Evaluating the enantioselective capability of a cellulose tris(3,5-dimethylphenyl carbamate)-based stationary phase towards 5,7,2'-trihydroxyflavanone

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In this study, an evaluation of the enantioselective of a chiral flavanone with 2'-OH substitution (5,7,2'- trihydroxyflavanone) on ring C was studied by high performance liquid chromatography using the cellulose tris(3,5- dimethylphenyl carbamate)-based stationary phase with n-hexane and iso-propanol doped with 0.1% (v/v) trifluoroacetic acid as a mobile phase.

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Nội dung Text: Evaluating the enantioselective capability of a cellulose tris(3,5-dimethylphenyl carbamate)-based stationary phase towards 5,7,2'-trihydroxyflavanone

Cite this paper: Vietnam J. Chem., 2023, 61(S2), 149-154 Research Article DOI: 10.1002/vjch.202300193 Evaluating the enantioselective capability of a cellulose tris(3,5-dimethylphenyl carbamate)-based stationary phase towards 5,7,2'-trihydroxyflavanone Nguyen Khanh Hung1,2, Nguyen Tuan Thanh1,2, Nguyen Thi Thuy Luyen1,2,4, Nguyen Huy Du1,2,3* 1 Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Road, District 5, Ho Chi Minh City 70000, Viet Nam 2 Vietnam National University of Ho Chi Minh City, Vo Truong Toan Road, Linh Trung Ward, Thu Duc City, Ho Chi Minh City 70000, Viet Nam 3 Central Laboratory of Analysis, University of Science, 227 Nguyen Van Cu Road, District 5, Ho Chi Minh City 70000, Viet Nam 4 Faculty of Geology, University of Science, 227 Nguyen Van Cu Road, District 5, Ho Chi Minh City 70000, Viet Nam Submitted June 6, 2023; Revised July 30, 2023; Accepted August 22, 2023 Abstract In this study, an evaluation of the enantioselective of a chiral flavanone with 2'-OH substitution (5,7,2'- trihydroxyflavanone) on ring C was studied by high performance liquid chromatography using the cellulose tris(3,5- dimethylphenyl carbamate)-based stationary phase with n-hexane and iso-propanol doped with 0.1% (v/v) trifluoroacetic acid as a mobile phase. Column temperature and mobile phase composition were investigated in the assessment of the chiral separation by considering the enantiomeric resolution factor (R s). Also, the absolute configurations of single enantiomers were determined by measuring CD spectra based on the exciton-coupling method. The results pointed out that the 2'-hydroxy group was capable of advancing the enantioselective of flavanones on the cellulose tris(3,5- dimethylphenyl carbamate)-based stationary phase when the column temperature was higher than 30 oC and the mobile phase was of 10% iso-propanol doped with 0.1% (v/v) TFA in n-hexane. The absolute configuration determination showed that the enantiomer with the 2S configuration was the first eluted and, consequently, the elution order of the enantiomers of 5,7,2'-trihydroxyflavanone at optimal conditions was in contrast to 5,7,4'-trihydroxyflavanone and 5,7- dihydroxyflavanone. The 2'-OH substitution on the phenyl moiety appears to be capable of inducing or altering the strength of inter-and intramolecular interactions when the chiral selectors are immobilized on the silica stationary phase. Keywords. Chiral separation, 5,7,2'-trihydroxyflavanone, enantioselective, HPLC. 1. INTRODUCTION based stationary phase is one of the most common chiral stationary phases (CSPs) used to separate Among the classes of flavanoids, flavanones are effectively enantiomers from racemate of organic considered as Citrus flavonoids due to their dominant compounds.[5] This CSPs has the ability of resolving content in Citrus fruits.[1,2] All flavanoids have a various flavanone with different substituents on C- chemical structure based on a fusion of chroman-4- ring. Currently, the biological activities of ()5,7,2'- one moiety (ring A and C) with C2-aryl group (ring trihydroxyflavanone (2'OH-TFVN) and its analogues B). Therefore, flavanones present a unique structural have been established and the synthetic route can only feature with a single chiral carbon center. yield a racemate of 2'-OH-TFVN.[6-9] However, the Trihydroxyflavanone (TFVN), which is one of HPLC method based on Cellulose tris(3,5- subclasses of flavanones[2] has been shown to have dimethylphenyl carbamate) CSPs are not available to more remarkable biological activities than their separate the single enantiomers of 5,7,2'- flavanone nuclei such as regulating hyperglycaemia, trihydroxyflavanone (2'OH-TFVN) efficiently thyroid dysfunction and lipid peroxidation in alloxan- whereas 4'-OH-TFVN was easily separable into its induced diabetic mice.[3,4] two enantiomers.