Novel S-Xanthenyl Protecting Groups for Cysteine and Their Applications for the Nα-9-Fluorenylmethyloxycarbonyl (Fmoc) Strategy of Peptide Synthesis

Yongxin Han, George Barany

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39 Scopus citations

Abstract

The 9H-xanthen-9-yl (Xan) and 2-methoxy-9H-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-9H-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 Nα-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-CH2Cl2-Et3SiH (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.

Original languageEnglish (US)
Pages (from-to)3841-3848
Number of pages8
JournalJournal of Organic Chemistry
Volume62
Issue number12
StatePublished - Dec 1 1997

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