Organocatalytic Enantio- and Diastereoselective Diels-Alder Reaction between 2,4-Dienals and α,β-Unsaturated Esters

Despite advances in the development of catalytic asymmetric Diels-Alder reactions, introducing alpha,beta-unsaturated esters as dienophiles remains challenging owing to their low reactivity. Herein, we report that a chiral aminocatalyst in conjunction with a chiral isothiourea catalyst or a Bronsted acid can promote enantioand diastereoselective Diels-Alder reactions between 2,4-dienals and alpha,beta-unsaturated esters. This method proceeds through the formation of chiral trienamine intermediates for the exo-cycloaddition with activated dienophiles, alpha,beta-unsaturated acylammonium species or protonated N-heteroaryl-substituted alkenes. Through synergistic activation of both dienes and ester dienophiles, densely functionalized cyclohexenes bearing multiple stereocenters can be afforded with up to > 25:1 dr and > 99% ee. Moreover, we show that variation of the configurations of the chiral catalysts and the olefin geometry allows the stereodivergent preparation of four stereoisomers of the enantiopure exo-products.