Abstract
A protocol for parallel solid-phase synthesis of ω-amino acid-elongated philanthotoxins was developed for exploration of structure-activity relationships for unnatural wasp toxin analogues. Several methods for on-resin activation of N -trityl-linked ω-amino acids were investigated, and the influence of chain length upon activation as pentafluorophenyl (Pfp) esters was examined. Comparison of Pfp-ester activation with phosphonium- and aminium/uronium-promoted coupling without pre-activation of the resin-bound carboxylic acids showed that only benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) exhibited a comparable efficiency. The present Pfp ester protocol gave high yields and purities of the resulting philanthotoxin analogues; however, in the case of γ-aminobutyric acid (GABA), use of PyBOP was required in order to avoid lactamization to 2-pyrrolidone.
Key words
amino acids - amides - coupling - solid-phase synthesis - philanthotoxins
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