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Article

Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity

by
Sarra Boudriga
1,*,
Saoussen Haddad
1,
Vikneswaran Murugaiyah
2,
Moheddine Askri
1,*,
Michael Knorr
3,*,
Carsten Strohmann
4 and
Christopher Golz
4
1
Department of Chemistry, Laboratory of Heterocyclic Chemistry Natural Product and Reactivity/CHPNR, Faculty of Science of Monastir, Monastir 5000, Tunisia
2
Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM 11800, Penang, Malaysia
3
Institut UTINAM-UMR CNRS 6213, Université Bourgogne Franche-Comté, 16 Route de Gray, 25030 Besançon, France
4
Technische Universität Dortmund, Anorganische Chemie Otto-Hahn-Straße 6, 44221 Dortmund, Germany
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(8), 1963; https://doi.org/10.3390/molecules25081963
Submission received: 3 April 2020 / Revised: 17 April 2020 / Accepted: 21 April 2020 / Published: 23 April 2020
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
Browse Figures
Versions Notes

Abstract

:
A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC50 of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes.

Graphical Abstract

1. Introduction

Spiroheterocyclic scaffolds have evoked immense research interest in the area of synthetic organic chemistry and medicinal chemistry [1,2] since they incorporate the ubiquitous substructures present in a broad range of bioactive natural isolates and synthetic compounds [3]. They possess a wide spectrum of useful properties, such as anti-cancer [4,5,6,7], acetylcholinesterase (AChE) inhibition [8,9], anti-proliferative [10,11], antimicrobial [12,13], photochromism [14,15,16], and hole-transporting abilities [17]. One major advantage that spiroheterocycles offer as core structures is their structural rigidity and inherent structural complexity and ability to project functionality in all three dimensions [2,18], which provides an enhanced affinity to biotargets [19,20,21]. Spiropyrrolidines bearing acenaphthylene-1,2-dione or oxindole moieties are particularly relevant spiroheterocycles owing key structural feature of a plethora of bioactive synthetic and natural compounds which often show diverse biological, therapeutic, and physical properties [7,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34] (Figure 1).
Among the typical synthetic strategies leading to these spiroheterocyclic scaffolds, the multicomponent 1,3-dipolar cycloaddition of electron-deficient exocyclic alkenes with azomethine ylides, generated in situ from α-aminoacids and 1,2-diketones, is the most widely reported one [35,36,37,38,39,40,41]. Its process simplicity combined with mild reaction conditions and atomic economy addresses several aspects required for combinatorial chemistry.
On the other hand, the succinimide moiety is a core constituent of numerous alkaloids including Hirsutellone A and B 7, drug molecules and various synthetic compounds possessing diverse bioactivities [42,43]. Some succinimide derivatives, for instance, are used as antimycobacterial for treatment of Mycobacteria infections, [44,45] to suppress cancer cell proliferation [46] and act as anticonvulsant agents [47,48] (Figure 2).
Therefore, spiro-compounds that merge spiropyrrolidine and succinimide frameworks (Figure 3) can show intriguing possibilities for biological or other pharmacological properties. Nevertheless, no rational strategy has been developed so far to construct such a motif.
Herein, and in continuation of our interest in azomethine ylide [3+2]-cycloaddition reaction and in the synthesis of novel spiroheterocycles [26,49,50,51,52,53], we report the synthesis of a novel series of dispiro[pyrrolidine-1-succinimide] derivatives by a one-pot three-component [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides 1, α-aminoacids 2 and the cyclic 1,2-diketones isatin 3a–b or acenaphtenequinone 3c. Furthermore, some selected heterocyclic compounds were screened in vitro to evaluate their cholinesterase inhibitory propensity.

2. Results and Discussion

2.1. Chemistry

The three-component 1,3-dipolar cycloaddition reaction of (E)-3-benzylidene-1-phenyl-succinimide 1a to azomethine ylide generated in situ from 2-phenylglycine 2 and the cyclic 1,2-diketone isatin 3a was chosen as a testing system to optimize the synthetic conditions (Scheme 1). The effects of solvents, reaction time, and temperature were examined, and the results are summarized in Table 1.
Unfortunately, dispiropyrrolidine 4a was obtained only in low yield when carrying out the reaction in water, toluene, or acetonitrile at room temperature (Table 1, entries 1–3). However, in refluxing acetonitrile, the [3+2]-cycloaddition proceeds smoothly affording the targeted dispiropyrrolidine with a significantly improved yield as a mixture of two regioisomers 4a and 5a in a 78:22 ratio (Table 1, entry 4). Next, the pilot reaction was examined in various protic solvents, such as EtOH, iPrOH, and MeOH (Table 1, entries 5–7). As shown in Table 1, methanol emerges as the solvent of choice, affording the targeted dispiropyrrolidines as a mixture of two regioisomers 4a and 5a, as single diastereoisomer, in good yield (77%) along with fairly high regiostereoselectivity (Table 1, entry 7). Then, we probed the reaction with MeOH/H2O mixtures both in a 1:1 and 2:1 ratio to further explore a more efficient and ecofriendly synthetic strategy (Table 1, entries 8–9). The most optimized reaction conditions for synthesizing dispiropyrrolidine 4a were achieved by using imide 1a (0.13 g, 0.5 mmol), 2-phenylglycine 2 (0.09 g, 1.2 eq.), and isatin 3a (0.073 g, 1 eq.) in MeOH/H2O (2:1 v/v, 10 mL) under reflux temperature for 6 h.
With the optimized synthetic protocol established (Table 1, entry 9), we extended the scope of this reaction to a wide range of α-arylidene-succinimides 1 bearing different substituents at the p-position of the aryl group or with heterocyclic group, as well as with various 1,2-diketones 3 (Scheme 2, Table 2).
As summarized in Table 2, enones 1 bearing an electron-neutral (H), electron-rich (e.g., 4-Me or 4-OMe) group or electron-withdrawing substituent (4-Cl or 3-Cl) at the phenyl ring reacted well yielding the dispiropyrrolidine derivatives 4a–4e in good to excellent yields (Table 2, entries 1–5). The reaction was even feasible with substrate 1 featuring pyridyl and furfuryl moieties, affording spiropyrrolidine 4f and 4g in excellent yields (Table 2, entries 6 and 7).
Pleasingly, also 5-chloroisatin 3b underwent the reaction smoothly providing the final products 4h–l in good yield along with high regioselectivities (Table 2, entries 8–12).
The generality of this protocol was further demonstrated by its compatibility with the cyclic 1,2-diketone acenaphthenequinone 3c (Table 2, entries 13–18). The reaction delivers the desired products 4m–r in excellent yields with a high level of regio- and diastereoselectivity.
In order to further demonstrate the synthetic utility of the multicomponent 1,3-dipolar cycloaddition procedure, we further examined the regio- and diastereoselectivity of the reaction of the dipolarophiles 1, the cyclic 1,2-diketones and sarcosine 6 as alternative α-aminoacid instead of 2-phenylglycine (Scheme 3).
The outcome indicated that this α-aminoacid is well compatible with this process, providing the cycloadducts 7a–h in excellent yields with high regio- and diastereoselectivity, irrespective of the electronic property and steric demand of the substituent on the aryl ring of the succinimides (Table 3, entries 1–8).

2.2. Spectroscopic and Crystallographic Characterization of the Isomeric Cycloadducts

The structure and the relative configuration of the isomeric spiropyrrolidines, which have been isolated as colorless solids, were deduced both from NMR spectroscopy and from X-ray structure determinations performed on cycloadducts 4b, 4m, 5m, and 7f. Relevant 1H and 13C chemical shifts of dispiropyrrolidines 4b, 5b, and 7f are shown in Figure 4, Figure 5 and Figure 6, respectively.
The 1H-NMR spectrum of 4b exhibits two mutually coupled doublets centered at δ 2.57 and 2.75 ppm corresponding to the diastereotopic 4″-CH2 groups, as well as two doublets at δ 5.55 and 4.30 ppm assigned to the pyrrolidine H-5 and H-4 protons, respectively. Their coupling constants of approximately 9.3 Hz indicate that these protons are in trans-relationship. The occurrence and the multiplicity of these signals clearly prove the regiochemistry of the cycloaddition reaction. In contrast, in the 1H-NMR spectrum of regioisomer 5b (Figure 5) the pyrrolidinyl protons H-5 and H-3 appear as two singlets resonating at δ 5.71 and 4.7 ppm, respectively. The 13C-NMR spectrum of the cycloadduct 4b displays two peaks at δ 66.3 and 60.3 ppm corresponding to C-5 and C-4, respectively. The two spirocarbons C-2 and C-3 resonate at δ 74.1 and 58.5 ppm, respectively. In addition, the presence of three carbonyl groups is confirmed by the occurrence of three low-field peaks at δ 173.4, 178.8 and 179 ppm.
The 1H-NMR spectrum of compounds 7f shows two characteristic singlets at δ 2.21 and 2.37 ppm corresponding to the -NCH3 and -CH3 protons, respectively. The presence of these signals proves the incorporation of both dipole and dipolarophile 1b. The triplet at δ 3.68 ppm and a multiplet at δ 4.62 ppm are assigned to the H-4 proton and the two geminal –CH2 protons of the spiropyrrolidine ring, respectively. Furthermore, the 13C-NMR spectrum of 7f displays two signals at δ 62.0 and 81.0 ppm attributed to two spiranic carbons C-3 and C-2, respectively. The resonances at 173.4, 178.6, 207.1 ppm are characteristic of the presence of three carbonyl groups belonging to the succinimide and acenaphthenequinone moieties.
The regio- and the stereochemical outcome of the cycloadditions were finally unambiguously ascertained by X-ray analysis of the crystal structure of cycloadducts 4b, 4m, 5m, and 7f, whose molecular structures are depicted in Figure 7, Figure 8, Figure 9 and Figure 10, respectively.
There are two independent molecules in the unit cell of 4b. In the packing, two molecules are associated pairwise through two intermolecular N-H····O hydrogen interactions (d(N ····O)2.8622(15) Å) with a N1-H1····O1’ angle of 169.3(18)°. As illustrated in Figure 7, a supramolecular six-membered cycle is thus formed. In contrast, no intermolecular N-H····O hydrogen bonding is present in the solid-state structure of derivative 4m (Figure 8).
A weak intermolecular N-H····O hydrogen interaction is present in the crystal structure of 5m, albeit with weaker bonding (d(N····O) 3.064(3), dN-H····O 2.230(2) Å) compared to 4b. Additionally, the O3 atom interacts weakly in an intramolecular manner with the H13 atom attached to C13 giving rise to a five-membered cycle (dC13-H····O13··2.391 Å) (Figure 9).
Elucidation of the four structures reveals (i) a cis-relationship between the carbonyl of the oxindole or acenaphthenequinone ring and the proton attached at C-10b0, and that (ii) the two carbonyl carbons of 1,2-diketone 3a–c moieties and the enone part are in trans-relationship. Thus, the cycloadducts are formed through an exo-approach between the (Z,E)-dipole and enones 1 as outlined in Scheme 4. The cycloaddition proceeds with high exo-diastereoselectivity affording in each case only one diastereomer.
On the basis of our experimental results and previous studies on the reaction mechanism [49,50,51,52,53], we propose in Scheme 4 a plausible mechanism for the regio- and stereoselective dispiropyrrolidine formation. The azomethine ylides d3 are generated in situ by decarboxylative condensation of cyclic 1,2-diketones 3 with aminoacids 2 or 6. The (Z,E)-dipole d3 then undergoes a 1,3-dipolar cycloaddition reaction with the dipolarophile 1 in a regio- and stereoselective manner (path A). The formation of the exo-regioisomer 5 via path A is more favorable because of the presence of a secondary orbital interaction (SOI) [49,54,55], which occurs between the oxygen atom of the carbonyl of the diketone and the carbon atom of the carbonyl of the dipolarophile as shown in Scheme 4. Conversely, the formation of the other regioisomers or diastereoisomers is less favorable because of steric or electronic repulsion in their corresponding transition states.

