Bridging chiral de - tert - butylcalix [ 4 ] arenes: Optical resolution based on column chromatography and structural characterization

: As the third - generation supramolecular main structure, calixarenes, especially chiral calixarenes, have been applied to various ﬁ elds. In this study, the bridging chiral de - tert - butylcalix [ 4 ] arene derivatives with an amide group attached to a chiral point was synthesized for the ﬁ rst time, which provided a new group for its structural derivation at the bridging chiral position. The racemic compound 2 was optically resolved by column chromato graphy on silica gel with the aid of the chiral auxiliary ( 1 S )-(+)- 10 - camphorsulfonyl chloride, and ﬁ nally a pair of optically pure bridging chiral de - tert - butylcalix [ 4 ] arene derivatives 4a and 4b were obtained. The results of experi mental and calculated ECD showed that compounds 4a and 4b were a pair of enantiomers, and their absolute con ﬁ g urations were designated S and R , respectively. This study provides new idea for the derivatization of speci ﬁ c chiral groups based on bridging chiral calix [ 4 ] arenes and their chiral resolution.

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-butylcalix [4]arenes 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 calix [4]arenes.

Results and discussion
Using de-tert-butylcalix [4]arenes as the starting material, bridging chiral de-tert-butylcalix [4]arene derivative 1 monobridge-substituted with an equatorial N,N′-dimethylformamidyl group could be prepared through a homologous anionic ortho-Fries rearrangement in high yield [9]. 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-butylcalix [4]arene with an equatorial amide  group 2. Subsequently, (1S)-(+)-10-camphorsulfonyl chloride was used as a chiral auxiliary, and under the action of Cs 2 CO 3 in CH 3 CN 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 ( α D

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[ ] = +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 1 H 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 orthobenzene 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.

Conclusion
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-butylcalix [4]arene and obtained the first bridging chiral de-tert-butylcalix [4]arene 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 calix [4]arene 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.

Experimental section
General information: All chemicals were purchased from commercial sources and used without further purification. 1 H nuclear magnetic resonance (NMR) and 13 C NMR spectra were recorded at 300 MHz ( 1 H) and at 75.5 MHz ( 13 C). CDCl 3 (δ 7.26 ppm) or TMS (δ 0.00 ppm) was used as an internal standard for 1 H NMR spectra, and CDCl 3 (δ 77.00 ppm) or TMS (δ 0.00 ppm) was used as an internal standard for 13 C 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 CH 2 Cl 2 (3 mL × 60 mL) and washed with saturated NaCl solution (3 mL × 60 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 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). 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.