Resolution process

During a resolution process, the R- and S-enantiomers compete for the free enzyme to form the noncovalent enzyme—substrate complexes ES and ER. These proceed to form transition-state intermediates [ES] and [ER] ... 

Saturation of the aromatic ring of pentopril analogues is also consistent with ACE inhibition as demonstrated by the oral activity of indolapril (23). The necessary heterocyclic component (21) can in principle be prepared by catalytic perhydrogenation (Rh/C, HOAc) of the corresponding indole. A single isomer predominates. The product is condensed by amide bond formation with the appropriate alanylhomophenylalanyl dipeptide ester 20 to give 22. Selective saponification to 23 could be accomplished by treatment with HCl gas. Use of the appropriate stereoisomers (prepared by resolution processes) produces chiral indolapril [8]. 

These are major disadvantage of the esterase resolution process. Since die optimum pH of die enzymic reaction is generally on the alkaline side, die esters used as substrates are non-enzymatically hydrolysed and die optical purity of die L-amino adds obtained is generally low. Also the substrate has to be protected at the amino group in most cases in order to prevent formation of diketopiperasines. The esterase method is not attractive in practice and to the best of our knowledge is not used on an industrial scale. 

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

Moreover, it is possible to open racemic azlactones by acyl bond cleavage to form protected amino acids in a dynamic kinetic resolution process. As azlactones suffer a fast racemization under the reaction conditions, eventually all starting material is converted [115]. 

Despite the improvements outlined above, the modest yield through the resolution process (around 30% yield of 97% ds salt) and the need for multiple crystallizations... 

Table 14.1 Enzymes frequently used in resolution processes ...

An excellent example for an enzymatic resolution process is reported for production of Pregabalin. This drug was approved by the US Food and Drug Administration (FDA) in 2004 against neurophatic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Several different routes have been developed based on asymmetric hydrogenation, crystallization and biocatalytic resolutions [16-20]. The most powerful and currently applied process is based on a lipase resolution, shown in Figure 14.3. This process is one of the very few... 

Of course, kinetic resolution processes are not optimal. In order to obtain >50% molar yields, racemization and recycling loops are required which often have a negative impact on solvent and/or energy consumption, as well as on waste production. Obviously, better... 

May O., Verseck, S., Bommarius, A. and Drauz, K. (2002) Development of dynamic kinetic resolution processes for biocatalytic production of natural and nonnatural L-amino acids. Organic Process Research Development, 6 (4), 452-457. 

As mentioned above, we planned to obtain optically pure styrenyl ethers through Zr-catalyzed kinetic resolution [5] subsequent metal-catalyzed rearrangement would afford optically pure chromenes. However, as shown in Scheme 11, the recovered starting material (40) was obtained with <10% ee (at 60% conversion) upon treatment with 10 mol% (,R)-(EBTHI)Zr-binol (3b) and five equivalents of EtMgCl (70°C, THF). We conjectured that, since the (EBT-HI)Zr-catalyzed reaction provides efficient resolution only when asymmetric alkylation occurs at the cyclic alkene site, competitive reaction at the styrenyl terminal olefin renders the resolution process ineffective. Analysis of the H NMR spectrum of the unpurified reaction mixture supported this contention. Indeed, as shown in Scheme 11, catalytic resolution of disubstituted styrene 49... 

The resolution process developed by Syntex is almost ideal (Pope Peachy resolution), with an efficient racemization and recycling of the unwanted (R) -enantiomer (yield >95% of (S)-naproxen from the racemate) and the chiral auxiliary (recovery >98%). 

After some early examples of bio-chemo combinations in the 1980s, there was then over a decade of silence , followed by clearly increasing interest from the mid-1990s in the field of dynamic kinetic resolution processes (i.e., chemocata-lyzed racemization combined with enantioselective enzymatic conversion, giving, in principle, 100% yield of an optically pure compound). 

The first steps include holding scientific workshops with key stakeholders, re-examining and clarifying the scope and interpretation of Part 11 (see Section 9.6.3), developing technical dispute resolution processes, and harmonizing inconsistencies between the different centers of the FDA. 

Dynamic kinetic resolution (DKR) is an extension to the kinetic resolution process, in which an enantioselective catalyst is usually used in tandem with a chemoselective catalyst. The chemoselective catalyst is used to racemize the starting material of the kinetic resolution process whilst leaving the product unchanged. As a consequence, the enantioselective catalyst is constantly supplied with fresh fast-reacting enantiomer so that the process can be driven to theoretical yields of up to 100 %. There are special cases where the starting material spontaneously racemizes under the reaction conditions and so a second catalyst is not required. 

Asymmetric routes to lamivudine have recently been reviewed. A number of these are biocatalytic, the most elegant of which is a highly enantioselective kinetic resolution process based on the use of cytidine deaminase from E. coli. The process is particularly impressive given that the reaction site is five atoms away from the nearest chiral centre (Scheme 1.38). 

Dynamic kinetic resolution (DKR) is a process in which the resolution process is coupled with in situ racemization of unreacted substrate. This has been shown to be a potential and feasible method to produce 100 % theoretical yield. We have developed a chemo-enzymatic DKR to obtain higher desired yield for (5)-ibuprofen. The combined base catalyst with lipase has resulted in high conversion and excellent ee of the product. 

The procedure shows that it is feasible to combine racemization with the kinetic resolution process (hence the DKR) of R,S)- ethoxyethyl ibuprofen ester. The chemical synthesis of the ester can be applied to any esters, as it is a common procedure. The immobilized lipase preparation procedure can also be used with any enzymes or support of choice. However, the enzyme loading will need to be optimized first. The procedures for the enzymatic kinetic resolution and DKR will need to be adjusted accordingly with different esters. Through this method, the enantiopurity of (5)-ibuprofen was found to be 99.4 % and the conversion was 85 %. It was demonstrated through our work that the synthesis of (5)-ibuprofen via DKR is highly dependent on the suitability of the reaction medium between enzymatic kinetic resolution and the racemization process. This is because the compatibility between both processes is crucial for the success of the DKR. The choice of base catalyst will vary from one reaction to another, but the basic procedures used in this work can be applied. DKRs of other profens have been reported by Lin and Tsai and Chen et al. ... 

To avoid the inherent limitations of a kinetic resolution process, the reaction was extended to desymmetrization of prochiral meso epoxides. A number of cyclic di-methylidene epoxides were synthesized and subjected to treatment with Et2Zn in the presence of Cu(OTf)2 and ligands 42 or 43. As in the case mentioned above, ligand 42 was superior in terms of selectivity. Cydohexane derivative 46 gave the ring-opened product with a 97% ee and in a 90% isolated yield, with a y/a ratio of 98 2 (Scheme 8.28). The other substrates investigated produced sigmficantly lower ees of between 66% and 85%. 

The maximum possible yield of one enantiomer in a kinetic resolution process is 50%. 

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