Solid-Phase Synthesis of Cyclic Lipopeptidotriazoles

Abstract

The solid-phase synthesis of cyclic lipopeptidotriazoles derived from the cyclic decapeptide c(Lys-Lys2-Leu-Lys-Lys5-Phe-Lys-Lys-Leu-Gln) (BPC194), incorporating a triazolyl ring at Lys2 and a hexanoyl group at Lys5, was studied. Four different strategies that required the use of five orthogonal protecting groups (Fmoc, tBu, All, pNZ, ivDde) were explored. The influence of the side-chain protection of Lys2 and Lys5 with the ivDde and pNZ groups was evaluated by incorporating Lys2(ivDde)/Lys5(pNZ) or Lys2(pNZ)/Lys5(ivDde). The order of removal of these protecting groups and of the introduction of the hexanoyl and triazolyl moieties was also studied. The best strategy included: (i) synthesis of a cyclic peptidyl resin bearing Lys2(ivDde) and Lys5(pNZ); (ii) pNZ group removal; (iii) acylation with hexanoic acid; (iv) ivDde group removal; and (v) acylation with propiolic acid followed by an azide–alkyne 1,3-dipolar cycloaddition. By using this protocol, a set of cyclic lipopeptidotriazoles was prepared in high purities.