Background: While proline can catalyze the asymmetric direct aldol reactions, its catalytic activity and catalyst turnover are both low. To improve the catalytic efficiency, many proline-based organocatalysts have been developed. In this regard, prolinamide-based bifunctional catalysts have been demonstrated by us and others to be highly efficient catalysts for the direct aldol reactions.
Methods: By carefully adjusting the hydrogen bonding ability of the remote β-amide hydrogen of the 1,2-diamine-based prolinamide bifunctional catalysts, the catalytic activity and the asymmetric induction of these catalysts were significantly improved for the direct aldol reaction between aldehydes and enolizable ketones.
Results: Using the β-acetamido- and β-tosylamidoprolinamide catalysts, the highly enantio- and diastereoselective direct aldol reactions between enolizable ketones and aldehydes were achieved (up to >99% ee, 98:2 dr). A low catalyst loading of only 2-5 mol % of β-tosylamidoprolinamide catalyst was needed to obtain the desired aldol products in good to high yields and high stereoselectivities.
Conclusion: Some highly efficient 1,2-diamine-based bifunctional prolinamide catalysts have been developed through probing the remote β-amide hydrogen for its hydrogen bonding capability. These catalysts are easy to synthesize and high enantioselectivities may be achieved at very low catalyst loadings.