As the third-generation supramolecular main structure, calixarenes, especially chiral calixarenes, have been applied to various fields. In this study, the bridging chiral de-tert-butylcalixarene derivatives with an amide group attached to a chiral point was synthesized for the first time, which provided a new group for its structural derivation at the bridging chiral position. The racemic compound 2 was optically resolved by column chromatography on silica gel with the aid of the chiral auxiliary (1S)-(+)-10-camphorsulfonyl chloride, and finally a pair of optically pure bridging chiral de-tert-butylcalixarene derivatives 4a and 4b were obtained. The results of experimental and calculated ECD showed that compounds 4a and 4b were a pair of enantiomers, and their absolute configurations were designated S and R, respectively. This study provides new idea for the derivatization of specific chiral groups based on bridging chiral calixarenes and their chiral resolution.
With its unique three-dimensional cavity structure, calixarene has become the third-generation supramolecular host molecule after crown ether and cyclodextrin. Calixarenes derivatives are widely used in biomedicine , nanoscience , and chemical sensors . In particular, the application of chiral calixarenes derivatives in chiral recognition [4,5] and molecular asymmetric catalysis [6,7,8] has broad application prospects.
Intrinsically chiral calixarenes contain two major family members: inherently chiral calixarenes [9,10] and bridging chiral calixarenes [11,12,13]. Inherently chiral calixarenes are derived from asymmetric substitution only on the phenyl rings and (or) oxygen atom. The bridging chiral calixarenes exhibit asymmetric substitution on the bridged methylene group. Figure 1 takes de-tert-butylcalixarenes as an example to show its two intrinsically chiral structures. Although inherently chiral calixarenes have been studied for decades and applied to many fields, its chiral recognition ability and asymmetric catalytic efficiency are often not satisfactory. The exciting thing is that the unique bridging chiral calixarenes will provide a platform for the construction of specific chiral hosts and catalysts and will point out a new direction for future development. However, there are two main reasons that limit the further application of bridging chiral calixarenes, one is the problem of optical purification of bridging chiral calixarenes, and the other is the lack of further derivable groups on the chiral structure, such as amide, amino, or carboxyl groups. Here, we focus on the derivation of amide group. As an important derivative group, amide can be modified to the required groups through reduction reaction, Hoffman degradation reaction, and so on.
In this study, we introduced an amide group on the chiral group of the chiral calixarenes for the first time and used chiral auxiliary (1S)-(+)-10-camphorsulfonyl chloride to perform optical resolution on it by column chromatography. The absolute configurations of the enantiomers 4a and 4b were determined by electron circular dichroism (ECD) experiment and calculation. This study provides a new method for the structure derivation and chiral resolution of bridging chiral calixarenes.
2 Results and discussion
Using de-tert-butylcalixarenes as the starting material, bridging chiral de-tert-butylcalixarene derivative 1 monobridge-substituted with an equatorial N,N′-dimethylformamidyl group could be prepared through a homologous anionic ortho-Fries rearrangement in high yield . As shown in the synthetic route of Figure 2, first, the N,N′-dimethylformamide group was hydrolyzed in toluene under the action of strong acid methanesulfonic acid and formed an unstable lactone structure with the phenol hydroxyl group on the ortho-benzene of the chiral center. The reaction solution did not require posttreatment, and ammonia water was added at 0°C to obtain the bridging chiral de-tert-butylcalixarene with an equatorial amide group 2. Subsequently, (1S)-(+)-10-camphorsulfonyl chloride was used as a chiral auxiliary, and under the action of Cs2CO3 in CH3CN at room temperature, a nucleophilic substitution reaction occurred with the phenolic hydroxyl group on compound 2 to obtain a pair of diastereomeric mixtures 3a and 3b. The molar ratio between the chiral auxiliary and compound 2 was 1:1. Fortunately, the R f values of the diastereomers 3a and 3b were 0.46 and 0.40, respectively, with visible separation points. They could be successfully separated through silica gel column chromatography, with the total yield reaching 86% (2a, 45%; 2b, 41%). Finally, the chiral auxiliary (1S)-(+)-10-camphorsulfonyl group on the diastereomers 3a and 3b was removed to obtain a pair of enantiomers 4a ( = –7.7) and 4b ( = +7.8) under alkaline conditions.
