Internal Savige-Fontana tryptathionylation in the synthesis of bicyclic peptide toxins and an unexpected chemical entree from Hpi-containing phakellistatin/omphalotin-like macrolactams.

Peptide cyclization strategies are important for the synthesis of cyclic and bicyclic peptides. Such macrolactams are of great interest due to their increased biol. activity compared to linear analogs. Herein, we describe the synthesis of a cyclic peptide contg. an Hpi toxicophore that is characteristic of phakellistatins and omphalotins. Interestingly a terminal Hpi forms the basis of the Savige-Fontana tryptathionylation reaction that affords the intraannular bridge in both amanitins and phalloidins. Using neat TFA to induce a Savige-Fontana tryptathionylation, the Hpi-contg. macrolactam peptide is converted to a bicyclic amatoxin analog. As such, this methodol. represents an efficient cyclization method for crosslinking peptides and unveils an unrealized relationship between two different classes of peptide natural products. Aspects for increasing the degree of chem. space in library generation will be discussed. [on SciFinder(R)]