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

Abstract

The purpose of this review is to highlight recent developments in the synthesis of chiral 1,4-dihydropyridines and their fused analogues. 1,4-Dihydropyridines are among the most active calcium antagonists that are used for the treatment of hypertension. Enantiomers of unsymmetrical 1,4-dihydropyridines often show different biological activities and may have even an opposite action profile. Hantzsch synthesis usually produces racemic mixtures of unsymmetrical 1,4-dihydropyridines. Therefore, the development of stereoselective synthesis of 1,4-dihydropyridines is one of the priorities of medicinal chemistry. Over the years, numerous methodologies have been developed for the production of enantiopure 1,4-dihydropyridines, such as stereoselective synthesis using chiral auxiliaries and chiral cyclocondensation partners, chromatographical methods, resolution of diastereomeric 1,4-dihydropyridine salts, enzyme catalysed kinetic resolution, or asymmetrisation of ester groups of 1,4-dihydropyridines. These approaches have been studied in detail and are relatively well established. The catalytic asymmetric approach holds the greatest promise in delivering the most practical and widely applicable methods. Substantial progress has been made toward the development of enantioselective organocatalytic methods for the construction of the chiral dihydropyridines. However, most of them do not provide a convenient way to pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates. Organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes also has great promise in the synthesis of pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates.

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. Resolution of racemic 2,6-dimethyl-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. *
1	cinchonidine	DMF-H2O (4:1)	32	99.5	S
2	cinchonidine	DMF-H2O (8:5)	41	>99.5	S
3	cinchonidine	DMF-H2O (1:1)	44	97.8	S
4	quinidine	DMF-H2O (8:5)	43	>99.5	R
5	quinidine	DMF-H2O (1:1)	46	96.6	R

* absolute configuration.

) [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. Lipase-catalysed kinetic resolution of racemic [(2-methylpropanoyl)oxy]methyl ester 1,4-DHP-3-carboxylates rac-2 [54,55].

Entry	Ar	Lipase	Solvent	t *, h	Conv. †, (%)	2 Abs. conf. /ees, (%)	3 Abs. conf. /eep, (%)	E-value ‡
1	2-NO2-C6H4	CRL	EtOAc	0.7	47	S/84	R/95	103
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	S/98	>200
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
6	3-CH3O-C6H4	CRL	EtOAc	10	39	S/40	R/62	6
7	4-Br-C6H4	Cal-B	MTBE	6	47	S/75	R/85	27
8	4-Br-C6H4	Cal-B	EtOAc	25	43	S/67	R/89	34
9	3-CH3O-C6H4	Cal-B	MTBE	9	41	S/62	R/88	29
10	3-CH3O-C6H4	Cal-B	EtOAc	21	34	S/49	R/95	63

* time; ^† conversion; ^‡ enantiomeric ratio.

). 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. Enzyme-catalysed kinetic resolution of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines rac-4 [56].

Entry	Compound	Enzyme	Temp *, °C	t, h	(-)-4 Yield, (%)	(-)-4 ees, (%)	(-)-3 Yield, (%)	Es-value †	Abs. conf.
1	a	Cal-B	25	48	49	82	47	22	Not known
2	b	Cal-B	25	165	46	80	48	20
3	c	Cal-B	25	51	46	77	47	16
4	d	Cal-B	25	264	46	65	46	8
5	a	Cal-B	45	18	49	95	47	104
6	b	Cal-B	45	48	46	92	48	65
7	c	Cal-B	45	26	46	99	46	>200
8	d	Cal-B	45	168	46	86	46	29
9	a	Acylase	25	96	47	52	48	5
10	b	Acylase	25	310	45	89	48	44
11	c	Acylase	25	100	48	38	47	3
12	d	Acylase	25	336	45	48	48	4

* temperature; ^† enantiomeric ratio (E_s-value) calculated according to Chen [57].

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. Some characteristic examples of iminium catalysed 1,4-DHPs 8 synthesis [58].

