Synthesis and Chemical Properties of Tetrazole Peptide Analogues

Tetrazole dipeptide analogues in which the amide bond is replaced with the tetrazole ring were synthesized from the corresponding Z or Pht protected dipeptide esters via the imidoyl chloride and imidoyl azide intermediates. of the various imidoyl chloride/imidoyl azide forming reagents that were investigated for this conversion, the best combination was found to consist of PC1₅/HN₃. The success of this reaction was found to be dependent upon the amino protecting group employed and also upon the amino acid sequence of the starting dipeptide. Racemization of the a-carbon of the N-terminal amino acid residue was found to occur during the formation of the tetrazole dipeptide analogue. A hypothetical mechanism involving the formation of a ketene amine intermediate is proposed to account for this racemization. Although racemization of the a-carbon of the C-terminal amino acid residue did not occur during tetrazole formation, it did take place when the tetrazole dipeptide ester was saponified with base, as well as when the tetrazole dipeptide acid was coupled with an amino acid ester by using diphenylphosphoryl azide as the coupling reagent. Racemization of the C-terminal amino acid residue did not take place when the normal mixed anhydride, DCC-HOBt, and N,N-bis[2-oxo-3-oxazolidinyi]-phosphorodiamidic chloride coupling methods were employed.