Synlett 2017; 28(15): 1956-1960
DOI: 10.1055/s-0036-1588862
cluster
© Georg Thieme Verlag Stuttgart · New York

Preparation of Peptide o-Aminoanilides Using a Modified Dawson's Linker for Microwave-Assisted Peptide Synthesis

Shugo Tsuda*
a  Peptide Institute, Inc., 7-2-9 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan   eMail: tsuda@peptide.co.jp   eMail: t.yoshiya@peptide.co.jp
,
Tsuyoshi Uemura
a  Peptide Institute, Inc., 7-2-9 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan   eMail: tsuda@peptide.co.jp   eMail: t.yoshiya@peptide.co.jp
,
Masayoshi Mochizuki
a  Peptide Institute, Inc., 7-2-9 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan   eMail: tsuda@peptide.co.jp   eMail: t.yoshiya@peptide.co.jp
,
Hideki Nishio
a  Peptide Institute, Inc., 7-2-9 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan   eMail: tsuda@peptide.co.jp   eMail: t.yoshiya@peptide.co.jp
b  Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
,
a  Peptide Institute, Inc., 7-2-9 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan   eMail: tsuda@peptide.co.jp   eMail: t.yoshiya@peptide.co.jp
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Publikationsverlauf

Received: 03. April 2017

Accepted after revision: 15. Mai 2017

Publikationsdatum:
21. Juni 2017 (online)


Published as part of the Cluster Recent Advances in Protein and Peptide Synthesis

Abstract

Based on the structure of Dawson’s 3,4-diaminobenzoic acid (Dbz) linker designed for Fmoc solid-phase peptide-thioester synthesis, the 4-amino-3-nitrobenzoic acid [Dbz(NO2)] linker was developed for microwave-assisted synthesis. The Dbz(NO2) linker can be readily converted into the Dbz linker by on-resin reduction with SnCl2 after construction of the protected peptide resin. Although epimerization of C-terminal amino acid restricts the use of Dbz(NO2) linker to the synthesis of peptide-Gly-thioester, use of this linker can prevent side reactions that arise when Dbz or Dbz(Aloc) linkers are used in the microwave-assisted synthesis of Gly-rich peptides.

Supporting Information

 
  • References and Notes

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  • 20 Resin 7: The peptide assemblies on the Fmoc-Gly-Dbz(NO2)-Leu-rink amide resin (0.10 mmol) were conducted using microwave-assisted Fmoc SPPS procedure as described in the Supporting Information. In order to evaluate peptide constructed on the resin, a part of the obtained resin 7 (5 mg) was treated with TFA/TIS/H2O (v/v, 95:2.5:2.5) for 1.5 h to yield a corresponding deprotected peptide. Analytical HPLC: t R = 14.2 min (10–60% MeCN/0.1% TFA for 25 min); LRMS (ESI+): m/z calcd for C45H67N14O13 [M + H]+ 1011.5; found: 1011.5. Compound 9: Resin 7 (0.10 mmol) was treated with 6 M SnCl2, 10 mM HCl/MeOH in DMF for 3 h. Resin 8 thus obtained was treated with TFA/TIS/H2O (v/v, 95:2.5:2.5) for 1.5 h to give a crude product 9. Analytical HPLC: t R = 12.1 min (10–60% MeCN/0.1% TFA for 25 min); LRMS (ESI+): m/z calcd for C45H69N14O11 [M + H]+: 981.5; found: 981.6. Compound 10: Crude 9 was activated using NaNO2, and thioesterified with sodium 2-sulfanylethanesulfonate to give the title compound. Analytical HPLC: t R = 8.5 min (10–60% MeCN/0.1% TFA for 25 min); LRMS (ESI+): m/z calcd for C45H69N14O11 [M + H]+: 859.3; found: 859.4. Compound 11: Resin 8 (0.05 mmol) was activated as described in ref. 6. Then, the resin was treated with TFA/TIS/H2O (v/v, 95:2.5:2.5) for 1.5 h to give the title product. Analytical HPLC: t R = 13.4 min (10–60% MeCN/0.1% TFA for 25 min); LRMS (ESI+): m/z calcd for C46H67N14O12 [M + H]+: 1007.5; found: 1007.5.
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