Peptide Synthesis via Oxidation of N-Acetyl-α-amino Acid Phenylhydrazides¹

Development of the Traceless Phenylhydrazide Linker for Solid‐Phase Synthesis

“…According to Method A for the oxidative cleavage of the hydrazide linker, the resin prepared above (313 mg, 37 mmol) was treated with [Cu(OAc) 2 ] in n-propylamine followed by extractive work-up to yield the title compound (6.8 [32] Polystyrene-bound 3-iodo-4-methylphenylhydrazide (58): According to Procedure E, polystyrene resin 17 b (700 mg, 0.29 mmol) was treated with N,N-diisopropylcarbodiimide (135 mL, 0.87 mmol), 1-hydroxybenzotriazole (133 mg, 0.87 mmol), triethylamine (122 mL, 0.87 mmol), and 3-iodo-4-methylphenylhydrazine (216 mg, 0.87 mmol) in methylene chloride (20 mL . According to Method A for the oxidative cleavage of the hydrazide linker, the resin prepared above (254 mg, 100 mmol) was treated with [Cu(OAc) 2 ] in n-propylamine followed by extractive work-up to yield the title compound (17.8 (15). The spectroscopic data are in agreement with reported values.…”

“…Phenylhydrazides can be oxidized in solution to acyldiazenes with NBS and pyridine in dichloromethane. [15,16] They can be isolated and they are reasonably stable in the absence of water and other nucleophiles. Based on these findings, a two-step process as delineated above was developed.…”

Protease-catalyzed peptide bond formation: application to synthesis of the COOH-terminal octapeptide of cholecystokinin.

“…II was obtained by incubation of Boc-Asp(Bzl)-OH and H-Tyr-N2H2Ph with papain to give Boc-Asp(Bzl)-Tyr-N2H2Ph (I) (33%). Subsequent replacement of the phenylhydrazide group of I by an ethyl ester using N-bromosuccinimide and ethanol (19) gave II (41%). Although the thermolysin-catalyzed coupling of Boc-Asp(Bzl)-OH and H-Phe-N2H2Ph was quite efficient (see below), formation of I in the presence of thermolysin did not work.…”

Solid-Phase Synthesis and Cyclative Cleavage of Quorum Sensing ­Depsipeptide Analogues by Acylphenyldiazene Activation

“…In all four syntheses, a N-terminal Cys prosthesis was appended via an e-aminohexanoic acid spacer (denoted 'X') to separate the peptidomimetic structure from the carrier protein surface ( Figure 1). In the past few years, acylhydrazine [16][17][18][19][20] 'masked activation' chemistry has seen a renaissance in solid-phase synthesis. Semenov and co-workers first adapted the acylphenylhydrazine to a solid-phase linkage format, 21 and it has since been exploited by Waldmann and others in a number of solid-phase synthesis applications.…”

“…16,17,19,20 As this chemistry has found only limited application in SPPS, [22][23][24] we performed a model study using panning reagent 1 to ensure the chiral integrity of cyclative cleavage products. In a separate, small-scale synthesis, panning reagent 1 was prepared with allo-Ile as the penultimate residue and cyclized as in the case of the all-L congener.…”