Solution‐phase submonomer diversification of aza‐dipeptide building blocks and their application in aza‐peptide and aza‐DKP synthesis

Abstract

Aza-peptides have been used as tools for studying SARs in programs aimed at drug discovery and chemical biology. Protected aza-dipeptides were synthesized by a solution-phase submonomer approach featuring alkylation of N-terminal benzophenone semicarbazone aza-Gly-Xaa dipeptides using different alkyl halides in the presence of potassium tert-butoxide as base. Benzophenone protected aza-dipeptide tert-butyl ester 31c was selectively deprotected at the C-terminal ester or N-terminal hydrazone to afford, respectively, aza-dipeptide acid and amine building blocks 36c and 40c, which were introduced into longer aza-peptides. Alternatively, removal of the benzophenone semicarbazone protection from aza-dipeptide methyl esters 29a-c led to intramolecular cyclization to produce aza-DKPs 39a-c. In light of the importance of aza-peptides and DKPs as therapeutic agents and probes of biological processes, this diversity-oriented solution-phase approach may provide useful tools for studying peptide science.

Analysis of N‐amino‐imidazolin‐2‐one peptide turn mimic 4‐position substituent effects on conformation by X‐ray crystallography

“…As previously reported, alkylation of 7 with propargyl bromide, Sonogashira cross‐coupling with iodobenzene, 5‐exo‐dig cyclization with NaH, and tert ‐butyl ester removal with trifluoroacetic acid gave 4‐benzyl N ‐amino‐imidazolin‐2‐one dipeptide 12 . Acid 12 was then coupled to iso ‐propylamine by activation as a mixed anhydride using iso ‐butyl chloroformate to afford amide 13 , which as described for 6 above, was treated with hydroxylamine hydrochloride in pyridine to remove the benzhydrylidene . The resulting N ‐amino imidazolinone hydrochloride was subsequently treated without purification with 4‐methoxybenzoyl chloride (200 mol%) and DIEA (300 mol%) in dichloromethane to provide N,N ‐bis( p ‐methoxybenzamido)−4‐benzyl‐imidazolin‐2‐one 3 in 56% yield from 13 .…”

“…In the case of the 4‐methyl analogue 2 , benzhydrylidene aza‐glycinyl‐ d ‐phenylalanine N ′‐ iso ‐propyl amide 4 was alkylated with propargyl bromide and potassium tert ‐butoxide in THF to afford in 71% yield aza‐propargylglycine 5 , which underwent NaH‐promoted 5‐ exo‐dig cyclization to give imidazol‐2‐one 6 in 78% yield . Removal of the benzhydrylidene protection was performed using hydroxylamine hydrochloride in pyridine . Without further purification, the resulting N ‐amino‐imidazolin‐2‐one was treated with excess 4‐methoxybenzoyl chloride (500 mol%) and di‐ iso ‐propylethylamine (2000 mol%) to afford N,N ‐bis( p ‐methoxybenzamido)−4‐methyl‐imidazolin‐2‐one 2 in 70% yield over two steps from the corresponding benzophenone‐protected N ‐amino imidazol‐2‐one 6 .…”

Synthesis and Evaluation of Azapeptide Prostaglandin F2α Receptor Modulators in Pursuit of Inhibitors of Preterm Labor

“…Aza-glycinyl proline tert-butyl ester 4 was synthesized as reported [6] and treated with potassium tert-butoxide and 4-methyl benzyl bromide to provide aza-(4-Me)Phe analog 5 in 84% yield [5,6]. Benzhydrylidene removal using hydroxylamine hydrochloride in pyridine [6], acylation of the resulting semicarbazide with phenylacetyl chloride, and tert-butyl ester removal in a TFA/DCM solution afforded the N-terminal aza-dipeptide 8. Coupling of aza-dipeptide 8 to dipeptide benzyl ester 9 [4] was performed using iso-butyl chloroformate and N-methyl morpholine to furnish aza-peptide benzyl ester 10.…”

Synthesis and alkylation of aza‐glycinyl dipeptide building blocks

“…This was prepared using the protocol described earlier for phenylalanine dipeptide 6a using benzophenone hydrazone (697 mg, 3.55 mmol, 1 eq), DSC (1 g, 3.90 mmol, 1.1 eq), DIEA (1.2 ml, 7.1 mmol, 2 eq) and glycine tert-butyl ester (595 mg, 3.55 mmol, 1 eq) in dry CH 2 Cl 2 (28 ml) and DMF (5 ml). Flash chromatography, using 20-50% EtOAc in hexane as solvent system, and evaporation of the collected fractions gave aza-dipeptide 6b (873 mg, 70% yield); mp 141-142, R f = 0.14 (8 : 2 hexane/EtOAc); δ 7.66 (s, 1H), 7.56 (m, 5H), 7.37 (m, 3H), 7.28 (m, 2H), 6.79 (s, 1H), 4.07 (d, J = 4.9 Hz, 2H), 1.54 (s, 9H); 13…”