2.3. Cholinesterase Inhibitory Activities

Some selected compounds were evaluated for their cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The principal role of AChE is termination of transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter acetylcholine (ACh) [56]. The findings are summarized in Table 4. IC50 determination was carried out only for those compounds having more than 50% inhibition at 5 μg/mL. The experimental details are provided in the Supplementary Materials.
In general, all tested compounds showed higher inhibition on AChE than BChE at similar concentration. Of the 17 synthesized compounds tested, five compounds exhibit an inhibition of more than 50%. Their respective IC50 values on AChE were in the range of 11.42 to 22.21 µM. The most active compound was 4n, which was only five times less potent than the reference drug, galanthamine [57]. Compounds 4d and 4e bearing chloro substituents on the phenyl ring of the diketone 3a skeleton display higher AChE inhibition than the methyl or methoxy substituents at para-position.
In contrast, compound 7b incorporating an isatin 3a motif, the methyl substituent at para-position exerted a higher AChE inhibition than in the case of the p-methoxy or p-chloro-substituted analogues 7c and 7d. In the case of compounds in series 7e–h bearing an acenaphtoquinone 3c moiety, the unsubstituted compound 7e shows better AChE inhibition than the para-substituted derivatives (chloro, methyl, or methoxy).
According to a molecular docking modelling study, the most potent AChE inhibitor, namely 4n, is docked at the active site of the TcAChE enzyme allowing to investigate their orientation and binding interactions with the amino acid residues composing the active side channel. The molecular docking results for compound 4n are summarized in Table 5. An adduct is formed via π–π interactions with the amino acid residues at the peripheral anionic site as shown in Figure 11, with a free energy of binding value of −10.69 kcal. This implies that compound 4n inhibits the enzyme by blocking the entry site, thus preventing the substrate entry into the active gorge [58].

3. Materials and Methods

3.1. Apparatus and General Information

NMR spectra were recorded with a Bruker-Spectrospin AC 300 spectrometer (Rheinstetten, Germany) operating at 300 MHz for 1H and 75 MHz for 13C. The following abbreviations were used to explain the multiplicities: bs = broad singlet, s = singlet, dd = doublet of doublet, d = doublet, t = triplet, m = multiplet. Elemental analyses were performed on a Perkin Elmer 2400 Series II Elemental CHNS analyzer (Waltham, MA, USA). Electrospray ionization (ESI) mass spectra were collected using a Q-TOF instrument supplied by WATERS (Agilent, Palo Alto, CA, USA). Materials: thin-layer chromatography (TLC): TLC plates (Merck, silica gel 60 F254 0.2 mm 200 × 200 nm) (Darmstadt, Germany); substances were detected using UV light at 254 nm.

