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.
Galaud
Fabrice
F
Département de Chimie, Université de Montréal, C.P.6128. Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7.
Lubell
William D
WD
D032701:Biomimetics; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006714:Homoserine / Q000737:chemistry*; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry*
D004151:Dipeptides; D007769:Lactams; D011108:Polymers; D013451:Sulfonic Acids; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D006714:Homoserine