Synthesis of a New Turn Mimic Bearing a β-Lactam Moiety

Abstract

A new turn mimic derived from PLG (prolyl-leucyl-glycine amide) containing a β-lactam in the turn area has been prepared. The β-lactam moiety was furnished by treating an Fmoc-protected leucine-derived diazo ketone 2 with a benzylidene-protected glycine ester in a photochemically induced Staudinger-type reaction. The trans-substituted β-lactams 3a/b are formed in 70% yield (dr 70:30). Separation of the isomers, deprotection and attachment of Fmoc-proline using the pentafluorphenyl ester activation protocol yielded the protected peptidomimetic 4 in 93% yield. Deprotection and amidation resulted in formation of the target substrate 1 in 82% yield but with a low purity. Better results were obtained using Nsc ({2-[(4-nitrophenyl)sulfonyl]ethoxy}carbonyl) as protection for proline. It could be cleaved yielding a spectroscopically pure product 1 whose structure was elucidated by X-ray crystallographic analysis. It shows an open turn conformation, i.e., the turn is not stabilized by a hydrogen bond between the termini of the turn region. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)