Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase 19F NMR spectroscopy

Fredrik K. Wallner; Sara Spjut; Dan Boström; Mikael Elofsson

doi:10.1039/B704472K

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Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase ¹⁹F NMR spectroscopy†

Fredrik K. Wallner,‡^a Sara Spjut,‡^a Dan Boström^b and Mikael Elofsson*^a

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* Corresponding authors

^a Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden
E-mail: mikael.elofsson@chem.umu.se
Fax: +46 90 13 88 85
Tel: +46 90 786 93 28

^b Energy Technology and Thermal Process Chemistry, Department of Applied Physics and Electronics, Umeå University, Umeå, Sweden

Abstract

Gel-phase ¹⁹F NMR spectroscopy is a useful monitoring technique for solid-phase organic chemistry due to the high information content it delivers and swift acquisition times, using standard NMR spectrometers. This paper describes the synthesis of the novel linker 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid in 29% yield over seven steps, using nucleophilic aromatic substitutions on 2,4,5-trifluorobenzonitrile as key steps. Following standard solid-phase synthesis a peptide could be cleaved from the linker using 20% TFA in CH₂Cl₂ in 30 minutes, in contrast to a previously described monoalkoxy linker that requires 90% TFA in water at elevated temperature. A resin-bound peptide could be successfully glycosylated using only two equivalents of a thioglycoside donor, activated with N-iodosuccinimide and trifluoromethanesulfonic acid, and subsequent cleavage and deprotection gave the target glycopeptide. Direct glycosylation of the linker itself followed by mild acidic cleavage gave a fully protected hemiacetal for further chemical manipulation.

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Article information

DOI: https://doi.org/10.1039/B704472K
Article type: Paper
Submitted: 23 Mar 2007
Accepted: 12 Jun 2007
First published: 28 Jun 2007

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Org. Biomol. Chem., 2007,5, 2464-2471

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Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase ¹⁹F NMR spectroscopy

F. K. Wallner, S. Spjut, D. Boström and M. Elofsson, Org. Biomol. Chem., 2007, 5, 2464 DOI: 10.1039/B704472K

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Organic & Biomolecular Chemistry