catalysts
Review Recent Approaches to Chiral 1,4-Dihydropyridines and their Fused Analogues
Martins Rucins 1, Aiva Plotniece 1 , Eiva Bernotiene 2, Wei-Bor Tsai 3 and Arkadij Sobolev 1,*
1 Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia; [email protected] (M.R.); [email protected] (A.P.) 2 Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariskiu·5, LT-08406 Vilnius, Lithuania; [email protected] 3 Department of Chemical Engineering, National Taiwan University, 1, Roosevelt Rd. Sec. 4, Taipei 106, Taiwan; [email protected] * Correspondence: [email protected]; Tel.: +371-67014928
Received: 11 August 2020; Accepted: 28 August 2020; Published: 4 September 2020
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
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,
Catalysts 2020, 10, 1019; doi:10.3390/catal10091019 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 1019 2 of 21 Catalysts 2020, 10, x FOR PEER REVIEW 2 of 22 selectivityand gradual, and onset gradual of activity. onset Someof activity. representatives Some representatives of the class areof the felodipine, class are isradipine,felodipine, nicardipineisradipine, nicardipine(second generation), (second generation), amlodipine, amlodipine, barnidipine, barnidipine, and lercanidipine and lercanidipine (third generation), (third generation), and cilnidipine and cilnidipine(fourth generation) (fourth generation) (Figure1)[6 (Figure–8]. 1) [6–8].
Figure 1. RepresentativesRepresentatives of of 1,4 1,4-dihydropyridine-dihydropyridine calcium channel blockers.
The analys analysisis of of the the structures structures shows shows that that most most of them of them are the are unsymmetrical the unsymmetrical ones. When ones. Whensubstituents substituents on the on left the side left differ side di fromffer from those those on the on theright right side side of ofa 1,4 a 1,4-DHP,-DHP, the the molecule molecule becomes becomes chiral, with C4 being the stereogenic centre [[9]9].. Enantiomers of unsymmetrica unsymmetricall 1,4 1,4-DHP-DHP often show differentdifferent biological activities and they could have even an opposite action profile.profile. For example, it was established that ( )-S-amlodipine [10], (+)-S-manidipine, and [11]( )-S-nitrendipine [11,12] were established that (−)-S-amlodipine [10], (+)-S-manidipine, and [11] (−)-S-nitrendipine [11,12] were more potent calcium channel blo blockersckers than the respective opposite enantiomers (Figure2 2).). TheThe samesame occurrence was described for barnidipine, where the most active was ((+)+)--S,,S--isomerisomer (Figure 11))[ [13]13]..
Catalysts 2020, 10, 1019 3 of 21 CatalystsCatalysts 20 202020, ,10 10, ,x x FOR FOR PEER PEER REVIEW REVIEW 33 of of 22 22
Figure 2. Structures of ( )-(S)-amlodipine, ( )-(S)-nitrendipine and (+)-(S)-manidipine. FigureFigure 2. 2. Structures Structures of of ( −(−)-)(S)-(S)-amlodipine,-amlodipine, ( −(−)-)(S)-(S)-nitrendipine-nitrendipine and and (+) (+)-(S)-(S)-manidipin-manidipine.e. The opposite effects on function of L-type channels were reported, for example, for derivative PN 202-791TheThe ando oppositepposite BAYK8644, effects effects where on on function function ( )-R-enantiomers of of L L--typetype channels channels of PN 202-791were were reported reported and (+,)- ,for Rfor-BAYK8644 example example, ,for werefor derivative derivative calcium − PNchannelPN 202 202--791 blockers,791 and and BAYK8644, while BAYK8644, the corresponding where where ( (−−))--RR--enantiomers (enantiomers+)-S-PN 202-791 of of PN PN and 202 202 ( -)--791791S-BAYK8644 and and (+) (+)--RR enantiomers--BAYK8644BAYK8644 were were were − calciumcalciumcalcium channel channel channel agonists blockers, blockers, (Figure while while3)[ 14 the– the16 ]. corresponding corresponding Currently ( )-( S (+))-amlodipine (+)--SS--PNPN 202 202 is--791791 marketed and and as((−−) levamlodipine)--SS--BAYK8644BAYK8644 − enantiomersandenantiomersS,S-barnidipine were were calcium calcium is marketed channel channel in Japan agonists agonists under (Figure (Figure the trade 3) 3) [14[14 name––16]16]. . of CurrentlyCurrently Hypoca (Astellas ( (−−))--((SS))--amlodipineamlodipine Pharma Inc, is is marketedTokyo,marketed Japan). as as levamlodipine levamlodipine and and SS,S,S--barnidipinebarnidipine is is marketed marketed in in Japan Japan under under the the trade trade name name of of HypocaHypoca (Astellas (Astellas Pharma Pharma Inc, Inc, Tokyo, Tokyo, Japan Japan).).
Figure 3. L FigureFigure 3. 3. Opposite Opposite effects eeffectsffects of ofof 1,4 1,4-dihyropyridine1,4-dihyropyridine-dihyropyridine derivatives derivativesderivatives on onon function functionfunction of ofof L L--typetype-type channels. channels.channels. L-type voltage operated calcium channels are well-known for their involvement in electrical LL--typetype voltage voltage operated operated calcium calcium channels channels are are well well--knownknown for for their their involvement involvement in in electrical electrical current generation; therefore, predominantly found in “excitable” cells, such as cardiomyocytes, currentcurrent generation generation; ; therefore,therefore, predominantly predominantly found found in in “excitable” “excitable” cells, cells, such such as as cardiomyocytes,cardiomyocytes, muscle cells or neurons. In addition to the well-known role of 1,4-DHPs on the treatment of musclemuscle cells cells or or neurons. neurons. In In addition addition to to the the well well--knownknown role role of of 1,4 1,4--DHPsDHPs on on the the treatment treatment of of cardiovascular system disorders, as efficient agents in the management of hypertension, their potential cardiovascularcardiovascular system system disorders, disorders, as as efficient efficient agents agents in in the the management management of of hypertension, hypertension, their their activity on the cells from other tissues and organs is increasingly being revealed. L-type voltage potentialpotential activityactivity onon thethe cellscells fromfrom otherother tissuestissues andand organsorgans isis increasinglyincreasingly beingbeing revealed.revealed. LL--typetype operated calcium channels are also abundantly expressed in a range of “non-excitable” cells, including voltagevoltage operated operated calcium calcium channels channels are are also also abundantly abundantly expressed expressed in in a a range range of of “non “non--excitable”excitable” cells, cells, mesenchymal stem cells, osteoblasts, and chondrocytes, and they seem to have a range of activities, includingincluding mesenchymal mesenchymal stem stem cells, cells, osteoblasts osteoblasts, ,and and chondrocytes, chondrocytes, and and they they seem seem to to have have a a range range of of including mechanotransduction [17,18]. Alterations in intracellular Ca2+ concentrations may initiate activitiesactivities, , including including mechanotransduction mechanotransduction [17[17,18],18]. . AlterationsAlterations in in intracellular intracellular Ca Ca2+2+ concentrations concentrations the downstream response of chondrocytes to mechanical stress via mechanosensitive ion-channels [19]. maymay initiateinitiate thethe downstreamdownstream responseresponse ofof chondrocyteschondrocytes toto mechanicalmechanical stressstress viavia mechanosensitivemechanosensitive Therefore, the potential in regulation of chondrogenesis processes through the regulation of ion ionion--channelschannels [19][19]. . Therefore,Therefore, the the potential potential in in regulation regulation of of chondrogen chondrogenesisesis processes processes through through thethe channels increasingly gain attention for stimulation of cartilage regeneration [20]. Mechanical loads regulationregulation of of ion ion channels channels increasingly increasingly gain gain attention attention for for stimulation stimulation of of cartilage cartilage regeneration regeneration [20] [20]. . trigger anabolic and catabolic responses in chondrocytes [21]. Noteworthy, the analysis of downstream MechanicalMechanical loadsloads triggertrigger anabolicanabolic andand cataboliccatabolic responsesresponses inin chondrocyteschondrocytes [21][21]. . Noteworthy,Noteworthy, the the signalling effects and functions suggested that the activated mechanotransductive pathways are distinct analysisanalysis of of downstream downstream signall signallinging effects effects and and functions functions suggested suggested that that the the activated activated in various loading modalities or electric stimuli [21,22]. Furthermore, the application of the same mechanotransductivemechanotransductive pathways pathways are are distinct distinct in in various various loading loading modalities modalities or or electric electric stimuli stimuli [21 [21,22],22]. . 1,4-DHP drug nifedipine generated different metabolic responses and inflammatory activity in different Furthermore,Furthermore, thethe applicationapplication of of the the same same 1,4 1,4--DHPDHP drug drug nifedipine nifedipine generated generated different different metabolic metabolic resporesponsesnses and and inflammatory inflammatory activity activity in in different different cell cell types, types, namely namely mesenchymal mesenchymal stem stem cells cells and and
Catalysts 2020, 10, 1019 4 of 21 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 [28–30]. 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 [1,37–40]. 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 [9,44–46].
