Partial [αMe]Aun scan of [l‐Leu11‐OMe]‐trichogin GA IV,a membrane active synthetic precursor of the natural lipopeptaibol

Abstract: We synthesized using solution‐phase methods three analogs of l ‐Leu¹¹‐OMe] trichogin GA IV, a membrane active synthetic precursor of the lipopeptaibol antibiotic in which the N‐terminal n‐octanoyl group and each of the three Aib residues in positions 1, 4 and 8 are replaced by an acetyl group and the lipophilic C^α,α‐disubstituted glycine l ‐(αMe)Aun, respectively partial (αMe)Aun scan]. FT‐IR absorption and CD analyses unequivocally show that the main three‐dimensional structural features of l ‐Leu¹¹‐OMe] trichogin GA IV are preserved in the analogs. Also, l ‐Leu¹¹‐OMe] trichogin GA IV and the three N^α‐acetylated l ‐(αMe)Aun analogs exhibit strictly comparable membrane‐modifying properties. Taken together, these results strongly favor the conclusion that a shift of the long hydrocarbon moiety from the N^α‐blocking group to the side‐chain of the 1, 4 or 8 residue does not have any significant effect on the conformational properties or the membrane activity of l ‐Leu¹¹‐OMe] trichogin GA IV and, by extension, of the natural lipopeptaibol.