Synthesis of pyrazolo[1,2-a]pyrazole-based peptide mimetics

The synthesis of U-shaped conformationally constrained analogues of peptides based on the 3-amino-2-oxo-1,5-diazabicyclo[3.3.0]octane-8-carboxylic acid scaffold was developed. [3+2] Cycloadditions of (1Z,4R*,5R*)-1-arylmethylidene-4-benzyloxycarbonylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to tert-butyl acrylate and tert-butyl methacrylate gave the corresponding racemic cycloadducts, in most cases as mixtures of isomers, which were separated by preparative chromatography. Selective deprotection of the C- and the N-terminal of these heterocyclic dipeptides followed by coupling with (S)-alanine derivatives and chromatographic separation furnished the non-racemic tripeptides as target compounds. The structures of racemic cycloadducts and non-racemic final products were determined by NMR spectroscopy and X-ray diffraction. The synthesized compounds were also evaluated for inhibition of MurD ligase and d-alanine:d-alanine ligase.