal-Oxide-Supported Catalysts: Sorbent for Environmental Application
Previous Article in Special Issue
Synthesis and Investigation of Pinane-Based Chiral Tridentate Ligands in the Asymmetric Addition of Diethylzinc to Aldehydes
Open AccessReview

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

1
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
2
Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariskiu 5, LT-08406 Vilnius, Lithuania
3
Department of Chemical Engineering, National Taiwan University, 1, Roosevelt Rd. Sec. 4, Taipei 106, Taiwan
*
Author to whom correspondence should be addressed.
Catalysts 2020, 10(9), 1019; https://doi.org/10.3390/catal10091019
Received: 11 August 2020 / Revised: 26 August 2020 / Accepted: 28 August 2020 / Published: 4 September 2020
(This article belongs to the Special Issue Catalysis in Heterocyclic and Organometallic Synthesis)

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.
Keywords: six-membered N-heterocycles; 1,4-dihydropyridines; calcium channel antagonists; chirality; enzyme-catalysed hydrolysis; resolution of diastereomeric salts; separation; multicomponent reactions; asymmetric synthesis; organocatalysis six-membered N-heterocycles; 1,4-dihydropyridines; calcium channel antagonists; chirality; enzyme-catalysed hydrolysis; resolution of diastereomeric salts; separation; multicomponent reactions; asymmetric synthesis; organocatalysis

1. Introduction

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]. It is worth underlining that, according to Triggle, 1,4-DHP is a privileged structure that can interact at diverse receptors and ion channels and receptors of the G-protein class, when scaffold is properly substituted [3]. 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, and gradual onset of activity. Some representatives of the class are felodipine, isradipine, nicardipine (second generation), amlodipine, barnidipine, and lercanidipine (third generation), and cilnidipine (fourth generation) (Figure 1) [6,7,8].
The analysis of the structures shows that most of them are the unsymmetrical ones. When substituents on the left side differ from those on the right side of a 1,4-DHP, the molecule becomes chiral, with C4 being the stereogenic centre [9]. Enantiomers of unsymmetrical 1,4-DHP often show different biological activities and they could have even an opposite action profile. For example, it was established that (−)-S-amlodipine [10], (+)-S-manidipine, and [11] (−)-S-nitrendipine [11,12] were more potent calcium channel blockers than the respective opposite enantiomers (Figure 2). The same occurrence was described for barnidipine, where the most active was (+)-S,S-isomer (Figure 1) [13].
The opposite effects on function of L-type channels were reported, for example, for derivative PN 202-791 and BAYK8644, where (−)-R-enantiomers of PN 202-791 and (+)-R-BAYK8644 were calcium channel blockers, while the corresponding (+)-S-PN 202-791 and (−)-S-BAYK8644 enantiomers were calcium channel agonists (Figure 3) [14,15,16]. Currently (−)-(S)-amlodipine is marketed as levamlodipine and S,S-barnidipine is marketed in Japan under the trade name of Hypoca (Astellas Pharma Inc, Tokyo, Japan).
L-type voltage operated calcium channels are well-known for their involvement in electrical current generation; therefore, predominantly found in “excitable” cells, such as cardiomyocytes, muscle cells or neurons. In addition to the well-known role of 1,4-DHPs on the treatment of cardiovascular system disorders, as efficient agents in the management of hypertension, their potential activity on the cells from other tissues and organs is increasingly being revealed. L-type voltage operated calcium channels are also abundantly expressed in a range of “non-excitable” cells, including mesenchymal stem cells, osteoblasts, and chondrocytes, and they seem to have a range of activities, including mechanotransduction [17,18]. Alterations in intracellular Ca2+ concentrations may initiate the downstream response of chondrocytes to mechanical stress via mechanosensitive ion-channels [19]. Therefore, the potential in regulation of chondrogenesis processes through the regulation of ion channels increasingly gain attention for stimulation of cartilage regeneration [20]. Mechanical loads trigger anabolic and catabolic responses in chondrocytes [21]. Noteworthy, the analysis of downstream signalling effects and functions suggested that the activated mechanotransductive pathways are distinct in various loading modalities or electric stimuli [21,22]. Furthermore, the application of the same 1,4-DHP drug nifedipine generated different metabolic responses and inflammatory activity in different cell types, namely mesenchymal stem cells and chondrocytes, while the effects of agonist BAYK8644 were also different, but not the opposite [18]. Those data further imply the diversity of regulatory mechanisms in VOCC L-type channels that emphasise the need of agents with different activities for each particular therapeutic application.
After synthesis, study and development of a class of calcium antagonists the interest is also growing towards other activities of 1,4-DHPs, such as neuroprotective [23], radioprotective [24], antimutagenic [25], antioxidative [26], anticancer [27], and antimicrobial [28,29,30]. Consequently, during the last decades, the development of new pyridinium moieties containing compounds based on a 1,4-DHP core has become an interesting area for medicinal chemistry research. Cationic 1,4-DHP amphiphiles having one or two cationic moieties and various length ester appendages, were found to be capable of transfecting pDNA into different cell lines in vitro [31,32], due to their self-assembling properties [33,34].

2. Stereoselective Synthesis of 1,4-Dihydropyridines

The synthesis of Hantzsch-type 1,4-DHPs remains to be an important field in organic chemistry. The most common way of synthesis of 1,4-DHPs is Hantzsch cyclisation and its modifications [35,36]. Information the scope and limitations of methods of synthesis and chemical properties of hydrogenated pyridine derivatives can be found in several good reviews and in citations therein [1,37,38,39,40]. However, classical Hantzsch synthesis usually produces only racemic mixtures of unsymmetrical 1,4-DHPs. Therefore, the development of stereoselective synthetic methods for obtaining of therapeutic agents is one of the main priorities of medicinal chemistry.
Over the years numerous methodologies have been developed for the production of enantiopure 1,4-DHP derivatives, such as stereoselective synthesis using chiral auxiliaries and chiral cyclocondensation partners [41], catalytic asymmetric synthesis [42], resolution of diastereomeric 1,4-DHP salts derived from chiral acids or bases [43], enzyme catalysed kinetic resolution, or asymmetrisation of enzymatically labile esters activated spacer groups [9,44,45,46].

2.1. Resolution of Racemic Basic 1,4-Dihydropyridine Derivatives

Among all of the separation techniques, preparative chiral chromatography on stationary phases is the most widely used technique for the direct analysis of enantiomers and it remains to be important way for the obtaining of 1,4-DHP enantiomers in the analytical scale.
Initially, the state of art for the preparation of (−)-(S)-amlodipine was based on a procedure where the key-step was chromatographic separation of its and (+)-S-2-phenylethanol diastereoisomeric derivative [47], its (−)-(1S)-camphanic acid derivatives [10] and by the resolution of intermediate racemic azido acid cinchonidine salts [48]. In the last decade, resolution of racemic amlodipine base to (+)-R and (−)-S isomer was performed using tartaric acids in dimethylformamide (DMF)/water mixture. Thus, (+)-L-tartrate salt of the unwanted R-isomer of amlodipine was crystallised in DMF/water mixture, while the salt of the required S-form was provided in DMF/water. The addition of water (15%) to DMF, as shown in Scheme 1, significantly improved the efficiency of resolution (yield 71%, enantiomeric excess (ee) 99%) [49].

2.2. Resolution of Racemic 1,4-Dihydropyridinedicarboxylic Acid Derivatives

The resolution of racemic 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was also achieved using commercially available Cinchona alkaloids (cinchonidine and quinidine) as the resolving agents. Under the optimum conditions, for both R- and S-enantiomers enantiomeric excess >99.5% was reached. The optimum conditions were approached by varying of the solvent, where the best results were found in the DMF/water mixture (8:5) (Table 1) [50].

