2 Z. A. Gurard-Levin and M. Mrksich, Annu. Rev. Anal. Chem.,
2008, 1, 767–800.
3 E. M. Sletten and C. R. Bertozzi, Acc. Chem. Res., 2011, 44,
666–676; C. P. R. Hackenberger and D. Schwarzer, Angew. Chem.,
Int. Ed., 2008, 47, 10030–10074.
4 A. Watzke, M. Kohn, M. Gutierrez-Rodriguez, R. Wacker,
¨
H. Schroder, R. Breinbauer, J. Kuhlmann, K. Alexandrov,
C. M. Niemeyer, R. S. Goody and H. Waldmann, Angew. Chem.,
Int. Ed., 2006, 45, 1408–1412; S. S. van Berkel, M. B. van Eldijk
and J. C. M. van Hest, Angew. Chem., Int. Ed., 2011, 50,
8806–8827.
5 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int.
Ed., 2001, 40, 2004; M. Meldal and C. W. Tornoe, Chem. Rev.,
2008, 108, 2952–3015.
6 J. A. Camarero, Y. Kwon and M. A. Coleman, J. Am. Chem. Soc.,
2004, 126, 14730–14731.
7 S. B. H. Kent, Chem. Soc. Rev., 2009, 38, 338–351.
8 S. Anderson, Langmuir, 2008, 24, 13962–13968.
9 B. Helms, I. van Baal, M. Merkx and E. W. Meijer, ChemBio-
Chem, 2007, 8, 1790–1794.
10 S. K. Mahto, C. J. Howard, J. C. Shimko and J. J. Ottesen,
ChemBioChem, 2011, 12, 2488–2494.
11 M. L. Lesaicherre, M. Uttamchandani, G. Y. J. Chen and
S. Q. Yao, Bioorg. Med. Chem. Lett., 2002, 12, 2079–2083.
12 G. M. Fang, H. K. Cui, J. S. Zheng and L. Liu, ChemBioChem,
2010, 11, 1061–1065.
13 Q. Wan, J. Chen, Y. Yuan and S. J. Danishefsky, J. Am. Chem.
Soc., 2008, 130, 15814–15816.
14 E. Ostuni, R. G. Chapman, R. E. Holmlin, S. Takayama and
G. M. Whitesides, Langmuir, 2001, 17, 5605–5620.
15 N. Laurent, R. Haddoub, J. Voglmeir, S. C. C. Wong, S. J. Gaskell
and S. L. Flitsch, ChemBioChem, 2008, 9, 2592–2596;
B. T. Houseman and M. Mrksich, Chem. Biol., 2002, 9, 443–454.
16 P. E. Dawson, T. W. Muir, I. Clarklewis and S. B. H. Kent,
Science, 1994, 266, 776–779.
17 E. C. B. Johnson and S. B. H. Kent, J. Am. Chem. Soc., 2006, 128,
6640–6646.
18 P. E. Dawson and S. B. H. Kent, Annu. Rev. Biochem., 2000, 69,
923–960; D. Macmillan, M. De Cecco, N. L. Reynolds,
L. F. A. Santos, P. E. Barran and J. R. Dorin, ChemBioChem,
2011, 12, 2133–2136.
Scheme 1 Synthesis of trivalent glycoclusters 21 and 23.
starting from the known building block 17.23 For the preparation
of the trivalent wedge 19 Fmoc-glycine (16) was coupled in
a HBTU/DIPEA-mediated reaction with 17 followed by
deprotection of the tBu esters with formic acid yielding
compound 19 in 85% over two steps. Mannosides were
introduced via peptide coupling following published chemistry24
giving 20 in a satisfying yield of 64%. Fmoc deprotection with
piperidine in DMF gave the trivalent cluster mannoside 21 in
89% yield. An amount of 21 was further functionalized with
Boc-L-Cys(Trt)-OH in another peptide coupling reaction yielding
22 in 58%. This step was followed by one step removal of the
Boc and Trityl protecting groups using TFA in DCM under
addition of TES followed by a treatment with basic ion exchange
resin Amberlyst A-21 following a literature protocol.25 After
size exclusion and reversed phase chromatography the Cys-
terminated ligand 23 was obtained in 65% yield.
The trivalent cluster mannosides manno-Cys 23 and manno-
Gly 21 were then compared in coupling experiments to the
gold array surfaces. From reaction mixtures containing 4 mM
each of 21 and 23 the manno-Cys product 27 was formed
exclusively (Table 1).
19 N. Laurent, J. Voglmeir and S. L. Flitsch, Chem. Commun., 2008,
4400–4412.
20 R. Sardzik, G. T. Noble, M. J. Weissenborn, A. Martin, S. J.
Webb and S. L. Flitsch, Beilstein J. Org. Chem., 2010, 6,
699–703; O. Bohorov, H. Andersson-Sand, J. Hoffmann and
O. Blixt, Glycobiology, 2006, 16, 21c–27c; O. Blixt, S. Head,
T. Mondala, C. Scanlan, M. E. Huflejt, R. Alvarez,
M. C. Bryan, F. Fazio, D. Calarese, J. Stevens, N. Razi,
D. J. Stevens, J. J. Skehel, I. van Die, D. R. Burton,
I. A. Wilson, R. Cummings, N. Bovin, C. H. Wong and
J. C. Paulson, Proc. Natl. Acad. Sci. U. S. A., 2004, 101,
17033–17038; M. Hartmann, A. K. Horst, P. Klemm and
T. K. Lindhorst, Chem. Commun., 2010, 46, 330–332.
21 M. Hartmann and T. K. Lindhorst, Eur. J. Org. Chem., 2011,
3583–3609.
Complex bioconjugates containing N-terminal cysteines can
be efficiently coupled to surfaces through amide bond formation
via native chemical ligation starting with activated oxo-esters on
the surface. These surface oxo-esters are easily prepared from
their carboxylic acids. Our studies have shown that the ligation in
the presence of imidazole is highly selective for cysteine derivatives
over competing amines.
This work was supported by the Royal Society (Wolfson
Award to SLF), the European Commission (MJW), the
EPSRC and the Evonik Foundation (JWW).
22 H. A. Shaikh, F. D. Sonnichsen and T. K. Lindhorst, Carbohydr.
¨
Res., 2008, 343, 1665–1674.
23 G. R. Newkome, R. K. Behera, C. N. Moorefield and G. R. Baker,
J. Org. Chem., 1991, 56, 7162–7167.
24 J. W. Wehner and T. K. Lindhorst, Synthesis, 2010, 3070–3082;
A. Schierholt, M. Hartmann and T. K. Lindhorst, Carbohydr.
Res., 2011, 346, 1519–1526.
Notes and references
1 G. MacBeath and S. L. Schreiber, Science, 2000, 289, 1760–1763;
D. Weinrich, P. Jonkheijm, C. M. Niemeyer and H. Waldmann,
Angew. Chem., Int. Ed., 2009, 48, 7744–7751; L. Berrade,
A. E. Garcia and J. A. Camarero, Pharm. Res., 2011, 28, 1480–1499.
25 N. Srinivasan, A. Yurek-George and A. Ganesan, Mol. Diversity,
2005, 9, 291–293.
c
4446 Chem. Commun., 2012, 48, 4444–4446
This journal is The Royal Society of Chemistry 2012