Controlled-Length Efficient Synthesis of Heterobifunctionalized Oligo Ethylene Glycols

Cristiano Zona; Giuseppe D’Orazio; Barbara La Ferla

doi:10.1055/s-0032-1318433

Synlett, Table of Contents

Synlett 2013; 24(6): 709-712
DOI: 10.1055/s-0032-1318433

letter

Controlled-Length Efficient Synthesis of Heterobifunctionalized Oligo Ethylene Glycols

Cristiano Zona

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy Fax: +39 0264483565 Email: barbara.laferla@unimib.it

,

Giuseppe D’Orazio

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy Fax: +39 0264483565 Email: barbara.laferla@unimib.it

,

Barbara La Ferla*

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy Fax: +39 0264483565 Email: barbara.laferla@unimib.it

› Author Affiliations

Abstract

All articles of this category

Abstract

A set of heterobifunctional oligo ethylene glycols have been synthesized in a straightforward and stepwise manner starting from inexpensive, commercially available, tetraethylene glycol. Introduction of terminal allyl moieties followed by reductive ozonolysis allowed controlled elongation. Mono-allyl derivatives were used for the elongation with a functionalized moiety and for successive introduction of different functional groups on the chain terminal.

Key words

ethylene glycols - heterobifunctional - spacers - biomolecule grafting - elongation