2.3. Lipase-catalysed Kinetic Resolution of Racemic Activated Esters of 1,4-Dihydropyridinecarboxylic Acid

Enzyme-catalysed approach to enantiopure 1,4-DHPs was pioneered by groups of Sih and Achiwa in 1991. Since then, this methodology was widely used for asymmetrisation or kinetic resolution of enzymatically labile esters activated spacer groups [44,45,46]. In the last decade, this approach was successfully applied by Tores et al. to kinetic resolution of various 1,4-DHPs and dihydropyridone derivatives (Table 2). Applying previously well-known [(2-methylpropanoyl) oxy]methyl ester as activating group [51,52,53] in the substrate and Candida rugosa (CRL) or Candida antarctica B (CAL-B) as enzyme good to excellent enantioselectivity was reached [54,55]. Interestingly, that besides frequently used as solvents wet ethers, CRL has been found very efficient in EtOAc, in spite of the fact that this solvent is also susceptible to be hydrolysed by the lipase. The best results of CRL catalysed kinetic resolutions in wet EtOAc were obtained when aryl substituent in the position four of 1,4-DHP rac-2 ring was 2- or 3-NO2-C6H4-, 2-Cl-5-NO2-C6H3-, naphthyl- in short reaction times not exceeding 2.5 h, with high enantioselectivity (E-value) ranging from 50 to >200. CAL-B has been also shown enantioselectivity toward similar substrates in the range of 11–63 (E-value), where the advantage of the use of EtOAc as reaction media was also proven. CAL-B shows better enantioselectivity toward substrates rac-2 having bromine or methoxy group in 4-aryl substituent in comparison with CRL. Thus, hydrolysis of 4-Br-C6H4- substituted 1,4-DHP rac-2 in methyl tert-butyl ether (MTBE)/water occluded with E 24–27, while in EtOAc E 34 was reached. The same occurrence was described for 3-CH3O-C6H4- substituted 1,4-DHP rac-2 where E 29-31 was in MTBE/water and E 63 was in EtOAc.
Enzyme-catalysed kinetic resolution of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines rac-4 has been performed by Krauze group using Amano Acylase (Aspergillus mellus) and Candida antarctica lipase B (CAL-B, Novozyme 435®) in wet diisopropyl ether (IPE) with dichloromethane (DCM) as an additive to improve the solubility of the substrate rac-4 [56]. Table 3 shows the most enantioselective examples. The enantioselectivity of CAL-B increased together with an increase of the temperature. Thus the best enantioselectivities of CAL-B were achieved at 45°C when the substituent at the position 4 of 1,4-DHP was substituted aryl (Table 3, entries 5–7). While Amano Acylase was less enantioselective toward the same substrate rac-4 showing no enantioselectivity at elevated temperatures (Table 3, entries 9–12).

