New Class Of Superbases

Cyclopropenimines can serve as highly effective “superbases” for enantioselective organocatalysis, researchers have discovered (J. Am. Chem. Soc., DOI: 10.1021/ja3015764). The findings could lead to easier and faster syntheses of novel chiral compounds for drug discovery and other applications.

In recent years, researchers have developed several types of organic bases to catalyze enantioselective proton-transfer reactions and yield optically enriched products. Most work has focused on chiral amidines and guanidines, but these species have limited basicity and low catalytic power.

Now, graduate student Jeffrey S. Bandar and associate professor of chemistry Tristan H. Lambert at Columbia University show that highly basic 2,3-bis(dialkylamino)cyclopropenimines are far more effective chiral organocatalysts.

Cyclopropenium ions, the catalytic bases’ protonated forms, are resonance-stabilized aromatics, making the cyclopropenimines highly basic. The basicity of cyclopropenimines is 3.5 orders of magnitude higher than that of comparable guanidines, and they catalyze reactions up to about 800 times faster.

Bandar and Lambert used a dicyclohexyl cyclopropenimine in a preparative-scale procedure to catalyze a rapid Michael addition. It yielded 25 g of product with 99% enantioselectivity. They synthesized the catalyst from inexpensive, readily available starting materials, obtained an X-ray structure of the protonated version, and proposed a mechanism for the catalyzed reaction.

Choon-Hong Tan of the National University of Singapore says the new catalysts “simply beat everyone else’s flat out. They are easy to make and can be scaled up, and reaction conditions are mild.” Their high basicity should allow them to catalyze a wide range of reactions, such as those that produce chiral active pharmaceutical ingredients, he adds.

Henk Hiemstra of the University of Amsterdam wonders whether the catalysts will work as well with other reactions. Still, he says, “I am amazed how easily the catalysts can be made and how well they function.” The discovery, he says, “could lead to a large amount of follow-up work with this catalyst type.”