Synthesis of a constrained enkephalin analog to illustrate a novel route to the piperazinone ring structure

Article abstract of DOI:10.1016/S0040-4039(97)10530-5

The synthesis of a constrained, piperazinone analog of Leu-enkephalin is presented. A key step in this synthesis was the use of the secondary amine, Boc-Tyr(OtBu)Ψ[CH₂NH]Gly-OMe, to ring open the β-lactone of Z-protected L-serine (the Vederas lactone). The resulting free acid was then coupled to H-Phe-Leu-OtBu in a one-pot fashion using standard carbodiimide coupling conditions. This linear precursor cyclized upon hydrogenolysis of the Z group to form the N⁴-substituted, 6-carboxy-derived piperazinone (5). Deprotection of compound 5 using 1:1 TFA:CH₂Cl₂ yielded the target compound 1.