Synthesis Of Constrained Cyclic Tetrapeptides Via Native Chemical Ligation Of Unprotected Selenoester

Cyclic peptides are a kind of important compounds which widely exist in plants,fungi,bacteria and marine organisms.They not only have important biological and medical functions,but also play important roles in the field of nanomaterials.Therefore,cyclic peptides have attracted a lot of attention in biological and chemical fields.At present,the cyclic pentapeptides and larger structures cyclic peptides have better synthetic methods,but for small structures cyclic peptides,still need effective synthetic methods.This paper focuses on the synthesis of cyclic tetrapeptides.Cyclotetrapeptides are a sort of cyclic compounds that have been proved to have a widely range of biological activities including cytotoxicity.The 12-membered ring structure is highly restrictive,leading to its intramolecular ring tension.Current methods for peptide cyclization generally give low yields,involves the native chemical ligation(NCL),salicylaldehyde-derived auxiliaries and peptide hydrazide activation,are accompanied by the potential dimerization and oligomerization byproducts.This paper presents an efficient strategy for the synthesis of cyclic tetrapeptide,namely native chemical ligation of unprotected selenoester,with unprotected N-teminal cysteinyl or derivatives was investigated.This method overcomes the limitation of conventional cyclization methods that cause propensity of epimerization.What’s more,the cyclization strategy could be performed in moderately high concentration without sulfur addition agents,and cyclodimerization by-product with low yield.Removable thiol-containing auxiliary methods have been developed to extend the cyclization site to non-cysteinyl residues including proline,and provides a method for the synthesis of natural cyclic tetrapeptides and active cyclic pentapeptides.