2.4. Organocatalytic Enantioselective Synthesis of 1,4-Dihydropyridines

The above-mentioned approaches have been studied in the detail and they are relatively well established. The catalytic asymmetric approach holds the greatest promise in delivering the most practical and widely applicable methods. During the last decade, substantial progress has been made in this field toward development of enantioselective organocatalytic methods for the direct construction of the chiral DHPs. However, most of them do not provide a convenient way to pharmacologically important 1,4-DHP-3,5-dicarboxylates. On the other hand, recently reported 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.
In 2008, the Jorgensen group reported the first examples of catalytic asymmetric four substituted 1,4-DHPs 8 synthesis using TMS-prolinol enabled iminium catalysis (Scheme 2) [58]. In this methodology, only non-aromatic α,β-unsaturated aldehydes 6 are able to give products 8 with high levels of stereoinduction (R1 = aryl, led to a low stereoselectivity).
With this method, it was possible to vary the substituents in the positions 1, 3, and 4 in the 1,4-dihydropyridine ring. In the cases of use of non-aromatic α,β-unsaturated aldehydes 6, moderate yields and high enantioselectivities of 1,4-DHPs 8 (88–95% ee) were achieved (Table 4, entries 1–4,6). Low to moderate enantioselectivities of catalysis were reached with aromatic aldehydes at 4 °C (Table 4, entries 5,9). High enantioselectivities of iminium catalysis were achieved for both kinds of α,β-unsaturated aldehydes 6: diketones (Table 4, entries 1–6,9–11) and β–ketoesters (Table 4, entries 7,8) [58]. From the tested catalysts, 2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilanyloxymethyl] pyrrolidine was identified as the most enantioselective.
In 2011, the Kanger group reported [59] the approach to enantiomerically enriched four substituted 1,4-DHPs 10 based on the use of diarylprolinol-TMS ether and benzoic acid as catalytic system previously developed by Jorgensen group [58]. In this via TMS-prolinol organocatalytic approach β-enaminones and β-enamino esters 9 were preformed prior to the aza-ene-type reaction with α,β-unsaturated aldehydes 6. With this method moderate to high enantioselectivities (71–96% ee) and yields (45–96%) of 1,4-DHPs 10 were approached. The method also allowed to vary substituents in the positions 1, 3, and 4 in the ring to afford three or four substituted 1,4-DHPs 10. Table 5 summarizes some characteristic examples.
From the recent achievements, the synthesis of fully substituted 1,4-DHP 13 was performed by Herrera’s group in 2017 (Table 6) [60]. Bis-cinchona catalyst activates the Michael addition reaction between malononitrile derivatives 12 and enamines 11, affording 4-aryl-6-amino-5-cyano-1,4-dihydropyridine-2,3-dicarboxylates 13 with moderate enantioselectivity. At the beginning hydroquinine 1,4-phthalazinediyl diether ((DHQ)2Phal), hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2Pyr), hydroquinine anthraquinone-1,4-diyl diether ((DHQ)2AQN), hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2Phal), hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)2Pyr), hydroquinidine (anthraquinone-1,4-diyl), diether ((DHQD)2AQN), and hydroquinine 4-chlorobenzoate (DHQ-4Cl-Bz) were studied as catalysts for the reaction of enamine 11 (R = CH3) and malononitrile 12a in toluene/EtOAc (9:1) as solvent for 72 h at 10 °C. Table 6 summarises the best results (Table 6, entries 1–5). The enantioselectivity appeared to be the highest for (DHQ)2Pyr where 80% of ee (Table 6, entry 6) was achieved. Further fine tuning of reaction conditions allowed to approach a slightly better enantioselectivity albeit to the reaction rate (Table 6, entries 9,11).
Recently, the synthesis of highly functionalised 1-benzamido-1,4-dihydropyridine derivatives 15 from hydrazones 14 and alkylidenemalononitrile 12b in the presence of β-isocupreidine as organocatalyst was reported with rather low enantioselectivity (up to 10–52% ee) by Herrera’s group [61]. From ten different chiral organocatalysts, β–isocupreidine was chosen as the most enantioselective. Table 7 summarizes some characteristic examples.
In 2015, Herrera’s group reported the synthesis of enantioenriched 2-oxospiro-[indole-3,4′-(1′,4′-dihydropyridine)] derivatives—spirocyclic 1,4-DHPs 17 having highly substituted DHP ring. Table 8 summarizes several characteristic examples [62].
The reaction of an enamines 15 with isatylidene malononitrile derivatives 16 was studied in the presence of various organocatalysts. It was found that only Takemoto’s thiourea [63] catalysed the reaction with low degree of enantioselectivity. Additional screening of the catalyst loading, the variation of the substituents of starting enamine 15 and isatylidene malononitrile 16, and the reaction conditions led to some improvement of enantioselectivity of the reaction from 44% to 58% ee. Not looking at low enantioselectivity, this is one of very few examples of synthesis of fully substituted 1,4-DHP derivatives.
In 2007, by Renaud group was reported mechanistically different chiral Brønsted acids catalysed enantioselective synthesis of four substituted 1,4-DHPs 19 [64]. Primary screening of two component reaction of N-benzyl β-aminobutenoate 18 with cinnamaldehyde 6 have shown that BINOL-derived phosphoric acid derivatives proved to be capable of catalysing the reaction in up to 50% enantiomeric excess at −7 °C in DCM (Scheme 3).
The extension of the above method to the three-component reaction was performed by Gong group in 2008 utilising chiral Brønsted acid catalysis (Scheme 4) [65] The ability to alter the substituents at the positions 1, 3, and 4 of 1,4-DHP ring was also demonstrated.
The mechanism of the reaction involves the formation of an α,β-unsaturated imine that is activated through hydrogen bonding interaction with the hydroxyl group of the organocatalyst and undergoes nucleophilic addition of β-ketoester. A wide range of cinnamaldehydes was employed, but contrary to the Jorgensen method the use of 2-hexenal led to a low enantioinduction. A serious limitation of these methods is the inability to introduce the substituents at 5- and 6- position of 1,4-DHP 8 ring.
In 2009, Gestwicki demonstrated the first examples of fully substituted bicyclic DHP 23 synthesis [66]. A good substrate scope was demonstrated for aromatic aldehydes (Scheme 5). On the other hand, the reactions are limited to the use as β-dicarbonyl components dimedone 20 and ethyl acetoacetate 21. When R of aldehyde component 22 is C6H5, 2,4-Cl2-C6H3, 4-Br-C6H4, 3,5-(CH3O)2-C6H3, 2-CF3-C6H4, 2,5-F2-C6H3, 4-C(CH3)3-C6H4, 2-naphthyl, 2-CN-C6H4, 3,4-(OH)2-C6H3, 2-Cl-C6H4, 4-C6H5-C6H4 high enantioselectivity of organocatalytic reaction ee > 95% can be reached.
In 2015, Zhang et al. reported H8-BINOL-type chiral imidodiphosphoric acid promoted enantioselective cyclisation of β,γ-unsaturated α-ketoesters 25, arylamines 24, and acetylacetone 7 (Table 9). The change of BINOL scaffold to H8-BINOL gave better yields and enantioselectivities. Among the H8-BINOL-based imidodiphosphoric acids, the derivative that was substituted with four phenyl groups was found to be the best catalyst for the reaction. Under the optimised conditions penta substituted 1,4-DHPs 26 were obtained with moderate yields (34–61%) and good to excellent selectivities (75–97% ee) [67]. Table 9 provides some representative examples.
In 2015, Wang’s group has developed a trio catalytic system comprised of arylamine 24, BINOL-derived phosphoric acid and hard metal Lewis acid (yttrium(III) trifluoromethanesulfonate, Y(OTf)3) (Table 10) [68]. The combined catalyst was capable of promoting an aza-Diels-Alder reaction of various substituted cinnamaldehydes 28, cyclic ketones 27, and arylamines 24. Binary acid (R)-TRIP/Y(OTf)3 catalysed reaction allowed the formation of fused DHPs 26 in 59–84% yields and good to excellent enantioselectivities in most of the cases (91–99% ee). Table 10 provides some representative examples.
The asymmetric synthesis of fused derivatives—chiral N-unsubstituted 4-isoxazolyl-quinolones 31—was performed applying the methodology elaborated by Gestwicki, from the isoxazole aldehydes 30, dimedone 20, and ethyl acetoacetate 21 using BINOL phosphate (R)-TRIP, as pioneered by Gong in moderate yields (Table 11) [69]. According to the provided chromatograms, the authors proposed that enantiomeric excess for obtained compounds was more than 90%.
Natale group in supplementing materials of the article [69] also provided BINOL phosphate (R)-TRIP catalysed synthesis of 1,4-DHP-3,5-dicarboxylate 33 with (S)-absolute configuration in 21% of yield from pre-formed isoxazolylidene acetoacetate 32, ethyl acetoacetate 21, and a source of ammonia. This is the first reported example of enantioselective organocatalytic synthesis of the scaffold of many pharmaceutically relevant 1,4-DHPs: 4-substituted 2,6-dimethyl-1,4-DHP-3,5-dicarboxylate 33. The authors proposed that the enantiomeric excess of the obtained compound was more than 90%, as in the above cases (Scheme 6).

2.5. Organocatalytic Desymmetrisation of Prochiral 1,4-Dihydropyridine-3,5-dicarbaldehydes

In 2019, enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 34 catalysed by chiral N-heterocyclic carbenes (NHC catalyst), an external oxidant, and an alcohol nucleophile leading to the highly enantioselective formation of 5-formyl-1,4-DHP-3-carboxylates 37 has been reported [70]. This approach is based on organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 38 but not on the direct construction of the chiral DHP core. After the search for the best reaction conditions, the following system was selected as an optimal: Desymmetrisation of 3,5-dicarbaldehydes was quinone 35 as oxidant (1 equiv) in the presence of aminoindanol derived pre-catalyst 36, which showed a better enantioselectivity, and base (N,N-diisopropylethylamine, DIPEA), and ethanol as the nucleophile (Table 12, entry 10).
The use of other bases potassium triethylamine (TEA), bis(trimethylsilyl)amide (KHMDS) and K3PO4 led to lover enantioselectivity. Chloroform was selected as the best for these reactions and solvents such as dicholoromethane, dichloroethane and acetonitrile were found less suitable. DHP ring oxidation was not observed under these conditions. The resulting 5-formyl-1,4-DHP-3-carboxylate 37 allows access to the class of pharmaceutically relevant 1,4-DHP-3,5-dicarboxylates.

3. Conclusions

The resolution of diastereomeric 1,4-DHP salts derived from chiral acids or bases, enzyme catalysed kinetic resolution, or asymmetrisation of enzymatically labile esters activated spacer groups, separation techniques, such as preparative chiral chromatography on stationary phases are the most widely used techniques for the obtaining of 1,4-DHP enantiomers. These approaches have been studied well in detail and they are relatively well established. The catalytic asymmetric approach holds the greatest promise in delivering the most practical and widely applicable methods. Recently, substantial progress has been made in this field and several enantioselective organocatalytic methods were developed for the direct construction of the chiral DHP core. However, the major deficiency of the methods lies in their limited scope and generality. Thus, the reported organocatalytic methods provided a way to partially substituted, spiro, or fused in most cases also N-substituted 1,4-DHPs. Organocatalytic approach to pharmacologically important enantiopure 1,4-DHP-3,5-dicarboxylates until recently remained quite unpractical. Subsequently, BINOL phosphate (R)-TRIP catalysed enantioselective synthesis of N-unsubstituted 4-isoxazolyl-2,6-dimethyl-1,4-DHP-3,5-dicarboxylate from isoxazolylidene acetoacetate and ethyl acetoacetate was reported. This can be considered as a substantial achievement in the synthesis of enantiopure 1,4-DHPs. On the other hand, recently reported organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes has great promise in the synthesis of pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates.

