LETTER
Heterobifunctionalized Oligo Ethylene Glycols
711
(13) Love, J. C.; Estroff, L. A.; Kriebel, J. K.; Nuzzo, R. G.;
do-amine 16 functionalities by respective in situ oxidation
(KH2PO4, NaClO2, H2O2) or reductive amination
(HCO2NH4, AcOH, NaCNBH3) of the intermediate alde-
hyde. All these functional groups are extremely versatile
and offer great opportunities to covalently link other enti-
ties by exploiting frequently adopted conjugation meth-
Whitesides, G. M. Chem. Rev. 2005, 105, 1103.
(14) Mrksich, M. Curr. Opin. Colloid Interface Sci. 1997, 2, 83.
(15) Kingshott, P.; Griesser, H. J. 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, C. R.; Bednarski, M. D. J. Org. Chem. 1991, 56,
4326.
(19) Cook, R. M.; Adams, J. H.; Hudson, D. Tetrahedron Lett.
1994, 35, 6777.
(20) Schwabacher, A. W.; Lane, J. W.; Schiesher, M. W.; Leigh,
K. M.; Johnson, C. W. J. Org. Chem. 1998, 63, 1727.
(21) Hervè, G.; Hahn, D. U.; Hervè, A. C.; Goodworth, K. J.;
Hill, A. M.; Hailes, H. C. Org. Biomol. Chem. 2003, 1, 427.
(22) Kohler, N.; Fryxell, G. E.; Zhang, M. J. Am. Chem. Soc.
2004, 126, 7206.
(23) Pilkington-Miska, M. A.; Sarkar, S.; Writer, M. J.; Barker,
S. E.; Shamlou, P. A.; Hart, S. L.; Hailes, H. C.; Tabor, A. B.
Eur. J. Org. Chem. 2008, 2900.
(24) Svedhem, S.; Hollander, C. Å.; Shi, J.; Konradsson, P.;
Liedberg, B.; Svensson, S. J. Org. Chem. 2001, 66, 4494.
(25) Loiseau, F.; Hii, K. K.; Hill, A. M. J. Org. Chem. 2004, 69,
639.
ods
(amide/peptide,
sulfide,
disulfide,
ester,
acetal/glycoside bonds). Furthermore, the azido and al-
kyne functionalities open the way to the exploitation of
the Huisgen ‘click’ azide-alkyne cycloaddition reaction,34
which currently finds many applications in the broad areas
of material science, drug discovery, and bioconjugation.
From compound 16 we also synthesized the biotin-azido
derivative 17 (biotin, EDC, HOBt), with the biotin moiety
being particularly attractive for macro-biomolecule graft-
ing.
In summary, we have demonstrated the efficient mono
and/or bidirectional elongation of EG4 obtained through
the introduction and chemical manipulation of the allyl
moiety.35,36 Moreover, we showed the possible conversion
of the terminal allyl into a set of different functional
groups, which are extremely useful for the generation of
heterobifunctional EGs derivatives.
Acknowledgment
(26) Ehteshami, G. R.; Sharma, S. D.; Porath, J.; Guzman, R. Z.
React. Funct. Polym. 1997, 35, 135.
CINMPIS Consortium has supported the work.
(27) Voelcker, N. H.; Klee, D.; Hanna, M.; Hoecker, H.; Bou, J.
J.; de Ilarduya, A. M.; Munoz-Guerra, S. Macromol. Chem.
Phys. 1999, 200, 1363.
Supporting Information for this article is available online at
m
iotSrat
ungIifoop
r
t
(28) Drioli, S.; Benedetti, F.; Bonora, G. M. React. Funct. Polym.
2001, 48, 119.
References and Notes
(29) La Ferla, B.; Zona, C.; Nicotra, F. Synlett 2009, 2325.
(30) Burkett, B. A.; Chan, T. H. Synlett 2004, 1007.
(31) Doyle, M. P.; 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.
(1) Harris, J. M. In Poly(ethylene glycol) Chemistry:
Biotechnical and Biomedical Applications; Harris, J. M.,
Ed.; Plenum Press: New York, 1992.
(2) Powell, G. M. In Polyethylene glycol. Handbook of Water
Soluble Gums and Resins; Davison, R. L., Ed.; McGraw-
Hill: New York, 1980, 18–21.
(34) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(3) Dreborg, S.; Akerblom, E. B. Crit. Rev. Ther. Drug Carrier
Syst. 1990, 6, 315.
(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
(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, B. A.; Grace, M.; Brassard, D.; Broders, R. Clin.
Ther. 2002, 24, 1363.
(8) Roberts, M. J.; Bently, M. D.; Harris, J. M. 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, G. S. 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, H. F.; Blanchemain, N.; Mayer, G.; Chai, F.;
Lefebvre, M.; Boschin, F. Surf. Coat. Technol. 2006, 200,
6318.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 709–712