Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component Povarov Reaction Using Enecarbamates as Dienophiles: Highly Diastereo- and Enantioselective Synthesis of Substituted 4-Aminotetrahydroquinolines
- 26 August 2011
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 133 (37), 14804-14813
- https://doi.org/10.1021/ja205891m
Abstract
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 (OMe) and electron-withdrawing groups (e.g., Cl, CF(3), NO(2)) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With β-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.This publication has 136 references indexed in Scilit:
- Brønsted-Acid-Catalyzed Asymmetric Multicomponent Reactions for the Facile Synthesis of Highly Enantioenriched Structurally Diverse Nitrogenous HeterocyclesAccounts of Chemical Research, 2011
- Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and SelectivitiesChemical Reviews, 2011
- Chiral Calcium VAPOL Phosphate Mediated Asymmetric Chlorination and Michael Reactions of 3-Substituted OxindolesJournal of the American Chemical Society, 2011
- Highly Enantioselective Catalytic Benzoyloxylation of 3‐Aryloxindoles Using Chiral VAPOL Calcium PhosphateAngewandte Chemie-International Edition, 2010
- Chiral Calcium Organophosphate-Catalyzed Enantioselective Electrophilic Amination of EnamidesOrganic Letters, 2010
- Asymmetric Amplification in Phosphoric Acid Catalyzed ReactionsAngewandte Chemie-International Edition, 2010
- Chiral Amine Synthesis – Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine ReductionAdvanced Synthesis & Catalysis, 2010
- Relay Catalysis by a Metal-Complex/Brønsted Acid Binary System in a Tandem Isomerization/Carbon−Carbon Bond Forming SequenceJournal of the American Chemical Society, 2008
- Straightforward Access to a Structurally Diverse Set of Oxacyclic Scaffolds through a Four‐Component ReactionAngewandte Chemie-International Edition, 2005
- Antitumor Agents. 181. Synthesis and Biological Evaluation of 6,7,2‘,3‘,4‘-Substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a New Class of Antimitotic Antitumor AgentsJournal of Medicinal Chemistry, 1998