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.

New Cyclic Cystine Bridged Peptides from the Sponge Suberites waedoensis

“…The presence of a disulfide linkage between the cysteine residues was also supported by the chemical shifts of the C β carbons at δ C 40.3 and 40.0, which were similar to those of other peptides possessing cysteines with a similar disulfide linkage [12]. For comparison, the shifts of free cysteine and cysteic acid were approximately δ C 25.5 and 50, respectively [13,14]. Thus, chujamide A ( 1 ) was determined to be a novel cyclic cystine bridged dodecapeptide.…”

Synthesis of C‐terminal glycine‐rich o‐aminoanilide peptides without overacylation for use in benzotriazole‐mediated native chemical ligation

“…Katritzky et al have demonstrated the utilization of Fmoc-N-protected C-terminal-Bt amino acids in the NCL synthesis of dipeptides containing cysteine. [24,25] Additional approaches have been developed to generate active esters through the formation of C-terminus-Bt peptides.…”

Long‐Range Chemical Ligation from N→N Acyl Migrations in Tryptophan Peptides via Cyclic Transition States of 10‐ to 18‐Members

“…We have reported ligations of S-acylated Cys-containing peptides to form the corresponding native peptides through long-range chemical ligations via 8-to 19-membered transition states. [24][25][26][27][28] This methodology utilizes the selective Sacylation of Cys-containing peptides by N-acyl benzotriazoles followed by microwave-assisted high-yielding chemical ligations of the resulting S-acyl isopeptides under mild conditions and with no auxiliary groups. However, the low abundance of Cys in the natural peptide sequence remains an obstacle.…”