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DOI: 10.1055/s-2006-950246
Synthesis of a Heterobifunctional PEG Spacer Terminated with Aminooxy and Bromide Functionality
Publication History
Publication Date:
09 October 2006 (online)
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Abstract
A simple and efficient synthesis of a novel heterobifunctional polyethylene glycol (PEG) spacer is described. The PEG spacer reagent is terminated with aminooxy and bromide functionality for ease of conjugation to a variety of electrophiles and/or nucleophiles.
Key words
heterobifunctional PEG - aminooxy - bioconjugation - molecular recognition - OEG - spacer
-
2a
Bailon P.Berthold W. Pharm. Sci. Technol. Today 1998, 352 -
2b
Veronese FM. Biomaterials 2001, 405 -
2c
Pasut G.Veronese FM. Adv. Polym. Sci. 2006, 95 - 3
Dreborg S.Akerblom EB. Crit. Rev. Ther. Drug Carrier Syst. 1990, 315 - 4 Smaller PEG units (MW <500), also referred to as oligoethylene glycol (OEG), often are employed as spacers; see, for example:
Engel A.Chatterjee SK.Al-Arifi A.Riemann D.Langner J.Nuhn P. Pharm. Res. 2003, 51 - For recent examples, see:
-
5a
Chen H.Chen Y.Sheardown H.Brook MA. Biomaterials 2005, 7418 -
5b
Otsuka H.Nagasaki Y.Kataoka A. Langmuir 2004, 11285 -
5c
Manta C.Ferraz N.Betancor L.Antunes G.Batista-Viera F.Carlsson J.Caldwell K. Enzyme Microb. Technol. 2003, 890 - For recent reviews, see:
-
6a
Kichler A. J. Gene Med. 2004, S3 -
6b
Kircheis R.Wightman L.Wagner E. Adv. Drug Delivery Rev. 2001, 341 - 7
Kleemann E.Neu M.Jekel N.Fink L.Schmehl T.Gessler T.Seeger W.Kissel T. J. Controlled Release 2005, 299 - 8
Kim WJ.Yockman JW.Lee M.Jeong LH.Kim Y.-H.Kim SW. J. Controlled Release 2005, 224 - 9
Roberts MJ.Bentley MD.Harris JM. Adv. Drug Delivery Rev. 2002, 459 - 10
Engel A.Chatterjee SK.Al-Arifi A.Nuhn P. J. Pharm. Sci. 2003, 2229 - 11
Loiseau FA.Hii KK.Hill AM. J. Org. Chem. 2004, 639 - 12
Goodson RJ.Katre NV. Biotechnology (N.Y.) 1990, 8: 343 - 13
Morpurgo M.Veronese FM.Kachensky D.Harris JM. Bioconjugate Chem. 1996, 7: 363 - 14
Woghiren C.Sharma B.Stein S. Bioconjugate Chem. 1993, 4: 314 - 15
Tumelty D.Carnevali M.Miranda LP. J. Am. Chem. Soc. 2003, 14238 -
16a
Lemieux GA.Yarema KJ.Jacobs CL.Bertozzi CR. J. Am. Chem. Soc. 1999, 4278 -
16b
Sadamoto R.Niikura K.Ueda T.Monde K.Fukuhara N.Nishimura S.-I. J. Am. Chem. Soc. 2004, 3755 - 17
Perouzel E.Jorgensen MR.Keller M.Miller AD. Bioconjugate Chem. 2003, 14: 884 - 18
Bertozzi CR.Bednarski MD. J. Org. Chem. 1991, 4326 -
20a
Grochowski E.Jurczak J. Synthesis 1976, 682 -
20b
Nicolaou KC.Groneberg RD. J. Am. Chem. Soc. 1990, 4085 -
20c
Su S.Giguere JR.Schaus SE.Porco JA. Tetrahedron 2004, 8645 - 21
Appel R. Angew. Chem., Int. Ed. Engl. 1975, 14: 801 - 23
Gaertner HF.Offord RE. Bioconjugate Chem. 1996, 7: 38
References and Notes
Present address: Department of Chemistry, University of Louisville, Louisville, KY 40292, USA
19For moisture-sensitive reactions, optimized yields were obtained only after drying the PEG intermediate by toluene azeotropic distillation immediately prior to use.
22
1H NMR and 13C NMR data (300 MHz and 75 MHz, respectively; in CDCl3) for all compounds: Compound 1a: 1H NMR: δ = 7.23 (br s, 1 H), 4.03 (m, 2 H), 3.82 (t, J = 6.3 Hz, 2 H), 3.74 (m, 2 H), 3.69 (app. s, 4 H), 3.48 (t, J = 6.3 Hz, 2 H), 1.48 (s, 9 H). 13C NMR: δ = 156.7, 81.7, 75.4, 71.2, 70.5, 70.4, 69.4, 30.2, 28.2.
Compound 1b: 1H NMR: δ = 7.59 (br s, 1 H), 4.03 (m, 2 H), 3.82 (t, J = 6.3 Hz, 2 H), 3.70-3.66 (m, 8 H), 3.48 (t, J = 6.3 Hz, 2 H), 1.48 (s, 9 H). 13C NMR: δ = 156.7, 81.5, 75.3, 71.2, 70.6 (3 C), 70.5, 69.3, 30.2, 28.2.
