STUDIES ON CONFORMATIONAL CONSEQUENCES OF I TO I-CHAIN CYCLIZATION INMODEL CYCLIC TETRAPEPTIDES(3 SIDE)

In an effort to explore the effect of ring size on the biologically ac tive conformation of cyclic analogs of the mating pheromone alpha-fact or (WHWLQLKPGQPMY) from Saccharomyces cerevisiae, eight cyclic tetrape ptides corresponding to the KPGQ portion of alpha-factor were synthesi zed. These N-alpha-acetyl/carboxyl amide terminal cyclic tetrapeptides were prepared on a 4-methylbenzhydrylamine resin using orthogonal Boc , Fmoc, OFm and OtBut protecting groups and HOBt-DIPC accelerated acti ve esters or urethane-protected N-carboxyanhydrides. On-resin cyclizat ion of the side-chain amino and carboxyl groups of the first and fourt h residues, respectively, was performed with the BOP reagent to genera te lactams containing 14-18 atoms. HF cleavage resulted in two product s, the desired cyclic tetrapeptide and a major side product. All pepti des were purified to near homogeneity (>99%) by using reversed-phase H PLC and were characterized by FARMS and H-1 NMR. Certain constrained c yclic tetrapeptides appear to be a mixture of isomers at room temperat ure as evidenced by HPLC and NMR. The major side product has been iden tified as a cycle dimer, obtained as a consequence of interchain cycli zation on the resin. CD analysis in several solvents gives evidence th at some of the cyclic tetrapeptides exist in beta-turn conformations. (C) Munksgaard 1995.