Author Contributions

Conceptualization, A.S. and M.R.; data collection M.R., E.B. and W.-B.T.; writing—original draft preparation, M.R., A.P.; writing—review and editing, A.S., E.B. and W.-B.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the project ‘’Development of injectable biomimetic hydrogels for engineering of cartilage tissue’’ of Mutual Funds Taiwan—Latvia—Lithuania financed by the State Education Development Agency Republic of Latvia (SEDA), agreement No LV-LT-TW/2020/1, the Research Council of Lithuania (LMTLT), agreement No S-LLT-18-4 and has been performed in a cooperation with the Taipei Mission in the Republic of Latvia, and PostDocLatvia project entitled ‘’Bifunctional amphiphilic lipid-like compounds - self-assembling properties and biological activities‘’ No 1.1.1.2/VIAA/2/18/371 for M.Rucins.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sharma, V.K.; Singh, S.K. Synthesis, utility and medicinal importance of 1,2- & 1,4-dihydropyridines. RSC Adv. 2017, 7, 2682–2732. [Google Scholar] [CrossRef]
  2. Klusa, V. Atypical 1,4-dihydropyridine derivatives, an approach to neuroprotection and memory enhancement. Pharmacol. Res. 2016, 113, 754–759. [Google Scholar] [CrossRef] [PubMed]
  3. Triggle, D.J. The 1,4-dihydropyridine nucleus: A pharmacophoric template part 1. Actions at ion channels. Mini Rev. Med. Chem. 2003, 3, 215–223. [Google Scholar] [CrossRef] [PubMed]
  4. Godfraind, T. Discovery and development of calcium channel blockers. Front. Pharmacol. 2017, 8, 286. [Google Scholar] [CrossRef] [PubMed]
  5. Vater, W.; Kroneberg, G.; Hoffmeister, F.; Saller, H.; Meng, K.; Oberdorf, A.; Puls, W.; Schlossmann, K.; Stoepel, K. Pharmacology of 4-(2′-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (Nifedipine, BAY a 1040). Arzneimittel-Forschung 1972, 22, 1–14. [Google Scholar] [PubMed]
  6. Chandra, K.S.; Ramesh, G. The fourth-generation Calcium channel blocker: Cilnidipine. Indian Heart J. 2013, 65, 691–695. [Google Scholar] [CrossRef]
  7. Vardanyan, R.; Hruby, V. Chapter 22—Antihypertensive Drugs. In Synthesis of Best-Seller Drugs; Vardanyan, R., Hruby, V., Eds.; Academic Press: Boston, MA, USA, 2016; pp. 329–356. ISBN 978-0-12-411492-0. [Google Scholar]
  8. Wang, A.L.; Iadecola, C.; Wang, G. New generations of dihydropyridines for treatment of hypertension. J. Geriatr. Cardiol. 2017, 14, 67–72. [Google Scholar]
  9. Goldmann, S.; Stoltefuss, J. 1,4-Dihydropyridines: Effects of Chirality and Conformation on the Calcium Antagonist and Calcium Agonist Activities. Angew. Chem. Int. Ed. Engl. 1991, 30, 1559–1578. [Google Scholar] [CrossRef]
  10. Goldmann, S.; Stoltefuss, J.; Born, L. Determination of the absolute configuration of the active amlodipine enantiomer as (-)-S: A correction. J. Med. Chem. 1992, 35, 3341–3344. [Google Scholar] [CrossRef]
  11. Cataldi, M.; Taglialatela, M.; Palagiano, F.; Secondo, A.; de Caprariis, P.; Amoroso, S.; di Renzo, G.; Annunziato, L. Effects of manidipine and nitrendipine enantiomers on the plateau phase of K+-induced intracellular Ca2+ increase in GH3 cells. Eur. J. Pharmacol. 1999, 376, 169–178. [Google Scholar] [CrossRef]
  12. Mikus, G.; Mast, V.; Ratge, D.; Wisser, H.; Eichelbaum, M. Stereoselectivity in cardiovascular and biochemical action of calcium antagonists: Studies with the enantiomers of the dihydropyridine nitrendipine. Clin. Pharmacol. Ther. 1995, 57, 52–61. [Google Scholar] [CrossRef]
  13. Sakai, T.; Teramura, T.; Okamiya, H.; Inagaki, O. A Review on Barnidipine: A Novel Calcium Antagonist. Cardiovasc. Drug Rev. 2007, 15, 273–290. [Google Scholar] [CrossRef]
  14. Wei, X.Y.; Luchowski, E.M.; Rutledge, A.; Su, C.M.; Triggle, D.J. Pharmacologic and radioligand binding analysis of the actions of 1,4-dihydropyridine activator-antagonist pairs in smooth muscle. J. Pharmacol. Exp. Ther. 1986, 239, 144–153. [Google Scholar] [PubMed]
  15. Franckowiak, G.; Bechem, M.; Schramm, M.; Thomas, G. The optical isomers of the 1,4-dihydropyridine BAY K 8644 show opposite effects on Ca channels. Eur. J. Pharmacol. 1985, 114, 223–226. [Google Scholar] [CrossRef]
  16. Hof, R.P.; Rüegg, U.T.; Hof, A.; Vogel, A. Stereoselectivity at the calcium channel: Opposite action of the enantiomers of a 1,4-dihydropyridine. J. Cardiovasc. Pharmacol. 1985, 7, 689–693. [Google Scholar] [CrossRef]
  17. Kawano, S.; Shoji, S.; Ichinose, S.; Yamagata, K.; Tagami, M.; Hiraoka, M. Characterization of Ca2+ signaling pathways in human mesenchymal stem cells. Cell Calcium 2002, 32, 165–174. [Google Scholar] [CrossRef]
  18. Uzieliene, I.; Bernotiene, E.; Rakauskiene, G.; Denkovskij, J.; Bagdonas, E.; Mackiewicz, Z.; Porvaneckas, N.; Kvederas, G.; Mobasheri, A. The Antihypertensive Drug Nifedipine Modulates the Metabolism of Chondrocytes and Human Bone Marrow-Derived Mesenchymal Stem Cells. Front. Endocrinol. 2019, 10, 756. [Google Scholar] [CrossRef]
  19. Guilak, F.; Zell, R.A.; Erickson, G.R.; Grande, D.A.; Rubin, C.T.; McLeod, K.J.; Donahue, H.J. Mechanically induced calcium waves in articular chondrocytes are inhibited by gadolinium and amiloride. J. Orthop. Res. 1999, 17, 421–429. [Google Scholar] [CrossRef]
  20. Uzieliene, I.; Bernotas, P.; Mobasheri, A.; Bernotiene, E. The role of physical stimuli on calcium channels in chondrogenic differentiation of mesenchymal stem cells. Int. J. Mol. Sci. 2018, 19, 2998. [Google Scholar] [CrossRef]