[10,11] Cellulose tris(3,5-dimethylphenyl carbamate)- As a result, this study was synthesized and 149 Wiley Online Library © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300193 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Nguyen Huy Du et al. evaluated many factors which were capable of Spectral data were collected at a scanning speed of affecting on the thermodynamic of enantioselectivity 120 nm/min over the wavelength range of 200-400 of OD-H chiral stationary phases based on synthetic nm. The data pitch was 1 nm, and the bandwidth was flavanones such as mobile phase composition and 2.00 nm. The average of the three scans was used as column temperature. After separation, the absolute the final data. configuration of each enantiomer was determined by The HPLC instruments include: The Agilent 1200 CD spectra measurement with the exciton-coupling Series HPLC system (Agilent Technologies Vietnam method. Co., Ltd., Vietnam), the Chiralcel OD-H column (250 mm x 4.6 mm, i.d., 5 µm), the Intersil SiO2 column 2. MATERIALS AND METHOD (150 mm × 4.6 mm, i.d., 5 µm) 2.1. Chemicals and instrumentation 2.2. Investigation of enantiomeric separation based on mobile phase composition n-Hexane, iso-propanol (Scharlau, Spain) and trifluoroacetic acid (Fisher Chemicals, UK) were of In these experiments, enantiomers of 5,7,2'- HPLC grade. Mobile phases were mixed from above trihydroxyflavanone were separated in several mobile solvents without filtration before analysis. The other phases with different ratios of n-hexane/iso-propanol chemicals and reagents were of analytical or synthetic on a cellulose tris(3,5-dimethylphenyl carbamate)- grades. based stationary phase (OD-H column). ()-5,7,2'-trihydroxyflavanone (2'OH-TFVN) The working solution was prepared by diluting were synthesized in-house, as reported previously by the stock solution with n-hexane. Nguyen et al.[7] Structural molecule of this flavanone was confirmed by 1H-NMR spectra (see figure 1). 2.3. Investigation of enantiomeric separation 5,7-dihydroxy-2-(2-hydroxyphenyl)chroman-4- based on column temperature one (5,7,2'−trihydroxyflavanone): 1H-NMR (500 MHz, Acetone-d6): δ 5.80 (dd, J = 13.0 Hz, 3.0 Hz, Based on the obtained date from above experiments, 1H), 3.08 (dd, J = 17.5 Hz, 3Hz, 1H), 2.84 (dd, J = 17 a number of follow-up experiments were conduct to Hz, 3Hz, 1H), 5.98 (d, J = 2.1 Hz, 1H), 6.02 (d, J = investigate the separation of enantiomers according to 2.1 Hz, 1H), 6.94 (dd, J = 8.2, 1.2 Hz, 1H), 7.22 (td, the column temperature on OD-H stationary phase. J = 8.2, 1.6 Hz, 1H), 7.53 (dd, J = 7.7, 1.4 Hz, 1H) Investigation of enantiomeric separation in non- H acidic mobile phase. O O After determining the optimal conditions of mobile phase composition and column temperature for enantiomeric separation of ()-5,7,2'- A C trihydroxyflavanone, this study continued to HO O investigate the efficiency of the enantioseparation B when eliminating trifluoroacetic acid from mobile H O phase. Figure 1: 5,7,2'-trihydroxyflavanone and possible 3. RESULTS AND DISCUSSION intramolecular interaction of 2'OH group and O1 atom 3.1. The optimization of enantiomeric separation In the process of enantiomeric separation, 5,7,2'- on cellulose tris(3,5-dimethylphenyl carbamate)- trihydroxyflavanone was weighted and dissolved in based stationary phase iso-propanol accurately to prepare the stock solution with a concentration of 0.2 g/L. The storage condition In principle, the 2'-hydroxy group of 2'OH-TFVN of this solution was 4oC in the refrigerator. was capable of forming the hydrogen bonding with In the process of circular dichroism (CD) spectra O-1 atom.[12] Therefore, this study evaluated the measurement, each enantiomer of 5,7,2’- enantiomeric resolution (Rs) and the retention factor trihydroxyflavanone obtained from the preparative of the first and second eluted enantiomeric peak of chromatography with optimal conditions was this compound according to the mobile phase dissolved in methanol at approximately 0.5 g/L. The composition and temperature of OD-H column CD spectrum of the enantiomers was measured by a because of the significant influences on the Chirascan Circular Dichroism spectrometer (Applied thermodynamic parameters of chiral separation.[13, 14] Photophysics, UK) using a 10 mm optical cell. (see tables 1 and 2). © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 150