Compound 3a: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.82 (t, J = 5.4 Hz, 2 H), 3.73-3.70 (m, 2 H), 3.66 (app. s, 4 H), 3.63 (m, 4 H), 2.17 (br s, 1 H), 1.05 (s. 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 72.5, 70.8, 70.5, 63.4, 61.8, 26.8, 19.2.
Compound 3b: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.82 (t, J = 5.4 Hz, 2 H), 3.73-3.70 (m, 2 H), 3.66-3.58 (m, 12 H), 2.25 (br s, 1 H), 1.05 (s, 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 72.5, 72.4, 70.7, 70.7, 70.4, 63.4, 61.8, 26.8, 19.2.
Compound 4a: 1H NMR: δ = 7.83-7.80 (m, 2 H), 7.72-7.70 (m, 2 H), 7.70-7.65 (m, 4 H), 7.44-7.35 (m, 6 H), 4.36 (m, 2 H), 3.86 (m, 2 H), 3.74 (t, J = 5.4 Hz, 2 H), 3.65-3.62 (m, 2 H), 3.58-3.56 (m, 2 H), 3.52 (t, J = 5.4 Hz, 2 H), 1.03 (s, 9 H). 13C NMR: δ = 163.4, 135.6, 134.4, 133.7, 129.6, 129.0, 127.6, 123.4, 77.2, 72.4, 70.8, 70.7, 69.4, 63.3, 26.8, 19.2.
Compound 4b: 1H NMR: δ = 7.84-7.81 (m, 2 H), 7.74-7.71 (m, 2 H), 7.70-7.66 (m, 4 H), 7.44-7.34 (m, 6 H), 4.36 (m, 2 H), 3.85 (m, 2 H), 3.79 (t, J = 5.4 Hz, 2 H), 3.67-3.63 (m, 2 H), 3.61-3.52 (m, 8 H), 1.04 (s, 9 H). 13C NMR: δ = 163.4, 135.6, 134.4, 133.7, 129.6, 129.0, 127.6, 77.2, 72.4, 70.8, 70.7, 70.6, 70.5, 69.3, 63.4, 26.8, 19.2.
Compound 5a: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.84 (m, 2 H), 3.81 (t, J = 5.4 Hz, 2 H), 3.69-3.59 (m, 8 H), 1.05 (s, 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 74.7, 72.4, 70.7, 70.6, 69.7, 63.4, 26.8, 19.2.
Compound 5b: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.85 (m, 2 H), 3.81 (t, J = 5.4 Hz, 2 H), 3.69-3.63 (m, 10 H), 3.60 (t, J = 5.4 Hz, 2 H), 1.05 (s, 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 74.6, 72.4, 70.7, 70.6, 70.5, 70.5, 69.7, 63.4, 26.8, 19.2.
Compound 6a: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.51 (br s, 1 H), 7.44-7.34 (m, 6 H), 4.01 (m, 2 H), 3.82 (t, J = 5.4 Hz, 2 H), 3.72 (m, 2 H), 3.68-3.62 (m, 4 H), 3.61 (t, J = 5.4 Hz, 2 Hz), 1.46 (s, 9 H), 1.05 (s, 9 H). 13C NMR: δ = 156.7, 135.6, 133.6, 129.6, 127.6, 81.5, 75.3, 72.4, 70.7, 70.6, 69.4, 63.4, 28.2, 26.8, 19.2.
Compound 6b: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.62 (br s, 1 H), 7.44-7.34 (m, 6 H), 4.01 (m, 2 H), 3.81 (t, J = 5.4 Hz, 2 H), 3.70 (m, 2 H), 3.67-3.62 (m, 8 H), 3.60 (t, J = 5.4 Hz, 2 H), 1.46 (s, 9 H), 1.05 (s, 9 H). 13C NMR: δ = 156.7, 135.6, 133.6, 129.6, 127.6, 81.4, 75.3, 72.3, 70.7, 70.6, 70.5, 70.5, 69.2, 63.4, 28.2, 26.8, 19.1.
Compound 7a: 1H NMR: δ = 7.82 (br s, 1 H), 4.03 (m, 2 H), 3.76-3.72 (m, 4 H), 3.69 (s, 4 H), 3.64-3.61 (m, 4 H), 2.84 (br s, 1 H), 1.48 (s, 9 H). 13C NMR: δ = 156.8, 81.6, 75.2, 72.6, 70.4, 70.2, 69.2, 61.6, 28.2.
Compound 7b: 1H NMR: δ = 8.08 (br s, 1 H), 4.02 (m, 2 H), 3.74-3.66 (m, 12 H), 3.63 (m, 2 H), 2.80 (br s, 1 H), 1.48 (s, 9 H). 13C NMR: δ = 156.9, 81.4, 75.1, 72.6, 70.6, 70.4, 70.4, 70.3, 69.0, 61.7, 28.2.
Compound 9 was obtained as a single isomer: 1H NMR (600 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.58-7.57 (m, 2 H), 7.38-7.36 (m, 3 H), 4.34 (t, J = 4.6 Hz, 2 H), 3.83-3.81 (m, 4 H), 3.70 (app. s, 4 H), 3.46 (t, J = 6.0 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 149.0, 132.2, 129.8, 128.7, 127.0, 73.5, 71.2, 70.7, 70.5, 69.7, 30.3.