The theoretical ECD spectra of 4a and 4b were calculated by quantum chemistry method, according to the relative spatial relationship between the bridging center and propyl group, and compared with those of methanol. As shown in Figure 3a, at room temperature, the experimental ECD spectra of 4a and 4b in MeOH at a concentration of 1.0 × 10−4 g/L showed a pair of excellent mirror images, proving that they were a pair of enantiomers. As shown in Figure 3b, the ECD spectra of compounds 4a and 4b calculated at TD-B3LYP/6-31G (d)//B3LYP/6-31G (d) level showed an acceptable fit with their experimental spectra in terms of band form and sign with respect to wavelength. According to the results of ECD experiment and calculation, the absolute configurations of compounds 4a and 4b could be assigned as S and R, respectively.
In the process of hydrolyzing N,N-dimethylformamide in compound 1, we tried many hydrolysis reagents, including strong acids such as p-toluenesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid, and trifluoroacetic acid, as well as some strong bases. However, these hydrolysis reagents were difficult to react. In the end, under our continuous attempts and efforts to replace the reaction solvent, we found that methane sulfonic acid had a good hydrolysis effect on the N,N-dimethylformamide group of compound 1. Compared with several strong acids tried before, methanesulfonic acid is more acidic, resulting in the hydrolysis of N,N-dimethylformamide. Interestingly, when analyzing the structure of compound 2, we were pleasantly surprised to find that during the hydrolysis of compound 1, a propoxy group in the structure was also hydrolyzed to a phenolic hydroxyl group, which had been confirmed by 1H NMR spectrum and high-resolution mass spectrometry. As shown in Figure 4, according to the intermolecular hydrogen bond (H-bond) interaction, the phenolic hydroxyl group after the hydrolysis of the propoxy group and the phenolic hydroxyl group on the two ortho-benzene rings, respectively, formed intramolecular H-bond interactions, which marked the chemical shift of the phenol hydroxyl group after the hydrolysis of propoxy group larger, and the peak shaped wider and shorter. This indicated that the activity of phenolic hydroxyl group after hydrolysis of propoxy group was significantly higher than that of phenolic hydroxyl group on two ortho-benzene rings, which was conducive to the hydrolysis of N,N-dimethylformamide and the formation of lactone. In addition, according to the hydrogen spectrum structure of compound 3a, it was found that after the resolution reagent reacted with the phenolic hydroxyl group, the broad and low peak disappeared, which further indicated that the resolution reagent reacted with the phenolic hydroxyl group after the hydrolysis of propoxy group.
As the main structure of the third-generation supramolecular, calixarenes have been widely used in various fields. This study focused on the structure of bridging chiral de-tert-butylcalixarene and obtained the first bridging chiral de-tert-butylcalixarene with an amide group attached to the chiral point. Using the chiral auxiliary (1S)-(+)-10-camphorsulfonyl chloride, the racemic compound 2 was optically resolved to obtain a pair of optically pure bridging chiral calixarene derivatives 4a and 4b, and the experimental and calculated results of ECD spectra proved that they were a pair of enantiomers. This study provides a new method for the derivatization and resolution of bridging chiral calixarenes.
4 Experimental section
General information: All chemicals were purchased from commercial sources and used without further purification. 1H nuclear magnetic resonance (NMR) and 13C NMR spectra were recorded at 300 MHz (1H) and at 75.5 MHz (13C). CDCl3 (δ 7.26 ppm) or TMS (δ 0.00 ppm) was used as an internal standard for 1H NMR spectra, and CDCl3 (δ 77.00 ppm) or TMS (δ 0.00 ppm) was used as an internal standard for 13C NMR spectra. The following abbreviations are used to indicate the multiplicity in NMR spectra: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and J indicates the NMR coupling constant measured in Hertz. The courses of the reactions were monitored by thin layer chromatography (TLC) using TLC aluminium sheets with Silica gel 60 GF254. The column chromatography was performed using Silica gel 60. Optical rotations were measured using a polarimeter with a 1 dm path length. Experimental circular dichroism spectra were recorded in a quartz cuvette of 1 mm optical path length. High-resolution mass spectra (HRMS) were measured on a mass spectrometer equipped with a time of flight (TOF) system and an electrospray ionization (ESI) ion source.
