T.-K. Lee et al. / Tetrahedron Letters 48 (2007) 389–391
Grignard method
391
Pseudo-activated linker method
References and notes
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. Andersson, L.; Blomberg, L.; Flegel, M.; Lepsa, L.;
Nilsson, B.; Verlander, M. Biopolymers 2000, 55, 227–
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50; Bruckdorfer, T.; Marder, O.; Albericio, F. Curr.
Pharm. Biotech. 2004, 5, 29–43.
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. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149–
Figure 1. Confocal microscopic images of cross-sectioned resin beads:
2153.
fluorescein isothiocyanate-coupled Trp(Boc)-CTC resin prepared by
3. Atherton, E.; Benoiton, N. L.; Brown, E.; Sheppard, R.
(a) pseudo-activated linker method and (b) Grignard method.
C.; Williams, B. J. J. Chem. Soc., Chem. Commun. 1981,
3
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36–337; Sieber, P. Tetrahedron Lett. 1987, 28, 6147–
150; Pedroso, E.; Grandas, A.; De Las Heras, X.;
Table 1. Loading levels of Fmoc-amino acid loaded 2-CTC resins and
purities of the peptide fragments synthesized using the corresponding
resins
Eritja, R.; Giralt, E. Tetrahedron Lett. 1986, 27, 743–
46.
7
4
5
. Barlos, K.; Chatzi, O.; Gatos, D.; Stavropoulos, G. Int. J.
Pept. Protein Res. 1991, 37, 513–520; Anne, C.; Fournie-
Zaluski, M.-C.; Roques, B. P.; Cornille, F. Tetrahedron
Lett. 1998, 39, 8973–8974; Zikos, C.; Livaniou, E.;
Leondiadis, L.; Ferderigos, N.; Ithakissios, D. S.; Evan-
gelatos, G. P. J. Pept. Sci. 2003, 9, 419–429.
. Kang, M. C.; Bray, B.; Lichty, M.; Mader, C.; Merutka,
G. U.S. Patent 6 015 881, 2000; Schneider, S. E.;
Bray, B. L.; Mader, C. J.; Friedrich, P. E.; Anderson,
M. W.; Taylor, T. S.; Boschernitzan, N.; Niemi, T. E.;
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Stoltenberg, L. E.; Lichty, M. J. Pept. Sci. 2005, 11, 744–
Fmoc-amino acid
loaded 2-CTC resin
Loading level
(mmol/g resin)
Peptide purity
(%) (sequence)
Fmoc-Gln-resin
Fmoc-Leu-resin
Fmoc-Trp(Boc)-resin
0.54
0.74
0.69
84 (T20 1–16)
95 (T20 17–26)
91 (T20 27–35)
peptides were found to be very pure by HPLC and ESI-
Mass analyses (Table 1) (see also Supplementary data).
We also compared our 2-CTC resin with the conven-
tional 2-CTC resin (prepared using the Grignard meth-
od). A well-known difficult sequence, fragment 65–74
7
53.
6
7
. Melby, L. R.; Strobach, D. R. J. Am. Chem. Soc. 1967, 89,
450–453.
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1
5
of the acyl carrier protein (ACP 65–74), was also syn-
thesized on both of the 2-CTC resins with Fmoc/tBu
strategy. The 2-CTC resin obtained using the pseudo-
activated linker method gave ACP 65–74 in higher
purity (76%) than the conventional 2-CTC resin (41%).
It is considered that such a difference in the synthetic
efficiency originates from the differences in the distri-
butions of the functional groups. As in the case of the
3
880–3887; Cramer, F.; K o¨ ster, H. Angew. Chem., Int. Ed.
Engl. 1968, 7, 473–474; Fr e´ chet, J. M. J.; Haque, K. E.
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2
-CTC resin obtained by the pseudo-activated linker
method, the functional groups in the core–shell type
structure were believed to be more accessible to the
incoming reagents.
9
22 890, 1999.
. Hidai, Y.; Kan, T.; Fukuyama, T. Tetrahedron Lett. 1999,
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9
4
In summary, we developed a simple and efficient method
for the preparation of 2-CTC resin using 1-chloro-2-
dichloro(phenyl)methyl)benzene as a pseudo-activated
linker. This 2-CTC resin has a good physical appearance
and efficient loading/cleavage properties. Moreover, it
also has a core–shell type structure, wherein the func-
tional groups are more concentrated at the surface layer
of the resin beads. With this new 2-CTC resin, four
peptide fragments (T20 1–16, T20 17–26, T20 27–35
and ACP 65–74) were prepared in high purity.
1
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Acknowledgments
1
1
1
This study was supported by a grant from the Korea
Health 21 R&D Project, Ministry of Health and Wel-
fare, Republic of Korea (A050432).
2
2
Org. Lett. 2004, 6, 3273–3276; Lee, T. K.; Ryoo, S. J.;
Byun, J. W.; Lee, S. M.; Lee, Y. S. J. Comb. Chem.
Supplementary data
2
005, 7, 170–173; Lee, T. K.; Lee, S. M.; Ryoo, S. J.;
Byun, J. W.; Lee, Y. S. Tetrahedron Lett. 2005, 46,
135–7138.
The analytical data and experimental procedures for the
compounds and peptide fragments. Supplementary data
7
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Chem. Soc. 1975, 97, 6584–6585.