3.2. General Procedure for Preparation of Cycloadducts 4 and 5

A mixture of 1 (3.0 mmol), 2-phenylglycine 2 (0.54 g, 3.6 mmol) and isatin derivatives 3 (3 mmol) was refluxed in MeOH/H2O (2:1 v/v, 10 mL) for 6h. After completion of the reaction (TLC), the solvent was removed under vacuum. The residue was chromatographed on silica gel employing ethylacetate-cyclohexane (3:7 v/v) as eluent to obtain the pure products 4 and 5.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4,5-diphenyl-pyrrolidine (4a). White solid (1.11 g, 74%); mp 161–163 °C; 1H-NMR: δ 2.55 (d, 1H, H-4˝, J = 18.9 Hz), 2.76 (d, 1H, H-4˝, J = 18.9 Hz), 4.34 (d, 1H, H-4, J = 9.3 Hz), 5.58 (d, 1H, H-5, J = 9.3 Hz), 6.77–6.81 (m, 3H, Ar-H), 6.96–7.01 (m, 1H, Ar-H), 7.17–7.36 (m, 10H, Ar-H), 7.44 (d, 2H, Ar-H; J = 7.2 Hz), 7.49–7.52 (m, 3H, Ar-H), 7.94 (bs, 1H, NH); 13C-NMR: δ 36.6, 60.7, 61.4, 66.5, 74.1, 109.6, 122.7, 126, 126.2, 126.8, 127.3, 128, 128.1, 128.4, 128.6, 129.8, 130.9, 136.5, 140.2, 140.6, 173.2, 178.7, 178.9; HRMS (ESI-TOF): calcd for C32H25N3O3 [M + H]+ 500.1974, found 500.1975.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[4.3″]-N-phenylsuccinimide-3,5-diphenyl-pyrrolidine (5a). White solid (0.18 g, 13%); mp 111–113 °C; 1H-NMR: δ 3.05 (d, 1H, H-4˝, J = 18.3 Hz), 3.32 (d, 1H, H-4˝, J = 18.3 Hz), 4.73 (s, 1H, H-4), 5.72 (s, 1H, H-5), 6.39–6.42 (m, 2H, Ar-H), 6.68 (d, 1H, Ar-H; J = 7.8 Hz), 7.13–7.28 (m, 10H, Ar-H), 7.36–7.38 (m, 3H, Ar-H), 7.56–7.29 (m, 2H, Ar-H), 7.82 (d, 2H, Ar-H, J = 7.2 Hz); 13C-NMR: δ 40.8, 59, 59.9, 71.7, 72.8, 109.5, 123.3, 124.4, 126.1, 127.4, 128, 128.2, 128.6, 129.5, 129.7, 130.6, 131.5, 133.8, 137.5, 140.5, 174.1, 178.9, 180.3; HRMS (ESI-TOF): calcd for C32H25N3O3 [M + H]+ 500.1974, found 500.1973.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-methylphenyl)-5-phenyl-pyrrolidine (4b). White solid (1.05 g, 69%); mp 152–154 °C; 1H-NMR: δ 2.30 (s, 3H, CH3), 2.57 (d, 1H, H-4˝, J = 19 Hz), 2.75 (d, 1H, H-4˝, J = 19 Hz), 4.3 (d, 1H, H-4, J = 9.3 Hz), 5.55 (d, 1H, H-5, J = 9.3 Hz), 6.77-7.80 (m, 3H, Ar-H), 6.99 (t, 1H, Ar-H, J = 7.5 Hz), 7.14 (d, 2H, Ar-H, J = 7.8 Hz), 7.19–7.40 (m, 10H, Ar-H), 7.51 (d, 2H, Ar-H, J = 6.3 Hz), 8.03 (bs, 1H, NH); 13C-NMR: δ 20.5, 36.6, 60.4, 61.4, 66.3, 74.1, 109.6, 122.7, 125.9, 126.1, 126.2, 126.9, 127.2, 128, 128.1, 128.4, 129.3, 129.6, 129.7, 131, 133.4, 137, 140.6, 173.4, 178.8, 179; HRMS (ESI-TOF): calcd for C33H27N3O3 [M + H]+ 514.2131, found 514.2131.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[4.3″]-N-phenylsuccinimide-3-(p-methylphenyl)-5-phenyl-pyrrolidine (5b). White solid (0.3g, 20%); mp 108–110 °C; 1H-NMR: δ 2.25 (s, 3H, CH3), 3.07 (d, 1H, H-4˝, J = 18.3 Hz), 3.31 (d, 1H, H-4˝, J = 18.3 Hz), 4.7 (s, 1H, H-4), 5.71 (s, 1H, H-5), 5.71 (d, 1H, Ar-H, J = 4.2 Hz), 6.37–7.40 (m, 2H, Ar-H), 6.69 (d, 1H, Ar-H, J = 7.2 Hz), 7-7.10 (m, 4H, Ar-H), 7.13–7.23 (m, 4H, Ar-H), 7.35–7.38 (m, 3H, Ar-H), 7.46 (bs, 1H, NH), 7.55–7.58 (m, 2H, Ar-H), 7.81 (d, 1H, Ar-H, J = 6.9 Hz); 13C-NMR: δ 20.4, 40.4, 58.5, 59.1, 71.2, 72.3, 109.1, 122.8, 125.6, 126.9, 127.7, 128.2, 128.9, 129.4, 131, 137.1, 137.3, 140, 173.8, 178.5, 180.1; HRMS (ESI-TOF): calcd for C33H27N3O3 [M + H+] 514.2131, found 514.2129.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-methoxylphenyl)-5-phenyl-pyrrolidine (4c). White solid (0.31 g, 60%); mp 133–135 °C; 1H-NMR: δ 2.64 (d, 1H, H-4˝, J = 19 Hz), 2.79 (d, 1H, H-4˝, J = 19 Hz), 3.82 (s, 3H, OCH3), 4.31 (d, 1H, H-4, J = 9.3 Hz), 5.52 (d, 1H, H-5, J = 9.3 Hz), 5.51–5.74 (m, 1H, Ar-H), 6.82–6.93 (m, 3H, Ar-H), 7.03 (d, 2H, Ar-H, J = 6.6 Hz), 7.05–7.07 (m, 1H, Ar-H), 7.22–7.42 (m, 9H, Ar-H), 7.55 (d, 3H, Ar-H, J = 9 Hz), 7.84 (bs, 1H, NH); 13C-NMR: δ 37.1, 55.2, 60.7, 61.9, 67.2, 74.6, 110.1, 114.5, 123.2, 126.4, 126.6, 126.7, 127.4, 127.8, 128.5, 128.7, 129, 130.3, 131.4, 141, 159.1, 174, 179.4, 179.6; HRMS (ESI-TOF): calcd for C33H27N3O4 [M + H]+ 530.2080, found 530.2079.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[4.3″]-N-phenylsuccinimide-3-(p-methoxylphenyl)-5-phenyl-pyrrolidine (5c). White solid (0.13 g, 25%); mp 110–112 °C; 1H-NMR: δ 3.09 (d, 1H, H-4˝, J = 18.1 Hz), 3.26 (d, 1H, H-4˝, J = 18.1 Hz) 3.7 (s, 3H, OCH3), 4.66 (s, 1H, H-4), 5.7 (s, 1H, H-5), 6.35–7.39 (m, 2H, Ar-H), 6.73 (d, 1H, Ar-H, J = 9.3 Hz), 7.07 (d, 1H, Ar-H, J = 8.7 Hz), 7.11 (d, 1H, Ar-H, J = 9 Hz), 7.12–7.22 (m, 4H, Ar-H), 7.34–7.36 (m, 2H, Ar-H), 7.54–7.57 (m, 2H, Ar-H), 7.80 (d, 1H, Ar-H, J = 6.6 Hz); 13C-NMR: δ 40.8, 55.1, 59, 59.3, 71.8, 72.8, 74.6, 1;9.5, 114.1, 123.3, 124.4, 125.6, 126.1, 127.4, 128.3, 128.7, 129.4, 131.8, 141, 159.2, 174.3, 179.1, 180.5; HRMS (ESI-TOF): calcd for C33H27N3O4 [M + H]+ 530.2080, found 530.2080.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-chlorophenyl)-5-phenyl-pyrrolidine (4d). White solid (1.29 g, 80%); mp 150–152 °C; 1H-NMR: δ 2.57 (d, 1H, H-4˝, J = 18.9 Hz), 2.81 (d, 1H, H-4˝, J = 18.9 Hz), 4.34 (d, 1H, H-4, J = 9.3 Hz), 5.62 (d, 1H, H-5, J = 9.3 Hz), 6.80–6.84 (m, 3H, Ar-H), 7.04–7.07 (m, 1H, Ar-H), 7.28–7.47 (m, 12H, Ar-H), 7.51–7.56 (m, 3H, Ar-H), 8.2 (bs, 1H, NH); 13C-NMR: δ 36.6, 60.1, 61.2, 67, 74.2, 109.7, 122.8, 125.5, 126, 127.5, 128.1, 128.3, 128.5, 128.8, 129.9, 130.7, 131.3, 135.2, 140, 140.6, 173.1, 178.8; HRMS (ESI-TOF): calcd for C32H24ClN3O3 [M + H+] 534.1584, found 534.1587.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(m-chlorophenyl)-5-phenyl-pyrrolidine (4e). White solid (1.29 g, 82%); mp 160–162 °C; 1H-NMR: δ 2.55 (d, 1H, H-4˝, J = 19.2 Hz), 2.76 (d, 1H, H-4˝, J = 19.2 Hz), 4.65 (d, 1H, H-4, J = 9.9 Hz), 5.61 (d, 1H, H-5, J = 9.9 Hz), 6.83–7.02 (m, 3H, Ar-H), 7.27–7.30 (m, 7H, Ar-H), 7.37–7.42 (m, 4H, Ar-H), 7.50–7.58 (m, 4H, Ar-H), 8.42 (bs, 1H, NH); 13C-NMR: δ 36.9, 60.6, 61.4, 67.1, 74.5, 110.6, 123.4, 125.7, 126.5, 126.6, 127.5, 128.2, 128.6, 128.7, 128.9, 129,130.4, 130.7, 131.2, 135, 139.1, 141.2, 173.4, 178.8, 179.3; HRMS (ESI-TOF): calcd for C32H24ClN3O3 [M + H]+ 534.1584, found 534.1583.