  21. Vaca-González, J.J.; Guevara, J.M.; Moncayo, M.A.; Castro-Abril, H.; Hata, Y.; Garzón-Alvarado, D.A. Biophysical Stimuli: A Review of Electrical and Mechanical Stimulation in Hyaline Cartilage. Cartilage 2019, 10, 157–172. [Google Scholar] [CrossRef]
  22. Steward, A.J.; Kelly, D.J.; Wagner, D.R. The role of calcium signalling in the chondrogenic response of mesenchymal stem cells to hydrostatic pressure. Eur. Cells Mater. 2014, 28, 358–371. [Google Scholar] [CrossRef]
  23. Siddiqi, F.H.; Menzies, F.M.; Lopez, A.; Stamatakou, E.; Karabiyik, C.; Ureshino, R.; Ricketts, T.; Jimenez-Sanchez, M.; Esteban, M.A.; Lai, L.; et al. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat. Commun. 2019, 10, 1718. [Google Scholar] [CrossRef] [PubMed]
  24. Zhang, Y.; Wang, J.; Li, Y.; Wang, F.; Yang, F.; Xu, W. Synthesis and Radioprotective Activity of Mitochondria Targeted Dihydropyridines in Vitro. Int. J. Mol. Sci. 2017, 18, 2233. [Google Scholar] [CrossRef] [PubMed]
  25. Leonova, E.; Ošiņa, K.; Duburs, G.; Bisenieks, E.; Germini, D.; Vassetzky, Y.; Sjakste, N. Metal ions modify DNA-protecting and mutagen-scavenging capacities of the AV-153 1,4-dihydropyridine. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2019, 845, 403077. [Google Scholar] [CrossRef]
  26. Da Costa Cabrera, D.; Santa-Helena, E.; Leal, H.P.; de Moura, R.R.; Nery, L.E.M.; Gonçalves, C.A.N.; Russowsky, D.; Montes D’Oca, M.G. Synthesis and antioxidant activity of new lipophilic dihydropyridines. Bioorg. Chem. 2019, 84, 1–16. [Google Scholar] [CrossRef] [PubMed]
  27. Nkosi, S.M.; Anand, K.; Anandakumar, S.; Singh, S.; Chuturgoon, A.A.; Gengan, R.M. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of novel quinoline bearing dihydropyridines. J. Photochem. Photobiol. B Biol. 2016, 165, 266–276. [Google Scholar] [CrossRef] [PubMed]
  28. Lentz, F.; Reiling, N.; Spengler, G.; Kincses, A.; Csonka, A.; Molnár, J.; Hilgeroth, A. Dually acting nonclassical 1,4-dihydropyridines promote the anti-tuberculosis (Tb) activities of clofazimine. Molecules 2019, 24, 2873. [Google Scholar] [CrossRef] [PubMed]
  29. González, A.; Casado, J.; Chueca, E.; Salillas, S.; Velázquez-Campoy, A.; Angarica, V.E.; Bénejat, L.; Guignard, J.; Giese, A.; Sancho, J.; et al. Repurposing dihydropyridines for treatment of helicobacter pylori infection. Pharmaceutics 2019, 11, 681. [Google Scholar] [CrossRef]
  30. Rucins, M.; Dimitrijevs, P.; Pajuste, K.; Petrichenko, O.; Jackevica, L.; Gulbe, A.; Kibilda, S.; Smits, K.; Plotniece, M.; Tirzite, D.; et al. Contribution of Molecular Structure to Self-Assembling and Biological Properties of Bifunctional Lipid-Like 4-(N-Alkylpyridinium)-1,4-Dihydropyridines. Pharmaceutics 2019, 11, 115. [Google Scholar] [CrossRef]
  31. Hyvönen, Z.; Plotniece, A.; Reine, I.; Chekavichus, B.; Duburs, G.; Urtti, A. Novel cationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery. Biochim. Biophys. Acta Biomembr. 2000, 1509, 451–466. [Google Scholar] [CrossRef]
  32. Apsite, G.; Timofejeva, I.; Vezane, A.; Vigante, B.; Rucins, M.; Sobolev, A.; Plotniece, M.; Pajuste, K.; Kozlovska, T.; Plotniece, A. Synthesis and comparative evaluation of novel cationic amphiphile C12-Man-Q as an efficient DNA delivery agent in vitro. Molecules 2018, 23, 1540. [Google Scholar] [CrossRef] [PubMed]
  33. Pajuste, K.; Hyvonen, Z.; Petrichenko, O.; Kaldre, D.; Rucins, M.; Cekavicus, B.; Ose, V.; Skrivele, B.; Gosteva, M.; Morin-Picardat, E.; et al. Gene delivery agents possessing antiradical activity: Self-assembling cationic amphiphilic 1,4-dihydropyridine derivatives. New J. Chem. 2013, 37, 3062–3075. [Google Scholar] [CrossRef]
  34. Petrichenko, O.; Rucins, M.; Vezane, A.; Timofejeva, I.; Sobolev, A.; Cekavicus, B.; Pajuste, K.; Plotniece, M.; Gosteva, M.; Kozlovska, T.; et al. Studies of the physicochemical and structural properties of self-assembling cationic pyridine derivatives as gene delivery agents. Chem. Phys. Lipids 2015, 191, 25–37. [Google Scholar] [CrossRef] [PubMed]
  35. Rucins, M.; Gosteva, M.; Domracheva, I.; Kanepe-Lapsa, I.; Belyakov, S.; Plotniece, M.; Pajuste, K.; Cekavicus, B.; Jekabsone, M.; Sobolev, A.; et al. Synthesis and Evaluation of Reducing Capacity and Calcium Channel Blocking Activity of Novel 3,5-Dipropargylcarbonyl-Substituted 1,4-Dihydropyridines. Chem. Heterocycl. Compd. 2015, 50, 1432–1443. [Google Scholar] [CrossRef]
  36. Rucins, M.; Kaldre, D.; Pajuste, K.; Fernandes, M.A.S.; Vicente, J.A.F.; Klimaviciusa, L.; Jaschenko, E.; Kanepe-Lapsa, I.; Shestakova, I.; Plotniece, M.; et al. Synthesis and studies of calcium channel blocking and antioxidant activities of novel 4-pyridinium and/or N-propargyl substituted 1,4-dihydropyridine derivatives. Comptes Rendus Chim. 2014, 17, 69–80. [Google Scholar] [CrossRef]
  37. Eisner, U.; Kuthan, J. Chemistry of dihydropyridines. Chem. Rev. 1972, 72, 1–42. [Google Scholar] [CrossRef]
  38. Kuthan, J.; Kurfurst, A. Development in dihydropyridine chemistry. Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 191–261. [Google Scholar] [CrossRef]
  39. Sausins, A.; Duburs, G. Synthesis of 1,4-dihydropyridines by cyclocondensation reactions. Heterocycles 1988, 27, 291–314. [Google Scholar] [CrossRef]
  40. Stout, D.M.; Meyers, A.I. Recent advances in the chemistry of dihydropyridines. Chem. Rev. 1982, 82, 223–243. [Google Scholar] [CrossRef]
