| Abstract
| - An orthogonal cyclization strategy has been developed to prepare cyclic peptides individually or asa mixture in aqueous solutions. In this strategy, we propose a dual activation by entropy and enthalpy throughAg+ ion coordination of the reactive ends of an unprotected peptide thioester to permit long-range acyl migration.As a result, both lactamization and lactonization of linear peptides can be realized simultaneously or selectivelyby controlling the reaction conditions. At pH 4, lactonization is favored due to the strong protonation of theamino moieties. However, at pH 5−5.7 lactamization of α-amine of the N-terminal amino acid is favored,particularly with DMSO as a cosolvent. At pH > 6, lactamization of the ε-amine of lysine becomes significant.Furthermore, the Ag+ ion complexation with the peptide thioester precursor in aqueous buffered solutionsmay facilitate entropy-favored ring−chain tautomerization, which in turn promotes formation of monomericcyclic products and thereby reduces unwanted oligomerization. Evidence supporting Ag+ ion-directed ring−chain tautomerization includes product distribution profiles, the concentration-independent nature of thecyclization, and lack of competition by intermolecular coupling with other unprotected peptide segments. TheN-terminal amino acid has been found to exert a profound effect in conferring high specificity toward end-to-end cyclization. Examination of 23 linear peptide precursors containing different Nα-amino acids showedthat the probability of lactamization is almost 20-fold greater in α-amines than ε-amines with N-terminal Gly,Asn, Asp, and Ser. Unprotected linear peptides ranging from 5 to 16 amino acid residues were cyclizedindividually or as a mixture with good to excellent yields. More importantly, this strategy paves the way fora new approach to synthesizing cyclic peptide libraries in which unprotected peptides are cyclized and releasedfrom the resin at the same time. The obtained libraries can, therefore, be used directly for bioassays withoutfurther chemical manipulations. This method is also useful for the synthesis of bicyclic peptides containingboth sulfur−sulfur and lactam linkages.
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