Download PDF
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)

    Permissions and Reprints All articles of this category

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

    References and Notes

  • 1a Adronov A. Fréchet JMJ. Chem. Commun.  2000,  1701 
    Google Scholar
  • 1b Gilat SL. Adronov A. Fréchet JMJ. Angew. Chem. Int. Ed.  1999,  38:  1422 
    Google Scholar
  • 2a Kleij AW. Gossage RA. Gebbink RJMK. Brinkmann N. Reijerse EJ. Kragl U. Lutz M. Speck AL. van Koten G. J. Am. Chem. Soc.  2000,  122:  12112 
    Google Scholar
  • 2b Mager M. Becke S. Windisch H. Denninger U. Angew. Chem. Int. Ed.  2001,  40:  1898 
    Google Scholar
  • 3 Kleiji AW. Gossage RA. Gebbink RJMK. Brinkmann N. Reijerse E. Vögtle F. Vicinelli V. Ceroni P. Maestri M. Balzani V. Angew. Chem. Int. Ed.  2002,  41:  3595 
    CrossrefGoogle Scholar
  • 4a Rajakumar P. Ganesan K. Jayavelu S. Murugesan K. Synth. Lett.  2005,  7:  1121 
    Google Scholar
  • 4b Gillies ER. Fréchet JMJ. J. Am. Chem. Soc.  2002,  124:  14137 
    Google Scholar
  • 4c Patri AK. Majoros IJ. Baker JR. Curr. Opin. Chem. Biol.  2002,  6:  466 
    Google Scholar
  • 4d Padilla De Jesus OL. Ihre HR. Gagne L. Fréchet JMJ. Szoka FC. Bioconjugate Chem.  2002,  13:  453 
    Google Scholar
  • 5a Wang Q. Chan TR. Hilgraf R. Fokin VV. Sharpless KB. Finn MG. J. Am. Chem. Soc.  2003,  125:  3192 
    Google Scholar
  • 5b Burley GA. Gierlich J. Mofid MR. Nir H. Tal S. Eichen Y. Carell T. J. Am. Chem. Soc.  2006,  128:  1398 
    Google Scholar
  • 6a Kukowska-Latallo JF. Candido KA. Cao Z. Nigavekar SS. Majoros IJ. Thomas TP. Balogh LP. Khan MK. Baker JR. Cancer Res.  2005,  65:  5317 
    Google Scholar
  • 6b Fuchs S. Otto H. Jehle S. Henklein P. Schlüter AD. Chem. Commun.  2005,  1830 
    Google Scholar
  • 6c Majoros IJ. Myc A. Thomas T. Mehta CB. Baker JR. Biomacromolecules  2006,  7:  572 
    Google Scholar
  • 7a Cloninger MJ. Curr. Opin. Chem. Biol.  2002,  6:  742 
    Google Scholar
  • 7b Boas U. Heegaard PMH. Chem. Soc. Rev.  2004,  33:  43 
    Google Scholar
  • 7c Shaunak S. Thomas S. Gianasi E. Godwin A. Jones E. Teo I. Mireskandari K. Luthert P. Duncan R. Patterson S. Khaw P. Brocchini S. Nat. Biotechnol.  2004,  22:  977 
    Google Scholar
  • 7d McCarthy TD. Karellas P. Henderson SA. Giannis M. O’Keefe DF. Heery G. Paull JRA. Matthews BR. Holan G. Mol. Pharm.  2005,  2:  312 
    Google Scholar
  • 7e Lee CC. MacKay JA. Fréchet JMJ. Szoka FC. Nat. Biotechnol.  2005,  23:  1517 
    Google Scholar
  • 8a Zhang Q. Ning Z. Yan Y. Qian S. Tian H. Macromol. Rapid Commun.  2008,  29:  193 
    Google Scholar
  • 8b Zhang Q. Ning Z. Tian H. Dyes Pigments  2009,  81:  80 
    Google Scholar
  • 9 Lee YC. Lee RT. Acc. Chem. Res.  1995,  28:  321 
    CrossrefGoogle Scholar
  • 10 Tornoe CM. Christensen C. Meldal MJ. J. Org. Chem.  2002,  67:  3057 
    CrossrefPubMedGoogle Scholar
  • 11 Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 
    Google Scholar
  • 12 Deguise I. Lagnoux D. Roy R. New J. Chem.  2007,  31:  1321 
    CrossrefGoogle Scholar
  • 13 Chabre YM. Contino-Pepin C. Placide V. Shiao TC. Roy R. J. Org. Chem.  2008,  73:  5602 
    CrossrefGoogle Scholar
  • 14 Rajakumar P. Ganesan K. Tetrahedron: Asymmetry  2005,  16:  2295 
    CrossrefGoogle Scholar
  • 15a Maikoch M. Schleicher K. Drockenmuller E. Hawker CJ. Russell T. Wu P. Forkin VV. Macromolecules  2005,  38:  3663 
    Google Scholar
  • 15b Fernandez-Megia E. Correa J. Riguera R. Biomacromolecules  2006,  7:  3104 
    Google Scholar
  • 16a Mourer M. Hapiot F. Tilloy S. Monflier E. Menuel S. Eur. J. Org. Chem.  2008,  5723 
    Google Scholar
  • 16b Coogan MP. Robert L. Jenkins A. Nutz E. J. Organomet. Chem.  2004,  689:  694 
    Google Scholar
17

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.

18

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.

19

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.

20

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.

21

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.

22

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.

23

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.

24

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.