Continuous dynamic resolution processes

The only difference is that in conventional kinetic resolution the enantiomer (5)-substrate is left behind as unreacted starting material while in case of dynamic kinetic resolution the substrate is continuously isomerised during the resolution process, thus (R) and ( )-substrates are in equilibrium, which allows for the possibility of converting all starting materials of (A)-substrate into (A)-product. Several conditions should be applied and are reviewed in literature.21 For instance, Backvall et al20 used a combination of enzyme and transition metal complex (Ru-catalyst) to perform the DKR of a set of secondary alcohols. Depending on the substrate, the chemical yield was ranging from 60 to 88 % with more... 

It is well-known that catalytic amounts of aldehyde can induce racemization of a-amino acids through the reversible formation of Schiff bases.61 Combination of this technology with a classic resolution leads to an elegant asymmetric transformation of L-proline to D-proline (Scheme 6.8).62 63 When L-proline is heated with one equivalent of D-tartaric acid and a catalytic amount of n-butyraldehyde in butyric acid, it first racemizes as a result of the reversible formation of the proline-butyraldehyde Schiff base. The newly generated D-proline forms an insoluble salt with D-tartaric acid and precipitates out of the solution, whereas the soluble L-proline is continuously being racemized. The net effect is the continuous transformation of the soluble L-proline to the insoluble D-proline-D-tartaric acid complex, resulting in near-complete conversion. Treatment of the D-proline-D-tartaric acid complex with concentrated ammonia in methanol liberates the D-proline (16) (99% ee, with 80-90% overall yield from L-proline). This is a typical example of a dynamic resolution where L-proline is completely converted to D-proline with simultaneous in situ racemization. As far as the process is concerned, this is an ideal case because no extra step is required for recycle and racemization of the undesired enantiomer and a 100% chemical yield is achievable. The only drawback of this process is the use of stoichiometric amount of D-tartaric acid, which is the unnatural form of tartaric acid and is relatively expensive. Fortunately, more than 90% of the D-tartaric acid is recovered at the end of the process as the diammonium salt that can be recycled after conversion to the free acid.64... 

Roengpithya, C., Patterson, D.A., Livingston, A.G., Taylor, P.C., Irwin, J.L., and Parrett, M.R. (2007) Towards a continuous dynamic kinetic resolution of 1-phenylethylamine using a membrane assisted, two vessel process. Chem. Commun., 3642-3643. doi 10.1039/B709035H... 

We finally believe that novel methodologies of multienzyme processes for dynamic resolutions will be developed, whereas the applications of DKR in organic synthesis will continue to fascinate researchers in academia as well as in pharmaceutical industry. 

Dynamic Kinetic Resolution Synthesis of a Fluorinated Amino Acid Ester Amide by a Continuous Process Lipase-mediated Ethanolysis of an Azalactone... 

The resolution was then based on the enzymatic propanolysis of this derivative in dioxane as solvent. Lip Novozyme 435 selectively cleaves the L-form of the oxazolone producing an L-enriched (81-87% ee) 2-acetamido-3-(heteroaryl)propionic acid propyl ester, the dynamic aspect of the process being based on the continual racemization of the residual oxazolone. The propyl group was then removed with alkali and a second selective enzymatic step to remove the acetyl protecting group with Fluka Acylase 1 produced the L-amino acid at better than 99% ee (Scheme 13). 

A prominent example of chemoenzymatic catalysis in bio-organic chemistry is the dynamic kinetic resolution (DKR) of secondary alcohols (Scheme 9) [94, 95] and amines [96-99], In this process, a lipase is employed as an enantioselective acylation catalyst, and a metal-based catalyst ensures continuous racemization of the unreactive enantiomer. 

It is worth noting here that with two enzymes displaying opposite enantioselec-tivity it is possible to produce both enantiomers of the ester products. If the remaining alcohols can be continuously and rapidly racemized during the much slower acylation reaction, either the R- or S-esters can be obtained in high yields (>>5096) from reactions catalyzed by two hydrolases that display opposite enantio-preference. The combined process of racemization and simultaneous resolution, dynamic kinetic resolution (DKR), is described in Chapter 6. 

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