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 Scheme1, significantly improved the e fficiency of resolution (yield 71%, enantiomeric excess (ee) 99%) [49]. Catalysts 2020, 10, x FOR PEER REVIEW 5 of 22
Catalysts 2020, 10, 1019 5 of 21 Catalysts 2020, 10, x FOR PEER REVIEW 5 of 22
Scheme 1. Resolution of amlodipine with tartaric acid [49].
2.2. Resolution of Racemic 1,4-Dihydropyridinedicarboxylic Acid Derivatives SchemeScheme 1. Resolution 1. Resolution of amlodipine of amlodipine with tartaric with tartaric acid [4 acid9]. [49]. The resolution of racemic 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4- 2.2. Resolution of Racemic 1,4-Dihydropyridinedicarboxylic Acid Derivatives 2.2.dihydropyridine Resolution of Racemic-3-carboxylic 1,4-Dihydropyridinedicarboxylic acid was also achieved Acid D erivativesusing commercially available Cinchona alkaloidsTheThe resolution(cinchonidine resolution of racemic ofand quinidine)racemic 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine- as 2,6 the-dimethyl resolving-5-methoxycarbonyl agents. Under the-4- (3optimum-nitrophenyl) conditions,-1,4- for dihydropyridineboth3-carboxylic R- and S acid--enant3-carboxylic wasiomers also achievedenantiomeric acid was using also excess commercially achieved >99.5% using was available commerciallyreached. Cinchona The optimum available alkaloids conditions Cinchona (cinchonidine were alkaloidsapproachedand quinidine) (cinchonidine by asvarying the and resolving of quinidine) the solvent, agents. as thewhere Under resolving the best optimum agents. results conditions,Under were the found optimum for in both the Rconditions, DMF/water- and S-enantiomers for mixture both(8:5)enantiomeric R -(Table and S -1)enant excess[50]iomers. >99.5% enantiomeric was reached. excess The >99.5% optimum was conditionsreached. The were optimum approached conditions by varying were of the approachedsolvent, where by varying the best of the results solvent, were where found the in best the DMFresults/water were mixturefound in (8:5) the DMF/water (Table1)[50 mixture]. (8:5) (TableTable 1) [50] 1. . Resolution of racemic 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4- dihydropyridineTable 1. Resolution- 3- ofcarboxylic racemic 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-acid 1 with cinchonidine or quinidine [50]. Table3-carboxylic 1. Resolution acid 1 with cinchonidine of racemic or quinidine 2,6-dimethyl [50-5].-methoxycarbonyl-4-(3-nitrophenyl)-1,4- dihydropyridine- 3-carboxylic acid 1 with cinchonidine or quinidine [50].
Entry Resolving Agent Solvent Ratio Yield, (%) ee, (%) Abs. conf. * Entry Resolving Agent Solvent Ratio Yield, (%) ee, (%) Abs. conf. * 1 cinchonidine DMF-H O (4:1) 32 99.5 S Entry1 Resolvingcinchonidine Agent SolventDMF Ratio-H2O2 (4:Yield,1) (%)32 ee, (%) 99.5Abs. conf. *S 2 cinchonidine DMF-H2O (8:5) 41 >99.5 S 1 2 cinchonidinecinchonidine DMFDMF-H2O-H (42:O1) (8:5) 32 41 99.5 >99.5 S S 3 cinchonidine DMF-H2O (1:1) 44 97.8 S 3 cinchonidine DMF2 -H2O (1:1) 44 97.8 S 2 4cinchonidine quinidine DMF- DMF-HH O (8:5)2O (8:5)41 43 >99.5 >99.5S R 3 54 cinchoquinidine quinidinenidine DMFDMF- DMF-HH2O-H (12:O21O) (8:5) (1:1) 44 43 46 97.8 >99.5 96.6 S R R 4 5 quinidinequinidine DMFDMF-H* absolute2O-H (8:5)2O configuration. (1:1) 43 46 >99.5 96.6 R R 5 quinidine DMF*- Habsolute2O (1:1 )configuration 46 96.6 R 2.3. Lipase-catalysed Kinetic Resolution* absolute of Racemic configuration Activated Esters of 1,4-Dihydropyridinecarboxylic Acid 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 2.3. Lipase-catalysed Kinetic Resolution of Racemic Activated Esters of 1,4-Dihydropyridinecarboxylic Acid in 1991.Enzyme Since-catalysed then, this approach methodology to enantiopure was widely 1,4 used-DHPs for asymmetrisation was pioneered orby kinetic groups resolution of Sih and of AchiwaenzymaticallyEnzyme in- catalysed 1991. labile Since approach esters then activated, this to enantiopure methodology spacer groups 1,4 - wasDHPs [ 44 widely – was46]. pioneered In used the for last by asymmetrisation decade, groups this of Sih approach andor kinetic was Achiwa in 1991. Since then, this methodology was widely used for asymmetrisation or kinetic successfully applied by Tores et al. to kinetic resolution of various 1,4-DHPs and dihydropyridone
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Catalystsresolution2020, 10 of, 1019 enzymatically labile esters activated spacer groups [44–46]. In the last decade, this6 of 21 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) derivativesoxy]methyl (Table ester2 as). Applyingactivating group previously [51–53 well-known] in the substrate [(2-methylpropanoyl) and Candida rugosa oxy]methyl (CRL) or Candida ester as activatingantarctica group B (CAL [51-B)– 53as ]enzyme in the substrate good to excellent and Candida enantioselectivity rugosa (CRL) was or Candidareached [54 antarctica,55]. InterestinglyB (CAL-B), as enzymethat besides good tofrequently excellent used enantioselectivity as solvents wet was ethers, reached CRL [has54,55 been]. Interestingly, found very efficient that besides in EtOAc, frequently in usedspite as of solvents the fact t wethat this ethers, solvent CRL is hasalso beensusceptible found to very be hydrolysed efficient in by EtOAc, the lipase. in spiteThe best of the results fact of that thisCRL solvent catalysed is also kinetic susceptible resolutions to in be wet hydrolysed EtOAc were by obtained the lipase. when The aryl best substituent results of in CRLthe position catalysed kineticfour of resolutions 1,4-DHP rac in-2 wet ring EtOAc was 2- were or 3-NO obtained2-C6H4- when, 2-Cl- aryl5-NO substituent2-C6H3-, naphthyl in the-position in short reaction four of 1,4-DHPtimes rac-not2 ring exceeding was 2- 2.5 or h, 3-NO with2-C high6H 4enantioselectivity-, 2-Cl-5-NO2-C6 H(E3--,value) naphthyl- ranging in from short 50 reaction to >200. times CAL not-B has exceeding been 2.5also h, withshown high enantioselectivity enantioselectivity toward (E-value) similar ranging substrates from in the 50 torange>200. of CAL-B11–63 (E has-value) been, where also shown the enantioselectivityadvantage of the toward use ofsimilar EtOAc substrates as reaction in the media range wasof 11–63 also (Eproven.-value), CALwhere-B the shows advantage better of theenantioselectivity use of EtOAc as toward reaction substrates media was rac- also2 having proven. bromine CAL-B or methoxy shows better group enantioselectivity in 4-aryl substituent toward in substratescomparisonrac- 2withhaving CRL. bromine Thus, hydrolysis or methoxy of 4 group-Br-C6 inH4 4-aryl- substituted substituent 1,4-DHP in comparison rac-2 in methyl with tert CRL.-butyl Thus, ether (MTBE)/water occluded with E 24–27, while in EtOAc E 34 was reached. The same occurrence hydrolysis of 4-Br-C6H4- substituted 1,4-DHP rac-2 in methyl tert-butyl ether (MTBE)/water occluded was described for 3-CH3O-C6H4- substituted 1,4-DHP rac-2 where E 29-31 was in MTBE/water and E with E 24–27, while in EtOAc E 34 was reached. The same occurrence was described for 3-CH O-C H - 63 was in EtOAc. 3 6 4 substituted 1,4-DHP rac-2 where E 29-31 was in MTBE/water and E 63 was in EtOAc. Table 2. Lipase-catalysed kinetic resolution of racemic [(2-methylpropanoyl)oxy]methyl ester 1,4- Table 2. Lipase-catalysed kinetic resolution of racemic [(2-methylpropanoyl)oxy]methyl ester DHP-3-carboxylates rac-2 [54,55]. 1,4-DHP-3-carboxylates rac-2 [54,55].
