Cyclotetrapeptides and cyclopentapeptides: occurrence and synthesis

Area of Science:

• Synthetic organic chemistry
• Peptide chemistry
• Natural product synthesis

Background:

• Previous reports described cancerostatic all-L-cyclotetrapeptides isolated from tunicates.
• The structures of cyclo(Pro-Leu)2, cyclo(Pro-Val)2, and cyclo(Pro-Phe)2 were questioned.
• The identity of synthetic compounds claimed to match these natural products was also doubted.

Purpose of the Study:

• To re-evaluate the structures of reported natural cyclotetrapeptides.
• To investigate the synthesis of specific cyclic peptides, including a tyrosinase inhibitor and an all-L-cyclopentapeptide.

Main Methods:

• Chemical synthesis of cyclic peptides.
• Analysis of reaction products to determine peptide ring size and stereochemistry.
• Investigation of various ring closure positions for peptide synthesis.

Main Results:

• Synthetic compounds claimed to be cyclotetrapeptides were identified as cyclooctapeptides.
• Synthesis of the tyrosinase inhibitor cyclo(Pro-Val-Pro-Tyr) was unsuccessful; instead, cyclo(Pro-Val-Pro-D-Tyr) was formed from both L- and D-tyrosine precursors.
• Synthesis of the all-L-cyclopentapeptide cyclo(Pro-Ala-Ala-Phe-Leu) yielded the desired product in 21% yield only when cyclization occurred at the leucine nitrogen; other positions resulted in dimers or mixtures.

Conclusions:

• The structures of previously reported tunicate-derived cyclotetrapeptides are likely incorrect.
• Stereochemical control during peptide ring closure is crucial and can lead to unexpected product formation.
• The synthesis of specific cyclic peptides requires careful optimization of reaction conditions and cyclization sites.