Stepwise Automated Solid Phase Synthesis of Naturally Occurring Peptaibols Using FMOC Amino Acid Fluorides

The standard methods of stepwise solid phase synthesis according to Merrifield could not previously be applied to the synthesis of the important naturally occurring peptaibols because of difficulties arising from the pronounced steric hindrance caused by α,α-dialkylated amino acids (incomplete coupling, especially to adjacent similarly constituted units, racemization due to slow coupling to hindered amino acids, etc.), chain degradation due to the presence of acid-labile Aib-Pro linkages, and the lack of any general method for the loading of C-terminal amino alcohols to resin supports. Following recent work on model systems, it is now shown that the adoption of Fmoc amino acid fluorides as coupling reagents makes possible the facile, general assembly of such peptides. The method was demonstrated for alamethicin F30 and F50, satumisporin SA III, and trichotoxin A50-J. The crude products were of remarkable purity. Amino acid analysis, mass spectral data, and comparison of the synthetic alamethicins with samples of naturally occurring material confirmed the success of the syntheses. No significant amount of racemization (<0.8%) was found for any of the chiral amino acids present. The first step of the synthesis involved a new general method for assembly of C-terminal peptide alcohols via the use of o-chlorotrityl resin. In addition, model studies on the question of racemization during the coupling of Fmoc amino acid fluorides are reported. © 1995, American Chemical Society. All rights reserved.