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(2-pyridyl)-5-phenyl-pyrrolidine (4f). White solid (1.29 g, 87%); mp 152–154 °C; 1H-NMR: 2.57 (d, 1H, H-4˝, J = 18.9 Hz), 2.81 (d, 1H, H-4˝, J = 18.9 Hz), 4.34 (d, 1H, H-4, J = 9 Hz), 5.57 (d, 1H, H-5, J = 9 Hz), 6.83-6.93 (m, 2H, Ar-H), 7.04 (t, 1H, Ar-H, J = 7.5 Hz), 7.24–7.43 (m, 11H, Ar-H), 7.52–7.58 (m, 4H, Ar-H), 7.97 (bs, 1H, NH); 13C-NMR: δ 37.1, 60.1, 61.7, 67.3, 74.7, 110.2, 123.3, 125.9, 126.5, 126.6, 127.3, 126.8, 128.1, 128.6, 128.9, 130.3, 130.5, 131.3, 135, 139.4, 140.4, 141, 173.4, 179.1, 179.2; Anal Calcd for C31H24N4O3: C, 74.38; H, 4.83; N, 11.19 %; found: C, 74.28; H, 4.8; N, 11.09%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(2-furfuryl)-5-phenyl-pyrrolidine (4g). White solid (1.17 g, 80%); mp 152–154 °C; 1H-NMR: δ 2.56 (d, 1H, H-4˝, J = 18.9 Hz), 2.7 (d, 1H, H-4˝, J = 18.9 Hz), 4.44 (d, 1H, H-4, J = 9 Hz), 5.6 (d, 1H, H-5, J = 9 Hz), 6.7 (s, 1H, Ar-H), 6.7 (d, 1H, Ar-H, J = 3 Hz), 6.82 (d, 1H, Ar-H, J = 7.8 Hz), 6.95-7.03 (m, 3H, Ar-H), 7.28–7.42 (m, 8H, Ar-H), 7.59 (d, 1H, Ar-H, J = 7.5 Hz), 7.67 (d, 2H, Ar-H, J = 7.2 Hz), 8.37 (bs, 1H, NH); 13C-NMR: δ 35.9, 54.5, 60.5, 65, 74.4, 110, 110.5, 111, 123.2, 124.9, 125.9, 126.5, 127.6, 128.2, 128.7, 128.9, 129.1, 130.6, 140.1, 141.4, 142.6, 151.7, 173.8, 178.2, 179.2; Anal Calcd for C30H23N3O4: C, 73.61; H, 4.74; N, 8.58%; found: C, 73.52; H, 4.8; N, 8.66%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]-4’-chlorooxindole-spiro[3.3″]-N-phenylsuccinimide-4,5-diphenyl-pyrrolidine (4h). White solid (1.11 g, 69%); mp 152–154 °C; 1H-NMR: δ 2.62 (d, 1H, H-4˝, J = 19 Hz), 2.72 (d, 1H, H-4˝, J = 19 Hz), 4.35 (d, 1H, H-4, J = 9 Hz), 5.63 (d, 1H, H-5, J = 9.3 Hz), 6.8 (d, 1H, Ar-H, J = 8.1 Hz), 6.92 (d, 2H, Ar-H, J = 7.8 Hz), 7.18 (d, 2H, Ar-H, J = 7.5 Hz), 7.28–7.51 (m, 10H, Ar-H), 7.56–7.51 (m, 3H, Ar-H); 13C-NMR: δ 36.9, 60.5, 61.4, 66.6, 74.2, 111.5, 126.4, 127.2, 127.5, 128.1, 128.6, 128.8, 129, 129.2, 129.8, 129.9, 130.1, 130.5, 131.2, 133.3, 137.7, 139.7, 173.7, 179.3; Anal Calcd for C32H24ClN3O3: C, 71.97; H, 4.53; N, 7.87%; found: C, 72.01; H, 4.48; N, 8.91%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]-4’-chlorooxindole-spiro[4.3″]-N-phenylsuccinimide-3,5-diphenyl-pyrrolidine (5h). White solid (0.24 g, 16%); mp 102–104 °C; 1H-NMR: δ 3.04 (d, 1H, H-4˝, J = 18.3 Hz), 3.31 (d, 1H, H-4˝, J = 18.3 Hz), 4.7 (s, 1H, H-4), 5.75 (s, 1H, H-5), 6.4–6.43 (m, 2H, Ar-H), 6.61 (d, 1H, Ar-H, J = 8.1 Hz), 7.15–7.58 (m, 11H, Ar-H), 7.69–7.48 (m, 4H, Ar-H); 13C-NMR: δ 40.5, 58.7, 59.9, 71.7, 72.6, 110.9, 125, 126.1, 127.4, 128, 128.3, 128.4, 128.7, 128.8, 128.9, 129.7, 130.5, 131, 131.3, 133.2, 136.6, 139.2, 173.8, 178.7, 179.7; Anal Calcd for C32H24ClN3O3: C, 71.97; H, 4.53; N, 7.87%; found: C, 71.87; H, 4.68; N, 7.80%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]-4’-chlorooxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-methylphenyl)-5-phenyl-pyrrolidine (4i). White solid (1.2 g, 74%); mp 158–160 °C; 1H-NMR: δ 2.07 (s, 3H, CH3), 2.6 (d, 1H, H-4˝, J = 19.2 Hz), 2.73 (d, 1H, H-4˝, J = 19.2 Hz), 4.37 (d, 1H, H-4, J = 9 Hz), 5.64 (d, 1H, H-5, J = 9 Hz), 6.78 (d, 1H, Ar-H, J = 8.4 Hz), 6.9–6.93 (m, 2H, Ar-H), 7.25-7.46 (m, 9H, Ar-H), 7.49 (d, 2H, Ar-H, J = 7.2 Hz), 7.55–7.59 (m, 3H, Ar-H), 8.55 (bs, 1H, NH); 13C-NMR: δ 20.5, 36.5, 59.9, 61, 66.4, 73.9, 110.9, 125.9, 126.6, 127.5, 128.1, 128.3, 128.4, 128.7, 129.8, 130, 130.7, 139.2, 170.7, 173.2, 178.8; Anal Calcd for C33H26ClN3O3: C, 72.32; H, 4.78; N, 7.67 %; found: C, 72.39; H, 4.70; N, 7.71%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]-4’-chlorooxindole-spiro[4.3″]-N-phenylsuccinimide-3-(p-methylphenyl)-5-phenyl-pyrrolidine (5i). White solid (0.21 g, 13%); mp 106–108 °C; 1H-NMR: δ 2.29 (s, 3H, CH3), 2.97 (d, 1H, H-4˝, J = 19.2 Hz), 3.21 (d, 1H, H-4˝, J = 19.2 Hz), 4.68 (s, 1H, H-4), 5.74 (s, 1H, H-5), 6.32–6.35 (m, 2H, Ar-H), 6.75 (d, 1H, Ar-H, J = 8.1 Hz), 7.05–7.09 (m, 2H, Ar-H), 7.15-7.18 (m, 5H, Ar-H), 7.27–7.29 (m, 5H, Ar-H), 7.48–7.51 (m, 2H, Ar-H); 13C-NMR: δ 21, 40.5, 58.6, 59.5, 71.6, 72.4, 111, 124.9, 126.1, 127.4, 128.4, 128.6, 128.8, 129.1, 129.6, 129.7, 130.4, 131, 131.3, 136.6, 138.2, 139.2, 174, 178.8, 179.7; Anal Calcd for C33H26ClN3O3: C, 72.32; H, 4.78; N, 7.67%; found: C, 72.27; H, 4.83; N, 7.73%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]-4’-chlorooxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-methoxyphenyl)-5-phenyl-pyrrolidine (4j). White solid (1.41 g, 84%); mp 152–154 °C; 1H-NMR: δ 2.62 (d, 1H, H-4˝, J = 19.2 Hz), 2.72 (d, 1H, H-4˝, J = 19.2 Hz), 3.79 (s, 3H, OCH3), 4.28 (d, 1H, H-4, J = 9 Hz), 5.53 (d, 1H, H-5, J = 9 Hz), 6.67 (d, 1H, Ar-H, J = 8.4 Hz), 6.90 (d, 4H, Ar-H, J = 8.1 Hz), 7.23–7.31 (m, 4H, Ar-H), 7.34–7.45 (m, 5H, Ar-H), 7.53–7.56 (m, 3H, Ar-H); 13C-NMR: δ 36.5, 54.7, 60, 61.1, 66.6, 73.9, 110.9, 114, 125.8, 126.6, 126.7, 126.9, 127.5, 128.1, 128.2, 128.3, 128.7, 129.9, 130.7, 131, 158.7, 173.4, 178.9; Anal Calcd for C33H26ClN3O4: C, 70.27; H, 4.65; N, 7.45%; found: C, 70.2; H, 4.72; N, 7.55%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]-4’-chlorooxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-chlorophenyl)-5-phenyl-pyrrolidine (4k). White solid (1.37 g, 81%); mp 145–147 °C; 1H-NMR: 2.56 (d, 1H, H-4˝, J = 19 Hz), 2.69 (d, 1H, H-4˝, J = 19 Hz), 4.38 (d, 1H, H-4, J = 9.3 Hz), 5.64 (d, 1H, H-5, J = 9.3 Hz), 6.84–6.93 (m, 3H, Ar-H), 7.28–7.78 (m, 14H, Ar-H), 8.52 (bs, 1H, NH); 13C-NMR: δ 36.7, 60, 61, 66.9, 73.9, 111.7, 125.7, 126.3, 127.2, 127.4, 128.4, 128.7, 128.9, 129, 129.2, 129.4, 130.8, 131.1, 131.7, 134.2, 139.6, 173.4, 179; Anal Calcd for C32H23Cl2N3O3: C, 67.61; H, 4.08; N, 7.39 %; found: C, 67.53; H, 4.16; N, 7.32%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]-4’-chlorooxindole-spiro[3.3″]-N-phenylsuccinimide-4-(m-chlorophenyl)-5-phenyl-pyrrolidine (4l). White solid (1.5 g, 88%); mp 155–157 °C; 1H-NMR: δ 2.51 (d, 1H, H-4˝, J = 19.2 Hz), 2.66 (d, 1H, H-4˝, J = 19.2 Hz), 4.31 (d, 1H, H-4, J = 9 Hz), 5.57 (d, 1H, H-5, J = 9 Hz), 6.79 (d, 1H, Ar-H, J = 8.1 Hz), 6.86–6.9 (m, 2H, Ar-H), 7.22–7.41 (m, 10H, Ar-H), 7.51–7.53 (m, 4H, Ar-H); 13C-NMR: δ 36.8, 60.2, 61.1, 66.9, 74.3, 111.7, 126.3, 127.1, 127.4, 128.3, 128.6; 128.7, 128.9, 129, 129.2, 129.7, 130.4, 130.5, 130.7, 131.1, 135.1, 138.8, 139.7, 173.1, 179; C, 67.61; H, 4.08; N, 7.39%; found: C, 67.7; H, 4.15; N, 7.44%.
