Enantioselective synthesis of complex fused heterocycles via chiral phosphoric-acid catalyzed intramolecular inverse-electron demand aza-Diels-Alder reaction.

A stable asymmetric intramolecular Povarov reaction has been established to provide an efficient method to access structurally diverse trans,trans-trisubstituted tetrahydrochromeno[4,3-b]quinolines in high stereoselectivities of up to >99:1 dr and 99% ee, without any purification step. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using 0.2 mol % of chiral phosphoric acid, providing the cycloadducts without any loss in yield and enantioselectivity. The theoretical studies revealed that the reaction occurred through a sequential Mannich reaction and an intramolecular Friedel-Crafts reaction, wherein the phosphoric acid acted as bifunctional catalyst to activate para-phenolic dienophile and N-2-hydroxy-2-azadienes, simultaneously.