Emerimicins III and IV and Their Ethylalanine Epimers. Facilitated Chemical-Enzymatic Synthesis and a Qualitative Evaluation of Their Solution Structures

The peptaibol antibiotics, emerimicin III and IV (Ac-Phe¹-MeA²-MeA³-MeA⁴-Val⁵-Gly⁶-Leu⁷-MeA⁸-MeA⁹-Hyp¹⁰-Gln¹¹-R-EtA¹²-Hyp¹³-Xxx¹⁴-Phol¹⁵, where Xxx = Ala for emerimicin III and Xxx = MeA for emerimicin IV) and their EtA¹² epimers have been synthesized using a combined approach involving solution-phase fragment condensation with a final papain-mediated coupling of the 1–6 and 7–15 fragments. The yield of this final step, ranging from 62 to 80% for the four peptides, was a dramatic improvement over efforts to couple these fragments chemically using DCC/HOBt. A qualitative evaluation of the solution structures of these peptides in DMSO is consistent with a right-handed, predominantly 3₁₀ helical conformation throughout the length of the sequence. The antibacterial activity of synthetic emerimicins III and IV was found to be comparable to the native material. The absolute stereochemistry at position 12 has minimal effect on either the biological activity or the solution conformation of the emerimicins.