New chalcone-3- O -glycoside derivatives: Synthesis and characterization

Abstract

Seven novel carbohydrate conjugates of new chalcone-3-O-glycosides were synthesized and characterized. Starting from the substituted 3′-hydroxyarylmethylacetophenone derivatives (chalcones) with α-acetobromoglucose in anhydrous acetone were synthesized 2,3,4,6-tetra-O-acetyl-3′-O-β-d-glucopyranosyloxychalcones. Deblocking the latter with CH₃ONa in dry methanol results in substituted chalcone-3-O-glycosides (3′-O-β-d-glucopyranosyloxychalcones). The structures of the newly synthesized chalcone-3-O-glycosides were characterized based on ¹H nuclear magnetic resonance, ¹³C nuclear magnetic resonance, mass spectroscopy, and Fourier-transform infrared spectroscopy.

Introduction

Chalcones, compounds bearing the 1,3-diaryl-2-propen-1-one system, play a vital role in chemical compounds associated with diverse pharmacological activities. ¹ Due to their flexible structures, chalcones can bind effectively to many kinds of enzymes or receptors and exhibit a broad spectrum of biological activities such as anticancer, ² anti-HIV, ³ anti-inflammatory,^4,5 anti-invasive,^6,7 and antibacterial properties. ⁸

Glycosylation of small biologically active molecules, either of natural or synthetic origin, has an effect on their solubility, and bioactivity. Notably, β-glucosylation improves the drug’s targeting to cells as well as their “solubility” in cell membranes.^9,10 O-glycosides are a family of carbohydrates widely found in plants with carbon–oxygen bond formation employing activated sugar.^11,12 Phenolic hydroxyl groups occur in the free state or in combined form as O-glycosides in plants where they play many interesting biological activities, such as antitumor activity and inhibitors of the metabolic process. ¹³

Much attention has been paid to chalcones as potential biological agents after the discovery of the natural chalcone-O-glycosides which demonstrated a broad spectrum of antibiotic, antifungal, and anti-HIV activity. ¹⁴ The isolation of some chalcone glycosides (see Scheme 1) from the aerial parts of Brassica rapa L. “hidabeni” has been reported. ¹⁵ However, to the best of the author’s knowledge, few reports have been dedicated to the synthesis and inhibitory activity of chalcone derivatives containing an O-glycoside skeleton.

Scheme 1.

Structures of isolated chalcone glycosides from Brassica rapa L. “hidabeni.”

In this study, preliminary results in the organic synthesis of some new chalcone-3-O-glycosides will be reported. Scheme 2 shows the synthetic analysis of the target molecules. Target molecules in this study are chalcones with various sugar substitutions at 3-position.

Scheme 2.

General route for the synthesis of chalcone-3-O-glycosides (5a–g).

Results and discussion

First, substituted chalcones starting from 3-hydroxyacetophenone and different aldehydes were synthesized at room temperature according to the Claisen–Schmidt condensation method, which is a single-step process and a practical method for the synthesis of substituted chalcone derivatives (Scheme 2). ¹⁶

In the second step, O-glucosylation reactions were performed by condensing α-acetobromoglucose (ACBG) and 3-hyroxychalcones (3a–g) at 0–5 °C using 5% aqueous potassium hydroxide (KOH) solution in dry acetone under an inert atmosphere. ¹³ Deacetylation by methanolic MeONa solution gave, after purification, chalcone-3-O-glycosides (5a–g) in good yield in favor of the β-anomer from 2,3,4,6-tetra-O-acetyl-3′-O-β-glucopyranosyloxybenzlideneacetophenones 4a–g see (Scheme 2). ¹⁷

The synthesis of chalcone-3-O-glycosides was achieved in this second step. The structures of all the compounds were confirmed by nuclear magnetic resonance (NMR), liquid chromatography–mass spectrometry (LC/MS–MS), and Fourier-transform infrared spectroscopy (FTIR; attenuated total reflection (ATR)), spectroscopy. The results were consistent with the predicted structures for all the new chalcone-3-O-glycosides, as described in section “Experiment”.

The β-configuration of the glycosidic bond was confirmed from ¹H NMR and ¹³C NMR. In the ¹H NMR spectrum of 5a–g, the anomeric proton appeared as a doublet at ~δ 5.03 (d, ~7.6 Hz) that confirmed the β-orientation of the sugar unit. ¹⁸ Characteristic pyranosyl ring protons were located at δ 3.40–3.96.

