A comprehensive understanding of the mechanism of the biomimetic total synthesis of brevianamide A

Recently, several studies on the chemical synthesis of brevianamide A ( BA ) were reported. In particular, a highly efficient and remarkably selective synthetic strategy was reported by Lawrence's group. However, a unified mechanistic understanding of these results is still lacking. We have carried out a DFT study and proposed a unified mechanism to understand these experimental results. Starting from intermediate 2 , the most favorable reaction sequence is a fast tautomerization, followed by a σ-migration of the base moiety, and a final inverse-electron demanding Diels-Alder reaction, resulting in the formation of the BA product stereoselectively. This reaction mechanism can also be applied to understand the biosynthesis of BA that involves enzymatic catalysis. Elucidation of a plausible reaction mechanism for the migration process in the biomimetic synthesis of brevianamide A and understanding of the reaction pathway could shed light on the biosynthetic pathways of bicyclo[2.2.2]diazaoctane alkaloids.