  41. Yamamoto, T.; Ohno, S.; Niwa, S.; Tokumasu, M.; Hagihara, M.; Koganei, H.; Fujita, S.; Takeda, T.; Saitou, Y.; Iwayama, S.; et al. Asymmetric synthesis and biological evaluations of (+)- and (−)-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylic acid derivatives blocking N-type calcium channels. Bioorg. Med. Chem. Lett. 2011, 21, 3317–3319. [Google Scholar] [CrossRef]
  42. Auria-Luna, F.; Marqués-López, E.; Herrera, R.P. Organocatalytic Enantioselective Synthesis of 1,4-Dihydropyridines. Adv. Synth. Catal. 2017, 359, 2161–2175. [Google Scholar] [CrossRef]
  43. Cheng, Z.G.; Dai, X.Y.; Li, L.W.; Wan, Q.; Ma, X.; Xiang, G.Y. Synthesis and characterization of impurities of barnidipine hydrochloride, an antihypertensive drug substance. Molecules 2014, 19, 1344–1352. [Google Scholar] [CrossRef]
  44. Achiwa, K.; Kato, T. Asymmetric Synthesis of Optically Active 1,4-Dihydropyridines as Calcium Antagonist. Curr. Org. Chem. 1999, 3, 77–106. [Google Scholar]
  45. Decroix, B.; Marchalín, S.; Chudík, M.; Mastihuba, V. Use of Enzymes in Preparation of Enantiopure 1,4-Dihydropyridines. Heterocycles 1998, 48, 1943. [Google Scholar] [CrossRef]
  46. Sobolev, A.; Franssen, M.C.R.; Duburs, G.; de Groot, A. Chemoenzymatic synthesis of enantiopure 1,4-dihydropyridine derivatives. Biocatal. Biotransform. 2004, 22, 231–252. [Google Scholar] [CrossRef]
  47. Arrowsmith, J.E.; Campbell, S.F.; Cross, P.E.; Stubbs, J.K.; Burges, R.A.; Gardiner, D.G.; Blackburn, K.J. Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J. Med. Chem. 1986, 29, 1696–1702. [Google Scholar] [CrossRef]
  48. Shibanuma, T.; Iwanani, M.; Okuda, K.; Takenaka, T.; Murakami, M. Synthesis of Optically Active 2-(N-Benzyl-N-methylamino)ethyl Methyl 2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nicardipine). Chem. Pharm. Bull. 1980, 28, 2809–2812. [Google Scholar] [CrossRef]
  49. Gotrane, D.M.; Deshmukh, R.D.; Ranade, P.V.; Sonawane, S.P.; Bhawal, B.M.; Gharpure, M.M.; Gurjar, M.K. A Novel Method for Resolution of Amlodipine. Org. Process Res. Dev. 2010, 14, 640–643. [Google Scholar] [CrossRef]
  50. Zhang, B.; He, W.; Shi, X.; Huan, M.; Huang, Q.; Zhou, S. Synthesis and biological activity of the calcium modulator (R) and (S)-3-methyl 5-pentyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. Bioorg. Med. Chem. Lett. 2010, 20, 805–808. [Google Scholar] [CrossRef]
  51. Sobolev, A.; Franssen, M.C.R.; Vigante, B.; Cekavicus, B.; Makarova, N.; Duburs, G.; de Groot, A. An efficient chemoenzymatic approach to enantiomerically pure 4-(2-(difluoromethoxy)phenyl) substituted 1,4-dihydropyridine-3,5-dicarboxylates. Tetrahedron Asymmetry 2001, 12, 3251–3256. [Google Scholar] [CrossRef]
  52. Sobolev, A.; Franssen, M.C.R.; Vigante, B.; Cekavicus, B.; Zhalubovskis, R.; Kooijman, H.; Spek, A.L.; Duburs, G.; de Groot, A. Effect of acyl chain length and branching on the enantioselectivity of Candida rugosa lipase in the kinetic resolution of 4-(2-difluoromethoxyphenyl)-substituted 1,4-dihydropyridine 3,5-diesters. J. Org. Chem. 2002, 67, 401–410. [Google Scholar] [CrossRef] [PubMed]
  53. Sobolev, A.; Franssen, M.C.R.; Poikans, J.; Duburs, G.; de Groot, A. Enantioselective lipase-catalysed kinetic resolution of acyloxymethyl and ethoxycarbonylmethyl esters of 1,4-dihydroisonicotinic acid derivatives. Tetrahedron Asymmetry 2002, 13, 2389–2397. [Google Scholar] [CrossRef]
  54. Torres, S.Y.; Verdecia, Y.; Rebolledo, F. Chemoenzymatic approach to optically active 1,4-dihydropyridine derivatives. Tetrahedron 2015, 71, 3976–3984. [Google Scholar] [CrossRef]
  55. Torres, S.Y.; Rebolledo, F. A Highly Efficient Synthesis of Optically Active Hybrid 1H-1,5-Benzodiazepine-1,4-Dihydropyridines. Synthesis 2016, 48, 1414–1420. [Google Scholar] [CrossRef]
  56. Andzans, Z.; Adlere, I.; Versilovskis, A.; Krasnova, L.; Grinberga, S.; Duburs, G.; Krauze, A. Effective method of lipase-catalyzed enantioresolution of 6-alkylsulfanyl-1,4-dihydropyridines. Heterocycles 2014, 89, 43–58. [Google Scholar] [CrossRef]
  57. Chen, C.S.; Fujimoto, Y.; Girdaukas, G.; Sih, C.J. Quantitative Analyses of Biochemical Kinetic Resolutions of Enantiomers. J. Am. Chem. Soc. 1982, 104, 7294–7299. [Google Scholar] [CrossRef]
  58. Franke, P.T.; Johansen, R.L.; Bertelsen, S.; Jørgensen, K.A. Organocatalytic Enantioselective One-Pot Synthesis and Application of Substituted 1,4-Dihydropyridines-Hantzsch Ester Analogues. Chem. Asian J. 2008, 3, 216–224. [Google Scholar] [CrossRef]
  59. Noole, A.; Borissova, M.; Lopp, M.; Onis Kanger, T. Enantioselective Organocatalytic Aza-Ene-Type Domino Reaction Leading to 1,4-Dihydropyridines. J. Org. Chem. 2011, 76, 1538–1545. [Google Scholar] [CrossRef]
  60. Auria-Luna, F.; Marqués-López, E.; Gimeno, M.C.; Heiran, R.; Mohammadi, S.; Herrera, R.P. Asymmetric Organocatalytic Synthesis of Substituted Chiral 1,4-Dihydropyridine Derivatives. J. Org. Chem. 2017, 82, 5516–5523. [Google Scholar] [CrossRef]
  61. Auria-Luna, F.; Marqués-López, E.; Herrera, R.P. First Organocatalytic Asymmetric Synthesis of 1-Benzamido-1,4-Dihydropyridine Derivatives. Molecules 2018, 23, 2692. [Google Scholar] [CrossRef]
  62. Auria-Luna, F.; Marqués-López, E.; Mohammadi, S.; Heiran, R.; Herrera, R. New Organocatalytic Asymmetric Synthesis of Highly Substituted Chiral 2-Oxospiro-(indole-3,4′- (1′,4′-dihydropyridine)) Derivatives. Molecules 2015, 20, 15807–15826. [Google Scholar] [CrossRef] [PubMed]
