Synthesis of Cyclic Hexapeptides Based on the Antibiotic Cyclic Decapeptide Loloatin C by an in situ Indirect Cyclization Method

Three cyclic hexapeptide units based on the parent loloatin C scaffold have been identified by a 'sliding window' method as part of an expeditious SAR search for the basis of the antibiotic activity of the loloatins. Modified Fmoc-based solid-phase synthesis was used to prepare cyclic(L-valyl-L-ornithyl-D-phenylalanyl-L-asparaginyl-L-aspartyl-L-trypto- phanyl) and cyclic(L-valyl-L-ornithyl-L-leucyl-L-trypto-phanyl-D-phenylalanyl-L-asparaginyl) in overall yields of 42%-47%. A new solution method combined with an in situ indirect cyclization was specifically developed to prepare cyclic(L-ornithyl-L-leucyl-D-tyrosyl-L-prolyl-L-tryptophanyl-D-phenylalanyl), involving cyclization of the linear peptide through the amino group in leucine, liberated selectively from the Fmoc-protected amine in situ, with the activated p-nitrophenyl ester of ornithine. The method was also effectively used for cyclization of the linear precursors of the first two cyclic hexapeptides. NOE analyses coupled with peptide backbone modelling were used to establish conformations of the target compounds. All have helix-like structures with γ-turns.