Entry	R1	R2	R3	Temp, °C	t1, h	t2, h	8
							Yield, (%)	ee, (%)
1	C2H5	CH3	C6H5	rt	18	1	55	90
2	Hex-3-en-yl	CH3	C6H5	rt	18	1	45	92
3	COOC2H5	CH3	C6H5	rt	18	24	31	88
4	(CH2)2OTBDMS	CH3	C6H5	rt	18	1	33	95
5	Furyl	CH3	C6H5	4	18	24	35	64
6	CH(CH3)2	CH3	C6H5	rt	18	1	33	92
7	C2H5	OCH3	C6H5	rt	18	1	41	91
8	CH3	OCH3	C6H5	4	18	24	39	82
9	C6H5	CH3	C6H5	4	72	1	60	38
10	C2H5	CH3	CH(CH3)2	rt	18	1	39	90
11	C2H5	CH3	4-Br-C6H4	rt	18	1	48	92

, 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. Organocatalytic reaction β-enaminones and β-enamino esters 9 with α,β-unsaturated aldehydes 6 [59].

Entry	R1	R2	R3	R4	t, h	10
						Yield, (%)	Abs. conf. /ee, (%)
1	C6H5	n-C4H9	H	C6H5	19	79	S/76
2	C6H5	n-C4H9	H	CH2C6H5	24	54	S/87
3	C6H5	n-C4H9	H	C(CH3)3	26	72	S/89
4	C6H5	n-C4H9	H	CH(CH3)2	20	75	S/93
5	4-NO2-C6H4	n-C4H9	H	CH(CH3)2	3	83	S/89
6	4-NO2-C6H4	OC2H5	CH3	CH(CH3)2	4	45	S/84
7	4-NO2-C6H4	OC2H5	CH3	CH2C6H5	4	70	S/89
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
10	n-C4H9	OC2H5	CH3	CH2C6H5	4	62	R/71

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. Cinchona-alkaloid catalysed synthesis of enantiomerically enriched 1,4-DHPs 13 [60].

Entry	Catalyst	R	Solvent	Temp, °C	t, h	13
						Yield, (%)	eep, (%)	Abs. conf.
1	(DHQ)2Phal	CH3	toluene/AcOEt (9:1)	10	72	91	66	Not known
2	(DHQ)2AQN	CH3	toluene/AcOEt (9:1)	10	72	22	54
3	(DHQD)2Phal	CH3	toluene/AcOEt (9:1)	10	72	47	64
4	(DHQD)2Pyr	CH3	toluene/AcOEt (9:1)	10	72	13	54
5	(DHQD)2AQN	CH3	toluene/AcOEt (9:1)	10	72	23	68
6	(DHQ)2Pyr	CH3	toluene/AcOEt (9:1)	10	72	81	80
7	(DHQ)2Pyr	CH3	toluene	10	72	88	82
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	(DHQ)2Pyr	C2H5	toluene/AcOEt (9:1)	10	72	97	76
11	(DHQ)2Pyr	C2H5	toluene/AcOEt (9:1)	-18	72	<5	90

) [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. β-isocupreidine catalysed synthesis of highly functionalised 1-benzamido1,4-dihydropyridine derivatives 15 [61].

Entry	Solvent	15
		Yield, (%)	eep, (%)
1	MeCN	56	10
2	AcOEt	54	40
3	DCM	35	Rac.
4	CHCl3	49	33
5	Et2O	39	40
6	MeOH	77	Rac
7	THF	48	52

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. Takemoto’s thiourea catalysed synthesis of spirocyclic1,4-DHPs 17 [62].

Entry	Catalyst Loading (mol %)	R	Ar	R1	17 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

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. Chiral imidodiphosphoric acid catalysed synthesis of 1,4-DHP 26 [67].

