SYNTHESIS OF RIGID, HETEROCYCLIC DIPEPTIDE ANALOGS

The preparation of rigid analogues of peptides can be a valuable technique for gaining information about the active conformation of biological ligands and/or for enhancing the protholytic stability and bioavailability of such systems. In the course of our studies directed toward the design of novel inhibitors of human renin,2 the aspartic proteinase responsible for initiation of the renin-angio-tensin system, we desired a rigid, heterocyclic mimic of an N-terminal phenylalanine containing dipeptide. The analogue that we chose to pursue (2) can be conceptually derived from a Phe-Xaa dipeptide 1 by a series of rigidi-fying events (Figure 1): (a) fixing the dihedral angle between the a and carbons of phenylalanine;3 (b) blocking rotation of the side-chain phenyl group;4 and (c) fixing the directionality of the amide carbonyl group with respect to the indole ring and prohibiting C-N amide-bond rotation.5 Attachment of 2 to any of a variety of transition-state. © 1990, American Chemical Society. All rights reserved.