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Synlett 2009(9): 1417-1422  
DOI: 10.1055/s-0029-1217170
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Click Chemistry Approach for the Synthesis of Water-Soluble Glycodendrimer with Triazole as Building Unit

Perumal Rajakumar*, Ramasamy Anandhan, Venkatesan Kalpana
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600025, India
Fax: +91(44)22300488; e-Mail: perumalrajakumar@hotmail.com;
Further Information

Publication History

Received 2 February 2009
Publication Date:
13 May 2009 (online)

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Abstract

A new family of chiral glycodendrimers scaffolds containing di-, tetra- and octavalent glucose residues as peripheral unit and with 1,2,3-triazole as building unit has been synthesized through Cu(I)-catalyzed click chemistry by convergent approach.

Key words

click chemistry - glycodendrimers - chiral (S)-BINOL - alkynes - azide - 1,2,3-triazole

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General Procedure for the Cu-Catalyzed Huisgen ‘Click Reaction’: Acetylenic derivative (1.0 mmol) was mixed with acetylated carbohydrate azide (2.1 mmol, 2.1 equiv) in t-BuOH and H2O mixture (1:1, 8 mL) solution. Sodium ascorbate (0.4 mmol, 0.4 equiv) was added as a solid, followed by the addition of CuSO4 (0.2 mmol, 0.2 equiv). The reaction was stirred overnight at r.t. The solvent was evaporated under reduced pressure and the crude product was dissolved in EtOAc (100 mL), washed with NH4Cl solution (50 mL), brine solution (50 mL) and H2O (50 mL) and then dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by column chromatog-raphy (SiO2) with hexane-EtOAc as eluent to give the corresponding triazole compound.

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General Procedure for the Conversion of Dendritic Chlorides to Azides: Dendritic chloride (1.0 mmol) was dissolved in acetone and H2O (4:1, 8 mL). NaN3 (1.5 mmol, 1.5 equiv) was added, and the mixture was heated at 60 ˚C for 3 h. The reaction mixture was cooled to r.t., acetone was evaporated and the reaction mixture was diluted with H2O (100 mL), and extracted with EtOAc (2 × 100 mL). The organic layer was washed with sat. NaCl (50 mL), dried over Na2SO4, and evaporated to give the dendritic azide.

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First-Generation Dendritic Azide 11: white solid; yield: 99%; R f 0.6 (EtOAc-hexane, 1:1); mp 133 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.78, 1.96, 2.00 (3 × s, 24 H), 3.92-3.97 (m, 2 H), 4.04-4.11 (m, 2 H), 4.21-4.26 (m, 4 H), 5.13 (s, 4 H), 5.18-5.21 (m, 2 H), 5.32-5.43 (m, 4 H), 5.84 (d, J = 2.7 Hz, 2 H), 6.50 (d, J = 2.1 Hz, 2 H), 6.57 (d, J = 2.1 Hz, 1 H), 7.86 (s, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 19.1, 19.5, 19.5, 19.6, 53.6, 60.6, 60.9, 66.8, 69.4, 71.7, 74.2, 84.8, 100.6, 106.8, 120.3, 137.0, 143.6, 158.6, 167.9, 168.4, 168.9, 169.5. MS (FAB): m/z = 987 [M+]. Anal. Calcd for C41H49N9O20: C, 49.85; H, 5.00; N, 12.76. Found: C, 49.81; H, 4.96; N, 12.51.

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Second-Generation Dendritic Azide 13: white solid; yield: 99%; R f 0.72 (EtOAc-hexane, 7:3); mp 159 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.82, 2.02, 2.05, 2.07 (4 × s, 48 H), 4.02-4.05 (m, 4 H), 4.11-4.17 (m, 4 H), 4.24 (d, J = 4.8 Hz, 2 H), 4.27-4.32 (m, 4 H), 5.14 (s, 8 H), 5.17 (s, 4 H), 5.27 (t, J = 9.6 Hz, 4 H), 5.39-5.50 (m, 12 H), 5.93 (d, J = 8.7 Hz, 4 H), 6.51 (s, 4 H), 6.59 (s, 2 H), 6.60 (s, 1 H), 6.64 (s, 2 H), 7.63 (s, 2 H), 7.96 (s, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 20.1, 20.5, 20.5, 20.6, 54.0, 54.6, 61.6, 61.8, 62.1, 67.7, 70.4, 72.6, 75.1, 85.8, 101.7, 107.9,107.7, 107.8, 121.6, 123.0, 137.0, 144.2, 144.3, 159.4, 159.7, 168.9, 169.4, 169.9, 170.5. MS (FAB): m/z = 2217 [M+]. Anal. Calcd for C95H109N21O42: C, 51.46; H, 4.95; N, 13.27. Found: C, 51.41; H, 4.90; N, 13.14.

