Cupric sulfate efficiently opens thiazolidine and selenazolidine rings, producing a protected N-terminal cysteine or selenocysteine derivative without the use of inert gas or solvent. This is a clear advantage over methods that use water-soluble palladium salts, which fail to react with the selenazolidine ring. This copper-mediated reaction proceeds with monovalent or divalent copper ions, and disulfide bond formation followed by ring-opening promotes the process. This copper-mediated reaction, which is compatible with the standard native chemical ligation conditions, was applied to the synthesis of the 77-mer CXCL14 protein.
Ring-opening by CuSO4 of a 1,3-thiazolidine carbonyl structure (Thz) as an N-terminal cysteine (Cys) residue revealed that an intramolecular S–acetamidomethyl cysteine (Cys(Acm)) can also be deprotected with concomitant formation of...
Sulfanylmethyl-installed dimethylaminopyridine, 2-sulfanylmethyl-4dimethylaminopyridine (2), has an acidic thiol group comparable to that in aryl thiols due to the formation of a zwitterion consisting of a thiolate anion and a pyridinium cation. It can be used as an additive for native chemical ligation. The alkyl thiol in 2 allows it to be used for the one-pot native chemical ligation−desulfurization protocol in peptide synthesis. The utility of 2 in the synthesis of cyclic peptides is demonstrated.
Lipidation of peptides is a promising means of modification that can improve the therapeutic character of biologically active peptides. Here, a novel lipidation protocol for peptides is described. The C−H sulfenylation of indole in peptides using S-p-methoxybenzyl cysteine sulfoxide under acidic conditions in the presence of ammonium chloride, anisole, and triisopropylsilane enables late-stage tryptophan-selective peptide lipidation. This developed protocol has been used successfully for the lipidation of glucagon-like peptides. Oral glucose tolerance tests in wild-type mice indicated that the resulting lipidated peptides stimulate insulin secretion and exhibit a more long-lasting blood-glucose-lowering effect than a parent nonlipidated peptide.
Covalent linking of side chains provides a method to produce cyclic or stapled peptides that are important in developing peptide-based drugs. A variety of crosslinking formats contribute to fixing the active conformer and prolonging its biological activity under physiological conditions. One format uses the cysteine thiol to participate in crosslinking through nucleophilic thiolate anions or thiyl radicals to form thioether and disulfide bonds. Removal of the S-protection from an S-protected Cys derivative generates the thiol, which functions as a nucleophile. S-Oxidation of a protected Cys allows the formation of a sulfoxide that operates as an umpolung electrophile. Herein, the applicability of S-p-methoxybenzyl Cys sulfoxide (Cys(MBzl)(O)) to the formation of a thioether linkage between tryptophan and Cys has been investigated. The reaction of peptides containing Cys(MBzl)(O) and Trp with trifluoromethanesulfonic acid (TFMSA) or methanesulfonic acid (MSA) in TFA in the presence of guanidine hydrochloride (Gn • HCl) proceeded to give cyclic or stapled peptides possessing the Cys-Trp thioether linkage. In this reaction, strong acids such as TFMSA or MSA are necessary to activate the sulfoxide. Additionally, Gn • HCl plays a critical role in producing an electrophilic Cys derivative that combines with the indole by aromatic electrophilic substitution. The findings led us to conclude that the less-electrophilic Cys(MBzl)(O) serves as an acid-activated umpolung of a Cys nucleophile and is useful for S-arylationmediated peptide cyclization.
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