| Abstract
| - A simple and highly efficient Fmoc solid-phase protocol for synthesizing the antimicrobial decapeptidegramicidin S and various labeled analogues is presented. When preparing the linear precursor peptides(1a−e), a systematic permutation of the starting amino acid within the cyclic sequence gave differentyields between 51% and 93%. Also the subsequent step of cyclization gave widely diverging yieldsbetween 26% and 74%, depending again on the starting amino acid. The ease of cyclization was foundto correlate with the tendency of the respective linear precursor peptide to assume a preorganizedconformation, as observed by circular dichroism. The overall yield is thus critically dependent on thestarting amino acid and can be raised from 20% to 70% using dPhe. The choice of coupling agent andits counterion was found to play only a marginal role. Irrespective of being able to assume a preorganizedconformation, none of the linear precursor peptides exhibited any antimicrobial or hemolytic activity.Using the optimized protocol, which involves only simple Fmoc-couplings and requires no intermittentpurification steps, several gramicidin S analogues (3−8) containing 19F-labeled phenylglycine derivativesand/or 15N-labeled amino acids were synthesized for solid-state NMR structure analysis.
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