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300193 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Evaluating the enantioselective capability of ... Table 1: Thermodynamic parameters of column temperature was in the range of 5-30oC, and ()-5,7,2'-trihydroxyflavanone in mobile phase became higher when the column temperature was composition investigation at 30oC lower than 5oC or higher than 30oC (see table 2). The separation of the two enantiomers was resolved to be Entry %IPA (v/v) a Rs  k1 k2 most effective at a column temperature of 30oC when 1 5 - - - - Rs was at its good value for separation and  was not 2 7.5 4.18 1.27 8.53 10.85 too low. 3 10 2.73 1.20 4.15 4.98 4 20 1.63 1.18 0.93 1.10 5 30 1.16 1.18 0.46 0.54 a Percentage of iso-propanol (IPA) doped with 0.1% (v/v) of TFA in n-hexane at a flow rate of 1 mL/min; t0 = 2.85 min; injection volume 20 L;  = 290 nm. Figure 3: Plot of lnk vs 1/T for the separation of ()-5,7,2'-trihydroxyflavanone Table 2: Enantiomeric resolution (Rs) of ()-5,7,2'-trihydroxyflavanone phase in temperature investigation Entry T(oC) Rs  k1 k2 1 0.5 1.71 1.24 5.16 6.41 Figure 2: The first eluted enantiomer (k1) and 2 5 1.09 1.17 4.67 5.48 enantiomeric resolution (RS) of 2'-OH-TFVN 3 10 1.20 1.17 4.60 5.38 4 20 1.36 1.16 4.42 5.12 In the investigation of %IPA of 5% in the 5 30 1.50 1.14 4.27 4.87 composition of mobile phase, the signal of analyte 6 40 1.80 1.11 4.12 4.66 was unable to be recorded due to the very weak of HPLC conditions: %IPA = 7.5% (iso-propanol doped elution strength leading to the increasing of analysis with 0.1% (v/v) of TFA in n-hexane); flow rate of time as well as the low solubility of 2'OH-TFVN in 1 mL/min; t0 = 2.85 min; injection volume 20 L;  = the mobile phase. The results showed that (see Table 290 nm. 1) the Rs value decreased relatively quickly along with the retention of TFVN on OD-H column with the Caccamese et al. showed that the (S)-enantiomer increasing of iso-propanol content. The %IPA value of 2'OH-TFVN was eluted as the first peak, but the of 10% (v/v) performed the relatively high selectivity (S)-enantiomer of with 4'-hydroxyl group was eluted value with high resolution (S and R enantiomer). as the second peak on the OD-H column.[14] Our Notably, the retention factor, k, for both enantiomers findings showed that the enantio-separation of 2'OH- was reduced by approximately 2 times compared to TFVN on the OD-H column could be improved, the ratio of 7.5% (v/v) IPA, which was advantageous suggested that the enantio-separation of 2'OH-TFVN in terms of analysis time. The thermodynamic appear to be influenced by two opposing elution parameters of the enantiomer analysis, however, were trends. Indeed, the intermolecular hydrogen bond not guaranteed to be big enough if the IPA between the 2'-OH group and its binding sites on the concentration was too high. Therefore, a value of OD-H stationary phase will diminish when forming 10% (v/v) of IPA would be used for further the intramolecular hydrogen bond between O1–atom investigation of the enantiomeric separation and 2'-OH group. Furthermore, this intramolecular temperature. hydrogen bonding will be decayed when the column For the temparature investigation, the TFVN with temperature was high enough. On the other hand, our 2'-OH group showed the low Rs values when the results revealed that intramolecular hydrogen bond © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 151
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300193 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Nguyen Huy Du et al. between O1–atom and 2'-hydroxyl group rather utilization of CD spectrum in conjunction with NMR potent. Indeed, to better understand the spectroscopic data.[18] In the 1H-NMR spectra of thermodynamic process of separation, 5,7,2'-trihydroxyflavanone the signals of the H2 thermodynamic parameters need to be calculated proton; and the diastereotopic H3ax and H3eq protons based on the Van’t Hoff equation description to appeared at 5.80 ppm, 3.08, and 2.84 ppm as three clarify the dependence between lnk and 1/T.[13, 14] doublets of doublets, respectively. The value of the From there, a clearer view of the internal hydrogen coupling constant between H2 and H3ax was so large bonding of 2'OH and O1 atoms was obtained. The (J2,3ax = 17.0 Hz) which can only arise from a trans- slopes of regresstion linears related to the molar diaxial coupling, thus H2 was axial, and the 2-phenyl enthalpy change (H/R) of chiral separations. group had equatorial orientation. In addition, the Obviously, the difference in linear slope at 0-5 oC and simulation of 3D-(2S) and (2R) conformation by 5-40 oC indicated that the thermodynamic parameters MOE.2022 software also verified the compatability had changed. This has suggested that intramolecular of NMR spectra and the equatorial orientation of hydrogen bonding between 2'OH and O1 atom have phenyl group (see figure 5). an effect on the chiral regconition of 2'OH-TFVN on The ECD spectra of 5,7,2'-trihydroxyflavanone the OD-H column stationary phase. enantiomers shown in figure 4 were mirror images of each other, indicating their enantiomeric nature.