S-2,4,6-Trimethoxybenzyl (Tmob): A Novel Cysteine Protecting Group for the N^α-(9-Fluorenylmethoxycarbonyl) (Fmoc) Strategy of Peptide Synthesis

The S-2,4,6-trimethoxybenzyl (Tmob) group can be introduced onto sulfhydryl functions from the corresponding alcohol, with acid catalysis, and is in turn removed rapidly by treatment with 30% trifluoroacetic acid-dichloromethane in the presence of phenol, thioanisole, and water (5% each) or 6% trifluoroacetic acid-dichloromethane in the presence of triethylsilane or triisopropylsilane (0.5%). The appropriate cysteine derivative was prepared and applied with other N^α-Fmoc protected amino acids to the solid-phase syntheses of several model peptides. Acidolytic deblocking in the presence of cation scavengers and reducing agents gave the free thiol, whereas oxidative deblocking with iodine or thallium(III) trifluoroacetate provided an intramolecular disulfide. The chemistry of the S-Tmob group compares favorably to established chemistries with the acid-labile and oxidizable S-triphenylmethyl (trityl, Trt) group, as well as with the oxidizable S-acetamidomethyl (Acm) group.