(2R*,3S*,4R*,5R*)-spiro[2,2’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4,5-diphenyl-pyrrolidine (4m). White solid (1.44 g, 90%); mp 150-152°C; 1H-NMR: δ 2.55 (q, 2H, H-4˝, J = 20 Hz), 4.46 (d, 1H, H-4, J = 9.3 Hz), 5.63 (d, 1H, H-5, J = 9.3 Hz), 6.72–7.75 (m, 2H, Ar-H), 7.25-7.74 (m, 15H, Ar-H), 7.85-7.92 (m, 2H, Ar-H), 7.98 (d, 1H, Ar-H, J = 6.9 Hz), 8.12 (d, 1H, Ar-H, J = 8.1 Hz); 13C-NMR: δ 36.4, 61.1, 62.1, 67.1, 77.7, 123.3, 126.1, 126.4, 127.4, 127.8, 128.5, 128.8, 128.9, 129.1, 129.2, 130.2, 130.3, 130.7, 130.8, 131.4, 132.4; 135.3, 135.9, 137.1, 141.2, 173.1, 179.9, 205.6; HRMS (ESI-TOF): calcd for C36H27N2O3 [M + H]+ 535.2022, found 535.2016.
(2R*,3S*,4R*,5R*)-spiro[2,3’]acenaphthene-1’-one-spiro[4.3″]-N-phenylsuccinimide-4,5-diphenyl-pyrrolidine (5m). White solid (1.44 g, 88%); mp 140–142 °C; 1H-NMR: δ 3.07 (d, 1H, H-4˝, J = 18.3 Hz), 3.41 (d, 1H, H-4˝, J = 18.3 Hz), 4.99 (s, 1H, H-3), 5.75 (s, 1H, H-5), 6.4–6.43 (m, 2H, Ar-H), 6.99–7.08 (m, 5H, Ar-H), 7.22-7.29 (m, 3H, Ar-H), 7.36–7.38 (m, 3H, Ar-H), 7.59–7.85 (m, 6H, Ar-H), 8.01–8.12 (m, 2H, Ar-H); 13C-NMR: δ 40.9, 59.9, 73.4, 75.4, 77.4, 120.4, 121.3, 125.2, 126.2, 127.5, 127.7, 128.2; 128.3, 128.6, 128.7, 128.2, 128.3, 128.6, 128.7, 129.1, 130.3, 130.7, 131.5, 131.6, 131.8, 134.2, 137.5, 139.5, 142.5, 174.3, 179.1, 207.7; HRMS (ESI-TOF): calcd for C36H27N2O3 [M + H]+ 535.2022, found 535.2020.
(2R*,3S*,4R*,5R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(p-methylphenyl)-5-phenyl-pyrrolidine (4n). White solid (1.44 g, 88%); mp 140–242 °C; 1H-NMR: δ 2.37 (s, 3H, CH3), 2.6 (s, 2H, H-4˝), 4.47 (d, 1H, H-4, J = 9.3 Hz), 5.66 (d, 1H, H-5, J = 9.3 Hz), 6.77–6.80 (m, 2H, Ar-H), 7.22–7.40 (m, 8H, Ar-H), 7.45 (d, 2H, Ar-H, J = 7.8 Hz), 7.61–7.69 (m, 3H, Ar-H), 7.77–7.82 (m, 1H, Ar-H), 7.90–7.97 (m, 2H, Ar-H), 8.03 (d, 1H, Ar-H, J = 6.9 Hz), 8.17 (d, 1H, Ar-H, J = 8.4 Hz); 13C-NMR: δ 21, 36.4, 61.8, 62.1, 66.9, 77.7, 122.2, 123.3, 126, 126.4, 126.8, 127.4, 127.7, 128.5, 128.8, 128.9, 129.9, 130.1, 130.7, 130.9, 131.5, 132.3, 133.9, 136.1, 137.5, 141.2, 142.5, 173.5, 180, 205.4; HRMS (ESI-TOF): calcd for C37H28N2O3 [M + H]+ 549.2178, found 549.2183.
(2R*,3S*,4R*,5R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(p-methoxyphenyl)-5-phenyl-pyrrolidine (4o). White solid (1.47 g, 87%); mp 151–153 °C; 1H-NMR: δ 2.55 (q, 2H, H-4˝), 4.39 (d, 1H, H-4, J = 9 Hz), 3.79 (s, 3H, OCH3), 5.57 (d, 1H, H-5, J = 9 Hz), 6.78–6.94 (m, 1H, Ar-H), 6.99–7.12 (m, 4H, Ar-H), 7.28–7.51 (m, 3H, Ar-H), 7.61–7.63 (m, 2H, Ar-H), 7.68–8.21(m, 10H, Ar-H); 13C-NMR: δ 39.3, 55.2, 61.6, 62, 67, 77.7, 114.6, 122.2, 123.3, 126.1, 126.4, 127.4, 127.7, 128.5, 128.6, 128.8, 129, 130.7, 130.8, 131.4, 131.5, 132.4, 136, 141.3, 142.5, 159.2, 173.6, 180.1, 205.6; HRMS (ESI-TOF): calcd for C37H28N2O4 [M + H]+ 565.2127, found 565.2127.
(2R*,3S*,4R*,5R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(p-chlorophenyl)-5-phenyl-pyrrolidine (4p). White solid (1.53 g, 90%); mp 155–157 °C; 1H-NMR: δ 2.52 (d, 1H, H-4˝, J = 18.9 Hz), 2.6 (d, 1H, H-4˝, J = 18.9 Hz), 4.45 (d, 1H, H-4, J = 9.3 Hz), 5.59 (d, 1H, H-5, J = 9.3 Hz), 6.77–6.80 (m, 2H, Ar-H), 7.27–7.66 (m, 13H, Ar-H), 7.69–7.89 (m, 2H, Ar-H), 7.95–8.05 (m, 2H, Ar-H), 8.19 (d, 1H, Ar-H, J = 8.1 Hz); 13C-NMR: δ 36.4, 61.6, 61.8, 67.5, 77.8, 122.3, 123.7, 126.2, 126.3, 127.3, 127.9, 128.6, 128.8, 128.9, 129.1, 129.4, 129.5, 130.8, 131.2, 131.4, 131.7, 132.5, 133.8, 133.9, 135.7, 135.8, 140.8, 142.6, 172.5, 173.1, 179.9, 205.5; Anal Calcd for C36H25ClN2O3: C, 75.98; H, 4.43; N, 4.92%; found: C, 75.9; H, 4.38; N, 5.03 %.
(2R*,3S*,4R*,5R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(m-chlorophenyl)-5-phenyl-pyrrolidine (4q). White solid (1.56 g, 92%); mp 135–137 °C; 1H-NMR: δ 2.5 (d, 1H, H-4˝, J = 19.2 Hz), 2.58 (d, 1H, H-4˝, J = 19.2 Hz), 4.45 (d, 1H, H-4, J = 9.3 Hz), 5.65 (d, 1H, H-5, J = 9.3 Hz), 6.76-6.82 (m, 2H, Ar-H), 7.27–7.41 (m, 8H, Ar-H), 7.51 (d, 1H, Ar-H, J = 7.2 Hz), 7.57–7.67 (m, 4H, Ar-H), 7.79 (d, 2H, Ar-H, J = 7.5 Hz), 7.79 (d, 1H, Ar-H, J = 7.5 Hz), 8.05 (d, 1H, Ar-H, J = 6.9 Hz), 8.18 (d, 1H, Ar-H, J = 8.1 Hz); 13C-NMR: δ 36.3, 61.5, 61.6, 67.3, 77.5, 122.6, 123.3, 125.4, 126.1, 126.4, 127.4, 128.1, 128.3, 128.5, 128.7, 128.8, 129, 130.4, 131.5, 131.2, 132.6, 135, 135.1, 139.2, 140.2, 142.6, 173.1, 179.9, 204.9; Anal Calcd for C36H25ClN2O3: C, 75.98; H, 4.43; N, 4.92%; found: C, 76.01; H, 4.46; N, 4.88%.
(2R*,3S*,4R*,5R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(2-pyridyl)-5-phenyl-pyrrolidine (4r). White solid (1.5 g, 93%); mp 122–124 °C; 1H-NMR: δ 2.67 (d, 1H, H-4˝, J = 18.7 Hz), 2.77 (d, 1H, H-4˝, J = 18.7 Hz), 4.82 (d, 1H, H-4, J = 9.6 Hz), 5.81 (d, 1H, H-5, J = 9.6 Hz), 7.75 (d, 2H, Ar-H, J = 7.5 Hz), 7.02–7.32 (m, 7H, Ar-H), 7.66–7.78 (m, 6H, Ar-H), 7.89–7.99 (m, 3H, Ar-H), 8.16 (d, 1H, Ar-H, J = 8.1 Hz), 8.61 (d, 1H, Ar-H, J = 4.2 Hz); 13C-NMR: δ 36.3, 61.5, 61.6, 67.3, 77.5, 122.6, 123.3, 125.4, 126.1, 126.4, 127.4, 128.1, 128.3, 128.5, 128.7, 128.8, 129, 130.4, 131.5, 131.2, 132.6, 135, 135.1, 139.2, 140.2, 142.6, 173.1, 179.9, 204.9; Anal Calcd for C35H25N3O3: C, 78.49; H, 4.7; N, 7.85 %; found: C, 78.41; H, 4.75; N, 7.8%.