In the proton-decoupled ¹³C NMR, the anomeric carbon was located at δ ~101.00, which is consistent with the formation of the β-glucoside 5a–g. The mass spectrum of 3-((2E)-3-(2-thienyl)prop-2-enol-yl)phenyl hexopyranoside (5a) also confirmed the proposed structure of the chalcone-3-O-glycoside. The molecular ion peak was observed at m/z 393.0825 as (M+H)⁺, (1 0 0; see Electronic Supplementary Information (ESI)).

The structure of 3-((2E)-3-(2-thienyl)prop-2-enol-yl)phenyl hexopyranoside (5a) was confirmed by the appearance of the –C=O band at 1651 cm⁻¹ in the FTIR spectrum. The characteristic bands at 3343 and 1651 cm⁻¹ indicated the existence of –OH and –C=O groups, respectively.

In the ¹H NMR spectra of the synthesized chalcone-3-O-glycoside derivatives (5a–g), the α,β-protons resonated as doublet doublets (dd) between δ 7.74 and 7.59, which is characteristic for α,β-unsaturated carbonyl compounds. The olefinic H-atoms of chalcone-3-O-glycoside (5a–g) were shown to be trans based on their J values of 15.4–15.7 Hz for H_α and H_β. ¹⁹

In the ¹³C NMR spectra of the compound 5e, the characteristic carbon–fluorine signals appear at 131.32/131.29 $({\mathrm{C}}_2^{″})$ , 115.74/115.52 $({\mathrm{C}}_3^{″})$ , 165.44/162.95 $({\mathrm{C}}_4^{″})$ , 131.32/131.29 $({\mathrm{C}}_5^{″})$ , and 115.74/115.52 $({\mathrm{C}}_6^{″})$ (see ESI). ²⁰

The mass spectra of compounds 5a–g showed molecular ion peaks at the appropriate m/z values confirming their molecular mass. In the ¹H and ¹³C NMR spectra of compounds 5a–g, in particular, anomeric protons and anomeric carbons showed peaks at, respectively, δ_H 5.03 (1H, d) and δ_C 101.00 ppm; which are an indication of the β-configuration of the chalcone-3-O-glycosides (5a–g).

Conclusion

The synthesis of seven new chalcone-3-O-glycosides, which can be used to make more glycosylated chalcone, is reported in this study. The structures of the synthesized chalcone and chalcone-3-O-glycoside have been confirmed by NMR, LC/MS–MS, and FTIR (ATR) spectroscopy. Chalcones are important α,β-unsaturated ketones and constitute a class of naturally occurring substances, which are very attractive bioactive starting materials for the synthesis of substituted chalcone-O-glycosides.

Experiment

¹ H and ¹³C NMR spectra were recorded on a 400 (100)-MHz Bruker Avance spectrometer in methanol-d₄; δ is given in ppm relative to Me₄Si (tetramethylsilane (TMS)) as an internal standard. The following abbreviations are used: s = singlet, d = doublet, dd = doublet doublet, t = triplet, m =multiplet, bs =broad singlet, bd = broad doublet. The high-resolution accurate masses were determined using Micromass Quattro LC–MS/MS. The IR spectra were recorded on a Perkin Elmer 1600 Fourier transform infrared (FTIR-ATR) spectrophotometer. Compounds 3a–g were synthesized by the method described by Narender et al. ²¹ NMR, MS, IR data, and melting point of the known compounds were consistent with those reported previously.^22–28

Synthesis of chalcones (3a–g): general procedure

Compounds 3a–g were synthesized according to the previously reported procedure.^22–28

Synthesis of 2,3,4,6-tetra-O-acetyl-3′-O-β-glucopyranosyloxybenzlideneacetophenones (4a–g): general procedure

The 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (0.411 g, 1 mmol) was dissolved in dry acetone (20 mL) and cooled to 0–3 °C. To this, a solution of the potassium salt of 3′-hydroxybenzylideneacetophenones (1 mmol) in 5% methanolic KOH (10 mL) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at 0–3 °C for 8 h and the reaction was allowed to proceed for an additional 10 h at room temperature. After stirring for 19 h, the resultant solution was partitioned with EtOAc, distilled water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified using silica gel 230–400 mesh eluting with 20% MeOH in CHCl₃ to obtain compounds 4a–g as orange syrups.

The general method for 3′-O-β-glucopyranosyloxybenzlideneacetophenones 5a–g

A freshly prepared solution of MeONa–MeOH (3 mL, 0.05 M) was added to a solution of 2,3,4,6-tetra-O-acetyl-3′-O-β-glucopyranosyloxybenzlideneacetophenones 4a–g (0.1 g) in 20 mL dry methanol and kept at room temperature under a nitrogen atmosphere. The progress of the reaction was followed by silica gel thin-layer chromatography (TLC; CHCl₃–MeOH, 3:1). The reaction was stopped after 24 h. The mixture was extracted with EtOAc (3 × 10 mL), the combined organic phases were successively washed with H₂O (2 × 10 mL), dried over Na₂SO₄ and concentrated. The syrupy residue was purified on silica gel using CHCl₃–MeOH (9/1 to 7/3, then 6/4, v/v).

