Cyclotetrapeptides and cyclopentapeptides: occurrence and synthesis.

The structures reported for the three cancerostatic all-L-cyclotetrapeptides cyclo(Pro-Leu)2, cyclo(Pro-Val)2 and cyclo(Pro-Phe)2 isolated from a tunicate seem questionable. The synthetic compounds claimed to be identical to the naturally occurring cyclotetrapeptides are in fact not cyclotetrapeptides but rather cyclooctapeptides. We have not been able to prepare the tyrosinase inhibitor cyclo(Pro-Val-Pro-Tyr). Ring closure of H-Pro-Val-Pro-Tyr-OC6F5 gave rise to 31% of cyclo(Pro-Val-Pro-D-Tyr). The same product was obtained in 53% yield from H-Pro-Val-Pro-D-Tyr-OC6F5. For the ring closure to the all-L-cyclopentapeptide cyclo(Pro-Ala-Ala-Phe-Leu), all ring closure positions have been investigated. The reaction at the nitrogen atom of leucine leads to 21% of the all-L-cyclopentapeptide. Dimers or mixtures of monomers and dimers result from reaction at all other positions.