Total Synthesis of the 2,5-Disubstituted γ-Pyrone E1 UAE Inhibitor Himeic Acid A

The first total synthesis of the E1 ubiquitin-activating enzyme inhibitor, himeic acid A, is reported. A McCombie reaction was used to form the core gamma-pyrone via a 6 pi-electrocyclization. A dioxenone ring-opening/acyl ketene trapping reaction with a primary amide provided the unusual unsymmetrical imide functionality. Other key steps include the use of an Evans auxiliary alkylation (d.r. >= 95:5) to install the (S)-2-methyl succinic acid fragment and a cross-metathesis to install the unsaturated side-chain.

Automated summary

The first total synthesis of the E1 ubiquitin-activating enzyme inhibitor, himeic acid A, is described. Key steps include the use of a McCombie reaction and a dioxenone ring-opening/acyl ketene trapping reaction to form the core structure, as well as the installation of the (S)-2-methyl succinic acid fragment and the unsaturated side-chain.