Unprotected S-acylated cysteine isopeptides containing a-, b-or c-amino acid units have been synthesized, and their conversion to native hexapeptides by S-to the N-terminus ligations involving 17-, 18-and 19-membered cyclic transition states have been demonstrated both experimentally and computationally to be more favorable than intermolecular cross-ligations. Synthetic methods for peptides are of great interest: native chemical ligation (NCL) that chemically connects two unprotected peptides to yield a long-chain polypeptide has been intensively studied since first developed by Kent and co-workers (1).Alternative approaches to overcome the requirement in classical NCL of an N-terminal cysteine residue have included (i) traceless Staudinger ligation (2,3), (ii) NCL with a phenylalanine and valine analog bearing a sulfhydryl group at the b-position followed by removal of the sulfanyl group (4-6), (iii) NCL followed by the conversion of cysteine to serine (7), (iv) sugar-assisted ligation (8-10), and (v) cysteine-free 'direct aminolysis' methods (11). However, new ligation strategies are still in demand for the synthesis of underivatized and post-translational modified peptides and proteins.Native chemical ligation has been extensively studied in peptidic compounds bearing a cysteine residue at the N-terminus (12). Modified cysteine scaffolds have also been incorporated for the syntheses of novel peptides and proteins (13-16) and for surface immobilization (17). For instance, N-acylcysteines have found utility as photoactivatable analogs of glutathione (18) and for the synthesis of oxytocin-like peptides (19).Haase and Seitz showed that an internal cysteine with glycine or alanine as the N-terminal residue enhanced the rate of NCL. Ligation rate also depends on the ring size formed during the S fi N acyl transfer (20). Wong and coworkers (9,21) reported that N-terminal glycine favors second-generation sugar-assisted ligation in cysteine-containing and cysteine-free glycopeptides over sterically encumbered L-amino acids like valine, leucine, isoleucine, and proline. According to a generally accepted notion, the subsequent acyl shift should proceed via entropically favored 5-and 6-member ring intermediates to achieve useful rates. However, our group has tested the feasibility of chemical ligation of S-acylated cysteine peptides via 5-, 8-, 11-, and 14-membered cyclic transition states (22)(23)(24). We now report migration of the acyl group from S-acylated cysteine isopeptides containing a-, b-and c-amino acids via 17-, 18-and 19-membered cyclic transition states.

Cbz-(protected)-tri-and tetrapeptide conjugates with steroids, sugars, terpenes, and heterocycles were prepared using Cbz-(protected)-tri-and tetrapeptidoylbenzotriazoles as active intermediates.

(α‐Benzyloxycarbonyl‐aminoacyl)benzotriazolides (Cbz = benzyloxycarbonyl) underwent a coupling reaction with α‐hydrazino acids under microwave irradiation to form hybrid hydrazino dipeptides (42–71 %). Chiral acylations of β‐N‐Cbz‐α‐hydrazino acylbenzotriazolides were successfully carried out with N‐, S‐, O‐, and C‐nucleophiles in yields of 49–88 %.

Novel N-(Cbz-aminoacyl)thiosemicarbazides 3a-c were cyclized by treatment with sulfuric acid to give 1,3,4-thiadiazoles 4a-c. Compounds 4a-c reacted with N-(Cbz-aminoacyl)- and -dipeptidoylbenzotriazoles to afford chirally pure 1,3,4-thiadiazol-2-yl-substituted amino acids 6a-c and dipeptides 7a-c.

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