Sulfahydantoins as Tripeptide Constraints: Synthesis and Structure of Chiral Substituted 3-Oxo-1,2,5-thiadiazolidine 1,1-Dioxides

Abstract

A sulfahydantoin (3-oxo-1,2,5-thiadiazolidine 1,1-dioxides) motif is used as a new type of peptidic constraint to lock two consecutive amide nitrogens by a sulfonyl bridge. The 5-membered heterocyclic motif was prepared starting from proteogenic and synthetic amino acids and chlorosulfonyl isocyanate. Constrained dipeptides were obtained under alkaline conditions (methoxide 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 crystallographic analysis. In addition, the chemo-, regio-, and stereoselectivities of the reactions were studied. In the acylated derivatives, the sulfahydantoin constraint induces a unique backbone conformation with coplanarity of two consecutive peptide bonds.