STEPWISE AUTOMATED SOLID-PHASE SYNTHESIS OF NATURALLY-OCCURRING PEPTAIBOLS USING FMOC AMINO-ACID FLUORIDES

The standard methods of stepwise solid phase synthesis according to Me rrifield could not previously be applied to the synthesis of the impor tant naturally occurring peptaibols because of difficulties arising fr om the pronounced steric hindrance caused by alpha,alpha-dialkylated a mino acids (incomplete coupling, especially to adjacent similarly cons tituted units, racemization due to slow coupling to hindered amino aci ds, etc.), chain degradation due to the presence of acid-labile Aib-Pr o linkages, and the lack of any general method for the loading of C-te rminal amino alcohols to resin supports. Following recent work on mode l systems, it is now shown that the adoption of Fmoc amino acid fluori des as coupling reagents makes possible the facile, general assembly o f such peptides. The method was demonstrated for alamethicin F30 and F 50, saturnisporin SA III, and trichotoxin A50-J. The crude products we re of remarkable purity. Amino acid analysis, mass spectral data, and comparison of the synthetic alamethicins with samples of naturally occ urring 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 0-ch lorotrityl resin. In addition, model studies on the question of racemi zation during the coupling of Fmoc amino acid fluorides are reported.