3-[(2E)-3-(2-thienyl)prop-2-enol-yl]phenyl hexopyranoside (5a): Orange oil; yield 98 mg (25%); ¹H NMR (CD₃OD): δ 7.45 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 15.6 Hz, 1H), 7.75 (bs, 1H), 7.40 (bd, J = 7.8 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.16 (dd, J = 8.2, 4.6 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 5.06 (d, J = 7.6 Hz, 1H), 3.60–3.40 (m, 4H), 3.72 (dd, J = 12.4, 4.1 Hz, 1H), 3.94 (dd, J = 12.4, 2.1 Hz, 1H); ¹³C NMR (CD₃OD): δ 189.84, 122.13, 137.45, 139.21, 116.97, 158.03, 122.98, 129.60, 122.13, 140.01, 132.36, 128.24, 129.53, 101.00, 73.49, 76.84, 69.95, 76.52, 61.04; MS (ESI) m/z for C₁₉H₂₀O₇S [M+1]⁺: 393 (90), 282 (50); IR (ATR) (v, cm⁻¹): 3343, 2962, 1651, 1574, 1251, 1071, 711.

3-[(2E)-3-(4-nitrophenyl)prop-2-enol-yl]phenyl hexopyranoside (5b): Orange oil; yield 87 mg (20%); ¹H NMR (CD₃OD): δ 7.83 (d, J = 15.6 Hz, 1H), 7.93 (d, J = 15.6 Hz, 1H), 7.80 (bs, 1H), 7.40 (dd, J = 7.6, 3.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.84 (m, 1H), 8.00 (d, J = 7.8 Hz, 2H), 8.32 (d, J = 7.8 Hz, 2H), 5.06 (d, J = 7.6 Hz, 1H), 3.60–3.40 (m, 4H), 3.72 (dd, J = 12.4, 4.1 Hz, 1H), 3.94 (dd, J = 12.4, 2.1 Hz, 1H); ¹³C NMR (CD₃OD): δ 189.57, 123.68, 141.56, 138.83, 115.84, 158.08, 121.73, 129.65, 122.43, 141.12, 129.27, 125.42, 148.59,125.42, 129.27, 100.97, 74.34, 76.95, 70.22, 76.55, 61.17; MS (ESI) m/z for C₂₁H₂₁NO₉ [M+Na]⁺: 454 (25), 282 (100); IR (ATR) (v, cm⁻¹): 3364, 2926, 1669, 1515, 1337, 1246, 1046, 754.

3-[(2E)-3-(4-dimethylaminophenyl)prop-2-enol-yl]phenyl hexopyranoside (5c): Orange oil; yield 94 mg (22%); ¹H NMR (CD₃OD): δ 7.72 (d, J = 15.4 Hz, 1H), 7.78 (d, J = 15.4 Hz, 1H), 7.42 (s, 1H), 7.34 (dd, J = 9.4, 2.1 Hz, 1H), 7.48 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H), 6.78 (d, J = 7.8 Hz, 2H), 3.06 (s, 6H), 5.02 (d, J = 7.7 Hz, 1H), 3.60–3.40 (m, 4H), 3.74 (dd, J = 12.2, 3.7 Hz, 1H), 3.94 (dd, J = 12.2, 2.1 Hz, 1H); ¹³C NMR (CD₃OD): δ 190.70, 122.27, 146.83, 140.11, 116.00, 157.97, 122.27, 129.41, 122.06, 122.27, 130.58, 111.60, 152.65, 111.60, 130.28, 58.09, 101.03, 73.51, 76.88, 70.17, 76.53, 61.09; MS (ESI) m/z for C₂₃H₂₇NO₇ [M+1]⁺: 430 (95), 282 (15); IR (ATR) (v, cm⁻¹): 3376, 2923, 1644, 1571, 1243, 1076, 785.

