Syntheses of Hydrazino Peptides and Conjugates

Abstract

(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 %.

Synthesis of hybrid hydrazino peptides: protected vs unprotected chiral α-hydrazino acids

“…Solvent was evaporated and the product (yellow oil, 40 %) used without further purification. α-Hydrazino acids were prepared according the procedure described by Panda et al ( 2013 ), with slight modifications. d -Amino acid was dissolved in 2.5 M H 2 SO 4 (1.3 mL/mmol) and KBr (3.5 equiv.)…”

“…Electrophilic amination with N -Boc oxaziridines ensures optical integrity of the obtained hydrazino acids, however procedure suffers from the lack of reproducibility. Nucleophilic substitution of α-bromo acids with hydrazine is a rather simple and economic two-step procedure, but incomplete conversions were observed in some cases (Panda et al 2013 ). Also, the adjacent nitrogen atoms, Nα and Nβ are both reactive; therefore regioselectivity during the synthesis of hydrazino-based peptidomimetics arose as a central issue when using derivatives with unprotected Nα atom (Maraud and Vanderesse 2004 ).…”

Tandem Deprotection–Dimerization–Macrocyclization Route to C2 Symmetric cyclo‐Tetrapeptides

“…Compound 5 a was synthesized in a four‐step procedure starting from 1 a 26. 27 Cbz‐ N ‐protected β ‐amino acid 1 a was first converted into the benzotriazolide 2 a (Cbz=Carboxybenzyl); reaction of 2 a with proline gave 3 a , which was converted into Cbz‐dipeptidoyl benzotriazolide 4 a 28. 29 Stirring at a concentration of 12 m M under hydrogen in the presence of Pd/C (10 wt %) at 20 °C for 48 h, 4 a afforded 5 a (Scheme ) by tandem dimerization–macrocyclization: HPLC‐MS confirmed the major product is symmetrical cyclic tetrapeptide cyclo ‐( β ‐Ala‐ L ‐Pro‐) 2 5 a which, after purification by gradient chromatography (MeOH/ether) was obtained in 70 % isolated yield.…”

β2, 2‐Amino Acid N‐Carboxyanhydrides Relying on Sequential Enantioselective C(4)‐Functionalization of Pyrrolidin‐2,3‐diones and Regioselective Baeyer–Villiger Oxidation

“…Similarly, 33 reactedw ith benzylamine to provide 35 in 72 %y ield, and the coupling of b-NCA 29,p repared from 11 Aa as above, with glycine ethyl ester afforded the a-tetrasubstituted b-amino a-hydrazino acid derived peptide 36 in 75 %y ield. [51] This coupling reaction also tolerates dipeptides, even with relatively bulky groups, as shown in the preparation of product 37 through coupling of 32 with the corresponding dipeptide H 2 N-Val-Phe-OtBu.…”