Full Text

References

References and Notes
1 Harris JM In Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications. Harris JM. Plenum Press; New York: 1992
2 Powell GM In Polyethylene glycol. Handbook of Water Soluble Gums and Resins. Davison RL. McGraw-Hill; New York: 1980: 18-21
3 Dreborg S, Akerblom EB. Crit. Rev. Ther. Drug Carrier Syst. 1990; 6: 315
4 Yamaoka T, Tabata Y, Ikada Y. J. Pharm. Sci. 1994; 83: 601
5 Zalipsky S. Adv. Drug Delivery Rev. 1995; 16: 157
6 Zalipsky S. Bioconjugate Chem. 1995; 6: 150
7 Luxon BA, Grace M, Brassard D, Broders R. Clin. Ther. 2002; 24: 1363
8 Roberts MJ, Bently MD, Harris JM. Adv. Drug Delivery Rev. 2002; 54: 459
9 Bruckdorfer T. Eur. Biopharm. Rev. 2008; 96
10 Mourtas S, Canovi M, Zona C, Aurilia D, Niarakis A, La Ferla B, Salmona M, Nicotra F, Gobbi M, Antimisiaris GS. Biomaterials 2011; 32: 1635
11 Le Droumaguet B, Nicolas J, Brambilla D, Maksimenko A, Salvati E, De Kimpe L, Zona C, Airoldi C, Canovi M, Gobbi M, Noiray M, La Ferla B, Nicotra F, Scheper W, Flores O, Masserini M, Andrieux K, Couvreur P. ACS Nano 2012; 6: 5866
12 Hildebrand HF, Blanchemain N, Mayer G, Chai F, Lefebvre M, Boschin F. Surf. Coat. Technol. 2006; 200: 6318
13 Love JC, Estroff LA, Kriebel JK, Nuzzo RG, Whitesides GM. Chem. Rev. 2005; 105: 1103
14 Mrksich M. Curr. Opin. Colloid Interface Sci. 1997; 2: 83
15 Kingshott P, Griesser HJ. Curr. Opin. Solid State Mater. Sci. 1999; 4: 403
16 Novabiochem supply protected (P = Boc/Fmoc) P-NH-(PEG)_n-COOH (n ranging from 2 to 27) and prices from 300 to 1000 USD/g; N-Biotinyl-NH(PEG)₁₁-COOH (quantity and price on request); NanoCs present a considerable catalogue of mono- and di-funcionalized PEGs, but the products are not monodispersed. Same consideration for SigmaAldrich.
17 Zalipsky S. Bioconjugate Chem. 1995; 6: 150
18 Bertozzi CR, Bednarski MD. J. Org. Chem. 1991; 56: 4326
19 Cook RM, Adams JH, Hudson D. Tetrahedron Lett. 1994; 35: 6777
20 Schwabacher AW, Lane JW, Schiesher MW, Leigh KM, Johnson CW. J. Org. Chem. 1998; 63: 1727
21 Hervè G, Hahn DU, Hervè AC, Goodworth KJ, Hill AM, Hailes HC. Org. Biomol. Chem. 2003; 1: 427
22 Kohler N, Fryxell GE, Zhang M. J. Am. Chem. Soc. 2004; 126: 7206
23 Pilkington-Miska MA, Sarkar S, Writer MJ, Barker SE, Shamlou PA, Hart SL, Hailes HC, Tabor AB. Eur. J. Org. Chem. 2008; 2900
24 Svedhem S, Hollander CÅ, Shi J, Konradsson P, Liedberg B, Svensson S. J. Org. Chem. 2001; 66: 4494
25 Loiseau F, Hii KK, Hill AM. J. Org. Chem. 2004; 69: 639
26 Ehteshami GR, Sharma SD, Porath J, Guzman RZ. React. Funct. Polym. 1997; 35: 135
27 Voelcker NH, Klee D, Hanna M, Hoecker H, Bou JJ, de Ilarduya AM, Munoz-Guerra S. Macromol. Chem. Phys. 1999; 200: 1363
28 Drioli S, Benedetti F, Bonora GM. React. Funct. Polym. 2001; 48: 119
29 La Ferla B, Zona C, Nicotra F. Synlett 2009; 2325
30 Burkett BA, Chan TH. Synlett 2004; 1007
31 Doyle MP, Hu W. J. Org. Chem. 2000; 65: 8839
32 Tahtaoui C, Parrot I, Klotz P, Guillier F, Galzi J.-L, Hibert M, Ilien B. J. Med. Chem. 2004; 47: 4300
33 Buskas T, Söderberg E, Konradsso P, Fraser-Reid B. J. Org. Chem. 2000; 65: 958
34 Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2001; 40: 2004
35 Monoallylation of EG; Typical Procedure: To a solution of EG 1 (1 equiv) in anhydrous DMF (0.5 M) was slowly added NaH (60% w/w in mineral oil, 2 equiv) and the mixture was reacted for 20 min. Allyl bromide (1.4 equiv) was added dropwise to the solution, which was stirred at r.t. overnight. The reaction mixture was then filtered to remove the precipitate and the solvent was removed under vacuum to afford the crude product, which was further purified by flash chromatography (petroleum ether–EtOAc, 8:2→1:9, with 2% MeOH as additive) to afford the desired product monoallyl 3 (51%). ¹H NMR (400 MHz, CDCl₃): δ = 2.82 (s, 1 H, OH), 3.51–3.66 (m, 16 H), 3.94 (d, J = 5.7 Hz, 2 H, CH₂CH=CH₂), 5.13–5.26 (m, 2 H, CH₂CH=CH₂), 5.87–5.99 (m, 1 H, CH₂CH=CH₂).
36 Conversion of the Allyl Unit into a Terminal Ethylene Glycol Unit; Typical Procedure: O₃ gas was bubbled, at –78 °C, into a 0.03 M solution of 8 (1 equiv) in CH₂Cl₂. The solution was stirred at r.t. until the disappearance of starting material was observed, then Ar gas was bubbled through the mixture. After 15 min, NaBH₄ (2 equiv) was added to the resulting solution, which was allowed to react at r.t. until the disappearance of ozonide intermediates was observed. After the addition of acetone to quench unreacted NaBH₄, the solvent was removed in vacuum and the crude product was purified by flash chromatography (CH₂Cl₂–EtOH, 9.5:0.5) to afford 13 (81%). ¹H NMR (400 MHz, CDCl₃): δ = 3.70–3.65 (m, 2 H, HOCH₂CH₂O), 3.65–3.58 (m, 26 H, OCH₂CH₂O and HOCH₂CH₂O), 3.56 (t, J = 5.0 Hz, 2 H, OCH₂CH₂N₃), 3.34 (t, J = 5.0 Hz, 2 H, OCH₂CH₂N₃).

Supplementary Material

Supporting Information