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General Procedure for the De-O-acetylation (Zemplen Reaction): Acetylated dendrimers (1.0 mmol) was dissolved in a mixture of anhyd MeOH-anhyd THF-anhyd CH2Cl2 (16 mL, 6:1:1) and to this mixture was added a solution of sodium methoxide (1 M MeOH) until pH 9-10 was reached. The reaction was stirred at r.t. for 48 h. At the end, H2O was added for entire solubilization of desired compound and the solution was neutralized by addition of ion-exchange resin (Amberlite IR 120 H+) until pH 6-7 was attained. The solution was filtered and the solvent was removed in vacuo with rotary evaporator. The residue was then lyophilized to yield the fully deprotected glycodenrimer in a ca. 99% yield.

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Glycodendrimer 2: white solid; yield: 95%; [α]D ²5 +44.5
(c = 1, DMSO). IR (KBr): 3404, 1372, 1230, 1042, 826 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 3.21 (d, J = 8.4 Hz, 4 H), 3.55-3.66 (m, 8 H), 5.18 (q, J = 3.6 Hz, 4 H), 5.43 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 7.22 (t, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.75-7.78 (m, 4 H), 7.94 (d, J = 9.0 Hz, 2 H), 8.06 (d, J = 9.0 Hz, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 60.4, 62.2, 72.0, 76.4, 79.4, 87.2, 115.8, 119.3, 123.0, 123.9, 124.4, 126.5, 128.9, 129.5, 133.2, 143.2, 143.2, 153.4. MS (FAB): m/z = 772 [M+]. Anal. Calcd for C38H40N6O12: C, 59.06; H, 5.22; N, 10.88. Found: C, 59.03; H, 5.20; N, 10.87.

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Glycodendrimer 4: white solid; yield: 92%; [α]D ²5 +15.5
(c = 1, DMSO). IR (KBr): 3426, 1595, 1412, 1046, 834 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 3.00 (s, 8 H), 3.43-3.56 (m, 8 H), 4.85-4.94 (m, 12 H), 5.14 (s, 8 H), 5.31 (d, J = 9.0 Hz, 4 H), 5.54 (s, 4 H), 6.26 (s, 4 H), 6.53 (s, 2 H), 6.60 (d, J = 8.4 Hz, 2 H), 7.90 (t, J = 7.5 Hz, 2 H), 7.04 (t, J = 7.5 Hz, 2 H), 7.34 (s, 2 H), 7.45 (d, J = 9.0 Hz, 2 H), 7.65 (d, J = 9.0 Hz, 2 H), 7.76 (d, J = 9.0 Hz, 2 H), 8.20 (s, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 52.7, 60.5, 60.8, 62.3, 69.2, 72.0, 76.6, 79.4, 87.4, 100.8, 107.1, 115.8, 119.3, 123.8, 124.0, 124.3, 126.3, 128.0, 128.9, 129.4, 133.1, 137.7, 142.4, 143.5, 153.2, 159.3. MS (MALDI-TOF): m/z = 1665 [M+]. Anal. Calcd for C76H84N18O26: C, 54.80; H, 5.08; N, 15.14. Found: C, 54.79; H, 5.08; N, 15.11.

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Glycodendrimer 6: white solid; yield: 92%; [α]D ²5 +2.2
(c = 1, DMSO). IR (KBr): 3390, 1598, 1461, 1384, 1168, 1047, 828 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 3.24 (s, 16 H), 3.68-3.82 (m, 16 H), 5.07 (s, 8 H), 5.11 (s, 16 H), 5.18 (d, J = 4.8 Hz, 8 H), 5.32 (d, J = 3.6 Hz, 12 H), 5.44 (d, J = 9.0 Hz, 8 H), 5.54 (s, 8 H), 5.57 (s, 4 H), 6.45 (s, 4 H), 6.62 (s, 8 H), 6.71 (s, 2 H), 6.77 (s, 4 H), 6.81 (d, J = 8.4 Hz, 2 H), 7.10 (t, J = 7.8 Hz, 2 H), 7.24 (t, J = 6.6 Hz, 2 H), 7.52 (s, 2 H), 7.66 (d, J = 8.7 Hz, 2 H), 7.83 (d, J = 7.5 Hz, 2 H), 7.96 (d, J = 8.4 Hz, 2 H), 8.29 (s, 4 H), 8.32 (s, 8 H). ¹³C NMR (75 MHz, CDCl3): δ = 52.8, 60.5, 60.8, 62.2, 69.2, 72.0, 76.6, 79.4, 87.3, 100.9, 107.1, 115.7, 119.3, 123.8, 124.0, 124.3, 124.8, 125.7, 126.3, 127.8, 127.9, 128.8, 129.2, 129.3, 133.0, 137.6, 138.0, 142.4, 142.7, 143.5, 153.2, 159.1, 159.2. MS (MALDI-TOF): m/z = 3451 [M+]. Anal. Calcd for C152H172N42O54: C, 52.90; H, 5.02; N, 17.05. Found: C, 52.89; H, 5.02; N, 17.02.