Development of a functionalizable external β-turn mimic based on a cis-fused 1,7-naphthyridine scaffold

An intramolecular Diels-Alder strategy using 2(1H)-pyrazinones was applied to generate a substituted perhydro-1,7-naphthyridine ring system that served as a scaffold to construct the type VI beta-turn mimic 2, featuring a cis-amide linkage between the central i+1 and i+2 residues. The synthesis permits mimicking of the amino acid side chains of the central dipeptide, a unique feature for external-turn mimics. Modeling studies indicated that the cis-fused bicyclic system adopts a conformation suitable for induction of a beta-turn when the angular position 8a bears a non-H substituent. Extensive NMR analysis of an 8a-methyl derivative 25 confirmed its beta-turn-inducing properties in various solvents, including water. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).