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-NO
2-C
6H
4-, 2-Cl-5-NO
2-C
6H
3-, 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-C
6H
4- 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-CH
3O-C
6H
4- 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 (R
1 = 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 = CH
3) 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 C
6H
5, 2,4-Cl
2-C
6H
3, 4-Br-C
6H
4, 3,5-(CH
3O)
2-C
6H
3, 2-CF
3-C
6H
4, 2,5-F
2-C
6H
3, 4-C(CH
3)
3-C
6H
4, 2-naphthyl, 2-CN-C
6H
4, 3,4-(OH)
2-C
6H
3, 2-Cl-C
6H
4, 4-C
6H
5-C
6H
4 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).