Journal article

Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component Povarov Reaction Using Enecarbamates as Dienophiles: Highly Diastereo- and Enantioselective Synthesis of Substituted 4-Aminotetrahydroquinolines

A chiral phosphoric acid (5)-catalyzed three-component Povarov reaction of aldehydes 2, anilines 3, and enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines 1 in high yields with excellent diastereoselectivities (>95%) and almost complete enantioselectivities (up to >99% ee). The reaction was applicable to a wide range of anilines bearing electron-donating (0Me) and electron-withdrawing groups (e.g., Cl, CF3, NO2) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With)beta-substituted acyclic enecarbamates, 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from 10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally that the Povarov reaction involving enecarbamate as dienophile proceeded via a stepwise mechanism. The key role of the free NH function of the enecarbamate in the success of this transformation was demonstrated. NMR experiments indicating the catalyst substrate interaction as well as a linear correlation between catalyst and product ee's were also documented.


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