A Synthetic Approach for Hepta-Branched β-Cyclodextrins Bearing Heterogeneous Carbohydrate Residues at Their Primary Side via a One-Pot Process with a Simultaneous Click Chemistry Reaction

Abstract

In this study, a synthetic approach is reported for generating hepta-branched β-cyclodextrins (CDs) bearing heterogeneous carbohydrate residues at their primary side via a one-pot process with a simultaneous click chemistry reaction. The reactions were performed by reacting two or three different species of 2-propynylated glycosides with a hepta-azide functional β-CD at various reaction molar ratios. 2-Propynylated glycosides acted as heterogeneous carbohydrate sources embedded into a hepta-azide functional β-CD. The simultaneous click chemistry reactions generated several desired β-CD derivatives with varying densities of the heterogeneous carbohydrates in a one-pot process. The article describes the effects of the combination of 2-propynylated glycosides and the reaction molar ratios in the click chemistry reactions.

Key words

cyclodextrin - click chemistry reaction - carbohydrate-branched cyclodextrin - heteroglycoconjugate - heterogeneous carbohydrate - simultaneous reaction

Publication History

Received: 19 October 2023

Accepted after revision: 01 November 2023

Accepted Manuscript online:
01 November 2023

Article published online:
06 December 2023

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• 33 Click Chemistry Reaction; Typical Procedure (Click Reaction (A))Sodium ascorbate (5.6 mg, 0.028 mmol) and copper sulfate (9.7 mg, 0.039 mmol) were added to a solution of 1 (137.8 mg, 0.29 mmol) and 2 (111.1 mg, 0.29 mmol) and 5 (71.0 mg, 0.037 mmol) in THF (3.5 mL)–H₂O (3.5 mL). After the reaction mixture was heated to 70 °C under microwave irradiation at 18 W for 40 min, and stirring for 20 min, the reaction was quenched by adding sat. NaCl aq. (3 mL). The mixture was extracted with EtOAc (three times), and the combined organic solvent was dried over anhydrous Na₂SO₄. The organic solvent was filtered and evaporated under reduced pressure. The crude product was purified by preparative silica-gel TLC (CH₂Cl₂/MeOH = 20:1) to afford a mixture of compounds 6–11 (164.5 mg, total yield of 90%).Click reaction (A): A mixture of 6–11 (containing regioisomers); ¹H NMR (CDCl₃): δ = 1.86–2.06 (Ac), 3.58 (CD-4), 4.05–5.68 (αArb-1,2,3,4,5,6, αGlcNAc-1,2,3,4,5,6, CD-1,2,3,5,6, OCH₂-triazole), 6.87–7.00 (Ph), 7.83–7.91 (CH₂CCHN); ¹³C NMR (CDCl₃): δ = 20.5–23.0 (Ac), 50.0 (CD-6), 51.5 (αGlcNAc-2), 60.3–70.4 (αArb-2,3,4,5,6, αGlcNAc-3,4,5,6, CD-2,3,4,5, OCH₂-triazole), 95.1 (αArb-1), 96.3–96.5 (αGlcNAc-1, CD-1), 