Kinetic resolution

In organic chemistry, kinetic resolution is a means of differentiating two enantiomers in a racemic mixture. In kinetic resolution, two enantiomers react with different reaction rates in a chemical reaction with a chiral catalyst or reagent, resulting in an enantioenriched sample of the less reactive enantiomer. As opposed to chiral resolution, kinetic resolution does not rely on different physical properties of diastereomeric products, but rather on the different chemical properties of the racemic starting materials. The enantiomeric excess of the unreacted starting material continually rises as more product is formed, reaching 100% just before full completion of the reaction. Kinetic resolution relies upon differences in reactivity between enantiomers or enantiomeric complexes.
Kinetic resolution can be used for the preparation of chiral molecules in organic synthesis. Kinetic resolution reactions utilizing purely synthetic reagents and catalysts are much less common than the use of enzymatic kinetic resolution in application towards organic synthesis, although a number of useful synthetic techniques have been developed in the past 30 years.

History

The first reported kinetic resolution was achieved by Louis Pasteur. After reacting aqueous racemic ammonium tartrate with a mold from Penicillium glaucum, he reisolated the remaining tartrate and found it was levorotatory. The chiral microorganisms present in the mold catalyzed the metabolization of -tartrate selectively, leaving an excess of -tartrate.
Kinetic resolution by synthetic means was first reported by Marckwald and McKenzie in 1899 in the esterification of racemic mandelic acid with optically active -menthol. With an excess of the racemic acid present, they observed the formation of the ester derived from -mandelic acid to be quicker than the formation of the ester from -mandelic acid. The unreacted acid was observed to have a slight excess of -mandelic acid, and the ester was later shown to yield -mandelic acid upon saponification. The importance of this observation was that, in theory, if a half equivalent of -menthol had been used, a highly enantioenriched sample of -mandelic acid could have been prepared. This observation led to the successful kinetic resolution of other chiral acids, the beginning of the use of kinetic resolution in organic chemistry.

Theory

Kinetic resolution is a possible method for irreversibly differentiating a pair of enantiomers due to different activation energies. While both enantiomers are at the same Gibbs free energy level by definition, and the products of the reaction with both enantiomers are also at equal levels, the, or transition state energy, can differ. In the image below, the R enantiomer has a lower and would thus react faster than the S enantiomer.
The ideal kinetic resolution is that in which only one enantiomer reacts, i.e. k_R>>k_S. The selectivity of a kinetic resolution is related to the rate constants of the reaction of the R and S enantiomers, k_R and k_S respectively, by s=k_R/k_S, for k_R>k_S. This selectivity can also be referred to as the relative rates of reaction. This can be written in terms of the free energy difference between the high- and low-energy transitions states,.
The selectivity can also be expressed in terms of ee of the recovered starting material and conversion, if first-order kinetics are assumed.
If it is assumed that the S enantiomer of the starting material racemate will be recovered in excess, it is possible to express the concentrations of the S and R enantiomers as
where ee is the ee of the starting material. Note that for c=0, which signifies the beginning of the reaction,, where these signify the initial concentrations of the enantiomers. Then, for stoichiometric chiral resolving agent B*,
Note that, if the resolving agent is stoichiometric and achiral, with a chiral catalyst, the term does not appear. Regardless, with a similar expression for R, we can express s as
If we wish to express this in terms of the enantiomeric excess of the product, ee", we must make use of the fact that, for products R' and S' from R and S, respectively
From here, we see that
which gives us
which, when we plug into our expression for s derived above, yield
The conversion and selectivity factor can be expressed in terms of starting material and product enantiomeric excesses only:
Additionally, the expressions for c and ee can be parametrized to give explicit expressions for C and ee in terms of t. First, solving explicitly for and as functions of t yields
which, plugged into expressions for ee and c, gives
Without loss of generality, we can allow k_S=1, which gives k_R=s, simplifying the above expressions. Similarly, an expression for ee″ as a function of t can be derived
Thus, plots of ee and ee″ vs. c can be generated with t as the parameter and different values of s generating different curves, as shown below.
As can be seen, high enantiomeric excesses are much more readily attainable for the unreacted starting material. There is however a tradeoff between ee and conversion, with higher ee obtained at higher conversion, and therefore lower isolated yield. For example, with a selectivity factor of just 10, 99% ee is possible with approximately 70% conversion, resulting in a yield of about 30%. In contrast, in order to get good ee's and yield of the product, very high selectivity factors are necessary. For example, with a selectivity factor of 10, ee″ above approximately 80% is unattainable, and significantly lower ee″ values are obtained for more realistic conversions. A selectivity in excess of 50 is required for highly enantioenriched product, in reasonable yield.
This is a simplified version of the true kinetics of kinetic resolution. The assumption that the reaction is first order in substrate is limiting, and it is possible that the dependence on substrate may depend on conversion, resulting in a much more complicated picture. As a result, a common approach is to measure and report only yields and ee's, as the formula for k_rel only applies to an idealized kinetic resolution. It is simple to consider an initial substrate-catalyst complex forming, which could negate the first-order kinetics. However, the general conclusions drawn are still helpful to understand the effect of selectivity and conversion on ee.

