A PSEUDOPEPTIDE INCORPORATING THE TETRAHYDROPHTHALAZINE NUCLEUS, A CONSTRAINED AZA ANALOG OF PHENYLALANINE

Replacement of the alpha-carbon with a nitrogen in alpha-amino acids g ives rise to azaamino acids. Most examples of azaamino acids that have been incorporated into peptides are linear analogs, in which conforma tional effects are restricted to the immediate vicinity of the urea bo nd. 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 synthes ized tetrahydrophthalazine (THPhth) as a constrained phenylalanine ana log and elaborated it into the model pseudotripeptide l]-1,2,3,4-tetra hydro-2-phthalazinyl)carbonyl)}-L- alanine (1). As shown by NMR studie s, tetrahydrophthalazine 1A has a secondary structure in which psi THP hth is fixed at 16-18 degrees and there are two equal populations of c is and trans amide bonds from the N-terminal alanine. (C) Munksgaard 1 996.