title: Chemical ligation of S-scylated cysteine peptides to form native peptides via 5-, 11-, and 14-membered cyclic transition states.
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 Et(3)N. 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 CH(3)CN-H(2)O (7:3) in the presence of KHCO(3). (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 NaH(2)PO(4)/Na(2)HPO(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.
authors.affiliation: Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, USA. katritzky@chem.ufl.edu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Katritzky
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Tala
authors.forename: Nader E
authors.initials: NE
authors.lastname: Abo-Dya
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Ibrahim
authors.forename: Said A
authors.initials: SA
authors.lastname: El-Feky
authors.forename: Kapil
authors.initials: K
authors.lastname: Gyanda
authors.forename: Keyur M
authors.initials: KM
authors.lastname: Pandya
mesh_terms: D000215:Acylation; D003545:Cysteine / Q000737:chemistry*; D006878:Hydroxides / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008872:Microwaves; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D013379:Substrate Specificity; D013455:Sulfur / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry*
chemical_list: D006878:Hydroxides; D010455:Peptides; D010456:Peptides, Cyclic; D014230:Triazoles; D013455:Sulfur; C031356:hydroxide ion; D003545:Cysteine