3-[(2E)-3-(4-methoxyphenyl)prop-2-enol-yl]phenyl hexopyranoside (5d): Yellow oil; yield 124 mg (30%); ¹H NMR (CD₃OD): δ 7.60 (d, J = 15.7 Hz, 1H), 7.72 (d, J = 15.7 Hz, 1H), 7.74 (m, 1H), 7.38 (m, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.74 (m, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.00 (d, J = 7.6 Hz, 2H), 3.75 (s, 3H), 5.01 (d, J = 7.8 Hz, 1H), 3.60–3.40 (m, 4H), 3.74 (dd, J = 12.2, 4.1 Hz, 1H), 3.94 (dd, J = 12.3, 2.2 Hz, 1H); ¹³C NMR (CD₃OD): δ 190.56, 123.33, 146.83, 140.14, 139.57, 116.52, 158.00, 122.21, 129.41, 122.60, 127.79, 131.42, 114.13, 162.16, 131.42, 114.13, 54.53, 101.00, 73.50, 76.88, 69.94, 76.52, 61.10; MS (ESI) m/z for C₂₂H₂₄O₈ [M+1]⁺: 417 (100); IR (ATR) (v, cm⁻¹): 3290, 2924, 1656, 1585, 1250, 1022, 793.

3-[(2E)-3-(4-fluorophenyl)prop-2-enol-yl]phenyl hexopyranoside (5e): Yellow oil; yield 113 mg (28%); ¹H NMR (CD₃OD): δ 7.70 (d, J = 15.6 Hz, 1H), 7.82 (d, J = 15.6 Hz, 1H), 7.39 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.86–7.75 (m, 4H), 5.03 (d, J = 7.6 Hz, 1H), 3.60–3.40 (m, 4H), 3.72 (dd, J = 12.1, 4.0 Hz, 1H), 3.96 (bd, J = 12.2 Hz, 1H); ¹³C NMR (CD₃OD): δ 190.22, 122.69, 143.66, 139.23, 116.47, 158.01, 122.33, 129.58, 122.69, 131.47, 131.32/131.29, 115.74/115.52, 165.44/162.95, 131.32/131.29, 115.74/115.52, 103.98, 74.73, 76.78, 70.70, 76.52, 61.13; MS (ESI) m/z for C₂₁H₂₁FO₇ [M+1]⁺: 405 (100); IR (ATR) (v, cm⁻¹): 3310, 2926, 1672, 1580, 1225, 1045, 790.

3-[(2E)-3-(4-chlorophenyl)prop-2-enol-yl]phenyl hexopyranoside (5f): Yellow oil; yield 85 mg (20%); ¹H NMR (CD₃OD): δ 7.40 (d, J = 15.6 Hz, 1H), 7.52 (d, J = 15.6 Hz, 1H), 7.80 (m, 1H), 7.30 (m, 1H), 7.44 (m, 1H), 7.78 (m, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 5.01 (d, J = 7.7 Hz, 1H), 3.60–3.40 (m, 4H), 3.74 (dd, J = 12.3, 4.1 Hz, 1H), 3.94 (bd, J = 12.3 Hz, 1H); ¹³C NMR (CD₃OD): δ 190.09, 122.33, 143.33, 139.16, 116.16, 158.05, 122.20, 129.88, 122.33, 133.61, 129.59, 129.38, 136.12, 129.38, 129.88, 100.99, 73.50, 76.91, 69.98, 76.54, 61.13; MS (ESI) m/z for C₂₁H₂₁CIO₇ [M+1]⁺: 421 (90); IR (ATR) (v, cm⁻¹): 3348, 2919, 1658, 1579, 1245, 1010, 822, 782.

3-[(2E)-3-(4-bromophenyl)prop-2-enol-yl]phenyl hexopyranoside (5g): Yellow oil; yield 116 mg (25%); ¹H NMR (CD₃OD): δ 7.45 (d, J = 15.4 Hz, 1H), 7.48 (d, J = 15.4 Hz, 1H), 7.74 (bs, 1H), 7.33 (m, 1H), 7.40 (m, 1H), 7.78 (m, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 7.6 Hz, 2H), 5.03 (d, J = 7.8 Hz, 1H), 3.60–3.40 (m, 4H), 3.72 (dd, J = 12.1, 3.9 Hz, 1H), 3.95 (dd, J = 12.1, 1.3 Hz, 1H); ¹³C NMR (CD₃OD): δ 190.09, 124.40, 143.42, 139.13, 116.48, 158.02, 122.24, 129.60, 122.73, 133.96, 129.60, 131.58, 124.42, 129.60, 131.58, 100.97, 74.19, 76.89, 69.97, 76.53, 61.13; MS (ESI) m/z for C₂₁H₂₁BrO₇ [M]⁺: 465 (95); IR (ATR) (v, cm⁻¹): 3362, 2921, 1662, 1579, 1249, 1069, 776.

Supplemental Material

Supplementary_File – Supplemental material for New chalcone-3-O-glycoside derivatives: Synthesis and characterization

Supplemental material, Supplementary_File for New chalcone-3-O-glycoside derivatives: Synthesis and characterization by Gonca Çelik in Journal of Chemical Research