Cinchona Alkaloids

Cinchona alkaloids are extracted from the bark of Cinchona, which contains almost 30 alkaloids in the bark. Owing to its unique stereo configuration and multiple hydroxyl groups, the cinchona base catalysts have played a profound role in the field of asymmetric catalysis. Cinchona alkaloids can relieve fever and prevent various malaria. In addition, the cinchona alkaloid has a unique structural advantage as an organic catalyst, making it a potentially highly enantioselective organic catalyst.

Figure1. Important structural characteristics of cinchona base

Application:

The reaction of asymmetrically constructing carbon-carbon bonds is widely used to construct molecules of highly optically active and complex functional groups. In the past decade, organic catalysis has played an important role in this type of reaction. Cinchona alkaloids and their derivatives as catalysts or chiral ligands can asymmetrically catalyze many reactions that construct carbon-carbon bonds, such as Aldol reaction, Michael addition, Mannich reaction, Henry reaction, cycloaddition, Morita-Baylis-Hillman reaction, Friedel-Crafts reaction.

• Michael reaction: The Michael reaction is an essential and common method of generating C-C bonds. Because of the wide range of Michael acceptors and donors, there are hundreds of thousands of chiral catalysts that asymmetrically catalyze this reaction. Among them, the catalysts of cinchona alkaloids mainly include the following types: natural cinchona base, C-6'-hydroxy substituted cinchona base derivative, cinchona-derived urea and thiourea catalyst, C-9-primary amine substitution cinchona base derivative, cinchona derived phase transfer catalyst, and the like.
• Mannich reaction: Mannich reaction is a significant reaction in the synthesis of C-C bonds in organic synthesis, and has a wide range of applications in the pharmaceutical and agricultural fields. This reaction can synthesize a number of optically active nitrogen-containing compounds, such as amino acids, amino alcohols, amino metal carbonyl complexes. The general process for this type of reaction is the reaction of an enolizable substrate with an amine substrate to form a highly functional amino compound. Recently, it has been reported that a thiourea cinchona base derivative catalyzes a highly selective Mannich reaction of an α,α dicyanoolefin with an N-Boc aral amide.

Figure 2. Sulfur-type cinchona base derivatives catalyze the Mannich reaction of malonate with imine

• Aldol reaction: The Aldol reaction combines two relatively simple molecules into a relatively complex molecule with two stereocenters. The product produced by the Aldol reaction can be applied to the synthesis of many complex polyoxo-substituted compounds. Cinchona base and proline, two structurally advantageous catalysts, can be linked into one molecule to form a new class of catalysts. These catalysts catalyze the Aldol reaction of aldehydes and ketones, and the resulting product can obtain a good ee value.

Figure 3. A novel catalyst for the formation of cinchona base and proline

• Henry reaction: The Henry reaction is also called the nitroaldol reaction, and the reaction substrates involved are enolizable nitroalkanes and carbonyl compounds. It is also another important synthetic tool for building C-C bonds and can form up to two connected stereocenters. The product of the reaction can be converted to a number of nitrogen and oxygen-containing derivatives such as nitroolefins, amino alcohols, and amino acids. In the past two decades, many asymmetric metal catalysts have been well developed for the Henry reaction. For example, researchers have reported that cinchona base catalyze the Henry reaction of aromatic and aliphatic aldehydes with nitromethane or nitroethane.

References

1. Bartoli, G, Bosco, M., Carlone, A., et al. (2006). "Organocatalytic Asymmetric Conjugate Addition of 1,3-DicarbonylCompounds to Maleimides".  Angew. Chem. Int. Ed., 45 (30): 4966-4970.
2. Wang, J., Duan, W.; Zu, L., Wang, W.(2005). "Organocatalytic Asymmetric Michael Addition of 2,4-Pentandione to Nitroolefins". Org. Lett., 7(21):4713-4716.
3. Rai, V, Mobin, S. M., Namboothiri (2007). "Cinchonine catalyzed diastereo-and enantioselective Michael addition of a-fithiated phosphonates to nitroalkenes". Tetrahedron: Asymmetry, 18(22): 2719-2726.