2 3 Entry Ar Lipase Solvent t *, h Conv. , (%) E-Value † Abs. conf. /ee , (%) Abs. conf. /ee , (%) ‡ s 2 p 3 E- † 1 2-NO2-C6H4 CRL EtOAc 0.7 47 Conv. ,S /84 R/95 103 Entry Ar Lipase Solvent t *, h Abs. conf. Abs. conf. valu 2 3-NO2-C6H4 CRL EtOAc 1.5 50 (%) S/89 R/88 46 3 2-Cl-NO2-C6H3 CRL EtOAc 0.8 49 R/95 /ees, (%) S/98/eep, (%) >200e ‡ 4 Naphthyl CRL EtOAc 2.5 46 S/84 R/97 175 5 4-Br-C6H4 CRL EtOAc 23 51 S/60 R/58 7 1 2-NO2-C6H4 CRL EtOAc 0.7 47 S/84 R/95 103 6 3-CH3O-C6H4 CRL EtOAc 10 39 S/40 R/62 6 2 73-NO 4-Br-C2-C6H6H4 4 Cal-BCRLMTBE EtOAc6 1.5 47 50 S/75 S/89 R/85R/88 2746 8 4-Br-C6H4 Cal-B EtOAc 25 43 S/67 R/89 34 3 2-Cl-NO2-C6H3 CRL EtOAc 0.8 49 R/95 S/98 >200 9 3-CH3O-C6H4 Cal-B MTBE 9 41 S/62 R/88 29 4 10 Naphthyl3-CH3O-C6H 4 Cal-BCRLEtOAc EtOAc21 2.5 34 46 S/49 S/84 R/95R/97 63175
5 4-Br-C6H4 CRL * time;EtOAc† conversion; 23‡ enantiomeric51 ratio. S/60 R/58 7 6 3-CH3O-C6H4 CRL EtOAc 10 39 S/40 R/62 6 7 Enzyme-catalysed4-Br-C6H4 kineticCal-B resolution MTBE of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines6 47 S/75 R/85 27 rac8- 4 has been4-Br-C performed6H4 Cal by-B KrauzeEtOAc group 25using Amano43 AcylaseS/67 (AspergillusR/89 mellus )34 and ® Candida9 antarctica3-CH3O-C6lipaseH4 Cal B (CAL-B,-B MTBE Novozyme 9 435 )41 in wet diisopropylS/62 etherR/88 (IPE) with29 dichloromethane10 3-CH3O- (DCM)C6H4 asCal an-B additive EtOAc to improve 21 the solubility34 of theS/49 substrate racR-/954 [56 ]. Table63 3 shows the most enantioselective examples.* time; † conversion The enantioselectivity; ‡ enantiomeric ratio of. CAL-B increased together with an increase of the temperature. Thus the best enantioselectivities of CAL-B were achieved at 45◦C when Enzyme-catalysed kinetic resolution of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines the substituent at the position 4 of 1,4-DHP was substituted aryl (Table3, entries 5–7). While Amano rac-4 has been performed by Krauze group using Amano Acylase (Aspergillus mellus) and Candida Acylase was less enantioselective toward the same substrate rac-4 showing no enantioselectivity at antarctica lipase B (CAL-B, Novozyme 435®) in wet diisopropyl ether (IPE) with dichloromethane elevated(DCM) temperaturesas an additive (Table to improve3, entries the 9–12).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).
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Table 3. Enzyme-catalysed 3. Enzyme-catalysed kinetic resolution kinetic of resolution 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines of 6-methoxycarbonylethylsulfanyl-1,4- dihydropyridinesrac-4 [56]. rac-4 [56].
(-)-3 ((-)-4-)-4 (-(-)-4)-4 (-)-3 Entry Compound Enzyme TempTemp *, ◦ C*, t, h Yield, Es-ValueEs- † Abs.Abs. conf. Entry Compound Enzyme t, h Yield,Yield, (%) eeees, (%)s, Yield, °C (%) value † conf. 1 a Cal-B 25 48(%) 49 (%) 82 (%) 47 22 1 2a b Cal-BCal-B 2525 16548 49 46 82 80 47 48 22 20 3 c Cal-B 25 51 46 77 47 16 2 4b d Cal-BCal-B 2525 264165 46 46 80 65 48 46 20 8 3 5c a Cal-BCal-B 4525 1851 46 49 77 95 47 47 16 104 6 b Cal-B 45 48 46 92 48 65 Not known 4 7d c Cal-BCal-B 4525 264 26 46 46 65 99 46 46 >8200 5 8a d Cal-BCal-B 4545 16818 49 46 95 86 47 46 104 29 9 a Acylase 25 96 47 52 48 5 6 10b b AcylaseCal-B 2545 31048 46 45 92 89 48 48 65 44 Not 7 11c c AcylaseCal-B 2545 10026 46 48 99 38 46 47 >200 3 known 8 12d d AcylaseCal-B 2545 336168 46 45 86 48 46 48 29 4 9 a * temperature;Acylase† enantiomeric 25 ratio (E96s -value)47 calculated according52 to48 Chen [57]. 5 10 b Acylase 25 310 45 89 48 44 2.4. Organocatalytic Enantioselective Synthesis of 1,4-Dihydropyridines 11 c Acylase 25 100 48 38 47 3 12The above-mentionedd Acylase approaches 25 have been336 studied45 in the48 detail and48 they are4 relatively well established. The* temperature catalytic; asymmetric † enantiomeric approach ratio (Es-value) holds calculated the greatest according promise to Chen in delivering [57]. the most practical and widely applicable methods. During the last decade, substantial progress has been made in 2this.4. Organocatalytic field toward development Enantioselective of enantioselective Synthesis of 1,4- organocatalyticDihydropyridines methods for the direct construction of the chiral DHPs. However, most of them do not provide a convenient way to pharmacologically The above-mentioned approaches have been studied in the detail and they are relatively well important 1,4-DHP-3,5-dicarboxylates. On the other hand, recently reported organocatalytic established. The catalytic asymmetric approach holds the greatest promise in delivering the most enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes also has great practical and widely applicable methods. During the last decade, substantial progress has been made promise in the synthesis of pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates. in this field toward development of enantioselective organocatalytic methods for the direct In 2008, the Jorgensen group reported the first examples of catalytic asymmetric four substituted construction of the chiral DHPs. However, most of them do not provide a convenient way to 1,4-DHPs 8 synthesis using TMS-prolinol enabled iminium catalysis (Scheme2)[ 58]. In this pharmacologically important 1,4-DHP-3,5-dicarboxylates. On the other hand, recently reported methodology, only non-aromatic α,β-unsaturated aldehydes 6 are able to give products 8 with organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5- high levels of stereoinduction (R1 = aryl, led to a low stereoselectivity). 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).