Practicality

With the advent of asymmetric catalysis, it is necessary to consider the practicality of utilizing kinetic resolution for the preparation of enantiopure products. Even for a product which can be attained through an asymmetric catalytic or auxiliary-based route, the racemate may be significantly less expensive than the enantiopure material, resulting in heightened cost-effectiveness even with the inherent "loss" of 50% of the material. The following have been proposed as necessary conditions for a practical kinetic resolution:

inexpensive racemate and catalyst
no appropriate enantioselective, chiral pool, or classical resolution route is possible
resolution proceeds selectively at low catalyst loadings
separation of starting material and product is easy

To date, a number of catalysts for kinetic resolution have been developed that satisfy most, if not all of the above criteria, making them highly practical for use in organic synthesis. The following sections will discuss a number of key examples.

Reactions utilizing synthetic reagents

Acylation reactions

and colleagues have developed a methodology utilizing a chiral DMAP analogue to achieve excellent kinetic resolution of secondary alcohols. Initial studies utilizing ether as a solvent, low catalyst loadings, acetic anhydride as the acylating agent, and triethylamine at room temperature gave selectivities ranging from 14-52, corresponding to ee's of the recovered alcohol product as high as 99.2%. However, solvent screening proved that the use of tert-amyl alcohol increased both the reactivity and selectivity.
With the benchmark substrate 1-phenylethanol, this corresponded to 99% ee of the unreacted alcohol at 55% conversion when run at 0 °C. This system proved to be adept at resolution of a number of arylalkylcarbinols, with selectivities as high as 95 and low catalyst loadings of 1%, as shown below utilizing the -enantiomer of the catalyst. This resulted in highly enantioenriched alcohols at very low conversions, giving excellent yields as well. In addition, the high selectivities result in highly enantioenriched acylated products, with a 90% ee sample of acylated alcohol for o-tolylmethylcarbinol, with s=71.
In addition, Fu reported the first highly selective acylation of racemic diols. With low catalyst loading of 1%, enantioenriched diol was recovered in 98% ee and 43% yield, with the diacetate in 39% yield and 99% ee. The remainder of the material was recovered as a mixture of monoacetate.
The planar-chiral DMAP catalyst was also shown to be effective at kinetically resolving propargylic alcohols. In this case, though, selectivities were found to be highest without any base present. When run with 1 mol% of the catalyst at 0 °C, selectivities as high as 20 could be attained. The limitations of this method include the requirement of an unsaturated functionality, such as carbonyl or alkenes, at the remote alkynyl position. Alcohols resolved using the -enantiomer of the DMAP catalyst are shown below.
Fu also showed his chiral DMAP catalyst's ability to resolve allylic alcohols.
Effective selectivity was dependent upon the presence of either a geminal or cis substituent to the alcohol-bearing group, with a notable exception of a trans-phenyl alcohol which exhibited the highest selectivity. Using 1-2.5 mol% of the -enantiomer of the DMAP catalyst, the alcohols shown below were resolved in the presence of triethylamine.
While Fu's DMAP analogue catalyst worked exceptionally well to kinetically resolve racemic alcohols, it was not successful in use for the kinetic resolution of amines. A similar catalyst, PPY*, was developed that, in use with a novel acylating agent, allowed for the successful kinetic resolution acylation of amines. With 10 mol% -PPY* in chloroform at –50 °C, good to very good selectivities were observed in the acylation of amines, shown below. A similar protocol was developed for the kinetic resolution of indolines.