3.3. General Procedure for the Preparation of Cycloadducts 7a–h

A mixture of 1 (3.0 mmol), sarcosine 2 (3.6 mmol) and isatin 3a or acenaphthenequinone 3c (3 mmol) was refluxed in MeOH/H2O (2:1 v/v, 10 mL) for 6h. After completion of the reaction (TLC), the solvent was removed under vacuum. The residue was recrystallized from ethanol to obtain the pure product 7a–h.
(2R*,3S*,4R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-phenyl-N-methylpyrrolidine (7a). White solid (1.14 g, 85%); mp 152–154 °C; 1H-NMR: δ 2.29 (s, 3H, CH3), 2.5 (d, 1H, H-4˝, J = 18.9 Hz), 2.78 (d, 1H, H-4˝, J = 18.9 Hz), 3.62 (t, 1H, H-4), 4.07 (t, 1H, H-4), 4.54 (dd, 1H, H-5), 6.78–6.81 (m, 2H, Ar-H), 6.85 (d, 1H, Ar-H, J = 7.5 Hz), 7.02–7.07 (m, 1H, Ar-H), 7.28–7.44 (m, 8H, Ar-H), 7.5–7.53 (m, 2H, Ar-H), 7.61 (bs, 1H, NH); 13C-NMR: δ 34.6, 36.6, 49.3, 58.4, 61.3, 77.9, 109.4, 122.8, 124.6, 126.1, 127, 127.3, 128, 128.4, 128.6, 129.6, 131, 137.2, 140.9, 173.2, 176.9, 177.9; Anal Calcd for C27H23N3O3: C, 74.12; H, 5.3; N, 9.6%; found: C, 74.19; H, 5.25; N, 9.67%.
(2R*,3S*,4R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-methylphenyl)-N-methylpyrrolidine (7b). White solid (1.17 g, 88%); mp 135–137 °C; 1H-NMR: δ 2.28 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.51 (d, 1H, H-4˝, J = 18.7 Hz), 2.77 (d, 1H, H-4˝, J = 18.7 Hz), 3.58 (t, 1H, H-4), 4.05 (t, 1H, H-4), 4.51 (dd, 1H, H-5), 6.77–6.84 (m, 3H, Ar-H), 7–7.06 (m, 1H, Ar-H), 7.19–7.44 (m, 9H, Ar-H), 7.82 (bs, 1H, NH); 13C-NMR: δ 21, 35.1, 37, 49.5, 58.7, 61.7, 78.4, 109.9, 123.3, 125.1, 126.6, 127.6, 128.5, 128.8, 129.8, 129.9, 130.1, 131.6, 134.4, 137.6, 141.5, 173.7, 177.4, 178.4; Anal Calcd for C28H25N3O3: C, 74.48; H, 5.58; N, 9.31%; found: C, 74.41; H, 5.51; N, 9.4%.
(2R*,3S*,4R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-methoxyphenyl)-N-methylpyrrolidine (7c). White solid (1.35 g, 87%); mp 109–111 °C; 1H-NMR: δ 2.27 (s, 3H, CH3), 2.52 (d, 1H, H-4˝, J = 18.9 Hz), 2.75 (d, 1H, H-4˝, J = 18.9 Hz), 3.59 (t, 1H, H-4), 3.82 (s, 3H, OCH3), 4.01 (t, 1H, H-4), 4.48 (t, 1H, H-5), 6.78–6.84 (m, 3H, Ar-H), 6.92 (d, 2H, Ar-H, J = 8.7 Hz), 7.03 (t, 1H, Ar-H, J = 7.5 Hz), 7.29–7.42 (m, 7H, Ar-H), 7.56 (bs, 1H, NH); 13C-NMR: δ 35.1, 37, 49.2, 55.2, 58.9, 61.7, 78.4, 109.9, 114.5, 123.3, 125, 126.5, 127.7, 128.5, 128.8, 129.4, 130.1, 131.1, 131.6, 141.4, 159.3, 173.6, 177.2, 178.4; Anal Calcd for C28H25N3O4: C, 71.93; H, 5.39; N, 8.99%; found: C, 71.87; H, 5.3; N, 9.06%.
(2R*,3S*,4R*)-spiro[2,3’]oxindole-spiro[3.3″]-N-phenylsuccinimide-4-(p-chlorophenyl)-N-methylpyrrolidine (7d). White solid (1.14 g, 80%); mp 126–128 °C; 1H-NMR: δ 2.26 (s, 3H, CH3), 2.44 (d, 1H, H-4˝, J = 18.9 Hz), 2.75 (d, 1H, H-4˝, J = 18.9 Hz), 3.6 (t, 1H, H-4),3.98 (t, 1H, H-4), 4.48 (dd, 1H, H-5), 6.76–6.79 (m, 2H, Ar-H), 6.83 (d, 1H, Ar-H, J = 7.8 Hz), 7.04–7.38 (m, 7H, Ar-H), 7.45 (d, 2H, Ar-H, J = 8.7 Hz); 13C-NMR: δ 35, 37, 49, 59, 61.6, 78.4, 109.9, 123.4, 124.9, 126.5, 127.5, 128.5, 128.8, 129.2, 130.2, 131.5, 133.8, 136.2, 141.3, 173.3, 177.2, 178.1; Anal Calcd for C27H22ClN3O3: C, 68.71; H, 4.7; N, 8.9%; found: C, 68.81; H, 4.78; N, 8.86%.
(2R*,3S*,4R*)-spiro[2,3’] acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-phenyl-N-methylpyrrolidine (7e). White solid (1.2 g, 85%); mp 115–117 °C; 1H-NMR: δ 2.24 (s, 3H, CH3), 2.46 (d, 1H, H-4˝, J = 18.7 Hz), 2.66 (d, 1H, H-4˝, J = 18.7 Hz), 3.73 (m, 1H, H-4), 4.19 (t, 1H, H-4), 4.68 (t, 1H, H-5), 6.69–6.72 (m, 2H, Ar-H), 7.30–7.82 (m, 11H, Ar-H), 7.93–7.97 (m, 2H, Ar-H), 8.17 (d, 1H, Ar-H, J = 8.1 Hz); 13C-NMR: δ 34.5, 35.7, 49.9, 58.6, 61.6, 120.5, 123.6, 125.4, 125.8, 125.9, 127.4, 127.8, 127.9, 128.3, 128.4, 128.5, 128.6, 129.5, 129.7, 130.2, 131, 131.1, 132, 134.5, 134.8, 137.2, 142.5, 172.8, 178.1, 206.6; Anal Calcd for C31H24N2O3: C, 78.79; H, 5.12; N, 5.93%; found: C, 78.85; H, 5.04; N, 6.01%.
(2R*,3S*,4R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(p-methylphenyl)-N-methylpyrrolidine (7f). White solid (1.2 g, 83%); mp 102–104 °C; 1H-NMR: δ 2.21 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.45 (d, 1H, H-4˝, J = 18.9 Hz), 2.62 (d, 1H, H-4˝, J = 18.9 Hz), 3.68 (m, 1H, H-4), 4.14 (t, 1H, H-4), 4.62 (t, 1H, H-5), 6.66–6.69 (m, 2H, Ar-H), 7.22–7.32 (m, 5H, Ar-H), 7.42 (d, 2H, Ar-H, J = 8.1 Hz), 7.64–7.75 (m, 1H, Ar-H), 7.79 (d, 2H, Ar-H, J = 7.2 Hz), 7.90–7.94 (m, 2H, Ar-H), 8.15 (d, 1H, Ar-H, J = 8.1 Hz); 13C-NMR: δ 21, 35, 36.1, 50.1, 59, 62, 81, 121, 124.2, 125.8, 126.3, 128.3, 128.8, 129, 129.8, 130.2, 130.7, 131.5, 131.6, 132.4, 134.5, 135, 137.6, 143, 173.4, 178.6, 207.1; Anal Calcd for C32H26N2O3: C, 78.99; H, 5.39; N, 5.76%; found: C, 78.89; H, 5.31; N, 5.80 %.
(2R*,3S*,4R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(p-methoxyphenyl)-N-methylpyrrolidine (7g). White solid (1.29 g, 87%); mp 120–122 °C; 1H-NMR: δ 2.22 (s, 3H, CH3), 2.47 (d, 1H, H-4˝, J = 18.9 Hz), 2.58 (d, 1H, H-4˝, J = 18.9 Hz), 3.72 (m, 1H, H-4), 3.84 (s, 3H, OCH3), 4.12 (t, 1H, H-4), 4.59 (t, 1H, H-5), 6.69–6.73 (m, 2H, Ar-H), 6.97 (d, 2H, Ar-H, J = 8.7 Hz), 7.27-7.38 (m, 3H, Ar-H), 7.27-7.38 (m, 2H, Ar-H), 7.41-7.53 (m, 3H, Ar-H), 7.66–7.80 (m, 3H, Ar-H), 7.92–7.97 (m, 2H, Ar-H), 8.18 (d, 1H, Ar-H, J = 8.1 Hz); 13C-NMR: δ 34.6, 35.6, 49.4, 54.8, 58.8, 61.4, 80.4, 114.2, 120.6, 123.6, 125.5, 125.9, 126, 127.9, 128, 128.4, 128.6, 128.9, 130.2, 130.6, 130.8, 130.9, 131.7, 132.1, 134.2, 142.6, 158.7, 173.1, 178.4, 206.9; HRMS (ESI-TOF): calcd for C32H26N2O4 [M + H]+ 503.1971, found 503.1975.
(2R*,3S*,4R*)-spiro[2,3’]acenaphthene-1’-one-spiro[3.3″]-N-phenylsuccinimide-4-(p-chlorophenyl)-N-methylpyrrolidine (7h). White solid (1.2 g, 80%); mp 125–126 °C; 1H-NMR: δ 2.22 (s, 3H, CH3), 2.4 (d, 1H, H-4˝, J = 18.9 Hz), 2.59 (d, 1H, H-4˝, J = 18.9 Hz), 3.73 (t, 1H, H-4), 4.11 (t, 1H, H-4), 4.61 (t, 1H, H-5), 6.68–6.72 (m, 2H, Ar-H), 7.28–7.37 (m, 2H, Ar-H), 7.42(d, 2H, Ar-H, J = 8.4 Hz), 7.53 (d, 2H, Ar-H, J = 8.4 Hz), 7.61–7.82 (m, 3H, Ar-H), 7.93–7.99 (m, 3H, Ar-H), 8.20 (d, 1H, Ar-H, J = 8.1 Hz); 13C-NMR: δ 35, 36.2, 49.7, 59.4, 61.8, 80.9, 121.2, 124, 126.1, 126.3, 128.5, 128.6, 128.9, 129.4, 130.7, 131.2, 131.3, 131.5, 132.7, 133.8, 134.5, 136.3, 143.1, 173.2, 178.7, 207.5; Anal Calcd for C31H23ClN2O3: C, 73.44; H, 4.57; N, 5.53%; found: C, 73.39; H, 4.62; N, 5.47%.

3.4. Crystal Structure Determinations

A suitable crystal of 4b, 4m, 5m, and 7f was selected and mounted on an Xcalibur, Sapphire3 diffractometer (Abingdon, UK). The crystals were kept at 150(2) K during data collection. Using Olex2 [59], the structures were solved with the ShelXS [60], structure solution program using direct methods and refined with ShelXL [60], refinement package using least squares minimization. Data (excluding structure factors) for the structures of 4b, 4m, 5m, and 7f have been deposited at CCDC with deposition numbers 1958732, 1958733, 1958730, and 1958731. These data may be obtained free of charge from CCDC through www.ccdc.cam.ac.uk/data_request/cif. The main crystallographic data together with refinement details are summarized in Table 6.

3.5. Cholinesterase Inhibitory Assay

Acetylthiocholine iodide (ATCl), acetylcholinesterase (AChE, from electric eel), butyrylcholinesterase (BChE, from equine serum), S-butyrylthiocholine chloride, and 5, 50-dithiobis(2-nitrobenzoicacid) (Ellman’s reagent, DTNB) were purchased from Sigma–Aldrich (Kuala Lumpur, Malaysia).
Cholinesterase enzyme inhibitory potential of the test samples was determined following the method of Khaw et al. (2014) with slight modifications on the vehicle used. Briefly, test samples and galantamine were prepared in DMSO at the initial concentration of 0.5 mg/mL. The final concentration of DMSO in reaction mixture was 1%. At this concentration, DMSO has no inhibitory effect on both AChE and BChE enzymes. For AChE inhibitory assay, 140 µL of 0.1 M sodium phosphate buffer (pH 8) was added to a 96 wells microplate followed by 20 µL of test samples and 20 µL of 0.09 units/mL AChE enzyme. Then, 10 µL of 10 mM DTNB was added into each well followed by 10 µL of 14 mM of acetylthiocholine iodide. The absorbance of the colored end product was measured using Tecan Infinite 200 Pro Microplate Spectrophotometer at 412 nm for 30 min. Each test was conducted in triplicate. For BChE inhibitory assay, the same procedures were applied as AChE except for the use of enzyme and substrate, which were BChE from equine serum and S-butyrylthiocholine chloride. Absorbencies of the test samples were corrected by subtracting the absorbance of their respective blank (test samples in DMSO with substrate and DTNB, but without enzyme). A set of five concentrations was used to estimate the 50% inhibitory concentration (IC50) for the compounds showing more than 50% inhibition at 5µg/mL concentration.

