Bispyrrolidinoindoline Epi(poly)thiodioxopiperazines (BPI-ETPs) and Simplified Mimetics: Structural Characterization, Bioactivities, and Total Synthesis

Within the 2,5-dioxopiperazine-containing natural products generated by head-to-tail cyclization of peptides, those derived from tryptophan allow further structural diversification due to the rich chemical reactivity of the indole heterocycle, which can generate tetracyclic fragments of hexahydropyrrolo[2,3-b]indole or pyrrolidinoindoline skeleton fused to the 2,5-dioxopiperazine. Even more complex are the dimeric bispyrrolidinoindoline epi(poly)thiodioxopiperazines (BPI-ETPs), since they feature transannular (poly)sulfide bridges connecting C3 and C6 of their 2,5-dioxopiperazine rings. Homo- and heterodimers composed of diastereomeric epi(poly)thiodioxopiperazines increase the complexity of the family. Furthermore, putative biogenetically generated downstream metabolites with C11 and C11'-hydroxylated cores, as well as deoxygenated and/or oxidized side chain counterparts, have also been described. The isolation of these complex polycyclic tryptophan-derived alkaloids from the classical sources, their structural characterization, the description of the relevant biological activities and putative biogenetic routes, and the synthetic efforts to generate and confirm their structures and also to prepare and further evaluate structurally simple analogs will be reported.

Automated summary

This article introduces the natural products containing 2,5-dioxopiperazine generated by head-to-tail cyclization of peptides, with a focus on tryptophan-derived derivatives that allow for further structural diversification. The more complex dimeric bispyrrolidinoindoline epi(poly)thiodioxopiperazines and their derivatives are also discussed. The article covers the isolation, structural characterization, biological activities, putative biogenetic routes, and synthetic efforts related to these compounds, as well as the evaluation of structurally simple analogs.