Catalysts 2020, 10, 1019 8 of 21 Catalysts 2020, 10, x FOR PEER REVIEW 8 of 22
Scheme 2. IminiumIminium catalysed catalysed synthesis synthesis of of 1,4 1,4-DHPs-DHPs 8 [58]58]..
With this method method,, it it was was possible possible to to vary vary the the substituents substituents in inthe the positions positions 1, 3, 1, and 3,and 4 in 4the in 1,4 the- 1,4-dihydropyridinedihydropyridine ring. ring. In the In the cases cases of ofuse use of of non non-aromatic-aromatic α,βα,β-unsaturated-unsaturated aldehydes aldehydes 66,, moderate moderate yields and high enantioselectivities of of 1,4 1,4-DHPs-DHPs 88 (88(88–95%–95% ee) ee) were were achieved achieved (Table (Table 44,, entries 1–4,6).1–4,6). Low to to moderate moderate enantioselectivities enantioselectivities of ofcatalysis catalysis were were reached reached with with aromatic aromatic aldehydes aldehydes at 4°C at (Table 4 ◦C 4,(Table entries4, entries 5,9). High 5,9). Highenantioselectivities enantioselectivities of iminium of iminium catalysis catalysis were wereachieved achieved for both for bothkinds kinds of α,β of- unsaturatedα,β-unsaturated aldehydes aldehydes 6: diketones6: diketones (Table (Table 4, entries4, entries 1–6, 1–6,9–11)9–11) and andβ–ketβoesters–ketoesters (Table (Table 4, entries4, entries 7,8) [58]7,8). [58From]. From the the tested tested catalysts catalysts,, 2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilanyloxymethyl]2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilanyloxymethyl] pyrrolidine was identifiedidentified as the most enantioselective.
Table 4. Some characteristic examples of iminium catalysed 1,4 1,4-DHPs-DHPs 8 synthesissynthesis [[58]58]..
88 EntryEntry R1 R1 R2 R2 R3 R3 Temp,Temp,◦C °Ct1 , ht1, h t2,t h2, h Yield,Yield, (%) ee, ee, (%) (%)
2 5 3 6 5 11 C2H5 C H CH3 CH C 6H5 C H rtrt 1818 11 55 55 90 90 22 Hex-3-en-ylHex-3-en-yl CH 3 CH3C 6H5 C6H5 rtrt 1818 11 45 45 92 92 33 COOCCOOC2H5 2H5CH 3 CH3C 6H5 C6H5 rtrt 1818 2424 31 31 88 88 4 (CH ) OTBDMS CH C H rt 18 1 33 95 4 2(CH2 2)2OTBDMS3 CH3 6 5 C6H5 rt 18 1 33 95 5 Furyl CH3 C6H5 4 18 24 35 64 5 Furyl CH3 C6H5 4 18 24 35 64 6 CH(CH3)2 CH3 C6H5 rt 18 1 33 92 3 2 3 6 5 76 C2HCH(CH5 )OCH 3 CH C 6H5 C H rtrt 1818 11 33 41 92 91 87 CH3 C2H5 OCH3 OCHC3 6H5 C6H5 4rt 1818 241 41 39 91 82 98 C6H5 CH3 CH3 OCHC3 6H5 C6H5 44 7218 124 39 60 82 38 10 C2H5 CH3 CH(CH3)2 rt 18 1 39 90 9 C6H5 CH3 C6H5 4 72 1 60 38 11 C2H5 CH3 4-Br-C6H4 rt 18 1 48 92 10 C2H5 CH3 CH(CH3)2 rt 18 1 39 90 11 C2H5 CH3 4-Br-C6H4 rt 18 1 48 92 In 2011, the Kanger group reported [59] the approach to enantiomerically enriched four substituted 1,4-DHPsIn 201110 based, the onKanger the use group of diarylprolinol-TMS reported [59] the ether approach and benzoic to acidenantiomerically as catalytic system enriched previously four substituteddeveloped by1,4 Jorgensen-DHPs 10 groupbased [on58]. the In use this of via diarylprolinol TMS-prolinol-TMS organocatalytic ether and benzoic approach acidβ-enaminones as catalytic systemand β-enamino previously esters developed9 were preformed by Jorgensen prior group to the [58] aza-ene-type. In this via reaction TMS-prolinol with α organocatalytic,β-unsaturated approachaldehydes β6-.enaminones With this method and β- moderateenamino esters to high 9 enantioselectivitieswere preformed prior (71–96% to the ee) aza and-ene yields-type (45–96%)reaction withof 1,4-DHPs α,β-unsaturated10 were approached.aldehydes 6. With The methodthis method also moderate allowed to to vary highsubstituents enantioselectivities in thepositions (71–96% 1,ee) 3, and and yields 4 in the (45 ring–96%) to a offford 1,4- threeDHPs or 10 four were substituted approached. 1,4-DHPs The method10. Table also5 summarizes allowed to some vary substitcharacteristicuents in examples. 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.
Catalysts 2020, 10, 1019 9 of 21 Catalysts 2020, 10, x FOR PEER REVIEW 9 of 22
Table 5. 5. Organocatalytic reaction β --enaminonesenaminones and β --enaminoenamino esters 9 withwith α α,β,β-unsaturated-unsaturated aldehydes 6 [[59]59]..
10 1 2 3 4 10 EntryEntry RR1 RR2 R3R RR4 t,t, h h Yield,Yield, (%) (%) Abs. Abs. conf. conf. //ee,ee, (%) (%) 1 C H n-C H HC H 19 79 S/76 1 C66H55 n-C4H9 H C6H6 55 19 79 S/76 2 C6H5 n-C4H9 H CH2C6H5 24 54 S/87 2 C6H5 n-C4H9 H CH2C6H5 24 54 S/87 3 C6H5 n-C4H9 H C(CH3)3 26 72 S/89 3 4C C66HH55 nn-C-C4HH9 HH C(CHCH(CH3)33)2 2620 72 75 SS/89/93 5 4-NO -C H n-C H H CH(CH 3 83 S/89 4 C6H2 5 6 4 n-C4H9 H CH(CH3)23)2 20 75 S/93 6 4-NO2-C6H4 OC2H5 CH3 CH(CH3)2 4 45 S/84 5 4-NO2-C6H4 n-C4H9 H CH(CH3)2 3 83 S/89 7 4-NO2-C6H4 OC2H5 CH3 CH2C6H5 4 70 S/89 6 84-NO C2-HC56H4 OCn-C24HH59 CHH3 CH(CHCH(CH3)23)2 418 45 69 SR/84/93 7 94-NO n-C2-4CH69H4 OCn-C24HH59 CHH3 CHCH(CH2C6H3)25 417 70 96 SR/89/96 10 n-C4H9 OC2H5 CH3 CH2C6H5 4 62 R/71 8 C2H5 n-C4H9 H CH(CH3)2 18 69 R/93 9 n-C4H9 n-C4H9 H CH(CH3)2 17 96 R/96 From10 the recentn-C4H9 achievements,OC2H5 CH the3 CH synthesis2C6H5 of4 fully62 substituted 1,4-DHPR/71 13 was performed by Herrera’s group in 2017 (Table6)[ 60]. Bis-cinchona catalyst activates the MichaelFrom addition the recent reaction achievements, between the malononitrile synthesis of fully derivatives substituted12 1,4and-DHP enamines 13 was 11performed, affording by 4-aryl-6-amino-5-cyano-1,4-dihydropyridine-2,3-dicarboxylatesHerrera’s group in 2017 (Table 6) [60]. Bis-cinchona catalyst activates13 with the moderate Michael enantioselectivity.addition reaction between malononitrile derivatives 12 and enamines 11, affording 4-aryl-6-amino-5-cyano-1,4- At the beginning hydroquinine 1,4-phthalazinediyl diether ((DHQ)2Phal), hydroquinine dihydropyridine-2,3-dicarboxylates 13 with moderate enantioselectivity. At the beginning 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2Pyr), hydroquinine anthraquinone-1,4-diyl hydroquinine 1,4-phthalazinediyl diether ((DHQ)2Phal), hydroquinine 2,5-diphenyl-4,6- diether ((DHQ)2AQN), hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2Phal), pyrimidinediyl diether ((DHQ)2Pyr), hydroquinine anthraquinone-1,4-diyl diether ((DHQ)2AQN), hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)2Pyr), hydroquinidine hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2Phal), hydroquinidine-2,5-diphenyl-4,6- (anthraquinone-1,4-diyl), diether ((DHQD)2AQN), and hydroquinine 4-chlorobenzoate (DHQ-4Cl-Bz) pyrimidinediyl diether ((DHQD)2Pyr), hydroquinidine (anthraquinone-1,4-diyl), diether were studied as catalysts for the reaction of enamine 11 (R = CH3) and malononitrile 12a in ((DHQD)2AQN), and hydroquinine 4-chlorobenzoate (DHQ-4Cl-Bz) were studied as catalysts for the toluene/EtOAc (9:1) as solvent for 72 h at 10 ◦C. Table6 summarises the best results (Table6, entries 1–5). reaction of enamine 11 (R = CH3) and malononitrile 12a in toluene/EtOAc (9:1) as solvent for 72h at The enantioselectivity appeared to be the highest for (DHQ)2Pyr where 80% of ee (Table6, entry 6) was10°C. achieved. Table 6 summarises Further fine the tuningbest results of reaction (Table 6, conditions entries 1–5). allowed The enantioselectivity to approach a appeared slightly better to be enantioselectivitythe highest for (DHQ) albeit2Pyr to thewhere reaction 80% rateof ee (Table (Table6, entries6, entry 9,11). 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).
