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 (19)F NMR spectroscopy.
Gel-phase (19)F 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 CH(2)Cl(2) 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.
Wallner
Fredrik K
FK
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Spjut
Sara
S
Boström
Dan
D
Elofsson
Mikael
M
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry; D019342:Acetic Acid / Q000138:chemical synthesis* / Q000737:chemistry; D000478:Alkylation; D003432:Cross-Linking Reagents / Q000737:chemistry*; D019281:Dimerization; D005461:Fluorine / Q000737:chemistry*; D006031:Glycosylation; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D007554:Isotopes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D010642:Phenoxyacetates
C523642:2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid; D000085:Acetates; D003432:Cross-Linking Reagents; D006845:Hydrocarbons, Fluorinated; D007554:Isotopes; D010455:Peptides; D010642:Phenoxyacetates; D005461:Fluorine; D019342:Acetic Acid