Solid‐Phase Synthesis of Cyclic Lipopeptidotriazoles

The solid‐phase synthesis of cyclic lipopeptidotriazoles derived from the cyclic decapeptide c(Lys‐Lys 2 ‐Leu‐Lys‐Lys 5 ‐Phe‐Lys‐Lys‐Leu‐Gln) (BPC194), incorporating a triazolyl ring at Lys 2 and a hexanoyl group at Lys 5 , was studied. Four different strategies that required the use of five orthogonal protecting groups (Fmoc, t Bu, All, pNZ, ivDde) were explored. The influence of the side‐chain protection of Lys 2 and Lys 5 with the ivDde and pNZ groups was evaluated by incorporating Lys 2 (ivDde)/Lys 5 (pNZ) or Lys 2 (pNZ)/Lys 5 (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 Lys 2 (ivDde) and Lys 5 (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.