Catalytic Asymmetric Synthesis Of Chiral Nitrogen-Containing Heterocycles

Chiral nitrogen-containing heterocycles are widely present in bioactive molecules, chiral ligands, and catalysts. In this context, it is of great theoretical significance and application value to explore methods for the synthesis of these compounds. Although some catalytic asymmetric reactions have been developed for the construction of chiral nitrogen-containing heterocycles, they are related to very limited structures and in many cases the reaction efficiency and selectivity need improvement. We have realized catalytic asymmetric synthesis of some chiral five-to seven-membered nitrogen-containing heterocycles in a highly enantioselective manner through the geminal disubstitution of imines and the addition to cyclic imines.4-(2-aminoaryl)indoles smoothly underwent chiral phosphoric acid-catalyzed asymmetric Pictet-Spengler-type reaction with imines to give structurally diverse indolo[3,4-cd][1]benzazepines in good to excellent yields and enantioselectivity. This protocol not only extends, for the first time, the catalytic asymmetric Pictet-Spengler-type reaction to the construction of seven-membered ring systems, but also exhibits higher enantioselectivity than that for the corresponding aldehyde. Mechanism studies have shown that the imine N-substituent is able to affect reactivity and enantioselectivity through non-bonding interactions with catalyst and substrate.Chiral2-substituted dihydroquinazolinones have six-membered aminal-containing rings and possess diverse bioactivities. An asymmetric geminal disubstitution reaction of aromatic, α,β-unsaturated, and aliphatic imines with2-aminobenzamides has been developed in the presence of chiral phosphoric acid to give structurally diverse chiral2-substituted dihydroquinazolinones in good to excellent yields and enantioselectivity. It is noteworthy that this reaction exhibits higher enantioselectivity than that for the corresponding aldehyde. A plausible reaction mechanism has been proposed according to the ESI-MS spectroscopic analysis of the reaction mixture.A chiral phosphoric acid catalyzed asymmetric1,2-difunctionalization reaction of a-(benzothiazol-2-ylsulfonyl)carbonyl compounds with indolenines has been developed to give N-benzothiazol-2-substituted indolines in good yields and enantioselectivity. The reaction has been proposed to proceed through the Mannich addition followed by the Smiles rearrangement to give five-membered nitrogen-containing heterocycles.An asymmetric Mannich reaction of indolenines with methyl ketones at room temperature catalyzed by L-proline has been developed in a highly regioselective manner to give chiral2-acylmethylindolines in good to excellent yields and excellent enantioselectivity. These catalytic asymmetric reactions of indolenines with various nucleophiles not only provide straightforward access to chiral2-substituted indolines, but also expand the use of cyclic imines in the preparation of chiral nitrogen-containing heterocycles.