Simple and Facile l-Prolinamides Derived from Achiral Cycloalkylamines as Organocatalysts for the Highly Efficient Large-Scale Asymmetric Direct Aldol Reactions

Abstract

A series of N-cycloalkylprolinamides have been designed and synthesized from achiral cycloalkylamines in a facile manner. They promoted high stereoselectivity in the cross-aldol reaction. N-cyclopropylprolinamide performed best with a smallest carbocyclic ring, and the anti-aldol products could be obtained with up to 99:1 anti/syn and 99% ee. Carbocyclic ring was found to play a significant role in the formation of the aldol products. This simple catalyst can be efficiently used in large-scale reactions with the enantioselectivity being maintained at the same level, which offers great possibility for applications in industry.

Graphical Abstract

All of the catalysts 1a–e synthesized from achiral cycloalkylamines in a facile manner and their catalytic properties were studied in depth for the first time. All of the catalysts 1a–e exhibited great catalytic activity in the asymmetric aldol reaction in m-xylene using acetic acid as cocatalyst at −20 °C with only 5 mol% catalyst loading in 4 equivalents ketone, and the anti-aldol products could be obtained with up to 99:1 anti/syn and 99% ee. Compared with proline and prolinamide 1f, it is easily found that the carbocyclic ring of N-cycloalkyl-l-prolinamide could be anticipated in some way to enhance the enantioselectivity in m-xylene at low temperature. The results observed for 1a surpass those reported so far for simple prolinamide derivatives and are comparable to those for organocatalysts of much more structural complexity. Catalyst 1a can be efficiently used in large-scale reactions with the enantioselectivity being maintained at the same level, which offers great possibility for applications in industry.