CatalystsCatalysts2020 2020, ,10 10,, 1019 x FOR PEER REVIEW 10 of10 22 of 21
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].
13 Entry Catalyst R Solvent Temp, ◦C t, h 13 Temp, Yield, (%) eep, (%) Abs. conf. Entry Catalyst R Solvent t, h Yield, eep, Abs. °C 1 (DHQ)2Phal CH3 toluene/AcOEt (9:1) 10 72 91(%) (%) 66 conf. 2 (DHQ)2AQN CH3 toluene/AcOEt (9:1) 10 72 22 54 1 3 (DHQ)(DHQD)22PhalPhal CH3CH3 toluenetoluene/AcOEt/AcOEt (9:1) (9:1) 1010 7272 4791 66 64 2 4 (DHQ)(DHQD)2AQN2Pyr CH3CH3 toluenetoluene/AcOEt/AcOEt (9:1) (9:1) 1010 7272 1322 54 5 (DHQD)2AQN CH3 toluene/AcOEt (9:1) 10 72 23 68 3 (DHQD)2Phal CH3 toluene/AcOEt (9:1) 10 72 47 64 6 (DHQ)2Pyr CH3 toluene/AcOEt (9:1) 10 72 81 80 Not known 4 7(DHQD) (DHQ)2Pyr2Pyr CH3CH3 toluene/AcOEttoluene (9:1) 1010 7272 8813 54 82 5 8(DHQD) (DHQ)22PyrAQN CH3CH3 toluenetoluene/AcOEt/AcOEt (9:1) (9:1) 010 7272 3223 68 80 9 (DHQ)2Pyr CH3 toluene/AcOEt (9:1) 18 120 <5 85 Not 6 (DHQ)2Pyr CH3 toluene/AcOEt (9:1) − 10 72 81 80 10 (DHQ)2Pyr C2H5 toluene/AcOEt (9:1) 10 72 97 76 known 7 11(DHQ) (DHQ) 2PyrPyr C HCH3 toluene/AcOEttoluene (9:1) 1810 72 72 <588 82 90 2 2 5 − 8 (DHQ)2Pyr CH3 toluene/AcOEt (9:1) 0 72 32 80 9 (DHQ)2Pyr CH3 toluene/AcOEt (9:1) -18 120 <5 85 10 Recently,(DHQ) the2Pyr synthesis C2H of5 highlytoluene/AcOEt functionalised (9:1) 1-benzamido-1,4-dihydropyridine10 72 97 76 derivatives 1511from hydrazones(DHQ)2Pyr 14 Cand2H5 alkylidenemalononitriletoluene/AcOEt (9:1) 12b-18 in the72 presence <5 of β-isocupreidine90 as organocatalyst was reported with rather low enantioselectivity (up to 10–52% ee) by Herrera’s groupRecently, [61]. From the synthesis ten different of highly chiral functionalised organocatalysts, 1-benzamidoβ–isocupreidine-1,4-dihydropyridine was chosen derivatives as the most enantioselective.15 from hydrazones Table 147 summarizes and alkylidenemalononitrile some characteristic 12b examples. in the presence of β-isocupreidine as organocatalystIn 2015, Herrera’s was reported group with reportedrather low the enantioselectivity synthesis of (up enantioenriched to 10–52% ee) by 2-oxospiro-[indole-3, Herrera’s group [61]. From ten different chiral organocatalysts, β–isocupreidine was chosen as the most 40-(10,40-dihydropyridine)] derivatives—spirocyclic 1,4-DHPs 17 having highly substituted DHP ring.enantioselective. Table8 summarizes Table 7 summari several characteristiczes some characteristic examples examples [62]. .
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Catalysts 2020, 10, 1019 11 of 21 CatalystsTable 2020, 10 7., x FORβ-isocupreidine PEER REVIEW catalysed synthesis of highly functionalised 1-benzamido1,4- 11 of 22 dihydropyridine derivatives 15 [61]. Table 7. β-isocupreidine catalysed synthesis of highly functionalised 1-benzamido1,4- Table 7. β-isocupreidine catalysed synthesis of highly functionalised 1-benzamido1,4-dihydropyridine dihydropyridine derivatives 15 [61]. derivatives 15 [61].
15 Entry Solvent Yield, (%) eep, (%) 1 MeCN 56 10 2 AcOEt 54 15 1540 EntryEntry SolventSolvent 3 DCM Yield,35 (%) Rac.eep, (%) Yield, (%) eep, (%) 14 CHClMeCN3 4956 3310 1 MeCN 56 10 5 Et2O 39 40 22 AcOEt AcOEt 54 5440 40 6 MeOH 77 Rac 33 DCM DCM 35 35Rac. Rac. 7 THF 48 52 44 CHCl CHCl3 3 49 4933 33 55 Et2 EtO2 O39 3940 40 In 2015, Herrera’s group reported the synthesis of enantioenriched 2-oxospiro-[indole-3,4′-(1′,4′- 66 MeOH MeOH 77 77Rac Rac dihydropyridine)] derivatives—spirocyclic 1,4-DHPs 17 having highly substituted DHP ring. Table 77 THF THF 48 4852 52 8 summarizes several characteristic examples [62].
In 2015, Herrera’s group reported the synthesis of enantioenriched 2-oxospiro-[indole-3,4′-(1′,4′- TableTable 8. Takemoto’s8. Takemoto’s thiourea thiourea catalysedcatalysed synthesis synthesis of of spirocyclic1,4 spirocyclic1,4-DHPs-DHPs 17 [62]17. [62]. dihydropyridine)] derivatives—spirocyclic 1,4-DHPs 17 having highly substituted DHP ring. Table 8 summarizes several characteristic examples [62].
Table 8. Takemoto’s thiourea catalysed synthesis of spirocyclic1,4-DHPs 17 [62].
