Efficient oxidation of N-protected tryptophan and tryptophanyl-dipeptides by in situ generated dimethyldioxirane provides hexahydropyrroloindoline-containing synthons suitable for peptide synthesis and subsequent tryptathionylation

A series of hydroxypyrroloindoline (Hpi) containing dipeptides along with the corresponding monomeric Hpi-α-amino acid (Hpi-2-carboxylate), were prepared by reacting a series of N ^α-protected-tryptophans in aqueous or biphasic [water/cyclopentyl methyl ether (CPME)] solutions containing Oxone^® (potassium peroxymonosulfate) and acetone. This procedure avoids the tedious distillation of unstable dimethyldioxirane (DMDO), which is commonly used to oxidize indoles. Monomers N ^α-Boc-Hpi-OH and N ^α-Fmoc-Hpi-OH were readily incorporated by solid-phase peptide synthesis (SPPS) into a peptide containing a cysteine; in trifluoroacetic acid (TFA), the Hpi underwent intramolecular dehydrative condensation with the cysteine thiol to afford the anticipated tryptathionine crosslink. This eco- and user-friendly oxidative methodology greatly simplifies the synthesis of Hpi derivatives while enabling the synthesis of tryptathionine crosslinks characteristic of phalloidin and amanitin, two potent peptide toxins of present interest.