Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins and Formal Synthesis of Trichoderone A

Aspochalasins are leucine-derived cytochalasins. Their complexity is associated with a high degree of biosynthetic oxidation, herein inspiring a two-phase strategy in total synthesis. We thus describe the synthesis of a putative biomimetic tetracyclic intermediate. The constructive steps are an intramolecular Diels-Alder reaction to install the isoindolone core of cytochalasins, whose branched precursor was obtained from a stereoselective Ireland-Claisen rearrangement performed from a highly unsaturated substrate. This also constitutes a formal synthesis of trichoderone A.

Automated summary

Aspochalasins are leucine-derived cytochalasins with a high level of biosynthetic oxidation, inspiring a two-phase strategy in total synthesis. A putative biomimetic tetracyclic intermediate was synthesized through an intramolecular Diels-Alder reaction to install the isoindolone core of cytochalasins, with the branched precursor obtained from a stereoselective Ireland-Claisen rearrangement. This also represents a formal synthesis of trichoderone A.