17 Entry Catalyst Loading (mol %) R Ar R1 Yield, (%) eep, (%)
1 30 CH2C6H5 2,4-(H3CO)2-C6H3 H 30 42 2 20 CH2C6H5 2,4-(H3CO)2-C6H3 H 25 23 3 10 CH2C6H5 2,4-(H3CO)2-C6H3 H 29 11 4 30 CH2C6H5 2,4-(H3CO)2-C6H3 5-Br 82 48 5 30 CH2C6H5 2,4-(H3CO)2-C6H3 5,7-diCH3 40 30 6 30 CH2C6H5 2,4-(H3CO)2-C6H3 5-Cl 71 30 7 30 CH2C6H5 2,4-(H3CO)2-C6H3 5-NO2 65 58 8 30 CH2C6H5 3-H3CO-C6H4 H 65 30 9 30 Allyl 3-H3CO-C6H4 H 61 30 10 30 C2H5 3-H3CO-C6H4 H 49 32
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Catalyst 17 Entry Loading R Ar R1 Yield, (%) (mol %) eep, (%) 1 30 CH2C6H5 2,4-(H3CO)2-C6H3 H 30 42 2 20 CH2C6H5 2,4-(H3CO)2-C6H3 H 25 23 3 10 CH2C6H5 2,4-(H3CO)2-C6H3 H 29 11 4 30 CH2C6H5 2,4-(H3CO)2-C6H3 5-Br 82 48 5 30 CH2C6H5 2,4-(H3CO)2-C6H3 5,7-diCH3 40 30 6 30 CH2C6H5 2,4-(H3CO)2-C6H3 5-Cl 71 30 7 30 CH2C6H5 2,4-(H3CO)2-C6H3 5-NO2 65 58 8 30 CH2C6H5 3-H3CO-C6H4 H 65 30 9 30 Allyl 3-H3CO-C6H4 H 61 30 10 30 C2H5 3-H3CO-C6H4 H 49 32
CatalystsThe reaction2020, 10, 1019of an enamines 15 with isatylidene malononitrile derivatives 16 was studied12 of 21in the presence of various organocatalysts. It was found that only Takemoto’s thiourea [63] catalysed the reaction The with reaction low degree of an enamines of enantioselectivity.15 with isatylidene Additional malononitrile screening derivatives of the16 was catalyst studied loading, in the the variationpresence of the of varioussubstituents organocatalysts. of starting Itenamine was found 15 thatand onlyisatylidene Takemoto’s malononitrile thiourea [63 16], catalysed and the r theeaction conditionsreaction led with to low some degree improvement of enantioselectivity. of enantioselectivity Additional screening of the of reaction the catalyst from loading, 44% the to variation58% ee. Not lookingof the at substituents low enantioselectivity of starting enamine, this is15 oneand isatylideneof very few malononitrile examples of16 ,synthesis and the reaction of fully conditions substituted 1,4-DHPled to derivatives. some improvement of enantioselectivity of the reaction from 44% to 58% ee. Not looking at low enantioselectivity,In 2007, by Renaud this group is one of was very reported few examples mechanistically of synthesis ofdifferent fully substituted chiral Brønsted 1,4-DHP acids derivatives. catalysed 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 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 reaction of N-benzyl β-aminobutenoate 18 with cinnamaldehyde 6 have shown that BINOL-derived phosphoricphosphoric acid acid derivatives derivatives proved proved to to be be capable capable ofof catalysingcatalysing the the reaction reaction in upin up to 50%to 50% enantiomeric enantiomeric excessexcess at -7°C at 7in CDCM in DCM (Scheme (Scheme 3).3 ). − ◦
SchemeScheme 3. Brønsted 3. Brønsted acids acids catalysed catalysed enantioselective enantioselective synthesissynthesis of of 1,2,3,4 1,2,3,4 substituted substituted 1,4-DHPs 1,4-DHPs19 [ 6419]. [64]. The extension of the above method to the three-component reaction was performed by Gong groupThe extension in 2008 utilising of the chiral above Brønsted method acid to catalysis the three (Scheme-component4)[ 65] The reaction ability towas alter performed the substituents by Gong groupat the in positions 2008 utilising 1, 3, and chiral 4 of 1,4-DHP Brønsted ring acid was also catalysis demonstrated. (Scheme 4) [65] The ability to alter the substituentsThe mechanismat the positions of the reaction1, 3, and involves 4 of 1,4 the-DHP formation ring was of an alsoα,β -unsaturateddemonstrated. 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.
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Catalysts 2020, 10, 1019 13 of 21 Catalysts 2020, 10, x FOR PEER REVIEW 13 of 22
Scheme 4. Chiral BINOL-derived phosphoric acid catalysed synthesis of 1,4-DHPs 8 [65].
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 Scheme 4. Chiral BINOL BINOL-derived-derived phosphoric acid catalysed synthesis of 1,4 1,4-DHPs-DHPs 8 [[65]65].. limitation of these methods is the inability to introduce the substituents at 5- and 6- position of 1,4- DHPIn 8 ring. 2009, Gestwicki demonstrated the first examples of fully substituted bicyclic DHP 23 The mechanism of the reaction involves the formation of an α,β-unsaturated imine that is synthesisIn 2009 [66, Gestwicki]. A good demonstrated substrate scope the first was examples demonstrated of fully forsubstituted aromatic bicyclic aldehydes DHP 23 (Scheme synthesis5). activated through hydrogen bonding interaction with the hydroxyl group of the organocatalyst and On the other hand, the reactions are limited to the use as β-dicarbonyl components dimedone undergoes[66]. A good nucleophilic substrate scopeaddition was of demonstrated β-ketoester. A for w idearomatic range aldehydesof cinnamaldehydes (Scheme 5). was On employed the other, 20handand, the ethyl reactions acetoacetate are limited21. to When the use R as of β aldehyde-dicarbonyl component components22 dimedoneis C H , 2,4-Cl20 and-C ethylH , but contrary to the Jorgensen method the use of 2-hexenal led to a low enantioinduction.6 5 A 2serious6 3 4-Br-CacetoacetateH , 3,5-(CH 21. WhenO) R-C ofH aldehyde, 2-CF -C componentH , 2,5-F -C22 His C, 4-C(CH6H5, 2,4-Cl) -C2-CH6H3,, 2-naphthyl,4-Br-C6H4, 3,5 2-CN-C-(CH3O)H2-, limitation6 4 of these methods3 2 6 is3 the inability3 6 4 to introduce2 6 3the substituents3 3 6 at4 5- and 6- position of 61,44- 3,4-(OH)6 3 -C3 H6 ,4 2-Cl-C2 H6, 4-C3 H -C 3H3 high6 4 enantioselectivity of6 organocatalytic4 2 reaction6 3 ee 6> 95%4 DHPC H , 82 -ring.CF2 -6 C H3 , 2,5-F6-C4H , 46-C(CH5 6 ) -4C H , 2-naphthyl, 2-CN-C H , 3,4-(OH) -C H , 2-Cl-C H , 4- canC6H be5In-C reached.62009H4 high, Gestwicki enantioselectivity demonstrated of organocatalytic the first examples reaction of fully ee substituted > 95% can bebicyclic reached. 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.
Scheme 5. Chiral BINOL BINOL-derived-derived phosphoric acid catalysed synthesis of bicyclic 1,4-DHP1,4-DHP 23 [6666]]..
In 2015, 2015, ZhangZhang et et al. al. reported reported H8H8-BINOL-type-BINOL-type cchiralhiral imidodiphosphoric acid promoted enantioselective cyclisation cyclisation of of β,γβ,γ--unsaturatedunsaturated αα-ketoesters-ketoesters 2525, ,arylamines arylamines 2424, and, and acetylacetone acetylacetone 7 7(Table(Table 9).9). The The change change of of BINOL BINOL scaffold sca ffold to to H8 H8-BINOL-BINOL gave gave better better yields yields and enantioselectivities. Among the H8-BINOL-basedH8-BINOL-based imidodiphosphoric acids, the derivative that was substitutedsubstituted with four Scheme 5. Chiral BINOL-derived phosphoric acid catalysed synthesis of bicyclic 1,4-DHP 23 [66]. 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 In 2015, Zhang et al. reported H8-BINOL-type chiral imidodiphosphoric acid promoted selectivities (75–97% ee) [67]. Table9 provides some representative examples. 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
Catalysts 2020, 10, x FOR PEER REVIEW 14 of 22 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 Catalystsselectivities2020, 10(75, 1019–97% ee) [67]. Table 9 provides some representative examples. 14 of 21
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].
