In industrial applications enzymatic kinetic resolution (KR) is a commonly used technique for obtaining enantiomerically pure compounds. A KR is however limited to a maximum yield of 50%, since the enzyme only converts one of the enantiomers into product. In a dynamic kinetic resolution (DKR) the process of racemization is combined with resolution to overcome the limitation of KR. To obtain the equilibrium between the enantiomers an in situ conversion of the slow reacting enantiomer into the fast reacting one is occurring. The fast reacting enantiomer is therefore never depleted and the process will give a theoretical yield of 100% of the desired enantiopure product (Scheme 1).
Scheme 1. Schematic picture of a dynamic kinetic resolution.
In 1997 the Bäckvall group reported the first efficient chemoenzymatic DKR employing the Shvo complex for racemization and CALB to affect the kinetic resolution. This yielded (R)-phenyl acetate in 92% yield and >99.5% ee. The reaction was extended to a variety of different alcohols and these studies have attracted a lot of interest. In 2002 DSM Fine Chemicals developed a large scale industrial process based on this method for production of enantiomerically pure alcohols on ton scale.
The Shvo complex is heat activated and when applied in DKR it requires 60-70 °C and 24-72 h to reach completion. In 2004 there was a second breakthrough when the group discovered a new ruthenium catalyst, pentaphenylcyclopentadienyl catalyst I. This catalyst (I) is activated by base and can efficiently racemize alcohols at ambient temperature. For example, full racemization of 1-phenylethanol is achieved within 10 min. This complex has been successfully applied as racemization catalyst in various DKR processes. For example (R)-phenyl acetate can be obtained in quantitative yield with >99% ee within 3 h (Scheme 2).
Scheme 2. DKR with racemization catalyst I and CALB (Novozyme 435).
A successful DKR is a powerful method to obtain substrates in excellent enantiomeric excess. Since the beginning of this project in, the group has published more than 50 papers on the combination of enzymes and transition metal-catalyzed reactions. The concept has been applied to secondary and primary alcohols, different diols, allylic alcohols, primary amines, and allenes (Scheme 3). By altering the enzyme both (R) and (S)-products can be obtained. In addition to developing successful DKR systems, mechanistic studies on racemization have also been carried out with the focus on developing new and improved racemization catalysts.
Scheme 3. Scope of DKR.