All-L-Leu-Pro-Leu-Pro: a challenging cyclization.

In this paper, we report the difficult synthesis of cyclo(Leu-Pro-Leu-Pro). While the cyclization of Leu-Pro-Leu-D-Pro did not cause problems, the all-L-peptide afforded cyclodimer rather than cyclotetrapeptide (cyclomonomer). A first attempt using our reversible backbone substitution methodology failed. However, we were successful in obtaining the desired cyclo(Leu-Pro-Leu-Pro) by decreasing the concentration. The ratio of cyclomonomer to cyclodimer was raised to 1:1.1 using BOP and 1:0.6 using HATU under our high dilution condition. The structures of the cyclopeptides were confidently assigned by electrospray ionization mass spectrometry and NMR.