Homoserine-derived cyclic sulfamidate as chiral educt for the diversity-oriented synthesis of lactam-bridged dipeptides.

Introduction of structural constraint into peptides is an effective way for studying their conformation-activity relationships. Conformationally restrained dipeptidyl lactams, important building blocks for the synthesis of peptidomimetics, have now been synthesized from N-[9-(9-phenylfluorenyl)]-L-aspartic acid α-cumyl β-methyl diester as an inexpensive chiral educt. After selective reduction of the β-methyl ester with diisobutylaluminum hydride (DIBAL-H), homoserine 6 was treated with thionyl chloride, imidazole, and triethylamine to give sulfamidites 7. Diastereoisomers 7 were separated by chromatography and oxidation of the major sulfamidite (2R,4S)-7 with catalytic ruthenium trichloride afforded sulfamidate 8. A series of γ-lactam-bridged dipeptides was then obtained by ring opening of sulfamidate cumyl ester 8 with a series of amino esters, selective cumyl ester removal, and lactam formation. The resulting dipeptidyl lactams possessed aliphatic, aromatic, amino, thioether, and carboxylate side chains. A γ-lactam analog ofPro-Leu-Gly-NH 2 (PLG), 16, was synthesized to illustrate the potential for using this approach in the synthesis of biologically active peptide mimics.