Sulfahydantoins as tripeptide constraints: Synthesis and structure of chiral substituted 3-oxo-1,2,5-thiadiazolidine 1,1-dioxides

A sulfahydantoin (3-oxo-1,2,5-thiadiazolidine 1,1-dioxides) motif is used a s a new type of peptidic constraint to lock two consecutive amide nitrogens by a sulfonyl bridge. The 5-membered heterocyclic motif was prepared start ing from proteogenic and synthetic amino acids and chlorosulfonyl isocyanat e, Constrained dipeptides were obtained under alkaline conditions (methoxid e or tert-butoxide) by cyclization of symmetric and dissymmetric sulfamides . The absolute configuration of the chiral centers for the derivative L-Phe -D-Ala, a congener of the series, was established by X-ray diffraction crys tallographic analysis. In addition, the chemo-, regio-, and stereoselectivi ties of the reactions were studied. In the acylated derivatives, the sulfah ydantoin constraint induces a unique backbone conformation with coplanarity of two consecutive peptide bonds.