Cyclization of Linear Tetrapeptides Containing N-Methylated Amino Acids by using 1-Propanephosphonic Acid Anhydride

The cyclization of the linear tetrapeptides sequence H-NMePhe-Xaa(1)-NMePhe-Xaa(2)-OH (for which Xaa(1) = Xaa(2) = Ile, Val, or Leu; Xaa(1) = Val; Xaa(2) = Ile or Leu) by using 1-propanephosphonic acid anhydride was explored. An unanticipated finding is the cyclization towards cyclotetrapeptide conformers (kinetic products) that were highly prone to hydrolysis and that slowly interconvert into the more stable trans,cis,trans,cis (tctc) conformers (thermodynamic products).