Mimicking the Main Events of the Biosynthesis of Drimentines: Synthesis of Δ8′-Isodrimentine A and Related Compounds

Drimentines are a family of tetracyclic alkaloids biosynthetically originating from the condensation of sesquiterpene units onto cyclic dipeptides. A straightforward assembly of the fused pyrroloindoline-diketopiperazine core of drimentines is described herein and used for the synthesis of Delta(8')-isodrimentine A. The strategy involves a bio-inspired indole dearomatization of a tryptophan-containing cyclodipeptide by a drimane-type decaline followed by the intramolecular trapping of the resulting indolenine intermediate in an uninterrupted reactive sequence. The starting diketopiperazine was prepared by classical peptidic coupling and the drimane-type decaline from (+)-sclareolide. A fully biomimetic approach with a linear sesquiterpene unit is also reported and led to farnesylated pyrroloindoline-diketopiperazines, which correspond to the proposed biosynthetic precursors of both drimentines A and D. The end product Delta(8')-isodrimentine A and its congeners were evaluated in vitro for their cytotoxic activities against three human tumor cell lines.