Dynamic kinetic resolution in chemistry is a type of kinetic resolution where 100% of a racemic compound can be converted into an enantiopure compound. It is applied in asymmetric synthesis. Asymmetric synthesis has become a much explored field due to the challenge of creating a compound with a single 3D structure. Even more challenging is the ability to take a racemic mixture and have only one chiral product left after a reaction. One method that has become an exceedingly useful tool is dynamic kinetic resolution (DKR). DKR utilizes a center of a particular molecule that can be easily epimerized so that the (R) and (S) enantiomers can interconvert throughout the reaction process. At this point the catalyst can selectively lower the transition state energy of a single enantiomer, leading to almost 100% yield of one reaction pathway over the other. The figure below is an example of an energy diagram for a compound with an (R) and (S) isomer.
If a catalyst is able to increase ΔΔG‡ to a sufficient degree, then one pathway will dominate over the other, leading to a single chiral product. Manipulating kinetics therefore becomes a powerful way to achieve asymmetric products from racemic starting materials. There have been numerous uses of DKR in the literature that have provided new methods in pharmaceuticals as well as routes to natural products.
Applications
Noyori's asymmetric hydrogenation
One of the more classic applications of DKR is Noyori's asymmetric hydrogenation. The presence of an acidic center between two carbonyl groups allows for easy epimerization at the chiral center under basic conditions. To select for one of the four possible stereoisomers, a BINAP-Ru catalyst is used to control the outcome of the reaction through the steric bulk of the phosphorus ligand. Some of the early transformations are shown below.
To further understand the stereochemical outcome, one must look at the transition state geometry.
The steric bulk of the BINAP ligand coupled with the coordination of ruthenium to the carbonyl oxygen atoms results in high selectivity for hydrogen insertion on one face. This resulting stereochemistry of (R,S) and (R,R) is obtained in 94.5% yield while the other three stereoisomers range from 0.5-3% yield. Noyori's accomplishments of 1990 paved the way for even more useful applications of DKR.
Asymmetric conjugate reduction
About a decade later, Jurkauskas and Buchwald also utilized dynamic kinetic resolution towards the hydrogenation of conjugated systems. 1,4 addition to cyclic enones is quite common in many reaction schemes, however asymmetric reductions in the presence of an easily epimerizable center adds to the complexity when trying to modify only one center. Through the use of a copper catalyzed reaction however, Buchwald was able to obtain 1,4 reduction in great enantiomeric excess (ee). In order to achieve a high rate of epimerization, a strong bulky base like sodium t-butoxide was used to ensure rapid equilibrium.
Copper proved to be an excellent metal in this reaction due to its ability to complex with the oxygen when the hydrogen was added. Being a soft metal, copper greatly prefers 1,4 addition over 1,2 addition, with the alkene being a softer more polarizable electrophile. Again, BINAP became the ligand of choice due to its steric selectivity, lowering the transition state energy of starting material in the left column. In addition, PMHS was used as a relatively less reactive silane. This prevented loss of ee before deprotection with tetra-n-butylammonium fluoride (TBAF).
Asymmetric aldol reaction
In addition to hydrogenation reactions, other bonds have been formed using DKR and are highly successful. The aldol reaction has been extensively researched primarily because of the inherent challenge of forming a carbon-carbon bond. Ward and colleagues have been able to use the proline-catalyzed aldol reaction in tandem with dynamic kinetic resolution to obtain a high enantioselective reaction.
In this reaction proline catalyzes the reaction through creation of an enamine intermediate that is highly nucleophilic. The acid group on the catalyst helps facilitate the carbon-carbon bond formation by coordinating with the aldehyde oxygen. This greatly improves stereoselectivity and yield. Ward and his associates also found that by adding trace amounts of water to the DMSO solvent, it greatly increase the yield of the reaction, most likely by aiding proton transfer from proline to the newly forming alcohol.