NovelS-Xanthenyl Protecting Groups for Cysteine and Their Applications for theNα-9-Fluorenylmethyloxycarbonyl (Fmoc) Strategy of Peptide Synthesis¹⁻³

The 9 H -xanthen-9-yl (Xan) and 2-methoxy-9 H -xanthen-9-yl (2-Moxan) groups can be introduced onto sulfhydryl functions by S -alkylation reactions involving the corresponding xanthydrols, plus trifluoroacetic acid (TFA) as catalyst. Conversely, these groups are removed rapidly by acid in the presence of appropriate silane or thiol scavengers. The 3-methoxy-9 H -xanthen-9-yl (3-Moxan) derivative was also studied, but abandoned for several reasons including challenging synthesis, excessive lability to acid, and insufficient stability in the presence of base. The N α -9-fluorenylmethyloxycarbonyl (Fmoc), S -Xan or 2-Moxan-protected cysteine derivatives were prepared and applied to the solid-phase syntheses of several model peptides. Selective removal of S -Xan and S -2-Moxan groups, while retaining tris(alkoxybenzyl)amide (PAL) anchoring, is best accomplished with TFA−CH 2 Cl 2 −Et 3 SiH (1:98.5:0.5), 25 °C, 2 h. Alternatively, oxidative deprotection of S -Xan or S -2-Moxan with iodine (10−20 equiv) or thallium(III) tris(trifluoroacetate) [Tl(tfa) 3 ] (1−3 equiv) to provide disulfides can be carried out on peptide substrates both in solution and while polymer-bound. Compared to established chemistries with the acid-labile and oxidizable S -triphenylmethyl (Trt) group, S -Xan and S -2-Moxan gave equal or superior results in terms of peptide purities (including no detectable tryptophan alkylation) and overall yields.