Compound 2. A mixture of compound 1 (3.00 g, 5.06 mmol) and methanesulfonic acid (1.64 mL, 25.30 mmol) in toluene (100 mL) was stirred at 110°C for 3 h. After the reaction was completed by TLC analysis, the heating device was removed, and the reaction temperature was reduced to 0°C under the condition of ice bath. A 25% aqueous ammonia solution (40 mL) was slowly added dropwise, and the reaction was stopped after stirring for 1 h. The mixture was extracted with CH2Cl2 (3 mL × 60 mL) and washed with saturated NaCl solution (3 mL × 60 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (PE:EA = 3:1) to obtain the intermediate 2 (1.65 g, 62% yield).
Compound 2: White solid. M.p. 196.5–198.2°C. 1H NMR (400 MHz, DMSO-d 6) δ 9.14 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 7.49 (t, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.07–7.21 (m, 6H), 6.92 (dd, J = 1.6 Hz, J = 7.2 Hz, 1H), 6.83 (t, 1H), 6.61–6.68 (m, 2H), 6.55–6.60 (t, 1H), 5.57 (s, 1H), 4.14–4.24 (m, 2H), 4.10 (d, J = 13.6 Hz, 1H), 4.01–4.07 (m, 1H), 3.88–3.97 (m, 1H), 3.58 (d, J = 13.2 Hz), 3.47 (s, J = 12.8 Hz, 1H), 3.42 (d, J = 13.6 Hz, 1H), 1.92–2.02 (m, 2H), 1.21 (t, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 172.7, 150.8, 150.5, 150.4, 148.1, 132.8, 128.1, 128.0, 127.6, 127.6, 127.4 (3C), 127.3, 127.3, 127.1, 126.9, 126.5, 126.5, 125.5, 124.4, 119.8, 118.8, 118.3, 116.9, 77.0, 30.6, 29.8 (2C), 29.2, 21.7, 9.6 ppm. HRMS (ESI): calcd for C32H31NO5 [M + H]+ 510.2280; found 510.2278.
Compounds 3a and 3b. To a stirred solution of compound 2 (1.50 g, 2.86 mmol) in dry CH3CN (80 mL) was slowly added Cs2CO3 (2.80 g, 8.58 mmol) under ice-bath. After stirring for 10 min, (1S)-10-camphorsulfonyl chloride (1.08 g, 4.29 mmol) was added, the reaction was continued for 2.5 h at room temperature until the reaction was completed and quenched with dilute hydrochloric acid solution. The aqueous layer was extracted with CH2Cl2, extracted twice, and the combined organic layers were washed with saturated NaCl solution and dried over anhydrous Na2SO4. The resulting residue was purified by column chromatography on silica gel (PE: EA = 2:1) to obtain the intermediates 3a and 3b (0.93 g, 45% yield for 3a; 0.85 g, 41% yield for 3b).
Compound 3a: White solid. M.p. 225.5–227.3°C. 1H NMR (400 MHz, DMSO-d 6) δ 9.82 (s, 1H), 9.12 (s, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 7.05–7.19 (m, 6H), 6.97 (t, 1H), 6.85 (t, 1H), 6.62–6.72 (m, 2H), 5.74 (s, 1H), 4.53 (d, J = 13.2 Hz, 1H), 4.17–4.25 (m, 1H), 3.95–4.10 (m, 4H), 3.55–3.66 (m, 2H), 3.51 (d, J = 14.4 Hz, 1H), 3.50 (d, J = 14.4 Hz, 1H), 2.31–2.47 (m, 2H), 2.17–2.28 (m, 2H), 2.19 (t, 1H), 1.98–2.06 (m, 2H), 1.57–1.67 (m, 1H), 1.44–1.52 (m, 1H), 1.13 (t, 3H), 1.02 (s, 3H), 0.92 (s, 3H); 13C NMR (101 MHz, DMSO-d 6) δ 212.2, 171.1, 151.3, 150.4, 147.8, 141.8, 134.2, 133.4, 132.5, 130.4, 129.3, 129.2, 128.7, 128.2, 128.1, 127.7, 127.7, 127.5, 127.3, 127.2, 126.0, 124.9, 124.5, 124.0, 120.4, 118.6, 77.3, 56.5, 46.8, 46.2, 41.2, 40.9, 29.9, 29.8, 29.2, 28.9, 25.1, 24.0, 21.4, 18.2, 18.0, 8.8 ppm. HRMS (ESI): calcd for C32H31NO5 [M + H]+ 724.2944; found 724.2942.
