Studies on N-deprotection of ψ(CH2NH) pseudodipeptide methyl esters. Cyclization to 2-ketopiperazines

Abstract

N-Deprotection of Z- and Boc-aminomethylene pseudodipeptide methyl esters yielded not only the expected linear deprotected compounds but also the 2-ketopiperazine cyclic analogues. The extent of lactamization was found to be dependent on the nature of the amino acid, the sequence order, and the deprotection conditions. Hydrogenation of Z-pseudodipeptides containing N-terminal basic amino acids in acidic media afforded linear compounds, while replacement of these basic residues by Leu gave mixtures of linear and cyclic pseudodipeptides. The reverse-sequence analogues, with Lys or Arg at the C-terminus, yielded the corresponding 2-ketopiperazines as the only reaction products. Opposite results were obtained for C-terminal Leu derivatives in which almost no cyclization occurred. Hydrogenation under neutral conditions gave mainly cyclic derivatives, while linear analogues were predominant after treatment of Boc-protected pseudodipeptides with trifluoroacetic acid or HCl.