Solid-phase synthesis of peptide–heterocycle hybrids containing a tripeptide-derived 6,6-fused bicyclic subunit

The solid-phase synthesis of peptides incorporating a tripeptide-derived 6,6-fused bicyclic subunit is described. The bicyclic moiety (3,8,10-trisubstituted 2,9-dioxo-5-thia-1,8-diazabicyclo[4.4.0]decane) can be incorporated anywhere in a peptide sequence and is formed spontaneously upon TFA cleavage through condensation of an aldehyde with a backbone amide nitrogen and side-chain thiol, resulting in a thiazinone ring. The reaction is regio- and stereoselective and also allows for the incorporation of the bicyclic moiety, which may represent a constrained β-turn mimic, into a macrocyclic peptide.