( N -Hydroxy)amide-Mediated Rapid Head-to-Tail Cyclization of Unprotected Peptides in Water

Abstract Many naturally occurring cyclic peptides exist in a head-to-tail manner. However, this head-to-tail cyclization strategy faces significant challenges because the cyclization is an entropy-unfavorable process. Here, we report a (N-hydroxy)amide-mediated rapid head-to-tail cyclization of unprotected aminoacyl (N-hydroxy)peptide hydrazides with different lengths and sequences in water. In this protocol, nitrite oxidation of our prepared aminoacyl (N-hydroxy)peptide hydrazides at pH 3.0 formed the corresponding aminoacyl (N-hydroxy)peptide azides, intramolecular N,O-exchange of the peptide azides with their N-hydroxyls at pH 8.0 provided the cyclic O-acyl peptides, and O,N-acyl transfer of the cyclic O-acyl peptides yielded the cyclic (N-hydroxy)peptides. Reduction of the cyclic (N-hydroxy)peptides with zinc in water (pH 3.0) at 37 °C afforded cyclic peptides with native amide bonds. The protocol was successfully extended to the head-to-side-chain cyclization of a peptide containing Glu residue. This (N-hydroxy)amide-mediated chemoselective cyclization of linear peptides is not limited to some specific type of amino acid residues at the ligation sites. The present method exhibits some advantages, including use of unprotected linear peptide precursors, water as the solvent, which is conducive to the dissolution of linear peptide precursors and cyclic peptide products, diverse sequences with or without turn-inducing amino acid residues, facile and rapid cyclization (completion within 30 min), almost no epimerization and dimerization, high yields, and the obtained cyclic peptides with different ring sizes. Twenty-three cyclic peptides were synthesized, and seven of them are natural products with diverse biological activity. This (N-hydroxy)amide-mediated peptide cyclization provides a novel, effective, and general strategy for the synthesis of cyclic peptides.