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Synlett 2024; 35(12): 1417-1422
DOI: 10.1055/a-2202-4722
letter

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

Yoshiki Oda∗
a   Technology Joint Management Office, Tokai University, 4-1-1 ­Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
,
Takashi Yamanoi
b   Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-0295, Japan
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2202-4722
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Publication History

Received: 19 October 2023

Accepted after revision: 01 November 2023

Accepted Manuscript online:
01 November 2023

Article published online:
06 December 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
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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).