Entry	R1	R2	R3	26
				Yield, (%)	ee, (%)
1	4-NO2	3-OCH3	CH3	54	88
2	4-NO2	3-OCH3	C2H5	61	85
3	4-NO2	3-OCH3	CH(CH3)2	54	90
4	4-NO2	3-OCH3	CH2C6H5	51	89
5	4-NO2	3-Cl	CH(CH3)2	53	91
6	4-NO2	3-Br	CH(CH3)2	54	88
7	4-NO2	3-F	CH(CH3)2	53	87
8	4-NO2	3-CH3	CH(CH3)2	55	83
9	4-Br	3-Cl	CH(CH3)2	54	92
10	4-CN	3-Cl	CH(CH3)2	41	93
11	4-F	3-Br	C2H5	51	94
12	2,3,4-triCl	3-Cl	CH3	55	95

). 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. Chiral BINOL-derived phosphoric acid, hard metal Lewis acid, and amine catalysed synthesis of 1,4-DHP 29 [68].

Entry	Solvent	R1	Ar	X	t, h	29
						Yield, (%)	eep, (%)
1	toluene	4-Cl	C6H5	CH2	48	38	92
2	MeCN	4-Cl	C6H5	CH2	48	70	35
3	Neat	4-Cl	C6H5	CH2	48	15	80
4	MeOH	4-Cl	C6H5	CH2	48	67	93
5	1,4-dioxane	4-Cl	C6H5	CH2	48	44	43
6	H2O	4-Cl	C6H5	CH2	48	50	99
7	CHCl3	4-Cl	C6H5	CH2	24	87	69
8	acetone	4-Cl	C6H5	CH2	24	78	88
9	DCM	4-Cl	C6H5	CH2	24	81	98
10	DCE *	4-Cl	C6H5	CH2	24	78	98
11	DCE	4-CH3O	C6H5	CH2	18	79	99
12	DCE	H	C6H5	CH2	24	72	94
13	DCE	4-Br	C6H5	CH2	24	71	92
14	DCE	3-Cl	C6H5	CH2	30	66	99
15	DCE	4-Cl	4-CH3O-C6H4	CH2	24	73	98
16	DCE	4-Cl	4-Cl-C6H4	CH2	24	71	99
17	DCE	4-Cl	4-Br-C6H4	CH2	24	67	94
18	DCE	4-Cl	Naphthyl	CH2	40	59	94
19	DCE	4-Cl	4-NO2-C6H4	CH2	16	84	98
20	DCE	4-CH3O	C6H5	-	20	68	91
21	DCE	4-Cl	C6H5	-	24	60	94
22	DCE	4-Cl	4-NO2-C6H4	-	24	63	98
23	DCE	4-Cl	4-CH3O-C6H4	-	24	68	98
24	DCE	4-CH3O	4-NO2-C6H4	S	30	73	98
25	DCE	4-CH3O	4-NO2-C6H4	O	30	70	95

* 1,2-dichloroethane (DCE).

) [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. (R)-TRIP catalysed synthesis of fused 1,4-DHPs 31 [69].

Entry	Ar	31 Yield, (%)
1	C6H5	26
2	2-Br-C6H4	64
3	3-Br-C6H4	60
4	4-Br-C6H4	65

) [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. NHC-catalysed desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes 34 [70].

Entry	Solvent	Base (mol %)	T, °C	t, h	37 Yield (%)	38 Yield (%)	37 ee (%)
1	DCM	DIPEA (25)	r.t.	72	29	-	82
2	DCM	DIPEA (100)	r.t.	72	36	-	82
3	THF	DIPEA (100)	r.t.	72	31	12	3
4	MeCN	DIPEA (100)	r.t.	72	49	18	84
5	DCE	DIPEA (100)	r.t.	72	65	10	84
6	CHCl3	DIPEA (100)	r.t.	72	67	13	90
7	CHCl3	KHDMS (25)	r.t.	72	53	13	71
8	CHCl3	K3PO4 (25)	r.t.	72	74	11	82
9	CHCl3	TEA (25)	r.t.	72	52	10	88
10	CHCl3	DIPEA (100)	40	16	70	7	91

, 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.