115.5, 118.0 (Ph), 125.7 (CH₂CCH), 143.7 (CH₂ CCH), 150.5, 154.0 (Ph), 169.2-171.1 (C=O).Click reaction (B): A mixture of 12 (containing regioisomers); ¹H NMR (CDCl₃): δ = 2.03–2.08 (Ac), 3.56 (CD-4), 3.89–5.68 (αArb-1,2,3,4,5,6, βArb-1,2,3,4,5,6, CD-1,2,3,5,6, OCH₂-triazole), 6.84–7.00 (Ph), 7.77–7.79 (CH₂CCHN); ¹³C NMR (CDCl₃): δ = 20.5–20.6 (Ac), 50.0 (CD-6), 61.5-72.6 (αArb-2,3,4,5,6, βArb-2,3,4,5,6, CD-2,3,4,5, OCH₂-triazole), 95.0 (αArb-1), 96.2–96.7 (CD-1), 99.8 (βArb-1), 115.4–118.4 (Ph), 125.8 (CH₂CCH), 143.7 (CH₂ CCH), 150.5–151.2 (Ph), 169.2–170.5 (C=O).Click reaction (C): A mixture of 13–19 (containing regioisomers); ¹H NMR (CDCl₃): δ = 1.90–2.09 (Ac), 3.57–3.58 (CD-4), 4.04–5.68 (αArb-1,2,3,4,5,6, αMan-1,2,3,4,5,6, CD-1,2,3,5,6, OCH₂-triazole), 6.85–7.00 (Ph), 7.81–8.00 (CH₂CCHN); ¹³C NMR (CDCl₃): δ = 20.5–21.0 (Ac), 50.1 (CD-6), 60.3–70.0 (αArb-2,3,4,5,6, αMan-2,3,4,5,6, CD-2,3,4,5, OCH₂-triazole), 95.0 (αArb-1), 96.2–96.7 (CD-1), 96.8–97.0 (αMan-1), 115.4–118.0 (Ph), 125.7 (CH₂CCH), 143.3–143.7 (CH₂ CCH), 150.5–154.1 (Ph), 169.4–171.0 (C=O).Click reaction (D): A mixture of 20–24 (containing regioisomers); ¹H NMR (CDCl₃): δ = 1.77–1.97 (Ac), 3.47–3.48 (CD-4), 3.57–5.33 (βArb-1,2,3,4,5,6, αGlcNAc-1,2,3,4,5,6, CD-1,2,3,5,6, OCH₂-triazole), 6.29–6.84 (Ph), 7.62–7.78 (CH₂CCHN); ¹³C NMR (CDCl₃): δ = 20.9–23.1 (Ac), 50.0 (CD-6), 52.1 (αGlcNAc-2), 62.2–73.1 (αArb-2,3,4,5,6, αGlcNAc-3,4,5,6, CD-2,3,4,5, OCH₂-triazole), 96.0–97.0 (αGlcNAc-1, CD-1), 99.9 (βArb-1), 116.1, 119.1 (Ph), 126.6 (CH₂CCH), 144.3–144.5 (CH₂ CCH), 152.1, 155.0 (Ph), 170.2–172.0 (C=O).Click reaction (E); A mixture of 10, 11, 25 and 26 (containing regioisomers); ¹H NMR (CDCl₃): δ = 1.70–2.10 (Ac), 3.58 (CD-4), 3.95–5.68 (αArb-1,2,3,4,5,6, αGlcNAc-1,2,3,4,5,6, CD-1,2,3,5,6, OCH₂-triazole), 6.70–7.00 (Ph), 7.83–7.91 (CH₂CCHN); ¹³C NMR (CDCl₃): δ = 20.8–22.9 (Ac), 50.0 (CD-6), 51.7 (αGlcNAc-2), 61.0–70.9 (αArb-2,3,4,5,6, αGlcNAc-3,4,5,6, CD-2,3,4,5, OCH₂-triazole), 95.0 (αArb-1), 96.4–96.6 (αGlcNAc-1, CD-1), 115.5, 118.0 (Ph), 125.7 (CH₂CCH), 143.7 (CH₂ CCH), 150.5, 153.9 (Ph), 169.2-171.0 (C=O).Click reaction (F): A mixture of 27–31 (containing regioisomers); ¹H NMR (CDCl₃): δ = 1.85–2.54 (Ac), 3.59 (CD-4), 3.89–5.40 (βArb-1,2,3,4,5,6, αGlcNAc-1,2,3,4,5,6, αMan-1,2,3,4,5,6, CD-1,2,3,5,6, OCH₂-triazole), 6.70–7.32 (Ph), 7.83–7.84 (CH₂CCHN); ¹³C NMR (CDCl₃): δ = 20.5–22.9 (Ac), 50.0 (CD-6), 51.7 (αGlcNAc-2), 61.6–72.5 (βArb-2,3,4,5,6, αGlcNAc-3,4,5,6, αMan-2,3,4,5,6, CD-2,3,4,5, OCH₂-triazole), 96.0–97.0 (αGlcNAc-1, αMan-1, CD-1), 99.6 (βArb-1), 115.2, 118.2 (Ph), 125.7 (CH₂CCH), 143.7 (CH₂ CCH), 151.0, 154.0 (Ph), 169.0-170.8 (C=O).