Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis.

Abstract

The aromatization of terpenoid scaffold has received enduring attention as it introduces diverse structural alterations and endows bioactivity to the molecules. In this study, we discover a unique aromatization mechanism involving consecutive [1,2]-alkyl migrations initiated by intramolecular oxa/aza-nucleophilic addition in the biosynthesis of a family of eremophilane-like sesquiterpenoid derivatives, including farfugin A (1) and aza-janthinellin A (2a), a sesquiterpene-amino acid adduct. During this process, JanF, a flavoprotein functioning as a dehydrogenase, is demonstrated to be able to oxidize an allyl alcohol group of eremophilanes into an α,β-unsaturated aldehyde, thereby facilitating the binding of primary amines to the sesquiterpene skeleton. Furthermore, using JanF as a catalyst, we generate a series of aromatic aza-/thio-sesquiterpenoids (aza-janthinellins and thio-janthinellins), among which, thio-janthinellins exhibit potent cytotoxicity against human chronic myelogenous leukemia K562 cells. These findings advance our understanding of the biogenesis of aromatic compounds and enable the construction of diverse aza-/thio-terpenoids with enhanced biological activity.