3.6. Molecular Docking of Compound 4n

Molecular docking for 4m was performed using Autodock 3.0.5 (La Jolla, CA, USA) along with AutoDockTools (ADT) [61]. 4m was built using Hyperchem 8 and energy minimization was performed with convergence criterion of 0.05 kcal/molA. Crystal structure of AChE from Torpedo californica in complex with galanthamine was obtained from Protein Data Bank with PDB ID: 1W6R [62]. The protein was edited using ADT to remove all water molecules and all hydrogen atoms were added. Nonpolar hydrogen atoms and lone pairs were then merged, and each atom was assigned with Gasteiger partial charges. A grid box of 41 × 53 × 41 points, with a spacing of 0.375A° was positioned at the center of active-site gorge. One hundred independent dockings were carried out for each docking experiment. The lowest docked energy of each conformation in the most populated cluster was selected. Analysis and visualization of the docking results was done using BIOVIA Discovery Studio visualizer.

4. Conclusions

To conclude, we have developed an efficient and practical strategy for the multicomponent 1,3-dipolar cycloaddition of (E)-3-benzylidene-1-phenyl-succinimides, 1,2-cyclic diketones, and diverse α-aminoacids. This protocol enables the convenient synthesis of a novel class of dispiropyrrolidines fused succinimide in good to high yields with high diastereoselectivity. Noteworthy, some of the synthetized compounds showed good AChE inhibition. Compound 4n bearing a methyl substituent at the para-position of the phenyl ring exhibited the most potent AChE inhibition. The molecular docking simulation of this compound disclosed its interesting binding interaction to the active site channel of AChE enzymes.

Supplementary Materials

The following are available online, Figures S1–S64: 1H and 13C-NMR spectra, Additional information on Cholinesterase inhibitory assay, Experimental details concerning the Molecular Docking investigation of compound 4n.

