Application of the aza-Diels–Alder reaction in the synthesis of natural products

Abstract

The Diels–Alder reaction that involves a nitrogen atom in the diene or dienophile is termed the aza-Diels–Alder reaction. As well as the powerful all-carbon Diels–Alder reaction, the aza-Diels–Alder reaction has also played an important role in the total synthesis of natural products. Herein, we review various natural products using an aza-Diels–Alder reaction as a key step to their total synthesis, and divide the syntheses into inter- and intra-molecular aza-Diels–Alder reactions and a retro-aza-Diels–Alder reaction. Inter- and intra-molecular aza-Diels–Alder reactions involve an imine as an electron deficient dienophile and an imine as an electron deficient azadiene. The significance of the aza-Diels–Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels–Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.