Compound 3b: White solid. M.p. 232.4–234.2°C. 1H NMR (400 MHz, DMSO-d 6) δ 9.83 (s, 1H), 9.11 (s, 1H), 7.49–7.42 (m, 2H), 7.27 (m, 2H), 7.21–7.04 (m, 6H), 6.98 (t, 1H), 6.92–6.81 (m, 1H), 6.67 (m, 2H), 5.75 (s, 1H), 4.53 (d, J = 13.1 Hz, 1H), 4.26–4.15 (m, 2H), 4.05 (d, J = 2.0 Hz, 1H), 4.01 (d, J = 2.1 Hz, 1H), 3.82 (d, J = 14.3 Hz, 1H), 3.68–3.57 (m, 3H), 3.51 (d, J = 13.6 Hz, 1H), 2.44–2.34 (m, 2H), 2.28–2.19 (m, 2H), 2.13 (t, J = 4.5 Hz, 1H), 2.04–1.96 (m, 2H), 1.68–1.62 (m, 1H), 1.50–1.44 (m, 1H), 1.18–1.08 (m, 6H), 0.92 (s, 3H); 13C NMR (101 MHz, DMSO-d 6) δ 213.1, 172.0, 152.3, 151.4, 148.9, 143.1, 135.3, 134.5, 133.5, 131.5, 130.2, 130.2, 129.9, 129.3, 129.2, 128.8, 128.8, 128.6, 128.4, 128.2, 127.1, 126.1, 125.6, 125.0, 121.5, 119.7, 78.4, 57.5, 48.0, 46.8, 42.5, 41.9, 31.0, 30.8, 30.4, 30.0, 26.2, 25.4, 22.5, 19.2, 19.1, 9.9 ppm. HRMS (ESI): calcd for C32H31NO5 [M + H]+ 724.2944; found 724.2939.
Compounds 4a and 4b. To a solution of compound 3a (or 3b) (0.5 g, 0.69 mmol) in CH3CN (30 mL) and water (10 mL) was added NaOH (0.14 g, 3.45 mmol). The reaction mixture was heated to 80°C and stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure. The residue was neutralized with dilute hydrochloric acid and extracted with CH2Cl2 (30 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The product was further purified by silica gel column chromatography (PE:EA = 3:1) to give 4a (or 4b) as a white powder (0.34 g, 94% yield for 4a; 0.33 g, 92% yield for 4b).
Compound 4a: White solid. M.p. 192.4–196.3°C. 1H NMR (400 MHz, DMSO-d 6) δ 9.14 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 7.44–7.56 (m, 2H), 7.30 (d, J = 6.8 Hz, 1H), 7.05–7.21 (m, 6H), 6.92 (d, J = 7.2 Hz, 1H), 6.83 (t, 1H), 6.61–6.68 (m, 2H), 6.58 (t, 1H), 5.57 (s, 1H), 4.14–4.25 (m, 2H), 4.10 (d, J = 13.6 Hz, 1H), 3.99–4.06 (m, 1H), 3.89–3.97 (m, 1H), 3.58 (d, J = 13.2 Hz, 1H), 3.39–3.51 (m, 2H), 1.90–2.05 (m, 2H), 1.21 (t, 3H); 13C NMR (101 MHz, DMSO-d 6) δ 173.7, 151.9, 151.6, 151.5, 149.2, 133.9, 129.2, 129.1, 128.7, 128.7, 128.6, 128.5 (3C), 128.4, 128.3, 128.2, 127.9, 127.6, 127.6, 126.5, 125.5, 120.8, 119.9, 119.3, 78.1, 31.6, 30.9, 30.2, 30.0, 22.8, 10.7 ppm. HRMS (ESI): calcd for C32H31NO5 [M + H]+ 510.2280; found 510.2277.