Author Contributions

S.B., S.H., M.A., and V.M. conceived and performed the experiments; S.B. and M.K. wrote and coordinated the paper. M.K., C.S., and C.G. performed the crystallographic work. All authors read and approved the final manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: The sample of the compounds is not available from the authors.
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Figure 1. Clinical and biologically important spiropyrrolidines bearing acenaphthylene-1,2-dione or oxindole moieties.
Figure 1. Clinical and biologically important spiropyrrolidines bearing acenaphthylene-1,2-dione or oxindole moieties.
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Figure 2. Examples of bioactive molecules containing succinimide unit.
Figure 2. Examples of bioactive molecules containing succinimide unit.
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Figure 3. Design of novel succinimide-substituted dispiropyrrolidine derivatives.
Figure 3. Design of novel succinimide-substituted dispiropyrrolidine derivatives.
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Scheme 1. 1,3-Dipolar cycloaddition reaction for the synthesis of dispiropyrrolidine 4a.
Scheme 1. 1,3-Dipolar cycloaddition reaction for the synthesis of dispiropyrrolidine 4a.
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Molecules 25 01963 sch002 550
Scheme 2. Reaction of (E)-3-arylidene-1-phenylpyrrolidine-2,5-dione 1a–g with 2-phenylglycine 2 and cyclic 1,2-diketones 3.
Scheme 2. Reaction of (E)-3-arylidene-1-phenylpyrrolidine-2,5-dione 1a–g with 2-phenylglycine 2 and cyclic 1,2-diketones 3.
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Molecules 25 01963 sch003 550
Scheme 3. Reaction of (E)-3-arylidene-1-phenylpyrrolidine-2,5-diones 1a-f with sarcosine 6 and cyclic 1,2-diketones 3.
Scheme 3. Reaction of (E)-3-arylidene-1-phenylpyrrolidine-2,5-diones 1a-f with sarcosine 6 and cyclic 1,2-diketones 3.
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Figure 4. Selected 1H and 13C-NMR (red) chemical shifts of 4b.
Figure 4. Selected 1H and 13C-NMR (red) chemical shifts of 4b.
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Figure 5. Selected 1H and 13C-NMR (red) chemical shifts of 5b.
Figure 5. Selected 1H and 13C-NMR (red) chemical shifts of 5b.
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Figure 6. Selected 1H and 13C-NMR (red) chemical shifts of 7f.
Figure 6. Selected 1H and 13C-NMR (red) chemical shifts of 7f.
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Figure 7. (B) Ball and Sticks presentation of the molecular structure of 4b in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Only one of the two independent molecules in the unit cell is presented. Selected bond lengths (Å) and angles (°): C1–N1 1.4144(17), N1–C8 1.3437(19), C8–O1 1.2329(17), C8–C7 1.5556(18), C6–C7 1.5126(19), C7–N2 1.4488(18), N2–C27 1.4669(19), C11–O2 1.2060(17), C11–N3 1.36965(18), C10–N3 1.3959(17); C7–C9–C19103.62(10), C9–C19–C27105.21(11), C9–C19–C27105.21(11), C19–C27–N2102.89(11), C27–N2–C7108.10(11), N2–C7–C8114.02(11), N2–C7–C8114.02(11), C7–C8–N1108.41(11), C8–N1–C1111.33(11), N1–C1–C6109.24(11), C6–C7–C9115.09(11), C9–C10–N3109.24(11), C10–N3–C11112.56(11). (A) Pairwise association of two molecules in the packing through intermolecular N-H····O hydrogen bonding. d(N-H····O 2.00(2) Å.
Figure 7. (B) Ball and Sticks presentation of the molecular structure of 4b in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Only one of the two independent molecules in the unit cell is presented. Selected bond lengths (Å) and angles (°): C1–N1 1.4144(17), N1–C8 1.3437(19), C8–O1 1.2329(17), C8–C7 1.5556(18), C6–C7 1.5126(19), C7–N2 1.4488(18), N2–C27 1.4669(19), C11–O2 1.2060(17), C11–N3 1.36965(18), C10–N3 1.3959(17); C7–C9–C19103.62(10), C9–C19–C27105.21(11), C9–C19–C27105.21(11), C19–C27–N2102.89(11), C27–N2–C7108.10(11), N2–C7–C8114.02(11), N2–C7–C8114.02(11), C7–C8–N1108.41(11), C8–N1–C1111.33(11), N1–C1–C6109.24(11), C6–C7–C9115.09(11), C9–C10–N3109.24(11), C10–N3–C11112.56(11). (A) Pairwise association of two molecules in the packing through intermolecular N-H····O hydrogen bonding. d(N-H····O 2.00(2) Å.
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Figure 8. Ball and Sticks presentation of the molecular structure of 4m in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°):C6–N2 1.395(2), N2–C9 1.397(2), C6–O2 1.2093(18), C9–O3 1.2074(18), C13–O1 1.52152(18),C24–N1 1.461(2), N1–C18 1.4787(18); C8–C10–C6105.67(12), C10–C6–N2107.92(13), C6–N2–C9113.11(13), N2–C9–C8108.11(13), C9–C8–C24115.07(12), N1–C24–C8103.31(12), C24–N1–C18110.43(12), C7–C18–N1105.11(12), C18–C7–C8101.90(12), C7–C8–C10114.28(12).
Figure 8. Ball and Sticks presentation of the molecular structure of 4m in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°):C6–N2 1.395(2), N2–C9 1.397(2), C6–O2 1.2093(18), C9–O3 1.2074(18), C13–O1 1.52152(18),C24–N1 1.461(2), N1–C18 1.4787(18); C8–C10–C6105.67(12), C10–C6–N2107.92(13), C6–N2–C9113.11(13), N2–C9–C8108.11(13), C9–C8–C24115.07(12), N1–C24–C8103.31(12), C24–N1–C18110.43(12), C7–C18–N1105.11(12), C18–C7–C8101.90(12), C7–C8–C10114.28(12).
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Figure 9. (B) Ball and Sticks presentation of the molecular structure of 5m in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°): C12–N1 1.462(3), N1–C30 1.469(3), C1–O1 1.217(3), C22–O2 1.212(3), C23–O3 1.204(3), C22–N2 1.394(3), N2–C23 1.4787(18); C20–C13–C12 104.46(17), C12–N1–C30 106.91(17), N1–C30–C20 112.96(18), C20–C21–C22 104.86(18), N2–C22–C21 107.52(18), C22–N2–C23 112.24(19), N2–C23–C20 107.98(19), N2–C23–O3 124.4(6). (A) Association of two molecules in the packing through intermolecular N-H····O hydrogen bonding.
Figure 9. (B) Ball and Sticks presentation of the molecular structure of 5m in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°): C12–N1 1.462(3), N1–C30 1.469(3), C1–O1 1.217(3), C22–O2 1.212(3), C23–O3 1.204(3), C22–N2 1.394(3), N2–C23 1.4787(18); C20–C13–C12 104.46(17), C12–N1–C30 106.91(17), N1–C30–C20 112.96(18), C20–C21–C22 104.86(18), N2–C22–C21 107.52(18), C22–N2–C23 112.24(19), N2–C23–C20 107.98(19), N2–C23–O3 124.4(6). (A) Association of two molecules in the packing through intermolecular N-H····O hydrogen bonding.
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Figure 10. Ball and Sticks presentation of the molecular structure of 7f in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°):C24–N1 1.461(2), N1–C18 1.4784(18), C24–C8 1.587(2), C8–C9 1.525(2), C9–O3 1.2074(18), C9–N2 1.397(2), C6–N2 1.395(2), C6–O2 1.2093(18), C13–O1 1.2152(18); C7–C8–C24 99.71(12), C7–C8–C24 99.71(12), C24–C13–O1 123.67(14), C24–C8–C9 115.07(12), C8–C9–O3 127.87(14), C8–C9–N2 108.11(13), C9–N2–C6 113.11(13), N2–C6–O2 124.19(15).
Figure 10. Ball and Sticks presentation of the molecular structure of 7f in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°):C24–N1 1.461(2), N1–C18 1.4784(18), C24–C8 1.587(2), C8–C9 1.525(2), C9–O3 1.2074(18), C9–N2 1.397(2), C6–N2 1.395(2), C6–O2 1.2093(18), C13–O1 1.2152(18); C7–C8–C24 99.71(12), C7–C8–C24 99.71(12), C24–C13–O1 123.67(14), C24–C8–C9 115.07(12), C8–C9–O3 127.87(14), C8–C9–N2 108.11(13), C9–N2–C6 113.11(13), N2–C6–O2 124.19(15).
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Scheme 4. Proposed mechanism for the 1,3-dipolar cycloaddition of azomethine ylides d3,4 with (E)-3-arylidene-1-phenylpyrrolidine-2,5-dione.
Scheme 4. Proposed mechanism for the 1,3-dipolar cycloaddition of azomethine ylides d3,4 with (E)-3-arylidene-1-phenylpyrrolidine-2,5-dione.
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Figure 11. Binding interactions of 4n with the acetylcholinesterase domain.
Figure 11. Binding interactions of 4n with the acetylcholinesterase domain.
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Table
Table 1. Optimization of the reaction conditions for the 1,3-dipolar cycloaddition of dipolarophile 1a across 2-phenylglycine 2 and isatin 3a a.
Table 1. Optimization of the reaction conditions for the 1,3-dipolar cycloaddition of dipolarophile 1a across 2-phenylglycine 2 and isatin 3a a.
EntrySolventT (°C)Time (h)rr (4a:5a) bYield (%) c
1H2Ort2470:3025
2PhCH3rt2470:3029
3CH3CNrt2470:3035
4CH3CNreflux2478:2255
5EtOHreflux1278:2270
6iPrOHreflux1070:3065
7MeOHreflux678:2277
8MeOH/H2O 1:1reflux880:2065
9MeOH/H2O 2:1reflux685:1587
a The reaction was carried out in 0.5 mmol scale in solvent (10 mL), and the ratio of 1a/2/3a is 1:1.2:1. b The regioisomeric ratio (rr) was determined by the isolated yields of 4a and 5a. c Combined yield of isolated 4a and 5a.
Table
Table 2. Synthesis of dispiropyrrolidines 4 a.
Table 2. Synthesis of dispiropyrrolidines 4 a.
Entry1,2-diketoneArComp.rr (4:5) bYield (%) d
13aC6H54a + 5a85:1587
23ap-MeC6H44b + 5b78:22 c89
33ap-MeOC6H44c + 5c70:30 c85
43ap-ClC6H44d100:0080
53am-ClC6H44e100:0082
63a2-pyridyl4f100:0087
73a2-furfuryl4g100:0080
83bC6H54h + 5h81:19 c85
93bp-MeC6H44i + 5i85:1587
103bp-MeOC6H44j100:0084
113bp-ClC6H44k100:0081
123bm-ClC6H44l100:0088
133cC6H54m + 5m87:1390
143cp-MeC6H44n100:0088
153cp-MeOC6H44o100:0087
163cp-ClC6H44p100:0090
173cm-ClC6H44q100:0092
183c2-pyridyl4r100:0093
a The reaction was carried out in 3 mmol scale in MeOH/H2O (10 mL) at reflux for 6 h, and the ratio of 1/2/3 is 1:1.2:1. b Unless otherwise noted, the regioisomeric ratio (rr) was determined by the isolated yields of 4 and 5. c Determined by 1H-NMR analysis of the crude product. d Combined yields of isolated 4 and 5. e Failed to separate compound 5.
Table
Table 3. Synthesis of dispiropyrrolidines 7.
Table 3. Synthesis of dispiropyrrolidines 7.
EntryComp.1,2-diketoneArYield (%)
17a3aC6H585
27b3ap-MeC6H488
37c3ap-MeOC6H487
47d3ap-ClC6H480
57e3cC6H585
67f3cp-MeC6H483
77g3cp-MeOC6H487
87h3cp-ClC6H480
Table
Table 4. AChE and BChE inhibitory activities of spiroheterocyclic hybrids 4 and 7.
Table 4. AChE and BChE inhibitory activities of spiroheterocyclic hybrids 4 and 7.
CompoundDiketoneAminoacidAr% of Inhibition at 5 µg/mLAChE Inhibition, IC50
AChEBChEµg/mLµM
4a3a2C6H541.95 ± 0.01529.46 ± 0.015--
4b3a2p-MeC6H439.13 ± 0.0148.65 ± 0.011--
4c3a2p-MeOC6H442.34 ± 0.00123.33 ± 0.002--
4d3a2p-ClC6H450.09 ± 0.00631.36 ± 0.03211.75 ± 0.5822.21 ± 0.88
4e3a2m-ClC6H453.57 ± 0.00748.59 ± 0.0019.38 ± 0.4617.56 ± 0.70
4m3c2C6H549.10 ± 0.01117.98 ± 0.014--
4n3c2p-MeC6H470.56 ± 0.00214.20 ± 0.0006.10 ± 0.3011.42 ± 0.45
4o3c2p-MeOC6H435.55 ± 0.02321.37 ± 0.036--
4p3c2p-ClC6H442.55 ± 0.00720.93 ± 0.026--
7a3a2C6H530.39 ± 0.0174.16 ± 0.011--
7b3a6p-MeC6H451.25 ± 0.01520.62 ± 0.0208.27 ± 0.4116.02 ± 0.64
7c3a6p-MeOC6H442.78 ± 0.02311.00 ± 0.015--
7d3a6p-ClC6H440.24 ± 0.00214.15 ± 0.012--
7e3c6C6H560.00 ± 0.00924.72 ± 0.0009.65 ± 0.4820.44 ± 0.81
7f3c6p-MeC6H432.10 ± 0.00618.89 ± 0.020-
7g3c6p-MeOC6H443.00 ± 0.0017.29 ± 0.013-
7h3c6p-ClC6H438.10 ± 0.01427.11 ± 0.011-
Galantamine 0.60 ± 0.092.09 ± 0.11
Data presented as mean ± SD (n = 3).
Table
Table 5. Molecular docking of 4n.
Table 5. Molecular docking of 4n.
CompoundEnzymeFree Energy of Binding (kcal)ResidueActive SiteType of InteractionDistance
4nAChE−10.69TRP 279
TYR 70
TYR 334		Peripheral anionic siteπ-π5.13
5.59
4.95
5.50
Table
Table 6. Crystal data collection and structure refinement of 4b, 4j, 5j, and 7b.
Table 6. Crystal data collection and structure refinement of 4b, 4j, 5j, and 7b.
Compound/Formula4b
C66H54N6O6		4j
C36H26N3O3		5j
C36H26N2O3		7b
C32H26N2O3
Formula weight1027.15534.59534.59486.55
Temperature/K173(2)150(2)150(2)150(2)
Wavelength/Å0.710730.710730.710730.71069
Crystal systemTriclinicTriclinic OrthorhombicMonoclinic
Space groupP-1P-1P212121I2/a
a/Å12.6005(3)10.2431(6)11.2244(6)13.5410(11)
b/Å14.8515(4)11.2174(6)14.9261(6)16.0780(11)
c/Å16.7480(4)12.9289(6)15.9902(8)25.5975(19)
α69.932(2)°84.107(4)°90°90°
β71.396(2)°84.571(4)°90°96.332(7)°
γ76.6788(19)°33. 246(6)°90°90°
Volume/Å32764.18(13)1317.53(14)2678.9(2)5538.9(7)
Z2248
ρcalc g/cm31.2341.34841.3251.167
Absorp. coefficient/mm−10.0800.0860.0850.075
F(000)1080.01560.01120.02048.0
Crystal size/mm30.15 × 0.10 × 0.160.12 × 0.087 × 0.050.32 × 0.05 × 0.040.25 × 0.06 × 0.03
2 Theta range for data collection/°4.83 to 58.434.46 to 54.094.434 to 55.9944.868 to 58.304
Index ranges−17 ≤ h ≤ 17,−13 ≤ h ≤ 13,−13 ≤ h ≤ 14,−17 ≤ h ≤ 17,
−20 ≤ k ≤ 20,−14 ≤ k ≤ 14,−19 ≤ k ≤ 19,−21 ≤ k ≤ 21,
−22 ≤ l ≤ 22−16 ≤ l ≤ 16−21 ≤ l ≤ 21−34 ≤ l ≤ 34
Reflections collected144222276473937331906
Independent reflections14030 [R(int) = 0.0373]5732 [R(int) = 0.0502]6389 [R(int) = 0.0516]6779 [R(int) = 0.0848]
Refinement methodFull-matrix least-squares on F2Full-matrix least-squares on F2Full-matrix least-squares on F2Full-matrix least-squares on F2
Data/restraints/parameters1430/36/72145732/1/37456389/0/3746779/36/336
Goodness-of-fit on F21.0351.0401.0361.008
Final R indices [I > 2sigma(I)]R1 = 0.0507,R1 = 0.0461,R1 = 0.0441,R1 = 0.0480,
wR2 = 0.1342wR2 = 0.0883wR2 = 0.0804wR2 = 0.1172
Rindices (all data)R1 = 0.0666,R1 = 0.0734,R1 = 0.0616,R1 = 0.01227,
wR2 = 0.1450wR2 = 0.0986wR2 = 0.0863wR2 = 0.1374
Largest diff. peak and hole/e. Å−30.74 and −0.14500.24 and −0.250.18 and −0.270.22 and −0.25

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Boudriga, S.; Haddad, S.; Murugaiyah, V.; Askri, M.; Knorr, M.; Strohmann, C.; Golz, C. Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity. Molecules 2020, 25, 1963. https://doi.org/10.3390/molecules25081963

AMA Style

Boudriga S, Haddad S, Murugaiyah V, Askri M, Knorr M, Strohmann C, Golz C. Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity. Molecules. 2020; 25(8):1963. https://doi.org/10.3390/molecules25081963

Chicago/Turabian Style

Boudriga, Sarra, Saoussen Haddad, Vikneswaran Murugaiyah, Moheddine Askri, Michael Knorr, Carsten Strohmann, and Christopher Golz. 2020. "Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity" Molecules 25, no. 8: 1963. https://doi.org/10.3390/molecules25081963

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