Chemoenzymatic Total Syntheses of Artonin I with an Intermolecular Diels-Alderase

Abstract

Diels-Alder reaction is one of the most important transformations used in organic synthesis, with the ability to construct two new CC bonds and up to four chiral centers simultaneously. However, the biggest synthetic challenge in Diels-Alder reaction lies in controlling its regio-, diastereo-, and enantioselectivity. Using Stille cross-coupling and enzymatic Diels-Alder reaction as the key steps, the first chemoenzymatic total synthesis of artonin I is achieved in 30% overall yield over only seven steps. This enzymatic Diels-Alder reaction catalyzed by MaDA is featured with excellent endo- and enantioselectivity and high catalytic efficiency (k_cat /K_M = 362 ± 54 mm^-1 s^-1 ). These successful chemoenzymatic total syntheses of artonin I and dideoxyartonin I demonstrated the remarkable potential of the intermolecular Diels-Alderase MaDA in biocatalysis.

Keywords: Diels-Alderase; biocatalysis; chemoenzymatic synthesis; natural product; total synthesis.