[15] 3.2. The efficiency of isolating single enantiomers Basing on Safavi et al. study, the ring C of 2'OH- TFVN had the structure of half-chair conformation in In the process of enantioseparation, mobile phases which 2-aryl group existed predominantly in the doped with TFA is normally used to enhanced the equatorial orientation(19). 2'OH-TFVN enantiomer shape and resolution of analyte peaks.[16, 17] However, with the (2S)–configuration, therefore, showed a it is difficult to eliminate TFA from enantiomers after positive Cotton effect at around 330 nm (n→π* preparative HPLC due to the intense interaction transition) and a negative Cotton effect in the region between flavanones and TFA. Fortunately, after of 286-296 nm (π→π* transition); and 2'OH-TFVN conducting a lot of trials using the mobile phases with (2R)–configuration showed reversely Cotton without TFA, this study recognized that the effects. enantiomeric resolution value (Rs) was 2.50 and the k1 was 6.93, good enough to separate enantiomers (figure 6). As a result, the optimal conditions for enantioseparation of 5,7,2'-trihydroxyflavanone was of OD-H column at 30oC using non-acidic mobile phase of 7.5% iso-propanol in n-hexane. Based on the optimal HPLC condition, this study performed the isolation of the single enantiomers of 2'OH-TFVN. The chiral HPLC reruns of the collected elute showed that the enantiomeric excess (%ee) values of the first and second peak of 2'OH-TFVN were larger than 99% respectively. After filtration and evaporation of the collected elutes, the obtained Figure 4: The CD spectra of two enantiomer enantiomers were white powders. 4. CONCLUSION 3.3. The CD spectra results and the eluting order of enantiomers This research suggested the optimal conditions for the process of enantiomeric separation of 5,7,2'- The ECD spectra of enantiomers of (R) and (S) configuration of 5,7,2'-trihydroxyflavanone in trihydroxyflavanone on OD-H stationary phase using methanol was shown on figure 4, was summarized for a non-acidic mobile phase as a premise for the enantiomer identification, as followed: (2S, in separation of other enantiomers of other 2'OH MeOH): [θ]330 + 7,194; [θ]293 – 15,385; [θ]215 + flavanones. Consequently, after isolating, their 20,484; [θ]204 + 3,519. (2R, in MeOH): [θ]330 – 2,204; absolute configurations were determined by [θ]286 + 10,151; [θ]219 – 12,878; [θ]204 + 2,876. excitation-coupling method by CD spectra. According to previous study, the absolute Furthermore, the presence of the intramolecular configuration of flavanones was defined by hydrogen bonding between 2'-hydroxy group and O1- atom was also evaluated. To better understand the © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 152
25728288, 2023, S2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300193 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Evaluating the enantioselective capability of ... 2S 2R Figure 5: NMR spectra of C-ring conformation and the optimized conformations of (2S) and (2R)-5,7,2'- trihydroxyflavanone. These conformations were optimized by MOE.2022 software with AMBER12:EHT force field, solvated in gas phase and energy was minized to 0.0001 gradient mechanism of the 2'OH group influence on retention, List of abbreviations computational chemistry studies such as molecular TFA: Trifluoroacetic acid. dynamic simulations will be conducted in a follow-up eRs: Enantiomeric resolution. study CD spectrum: Circular Dichroism spectrum. HPLC: High performance liquid chromatography. TFVN: Trihydroxyflavanone. Conflict of interest statement. The authors declare that they have no competing interests. REFERENCES 1. T. Iwashina. The structure and distribution of the flavonoids in plants, J. Plant Res., 2000, 113(3), 287- 299 2. K. M. Brodowska. Natural flavonoids: Classification, Figure 6: Chromatogram of enantiomeric separation. potential role, and application of flavonoid analogues, Eur. J. Biol. Res., 2017, 7(2), 108-123. HPLC conditions: %IPA = 7.5% in n-hexane; flow rate of 1 mL/min; t0 = 2.85 min; injection volume 20 3. R. Mukai. Prenylation enhances the biological activity of dietary flavonoids by altering their bioavailability, L;  = 290 nm Biosci. Biotechnol. Biochem., 2018, 82(2), 207-215. 4. C. M. Santos, A. M. Silva. The antioxidant activity of Acknowledgements. We thank to all members of prenylflavonoids, Mol., 2020, 25(3), 696. Central Laboratory of Analysis for great supports in 5. K. Kalíková, M. Martínková, M. G. Schmid, Tesařová. this study. This research is funded by Vietnam Cellulose tris(3,5dimethylphenylcarbamate)‐based National University Ho Chi Minh City (VNU-HCM) chiral stationary phase for the enantioseparation of under grant number 562-2020-18-07. drugs in supercritical fluid chromatography: © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 153
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