26 26 1 2 3 EntryEntry R R1 R R2 R3 Yield,Yield, (%) (%) ee, (%) ee, (%)
11 4-NO4-NO2 2 3-OCH3-OCH3 3 CH33 54 5488 88 22 4-NO4-NO2 2 3-OCH3-OCH3 3 CC2HH55 61 6185 85 33 4-NO4-NO2 2 3-OCH3-OCH3 3 CH(CHCH(CH3))22 54 5490 90 44 4-NO4-NO2 2 3-OCH3-OCH3 3 CHCH22C66HH5 5 51 5189 89 55 4-NO4-NO2 2 3-Cl3-Cl CH(CHCH(CH3))22 53 5391 91 66 4-NO4-NO2 2 3-Br3-Br CH(CHCH(CH3))22 54 5488 88 77 4-NO4-NO2 2 3-F3-F CH(CHCH(CH3))22 53 5387 87 88 4-NO4-NO2 2 3-CH3-CH3 3 CH(CHCH(CH3))22 55 5583 83 99 4-Br4-Br 3-Cl3-Cl CH(CHCH(CH3))22 54 5492 92 1010 4-CN4-CN 3-Cl3-Cl CH(CHCH(CH3))22 41 4193 93 1111 4-F4-F 3-Br3-Br CC2HH55 51 5194 94 1212 2,3,4-triCl2,3,4-triCl 3-Cl3-Cl CH33 55 5595 95
In 2015, Wang’s group has developed a trio catalytic system comprised of arylamine 24, BINOL- derivedIn 2015,phosphoric Wang’s acid group and hard has metal developed Lewis aacid trio (yttrium(III) catalytic system trifluoromethanesulfonate, comprised of arylamine Y(OTf)243), (TableBINOL-derived 10) [68]. phosphoricThe combined acid catalyst and hard was metal capable Lewis of acid promot (yttrium(III)ing an aza trifluoromethanesulfonate,-Diels-Alder reaction of Y(OTf)various3 ) substituted (Table 10)[ 68 cinnamaldehydes]. The combined catalyst28, cyclic was ketones capable 27 of, promoting and arylamines an aza-Diels-Alder 24. Binary acid reaction (R)- TRIP/Y(OTf)of various substituted3 catalysed reaction cinnamaldehydes allowed the28 formation, cyclic ketones of fused27 DHPs, and 26 arylamines in 59–84%24 yiel.ds Binary and good acid (toR )-TRIP excellent/Y(OTf) enantioselectivities3 catalysed reaction in allowed most of the the formation cases (91 of– fused99% ee). DHPs Table26 in 10 59–84% provides yields some and representativegood to excellent examples enantioselectivities. in most of the cases (91–99% ee). Table 10 provides some representative examples.
Catalysts 20202020, 10, 1019x FOR PEER REVIEW 15 of 22 21
Table 10. Chiral BINOL-derived phosphoric acid, hard metal Lewis acid, and amine catalysed Table 10. Chiral BINOL-derived phosphoric acid, hard metal Lewis acid, and amine catalysed synthesis synthesis of 1,4-DHP 29 [68]. of 1,4-DHP 29 [68].
29 29 Entry SolventEntry SolventR1 R1 ArAr X X t, h t, h Yield,Yield, (%) (%) ee p, (%)eep, (%) 1 toluene 4-Cl C6H5 CH2 48 38 92 1 toluene 4-Cl C6H5 CH2 48 38 92 2 MeCN2 MeCN4-Cl 4-ClC C66HH55 CH2CH2 4848 7070 35 35 3 Neat3 Neat4-Cl 4-ClC C66HH55 CH2CH2 4848 1515 80 80 4 MeOH 4-Cl C H CH 48 67 93 4 MeOH 4-Cl C66H55 2CH2 48 67 93 5 1,4-dioxane 4-Cl C6H5 CH2 48 44 43 5 1,4-dioxane 4-Cl C6H5 CH2 48 44 43 6 H2O 4-Cl C6H5 CH2 48 50 99 6 H2O 4-Cl C6H5 CH2 48 50 99 7 CHCl3 4-Cl C6H5 CH2 24 87 69 7 CHCl83 acetone4-Cl 4-ClC C66HH55 CH2CH2 2424 7887 88 69 8 acetone9 DCM4-Cl 4-ClC C66HH55 CH2CH2 2424 8178 98 88 10 DCE * 4-Cl C H CH 24 78 98 9 DCM 4-Cl C66H55 2CH2 24 81 98 11 DCE 4-CH3O C6H5 CH2 18 79 99 10 DCE * 4-Cl C6H5 CH2 24 78 98 12 DCE H C6H5 CH2 24 72 94 11 DCE 4-CH3O C6H5 CH2 18 79 99 13 DCE 4-Br C6H5 CH2 24 71 92 12 DCE14 DCEH 3-ClC C66HH55 CH2CH2 3024 6672 99 94 13 DCE15 DCE4-Br 4-Cl 4-CHC6H3O-C5 6H4 CH2CH2 2424 7371 98 92 16 DCE 4-Cl 4-Cl-C H CH 24 71 99 14 DCE 3-Cl C6H65 4 2CH2 30 66 99 17 DCE 4-Cl 4-Br-C6H4 CH2 24 67 94 15 DCE 4-Cl 4-CH3O-C6H4 CH2 24 73 98 18 DCE 4-Cl Naphthyl CH2 40 59 94 6 4 2 16 DCE19 DCE4-Cl 4-Cl 44-NO-Cl-C2-CH6H 4 CH2CH 1624 8471 98 99 17 DCE20 DCE 4-Cl 4-CH3O 4-BrC-6CH65H4 -CH2 2024 6867 91 94 18 DCE21 DCE4-Cl 4-ClNaphthyl C6H5 -CH2 2440 6059 94 94 22 DCE 4-Cl 4-NO -C H - 24 63 98 19 DCE 4-Cl 4-NO2-2C6H6 4 4 CH2 16 84 98 23 DCE 4-Cl 4-CH3O-C6H4 - 24 68 98 20 DCE 4-CH3O C6H5 - 20 68 91 24 DCE 4-CH3O 4-NO2-C6H4 S 30 73 98 6 5 21 DCE25 DCE 4-Cl 4-CH3O 4-NOC H2-C 6H4 O- 3024 7060 95 94 22 DCE 4-Cl *4 1,2-dichloroethane-NO2-C6H4 (DCE).- 24 63 98 23 DCE 4-Cl 4-CH3O-C6H4 - 24 68 98 24 The asymmetricDCE synthesis4-CH3O of fused4 derivatives—chiral-NO2-C6H4 N-unsubstitutedS 30 4-isoxazolyl-quinolones73 98 3125—was performedDCE applying4-CH the3O methodology4-NO2-C elaborated6H4 byO Gestwicki, 30 from the isoxazole70 aldehydes95 30, dimedone 20, and ethyl acetoacetate* 1,221-usingdichloroethane BINOL phosphate(DCE) (R)-TRIP, as pioneered by Gong in moderate yields (Table 11)[69]. According to the provided chromatograms, the authors proposed that The asymmetric synthesis of fused derivatives—chiral N-unsubstituted 4-isoxazolyl-quinolones enantiomeric excess for obtained compounds was more than 90%. 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%.
Table 11. (R)-TRIP catalysed synthesis of fused 1,4-DHPs 31 [69].
