A pseudopeptide incorporating the tetrahydrophthalazine nucleus, a constrained aza analog of phenylalanine

Replacement of the alpha-carbon with a nitrogen in alpha-amino acids gives rise to azaamino acids. Most examples of azaamino acids that have been incorporated into peptides are linear analogs, in which conformational effects are restricted to the immediate vicinity of the urea bond. In contrast to the linear azaamino acids, the heterocyclic analogs might be expected to exhibit stronger conformational preferences, but examples of this class of azaamino acids are very limited. We synthesized tetrahydrophthalazine (THPhth) as a constrained phenylalanine analog and elaborated it into the model pseudotripeptide N-¿([N-alanyl]-1,2,3,4-tetrahydro-2-phthalazinyl)carbonyl)¿-L-alan ine (1). As shown by NMR studies, tetrahydrophthalazine 1A has a secondary structure in which psi THphth is fixed at 16-18 degrees and there are two equal populations of cis and trans amide bonds from the N-terminal alanine.