Compound 4b: White solid. M.p. 197.7.4–199.3°C. 1H NMR (400 MHz, DMSO-d 6) δ 9.10 (s, 1H), 8.67 (d, 2H), 7.45–7.57 (m, 2H), 7.31 (d, J = 6.8 Hz, 1 H), 7.05–7.20 (m, 6H), 6.92 (d, J = 7.2 Hz, 1H), 6.83 (t, 1H), 6.61–6.68 (m, 2H), 6.58 (t, 1H), 5.58 (s, 1H), 4.15–4.26 (m, 2H), 4.10 (d, J = 13.2 Hz, 1H), 3.99–4.07 (m, 1H), 3.88–3.98 (m, 1H), 3.58 (d, J = 13.6 Hz, 1H), 3.39–3.52 (m, 2H), 1.90–2.05 (m, 2H), 1.21 (t, 3H); 13C NMR (101 MHz, DMSO-d 6) δ 173.8, 151.9, 151.6, 151.5, 149.3, 133.9, 129.2, 129.1, 128.7, 128.7 (2C), 128.5 (3C), 128.4, 128.4, 128.2, 128.0, 127.6, 127.6, 126.6, 125.5, 120.8, 119.9, 119.4, 78.1, 31.6, 30.9, 30.2, 30.0, 22.8, 10.7 ppm. HRMS (ESI): calcd for C32H31NO5 [M + H]+ 510.2280; found 510.2278.
We thank Shandong Key Laboratory of Clinical Applied Pharmacology for its support.
Funding information: This study is supported by the Medical and Health Science and Technology Development Project of Shandong Province of China (202013050426, 2019WS598).
Author contributions: Wen-Shan Liu: conceptualization, writing – original draft, methodology; Hong-Ying Li: methodology, writing – original draft; Hai-Xia Zhang: formal analysis; Xiu-Yuan Han: data curation, validation; Xi-Chun Guo: software; and Chuan-Hua Ding: project administration, funding acquisition.
Conflict of interest: The authors report no conflicts of interest in this study.
Ethical approval: The conducted research is not related to either human or animal use.
Data availability statement: The data used to support the findings of this study are included within the supplementary information file.
 Rodik RV, Klymchenko AS, Mely Y, Kalchenko VI. Calixarenes and related macrocycles as gene delivery vehicles. J Incl Phenom Macrocycl Chem. 2014;80(3–4):189–200. 10.1007/s10847-014-0412-8.Search in Google Scholar
 Shirakawa S, Moriyama A, Shimizu S. Synthesis, optical resolution and enantiomeric recognition ability of novel, inherently chiral calixarenes: trial application to asymmetric reactions as organocatalysts. Eur J Org Chem. 2008;35:5957–64. 10.1002/ejoc.200800850.Search in Google Scholar
 Maftei CV, Fodor E, Jones PG, Franz MH, Davidescu CM, Neda I. Asymmetric calixarene derivatives as potential hosts in chiral recognition processes. Pure Appl Chem. 2015;87(4):415–39. 10.1515/pac-2014-1121.Search in Google Scholar
 Wezenberg SJ, Kleij AW. Cooperative activation in the hydrolytic kinetic resolution of epoxides by a bis-cobalt(III)salen-calixarene hybrid. Adv Synth Catal. 2010;352(1):85–91. 10.1002/adsc.200900673.Search in Google Scholar
 Akceylan E, Uyanik A, Eymur S, Sahin O, Yilmaz M. Calixarene-proline functionalized iron oxide magnetite nanoparticles (Calix-Pro-MN): an efficient recyclable organocatalyst for asymmetric aldol reaction in water. Appl Catal A Gen. 2015;499:205–12. 10.1016/j.apcata.2015.04.018.Search in Google Scholar
 Middel O, Greff Z, Taylor NJ, Verboom W, Reinhoudt DN, Snieckus V. The first lateral functionalization of calixarenes by a homologous anionic Ortho-Fries rearrangement. J Org Chem. 2000;65(3):667–75. 10.1021/jo990976y.Search in Google Scholar
 Xu WQ, Liu WS, Yan JX, Ma SK, Guo J, Liu JM, et al. An approach to optically pure bridging chiral p-tert-butylcalixarenes through a homologous anionic ortho-fries rearrangement. J Org Chem. 2016;81(22):10683–87. 10.1021/acs.joc.6b01682.Search in Google Scholar PubMed
 An FJ, Xu WQ, Zheng S, Ma SK, Li SY, Wang RL, et al. Bridging chiral calixarenes: description, optical resolution, and absolute configuration determination. Eur J Org Chem. 2016;5:1012–6. 10.1002/ejoc.201501467.Search in Google Scholar
 Liu WS, He D, Ma H, Weng XF, Ren SS, Liu X, et al. Bridging chiral de-tert-butylcalixarenes: diastereomeric crystallization-based optical resolution and determination of absolute configuration. ChemistrySelect. 2018;3(36):10153–56. 10.1002/slct.201802804.Search in Google Scholar
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