  63. Inokuma, T.; Hoashi, Y.; Takemoto, Y. Thiourea-catalyzed asymmetric michael addition of activated méthylene compounds to α,β-unsaturated imides: Dual activation of imide by intra- and intermolecular hydrogen bonding. J. Am. Chem. Soc. 2006, 128, 9413–9419. [Google Scholar] [CrossRef] [PubMed]
  64. Moreau, J.; Duboc, A.; Hubert, C.; Hurvois, J.P.; Renaud, J.L. Metal-free Brønsted acids catalyzed synthesis of functional 1,4-dihydropyridines. Tetrahedron Lett. 2007, 48, 8647–8650. [Google Scholar] [CrossRef]
  65. Jiang, J.; Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z. Organocatalytic Asymmetric Three-Component Cyclization of Cinnamaldehydes and Primary Amines with 1,3-Dicarbonyl Compounds: Straightforward Access to Enantiomerically Enriched Dihydropyridines. Angew. Chem. 2008, 47, 2458–2462. [Google Scholar] [CrossRef] [PubMed]
  66. Evans, C.G.; Gestwicki, J.E. Enantioselective organocatalytic hantzsch synthesis of polyhydroquinolines. Org. Lett. 2009, 11, 2957–2959. [Google Scholar] [CrossRef]
  67. An, D.; Zhu, Z.; Zhang, G.; Gao, Y.; Gao, J.; Han, X.; Zheng, L.; Zhang, S. H8-BINOL chiral imidodiphosphoric acids catalyzed cyclization reactions of β,γ-unsaturated α-ketoesters, arylamines and 1,3-dicarbonyl compounds: Enantioselective synthesis of 1,4-dihydropyridines. Tetrahedron Asymmetry 2015, 26, 897–906. [Google Scholar] [CrossRef]
  68. Deng, Y.; Kumar, S.; Wheeler, K.; Wang, H. Trio catalysis merging enamine, brønsted acid, and metal lewis acid catalysis: Asymmetric three-component aza-diels-alder reaction of substituted cinnamaldehydes, cyclic ketones, and arylamines. Chem. Eur. J. 2015, 21, 7874–7880. [Google Scholar] [CrossRef]
  69. Steiger, S.A.; Li, C.; Campana, C.F.; Natale, N.R. Lanthanide and asymmetric catalyzed syntheses of sterically hindered 4-isoxazolyl-1,4-dihydropyridines and 4-isoxazolyl-quinolones. Tetrahedron Lett. 2016, 57, 423–425. [Google Scholar] [CrossRef]
  70. Di Carmine, G.; Ragno, D.; Brandolese, A.; Bortolini, O.; Pecorari, D.; Sabuzi, F.; Mazzanti, A.; Massi, A. Enantioselective Desymmetrization of 1,4-Dihydropyridines by Oxidative NHC Catalysis. Chem. Eur. J. 2019, 25, 7469–7474. [Google Scholar] [CrossRef]
Figure 1. Representatives of 1,4-dihydropyridine calcium channel blockers.
Figure 1. Representatives of 1,4-dihydropyridine calcium channel blockers.
Catalysts 10 01019 g001
Figure 2. Structures of (−)-(S)-amlodipine, (−)-(S)-nitrendipine and (+)-(S)-manidipine.
Figure 2. Structures of (−)-(S)-amlodipine, (−)-(S)-nitrendipine and (+)-(S)-manidipine.
Catalysts 10 01019 g002
Figure 3. Opposite effects of 1,4-dihyropyridine derivatives on function of L-type channels.
Figure 3. Opposite effects of 1,4-dihyropyridine derivatives on function of L-type channels.
Catalysts 10 01019 g003
Scheme 1. Resolution of amlodipine with tartaric acid [49].
Scheme 1. Resolution of amlodipine with tartaric acid [49].
Catalysts 10 01019 sch001
Scheme 2. Iminium catalysed synthesis of 1,4-DHPs 8 [58].
Scheme 2. Iminium catalysed synthesis of 1,4-DHPs 8 [58].
Catalysts 10 01019 sch002
Scheme 3. Brønsted acids catalysed enantioselective synthesis of 1,2,3,4 substituted 1,4-DHPs 19 [64].
Scheme 3. Brønsted acids catalysed enantioselective synthesis of 1,2,3,4 substituted 1,4-DHPs 19 [64].
Catalysts 10 01019 sch003
Scheme 4. Chiral BINOL-derived phosphoric acid catalysed synthesis of 1,4-DHPs 8 [65].
Scheme 4. Chiral BINOL-derived phosphoric acid catalysed synthesis of 1,4-DHPs 8 [65].
Catalysts 10 01019 sch004
Scheme 5. Chiral BINOL-derived phosphoric acid catalysed synthesis of bicyclic 1,4-DHP 23 [66].
Scheme 5. Chiral BINOL-derived phosphoric acid catalysed synthesis of bicyclic 1,4-DHP 23 [66].
Catalysts 10 01019 sch005
Scheme 6. (R)-TRIP catalysed synthesis of 1,4-DHP-3,5-dicarboxylate 33 [69].
Scheme 6. (R)-TRIP catalysed synthesis of 1,4-DHP-3,5-dicarboxylate 33 [69].
Catalysts 10 01019 sch006
Table 1. Resolution of racemic 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine- 3-carboxylic acid 1 with cinchonidine or quinidine [50].
Table 1. Resolution of racemic 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine- 3-carboxylic acid 1 with cinchonidine or quinidine [50].
Catalysts 10 01019 i001
EntryResolving AgentSolvent RatioYield, (%)ee, (%)Abs. conf. *
1cinchonidineDMF-H2O (4:1)3299.5S
2cinchonidineDMF-H2O (8:5)41>99.5S
3cinchonidineDMF-H2O (1:1)4497.8S
4quinidineDMF-H2O (8:5)43>99.5R
5quinidineDMF-H2O (1:1)4696.6R
* absolute configuration.
Table 2. Lipase-catalysed kinetic resolution of racemic [(2-methylpropanoyl)oxy]methyl ester 1,4-DHP-3-carboxylates rac-2 [54,55].
Table 2. Lipase-catalysed kinetic resolution of racemic [(2-methylpropanoyl)oxy]methyl ester 1,4-DHP-3-carboxylates rac-2 [54,55].
Catalysts 10 01019 i002
EntryArLipaseSolventt *, hConv. , (%)2
Abs. conf. /ees, (%)
3
Abs. conf. /eep, (%)
E-value
12-NO2-C6H4CRLEtOAc0.747S/84R/95103
23-NO2-C6H4CRLEtOAc1.550S/89R/8846
32-Cl-NO2-C6H3CRLEtOAc0.849R/95S/98>200
4NaphthylCRLEtOAc2.546S/84R/97175
54-Br-C6H4CRLEtOAc2351S/60R/587
63-CH3O-C6H4CRLEtOAc1039S/40R/626
74-Br-C6H4Cal-BMTBE647S/75R/8527
84-Br-C6H4Cal-BEtOAc2543S/67R/8934
93-CH3O-C6H4Cal-BMTBE941S/62R/8829
103-CH3O-C6H4Cal-BEtOAc2134S/49R/9563
* time; conversion; enantiomeric ratio.
Table 3. Enzyme-catalysed kinetic resolution of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines rac-4 [56].
Table 3. Enzyme-catalysed kinetic resolution of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines rac-4 [56].
Catalysts 10 01019 i003
EntryCompoundEnzymeTemp *, °Ct, h(-)-4
