On-resin native chemical ligation for cyclic peptide synthesis

Judit Tulla-Puche, George Barany

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

A novel cysteine derivative, Nα -trityl-S-(9H-xanthen-9-yl)-L-cysteine [Trt-Cys(Xan)-OH] has been introduced for peptide synthesis, specifically for application to a new strategy for the preparation of cyclic peptides. The following steps were carried out to synthesize the cyclic model peptide cyclo(Cys-Thr-Abu-Gly-Gly-Ala-Arg-Pro-Asp-Phe): (i) side-chain anchoring of Fmoc-Asp-OAl via its free β-carboxyl as a p-alkoxybenzyl ester to a solid support; (ii) stepwise chain elongation of the peptide by standard Fmoc/tBu solid-phase chemistry; (iii) removal of the N-terminal Fmoc group; (iv) coupling of Trt-Cys(Xan)-OH; (v) selective Pd(0)-promoted cleavage of the C-terminal allyl ester; (vi) coupling of the C-terminal residue, i.e., H-Phe-SBzl, preactivated as a thioester; (vii) selective removal of the N α-Trt and S-Xan protecting groups under very mild acid conditions; (viii) on-resin cyclization by native chemical ligation in an aqueous milieu; and (ix) final acidolytic cleavage of the cyclic peptide from the resin. The strategy was evaluated for three supports: poly[N,N-dimethacrylamide-co-poly(ethylene glycol)] (PEGA), cross-linked ethoxylate acrylate resin (CLEAR), and poly(ethylene glycol)-polystyrene (PEG-PS) graft resin supports. For PEGA and CLEAR, the desired cyclic product was obtained in 76-86% overall yield with initial purities of ∼70%, whereas for PEG-PS (which does not swell nearly as well in water), results were inferior. Solid-phase native chemical ligation/cyclization methodology appears to have advantages of convenience and specificity, which make it promising for further generalization.

Original languageEnglish (US)
Pages (from-to)4101-4107
Number of pages7
JournalJournal of Organic Chemistry
Volume69
Issue number12
DOIs
StatePublished - Jun 11 2004

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