Synthesis of cyclic and acyclic partial retro-inverso modified enkephalins

The cyclic partial retro-inverso modified enkephalins, H-Tyr-cyclo[-D-Glu-Gly-gPhe-D-Leu-] (I), H-Tyr-cyclo[-D-A2bu-Gly-gPhe-R&S-mLeu-] (IIf, IIs), and H-Tyr-cyclo[-D-Glu-Gly-Phe-gLeu-] (III), have been synthesized by solution methodology. In a like manner, their corresponding acyclic analogs Ia-IIIa containing D-Ala2 have also been prepared. Gem-diaminoalkyl residues were generated by conversion of Boc-dipeptide carboxamide to the corresponding gem-diaminoalkyl "dipeptide" salt using [bis(trifluoroacetoxy)iodo] benzene. Cyclizations were achieved at high dilution utilizing diphenylphosphoryl azide as the coupling reagent.