Synthesis of Tetra(2-hydroxyethoxy)-Substituted Dibenzocyclooctyne Derivatives as Novel, Highly Hydrophilic Tool Compounds for Strain-Promoted 
Alkyne-Azide Cycloaddition Applications

Martin Golkowski; Thomas Ziegler

doi:10.1055/s-0032-1316875

Synthesis, Inhaltsverzeichnis

Synthesis 2013; 45(9): 1207-1214
DOI: 10.1055/s-0032-1316875

paper

Synthesis of Tetra(2-hydroxyethoxy)-Substituted Dibenzocyclooctyne Derivatives as Novel, Highly Hydrophilic Tool Compounds for Strain-Promoted Alkyne-Azide Cycloaddition Applications

Authors

Martin Golkowski*

Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany Fax: +49(7071)295244 eMail: Martin.Golkowski@uni-tuebingen.de
Thomas Ziegler

Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany Fax: +49(7071)295244 eMail: Martin.Golkowski@uni-tuebingen.de

Abstract

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Abstract

The synthesis of a novel, hydrophilic dibenzocyclooctyne derivative for strain-promoted alkyne-azide cycloaddition (SPAAC) is described. Starting from 2-(3,4-dimethoxyphenyl)acetaldehyde, the corresponding activated carbonate of 2,3,8,9-tetrakis(2-hydroxyethoxy)-5,6-dihydro-11,12-didehydrodibenzo[a,e][8]annulene, termed THE-DIBO, was prepared in seven steps and 24% overall yield. A water-soluble THE-DIBO analogue showed a k₂ value of (21.9 ± 0.2) × 10^–2 M^–1 s^–1 for SPAAC with 2-azidoethanol in water. The high hydrophilicity and steric bulk of THE-DIBO derivatives should to suppress nonspecific thiol-yne addition of proteins to strained alkynes observed for SPAAC labeling in complex proteomes.

Key words

alkynes - azides - conjugation - proteins - SPAAC - click chemistry - thiol-yne addition - bioorthogonal chemistry

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Referenzen

References
1 Huisgen R. Angew. Chem. 1963; 75: 742

2a Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596 ; Angew. Chem. 2002, 14, 2708
2b Tørnoe CW, Christensen C, Meldal M. J. Org. Chem. 2002; 67: 3057

3 Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2001; 40: 2004 ; Angew. Chem. 2001, 113, 2056
4 Meldal M, Tørnoe CW. Chem. Rev. 2008; 108: 2952
5 Sletten EM, Bertozzi CR. Angew. Chem. Int. Ed. 2009; 48: 6974 ; Angew. Chem. 2009, 121, 7108

6a Ning XH, Guo J, Wolfert MA, Boons GJ. Angew. Chem. Int. Ed. 2008; 47: 2253 ; Angew. Chem. 2008, 120, 2285
6b Debets MF, van Berkel SS, Dommerholt J, Dirks AJ, Rutjes FP. J. T, van Delft FL. Acc. Chem. Res. 2011; 44: 805
6c Manova R, van Beek TA, Zuilhof H. Angew. Chem. Int. Ed. 2011; 50: 5428 ; Angew. Chem. 2011, 123, 5540
6d Baskin JM, Prescher JA, Laughlin ST, Agard NJ, Chang PV, Miller IA, Lo A, Codelli JA, Bertozzi CR. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 16793

7a Beatty KE, Fisk JD, Smart BP, Lu YY, Szychowski J, Hangauer MJ, Baskin JM, Bertozzi CR, Tirrell DA. ChemBioChem 2010; 11: 2092
7b Temming RP, van Scherpenzeel M, te Brinke E, Schoffelen S, Gloerich J, Lefeber DJ, van Delft FL. Bioorg. Med. Chem. 2012; 20: 655

8 van Geel R, Pruijn GJ. M, van Delft FL, Boelens WC. Bioconjugate Chem. 2012; 23: 392
9 Dommerholt J, Schmidt S, Temming R, Hendriks LJ. A, Rutjes FP. J. T, van Hest JC. M, Lefeber DJ, Friedl P, van Delft FL. Angew. Chem. Int. Ed. 2010; 49: 9422 ; Angew. Chem. 2010, 122, 9612
10 Debets MF, van Berkel SS, Schoffelen S, Rutjes FP. J. T, van Hest JC. M, van Delft FL. Chem. Commun. 2010; 46: 97
11 Fairbanks BD, Sims EA, Anseth KS, Bowman CN. Macromolecules 2010; 43: 4113
12 Friscourt F, Ledin PA, Mbua NE, Flanagan-Steet HR, Wolfert MA, Steet R, Boons G.-J. J. Am. Chem. Soc. 2012; 134: 5381
13 Stöckmann H, Neves AA, Stairs S, Ireland-Zecchini H, Brindle KM, Leeper FJ. Chem. Sci. 2011; 2: 932
14 Dupont R, Cotelle P. Tetrahedron Lett. 1998; 39: 8457
15 Reimann E, Ettmayr CA. Monatsh. Chem. 2004; 135: 1289
16 Heslin JC, Moody CJ. J. Chem. Soc., Perkin Trans. 1 1988; 1417
17 Otto S, Engberts JB. F. N. Pure Appl. Chem. 2000; 72: 1365
18 Golkowski M, Pergola C, Werz O, Ziegler T. Org. Biomol. Chem. 2012; 10: 4496