High Yielding Synthesis of 3<i>a</i>-Hydroxypyrrolo[2,3-<i>b</i>]indoline Dipeptide Methyl Esters: Synthons for Expedient Introduction of the Hydroxypyrroloindoline Moiety into Larger Peptide-Based Natural Products and for the Creation of Tryptathionine Bridges

This work describes a rapid and high yielding oxidation of 14 tryptophanylated amino acid methyl
esters to the corresponding 3a-hydroxypyrrolo[2,3-b]indoline (Hpi) amino acids with generally facile
separation of syn-cis and anti-cis diastereomers. Structural X-ray diffraction data are presented
for both diastereomers of Tr-Hpi-Gly-OMe, which allow for a putative assignment of the other 13
pairs of diastereomers reported herein, based on correlations with 1H NMR chemical shifts. Selective
and high yielding deprotection at either the N or C terminus is described, allowing the Hpi motif
to be introduced efficiently into potential targets with minimal protecting group manipulation.
Two tripeptides containing Hpi and cysteine were prepared and treated with acid in the Savige−Fontana reaction to produce a cyclic tryptathionine linkage, characteristic of both amatoxins and
phallotoxins.