Total Synthesis of the α‐Helical Eicosapeptide Antibiotic Alamethicin

The voltage‐dependent membrane pore‐forming polypeptide antibiotic alamethicin F 30 (Ac‐Aib‐Pro‐Aib‐Ala‐Aib‐Ala‐Gln‐Aib‐Val‐Aib‐Gly‐Leu‐Aib‐Pro‐Val‐Aib‐Aib‐Glu‐Gln‐Phl, 1) was synthesized by segment condensations. It was obtained free of racemate ( <0.8% D‐components) via the segments 2 – 11 (4a) and 12–20 (3a) using the dicyclohexylcarbodiimide/1‐hydroxybenzotriazole and the mixed anhydride methods. The intermediates were unequivocally characterized by chromatographic and physical methods including 13C NMR, circular dichroism, and chiral phase gas chromatography. The segments 2–6 (5a) and 12–20 (3) were also proven by X‐ray structure determinations. — The final product 1 (150 mg) was obtained without HPLC separations in very high purity and in crystalline form. According to all analytical data and the comparison by spectroscopy and chromatographic analyses (HPLC, DC) the product 1 is identical with the main component F 30 of the microheterogeneous antibiotic metabolite isolated from Trichoderma viride. The antibiotic activities of synthetic alamethicin (1) and the stimulating effect on calcium/calmodulin‐dependent guanylate cyclase of Paramecium are identical with those of natural alamethicin. – The uniform synthetic alamethicin (1) shows perfectly homogeneous conductance states of single pores on measurements in lipid bilayer membranes which had not been reported so far for any synthetic or purified natural preparation.