Catalysts 2020, 10, 1019 16 of 21
Catalysts 2020, 10, x FOR PEER REVIEW 16 of 22 Catalysts 2020, 10, x FOR PEERTable REVIEW 11. (R)-TRIP catalysed synthesis of fused 1,4-DHPs 31 [69]. 16 of 22
31 31 Entry Ar 31 Entry Ar Yield, (%) Yield,Yield, (%)(%) 11 C6H C65H 5 26 26 1 C6H5 26 2 2-Br-C H 64 2 2-Br-C6H64 4 64 2 2-Br-C6H4 64 3 3-Br-C6H4 60 3 3-Br-C6H4 60 43 3-Br 4-Br-C-C6H64H 4 60 65 6 4 4 4-Br-C6H4 6565
NataleNatale group groupgroup in in susu supplementingpplementingpplementing materials materials of ofthe the article article [69][69] [ 69 alsoalso] also providedprovided provided BINOL BINOL BINOL phosphate phosphate phosphate ( R(R)-)- (TRIPRTRIP)-TRIP catalysed catalysed catalysed synthesissynthesis synthesis ofof 1,4 of1,4 1,4-DHP-3,5-dicarboxylate--DHPDHP-3,5-dicarboxylate 333333 withwithwith ((SS ())S--absolute)-absoluteabsolute configurationconfiguration configuration in in in 21% 21% 21% of of yieldyield from from from pre-formed pre pre--formedformed isoxazolylidene isoxazolylidisoxazolylidene acetoacetate acetoacetate32, ethyl3232,, ethyl ethyl acetoacetate acetoacetate acetoacetate21, and 2121 a, , source andand aa of source source ammonia. of of Thisammonia.ammonia. is the This Thisfirst is reported is the the first first example reported reported of example enantioselective of enantioselective organocatalytic organocatalytic organocatalytic synthesis of synthesis synthesis the sca ff ofold of the the of scaffoldmanyscaffold pharmaceutically of of many many pharmaceutically pharmaceutically relevant 1,4-DHPs: relevant 4-substituted 1,4-DHPs: 2,6-dimethyl-1,4-DHP-3,5-dicarboxylate 44--substitutedsubstituted 2,6 2,6--dimethyldimethyl-1,4-1,4-DHP-DHP-3,5-3,533- -. Thedicarboxylatedicarboxylate authors proposed 33 33.. TheThe authorsauthors that the proposedproposed enantiomeric that the excess enanti ofomeric the obtained excessexcess compoundofof thethe obtained obtained was compound morecompound than was 90%,was moreasmore in thethan than above 90% 90%,cases , asas inin (Schemethethe aboveabove6). casescases (Scheme 6).
Scheme 6. (R)-TRIP catalysed synthesis of 1,4-DHP-3,5-dicarboxylate 33 [69]. SchemeScheme 6.6. ((RR))--TRIPTRIP catalysed synthesis of 1,41,4--DHPDHP--3,53,5--dicarboxylatedicarboxylate 33 33 [ 69][69]. . 2.5. Organocatalytic Desymmetrisation of Prochiral 1,4-Dihydropyridine-3,5-dicarbaldehydes 2.2.55. .Organocatalytic Organocatalytic DDesymmetrisationesymmetrisation of Prochiral 1,4-Dihydropyridineihydropyridine--3,53,5--dicarbaldedicarbaldehydeshydes In 2019, enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes In 2019, enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5- 34 catalysedIn 2019 by, chiralenantioselective N-heterocyclic desymmetrisation carbenes (NHC catalyst), of prochiral an external oxidant,1,4-dihydropyridine3,5 and an alcohol- dicarbaldehydes 34 catalysed by chiral N-heterocyclic carbenes (NHC catalyst), an external oxidant, dicarbaldehydesnucleophile leading 34 catalysed to the highly by chiral enantioselective N-heterocyclic formation carbenes of (NHC 5-formyl-1,4-DHP-3-carboxylates catalyst), an external oxidant37, and an alcohol nucleophile leading to the highly enantioselective formation of 5-formyl-1,4-DHP-3- andhas beenan alcohol reported nucleophile [70]. This leading approach to isthe based highly on enantioselective organocatalytic enantioselectiveformation of 5-formyl desymmetrisation-1,4-DHP-3- carboxylates 37 has been reported [70]. This approach is based on organocatalytic enantioselective carboxylatesof prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 37 has been reported [70]. This approach38 butis based not on on the organocatalytic direct construction enantioselective of the chiral desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 38 but not on the direct desymmetrisationDHP core. After the of search prochiral for 1,4the-dihydropyridine3,5 best reaction conditions,-dicarbaldehydes the following 38 systembut not was on selected the direct as construction of the chiral DHP core. After the search for the best reaction conditions, the following 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 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 oxidant (1 equiv) in the presence of aminoindanol derived pre-catalyst 36, which showed a better
Catalysts 2020, 10, 1019 17 of 21
Catalysts 2020, 10, x FOR PEER REVIEW 17 of 22 an optimal: Desymmetrisation of 3,5-dicarbaldehydes was quinone 35 as oxidant (1 equiv) in the enantioselectivity, and base (N,N-diisopropylethylamine, DIPEA), and ethanol as the nucleophile presence of aminoindanol derived pre-catalyst 36, which showed a better enantioselectivity, and base (Table 12, entry 10). (N,N-diisopropylethylamine, DIPEA), and ethanol as the nucleophile (Table 12, entry 10). Table 12. NHC-catalysed desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes 34 Table[70] 12.. NHC-catalysed desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes 34 [70].
EntryEntry SolventSolvent BaseBase (mol (mol %) %) T,T,◦ °CC t, t,hh 37 Yield 37 Yield (%) (%) 38 Yield 38 (%) Yield (%)37 ee (%) 37 ee (%) 11 DCMDCM DIPEADIPEA (25) (25) r.t.r.t. 72 72 29 29- -82 82 2 DCM DIPEA (100) r.t. 72 36 - 82 2 DCM DIPEA (100) r.t. 72 36 - 82 3 THF DIPEA (100) r.t. 72 31 12 3 43 MeCNTHF DIPEADIPEA (100) (100) r.t.r.t. 72 72 31 4912 183 84 54 DCEMeCN DIPEADIPEA (100) (100) r.t.r.t. 72 72 49 6518 1084 84 65 CHClDCE3 DIPEADIPEA (100) (100) r.t.r.t. 72 72 65 6710 1384 90 7 CHCl KHDMS (25) r.t. 72 53 13 71 6 CHCl3 3 DIPEA (100) r.t. 72 67 13 90 8 CHCl3 K3PO4 (25) r.t. 72 74 11 82 7 CHCl3 KHDMS (25) r.t. 72 53 13 71 9 CHCl3 TEA (25) r.t. 72 52 10 88 8 CHCl3 K3PO4 (25) r.t. 72 74 11 82 10 CHCl3 DIPEA (100) 40 16 70 7 91 9 CHCl3 TEA (25) r.t. 72 52 10 88 10 CHCl3 DIPEA (100) 40 16 70 7 91 The use of other bases potassium triethylamine (TEA), bis(trimethylsilyl)amide (KHMDS) and K3PO4 Theled touse lover of other enantioselectivity. bases potassium Chloroformtriethylamine was (TEA), selected bis(trimethylsilyl)amide as the best for these (KHMDS) reactions and and solventsK3PO4 suchled to as lover dicholoromethane, enantioselectivity. dichloroethane Chloroform andwas acetonitrile selected as werethe best found for lessthese suitable. reactions DHP and ring oxidationsolvents was such not as observeddicholoromethane, under these dichloroethane conditions. Theand resultingacetonitrile 5-formyl-1,4-DHP-3-carboxylate were found less suitable. DHP 37 allowsring access oxidation to the was class not of pharmaceuticallyobserved under these relevant conditions. 1,4-DHP-3,5-dicarboxylates. 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 3. TheConclusions resolution of diastereomeric 1,4-DHP salts derived from chiral acids or bases, enzyme catalysedThe kinetic resolution resolution, of diastereomeric or asymmetrisation 1,4-DHP of salts enzymatically derived from labile chiral esters acids activated or bases, spacer enzyme groups, separationcatalysed techniques, kinetic resolution such, as or preparative asymmetrisation chiral of chromatography enzymatically labile on stationary esters activated phases spacer are the mostgroups, widely separation used techniques techniques, for such the as obtaining preparative of chiral 1,4-DHP chromatography enantiomers. on Thesestationary approaches phases are have beenthe studiedmost widely well used in detail techniques and theyfor the are obtaining relatively of 1,4 well-DHP established. enantiomers. The These catalytic approaches asymmetric have approachbeen studied holds well the in greatest detail andpromise they inare delivering relatively well the mostestablished. practical The and catalytic widely asymmetric applicable methods.approach Recently, holds the substantialgreatest promise progress in delivering has been the made most practical in this field and widely and several applicable enantioselective methods. organocatalyticRecently, substantial methods progress were developed has been for made the in direct this construction field and seve ofral the enantioselective chiral DHP core. organocatalytic methods were developed for the direct construction of the chiral DHP core. However, 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 Catalysts 2020, 10, 1019 18 of 21 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.
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