Yield, (%)
(-)-4
ees, (%)
(-)-3
Yield,
(%)
Es-value Abs. conf.
1aCal-B254849824722Not known
2bCal-B2516546804820
3cCal-B255146774716
4dCal-B252644665468
5aCal-B4518499547104
6bCal-B454846924865
7cCal-B4526469946>200
8dCal-B4516846864629
9aAcylase25964752485
10bAcylase2531045894844
11cAcylase251004838473
12dAcylase253364548484
* temperature; enantiomeric ratio (Es-value) calculated according to Chen [57].
Table 4. Some characteristic examples of iminium catalysed 1,4-DHPs 8 synthesis [58].
Table 4. Some characteristic examples of iminium catalysed 1,4-DHPs 8 synthesis [58].
EntryR1R2R3Temp, °Ct1, ht2, h8
Yield, (%)ee, (%)
1C2H5CH3C6H5rt1815590
2Hex-3-en-ylCH3C6H5rt1814592
3COOC2H5CH3C6H5rt18243188
4(CH2)2OTBDMSCH3C6H5rt1813395
5FurylCH3C6H5418243564
6CH(CH3)2CH3C6H5rt1813392
7C2H5OCH3C6H5rt1814191
8CH3OCH3C6H5418243982
9C6H5CH3C6H547216038
10C2H5CH3CH(CH3)2rt1813990
11C2H5CH34-Br-C6H4rt1814892
Table 5. Organocatalytic reaction β-enaminones and β-enamino esters 9 with α,β-unsaturated aldehydes 6 [59].
Table 5. Organocatalytic reaction β-enaminones and β-enamino esters 9 with α,β-unsaturated aldehydes 6 [59].
Catalysts 10 01019 i004
EntryR1R2R3R4t, h10
Yield, (%)Abs. conf. /ee, (%)
1C6H5n-C4H9HC6H51979S/76
2C6H5n-C4H9HCH2C6H52454S/87
3C6H5n-C4H9HC(CH3)32672S/89
4C6H5n-C4H9HCH(CH3)22075S/93
54-NO2-C6H4n-C4H9HCH(CH3)2383S/89
64-NO2-C6H4OC2H5CH3CH(CH3)2445S/84
74-NO2-C6H4OC2H5CH3CH2C6H5470S/89
8C2H5n-C4H9HCH(CH3)21869R/93
9n-C4H9n-C4H9HCH(CH3)21796R/96
10n-C4H9OC2H5CH3CH2C6H5462R/71
Table 6. Cinchona-alkaloid catalysed synthesis of enantiomerically enriched 1,4-DHPs 13 [60].
Table 6. Cinchona-alkaloid catalysed synthesis of enantiomerically enriched 1,4-DHPs 13 [60].
Catalysts 10 01019 i005
EntryCatalystRSolventTemp, °Ct, h13
Yield, (%)eep, (%)Abs. conf.
1(DHQ)2PhalCH3toluene/AcOEt (9:1)10729166Not known
2(DHQ)2AQNCH3toluene/AcOEt (9:1)10722254
3(DHQD)2PhalCH3toluene/AcOEt (9:1)10724764
4(DHQD)2PyrCH3toluene/AcOEt (9:1)10721354
5(DHQD)2AQNCH3toluene/AcOEt (9:1)10722368
6(DHQ)2PyrCH3toluene/AcOEt (9:1)10728180
7(DHQ)2PyrCH3toluene10728882
8(DHQ)2PyrCH3toluene/AcOEt (9:1)0723280
9(DHQ)2PyrCH3toluene/AcOEt (9:1)-18120<585
10(DHQ)2PyrC2H5toluene/AcOEt (9:1)10729776
11(DHQ)2PyrC2H5toluene/AcOEt (9:1)-1872<590
Table 7. β-isocupreidine catalysed synthesis of highly functionalised 1-benzamido1,4-dihydropyridine derivatives 15 [61].
Table 7. β-isocupreidine catalysed synthesis of highly functionalised 1-benzamido1,4-dihydropyridine derivatives 15 [61].
Catalysts 10 01019 i006
EntrySolvent15
Yield, (%)eep, (%)
1MeCN5610
2AcOEt5440
3DCM35Rac.
4CHCl34933
5Et2O3940
6MeOH77Rac
7THF4852
Table 8. Takemoto’s thiourea catalysed synthesis of spirocyclic1,4-DHPs 17 [62].
Table 8. Takemoto’s thiourea catalysed synthesis of spirocyclic1,4-DHPs 17 [62].
Catalysts 10 01019 i007
EntryCatalyst Loading (mol %)RArR117
Yield, (%)
eep, (%)
130CH2C6H52,4-(H3CO)2-C6H3H3042
220CH2C6H52,4-(H3CO)2-C6H3H2523
310CH2C6H52,4-(H3CO)2-C6H3H2911
430CH2C6H52,4-(H3CO)2-C6H35-Br8248
530CH2C6H52,4-(H3CO)2-C6H35,7-diCH34030
630CH2C6H52,4-(H3CO)2-C6H35-Cl7130
730CH2C6H52,4-(H3CO)2-C6H35-NO26558
830CH2C6H53-H3CO-C6H4H6530
930Allyl3-H3CO-C6H4H6130
1030C2H53-H3CO-C6H4H4932
Table 9. Chiral imidodiphosphoric acid catalysed synthesis of 1,4-DHP 26 [67].
Table 9. Chiral imidodiphosphoric acid catalysed synthesis of 1,4-DHP 26 [67].
Catalysts 10 01019 i008
EntryR1R2R326
Yield, (%)ee, (%)
14-NO23-OCH3CH35488
24-NO23-OCH3C2H56185
34-NO23-OCH3CH(CH3)25490
44-NO23-OCH3CH2C6H55189
54-NO23-ClCH(CH3)25391
64-NO23-BrCH(CH3)25488
74-NO23-FCH(CH3)25387
84-NO23-CH3CH(CH3)25583
94-Br3-ClCH(CH3)25492
104-CN3-ClCH(CH3)24193
114-F3-BrC2H55194
122,3,4-triCl3-ClCH35595
Table 10. Chiral BINOL-derived phosphoric acid, hard metal Lewis acid, and amine catalysed synthesis of 1,4-DHP 29 [68].
Table 10. Chiral BINOL-derived phosphoric acid, hard metal Lewis acid, and amine catalysed synthesis of 1,4-DHP 29 [68].
Catalysts 10 01019 i009
EntrySolventR1ArXt, h29
Yield, (%)eep, (%)
1toluene4-ClC6H5CH2483892
2MeCN4-ClC6H5CH2487035
3Neat4-ClC6H5CH2481580
4MeOH4-ClC6H5CH2486793
51,4-dioxane4-ClC6H5CH2484443
6H2O4-ClC6H5CH2485099
7CHCl34-ClC6H5CH2248769
8acetone4-ClC6H5CH2247888
9DCM4-ClC6H5CH2248198
10DCE *4-ClC6H5CH2247898
11DCE4-CH3OC6H5CH2187999
12DCEHC6H5CH2247294
13DCE4-BrC6H5CH2247192
14DCE3-ClC6H5CH2306699
15DCE4-Cl4-CH3O-C6H4CH2247398
16DCE4-Cl4-Cl-C6H4CH2247199
17DCE4-Cl4-Br-C6H4CH2246794
18DCE4-ClNaphthylCH2405994
19DCE4-Cl4-NO2-C6H4CH2168498
20DCE4-CH3OC6H5-206891
21DCE4-ClC6H5-246094
22DCE4-Cl4-NO2-C6H4-246398
23DCE4-Cl4-CH3O-C6H4-246898
24DCE4-CH3O4-NO2-C6H4S307398
25DCE4-CH3O4-NO2-C6H4O307095
* 1,2-dichloroethane (DCE).
Table 11. (R)-TRIP catalysed synthesis of fused 1,4-DHPs 31 [69].
Table 11. (R)-TRIP catalysed synthesis of fused 1,4-DHPs 31 [69].
Catalysts 10 01019 i010
EntryAr31
Yield, (%)
1C6H526
22-Br-C6H464
33-Br-C6H460
44-Br-C6H465
Table 12. NHC-catalysed desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes 34 [70].
Table 12. NHC-catalysed desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes 34 [70].
Catalysts 10 01019 i011
EntrySolventBase (mol %)T, °Ct, h37 Yield (%)38 Yield (%)37 ee (%)
1DCMDIPEA (25)r.t.7229-82
2DCMDIPEA (100)r.t.7236-82
3THFDIPEA (100)r.t.7231123
4MeCNDIPEA (100)r.t.72491884
5DCEDIPEA (100)r.t.72651084
6CHCl3DIPEA (100)r.t.72671390
7CHCl3KHDMS (25)r.t.72531371
8CHCl3K3PO4 (25)r.t.72741182
9CHCl3TEA (25)r.t.72521088
10CHCl3DIPEA (100)401670791
Back to TopTop