Chemical ligation of S-scylated cysteine peptides to form native peptides via 5-, 11-, and 14-membered cyclic transition states

Alan R. Katritzky, Srinivasa Tala, Nader E. Abo-Dya, Tarek S. Ibrahim, Said A. El-Feky, Kapil Gyanda, Keyur M. Pandya

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Cysteine-containing dipeptides 3a-l, (3b+3b′) (compound numbers in parentheses are used to indicate racemic mixtures; thus (3b+3b′) is the racemate of 3b and 3b′), and tripeptide 13 were synthesized in 68-96% yields by acylation of cysteine with N-(Pg-α-aminoacyl)- and N-(Pg-α-dipeptidoyl)benzotriazoles (where Pg stands for protecting group in the nomenclature for peptides throughout the paper) in the presence of Et3N. Cysteine-containing peptides 3a-l and 13 were S-acylated to give S-(Pg-α-aminoacyl)dipeptides 5a-l and S-(Pg-α-aminoacyl) tripeptide 14 without racemization in 47-90% yields using N-(Pg-α- aminoacyl)benzotriazoles 2 in CH3CN-H2O (7:3) in the presence of KHCO3. (In our peptide nomenclature, the prefixes di-, tri-, etc. refer to the number of amino acid residues in the main peptide chain; amino acid residues attached to sulfur are designated as S-acyl peptides. Thus we avoid use of the prefix "iso".) Selective S-acylations of serine peptide 3k and threonine peptide 3l containing free OH groups were thus achieved in 58% and 72% yield, respectively. S-(Pg-α-aminoacyl)cysteines 4a,b underwent native chemical ligations to form native dipeptides 3f,i via 5-membered cyclic transition states. Microwave irradiation of S-(Pg-α-aminoacyl)tripeptide 15 and S-(Pg-α-aminoacyl)tetrapeptide 17 in the presence of NaH2PO4/Na2HPO 4 buffer solution at pH 7.8 achieved chemical ligations, involving intramolecular migrations of acyl groups, via 11- and 14-membered cyclic transition states from the S-atom of a cysteine residue to a peptide terminal amino group to form native peptides 19 and 20 in isolated yields of 26% and 23%, respectively.

Original languageEnglish (US)
Pages (from-to)85-96
Number of pages12
JournalJournal of Organic Chemistry
Volume76
Issue number1
DOIs
StatePublished - Jan 7 2011

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    Katritzky, A. R., Tala, S., Abo-Dya, N. E., Ibrahim, T. S., El-Feky, S. A., Gyanda, K., & Pandya, K. M. (2011). Chemical ligation of S-scylated cysteine peptides to form native peptides via 5-, 11-, and 14-membered cyclic transition states. Journal of Organic Chemistry, 76(1), 85-96. https://doi.org/10.1021/jo1015757