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 alpha-cumyl beta-methyl diester as an inexpensive chiral educt. After selective reduction of the beta-methyl ester with diisobutylaluminum hydride (DIBAL-H), homoserine was treated with thionyl chloride, imidazole, and triethylamine to give sulfamidites. Diastereoisomers were separated by chromatography and oxidation of the major sulfamidite (2R,4S)- with catalytic ruthenium trichloride afforded sulfamidate. A series of gamma-lactam-bridged dipeptides was then obtained by ring opening of sulfamidate cumyl ester 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 gamma-lactam analog of Pro-Leu-Gly-NH2 (PLG), was synthesized to illustrate the potential for using this approach in the synthesis of biologically active peptide mimics. Copyright (c) 2005 Wiley Periodicals, Inc.