Racemates resolution, dynamic kinetic

Scheme 5.9 Base-promoted racemization in dynamic kinetic resolution of substrate 13.

Asymmetric synthesis can refer to any process which accesses homochiral products. We will focus on asymmetric synthesis from racemic or prochiral starting materials in the presence of an enantioselective catalyst (enzyme). There are four general methodologies commonly applied kinetic resolution, dynamic kinetic resolution, deracemization and... 

Scheme 2.1.4.24 Racemization and dynamic kinetic resolution of acetates ent-ldb and Idb in their Pd(0)/BPA-catalyzed reactions with KSAc.

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. 

Besides the level of enantioselectivity, a main drawback of kinetic resolution is the well known limitation of product yield to 50%. Among several strategies elaborated to overcome this barrier [66] and improve kinetic resolution, dynamic kinetic resolution (DKR), coupling kinetic resolution and in situ racemization, was applied to Baeyer-VUliger biooxidations. Such an approach theoretically enables the synthesis of a enantiomerically pure compound in 100% yield from a racemate. The key point is the ability of a given substrate to be easily racemized under conditions compatible with the kinetic resolution. From this point of view, ketones... 

The asymmetric processes discussed so far in this chapter have focused on reactions that create non-racemic, chiral products from achiral reagents by selective reaction at one prochiral face or position over the other. However, these principles can also be applied to reactions that separate enantiomers of an existing racemic mixture, channel both enantiomers of such a mixture to a single enantiomeric product, or that select between reaction at one of two diastereotopic functional groups in an achiral substrate. These reactions are also synthetically valuable and are called kinetic resolutions, dynamic kinetic resolutions, and desymmetrizations. An understanding of these reactions draws from the principles established so far in this chapter, but they also require some additional principles to be established that apply in a specific way to these classes of asymmetric transformations. Thus, the remainder of Chapter 14 introduces the fundamentals of these classes of asymmetric catalysis. 

Parvulescu, A., Janssens, J., Vanderleyden, J., and De Vos, D. (2010). Heterogeneous catalysts for racemization and dynamic kinetic resolution of amines and secondary alcohols. Top. Catal, 53,931-941. 

Choi JH, Kim YH, Nam SH, Shin ST, Kim M-J, Park J. Ami-nocyclopentadienyl ruthenium chloride catalytic racemization and dynamic kinetic resolution of alcohols at ambient temperature. Angew. Chem. Int. Ed. 2002 41 2373-2376. 

Scheme 9.20 Dynamic kinetic resolution of racemic epoxide...

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

For most chemical transformations, especially for industrial applications, the yield of 50% cannot be accepted. Since each enantiomer constitutes only 50% of the racemic mixture, the best way to increase the yield of the desired enantiomer is racemization of the unwanted one (Scheme 5.7). This reaction mustproceed simultaneously with the enzymatic kinetic resolution. In order to indicate the dynamic character of such processes, the term dynamic kinetic resolution has been introduced. 

Scheme 5.11 Dynamic kinetic resolution of alcohol 18 by combination of enzymatic transesterification and ruthenium-catalyzed racemization.

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]. 

Liang J, Ruble JC, Fu GC (1998) Dynamic kinetic resolutions catalyzed by a planar-chiral derivative of DMAP enantioselective synthesis of protected a-amino acids from racemic azlactones. J Org Chem 63 3154—3155... 

Catalytic transformation based on combined enzyme and metal catalysis is described as a new class of methodology for the synthesis of enantiopure compounds. This approach is particularly useful for dynamic kinetic resolution in which enzymatic resolution is coupled with metal-catalyzed racemization for the conversion of a racemic substrate to a single enantiomeric product. 

The novel phenomenon of converting racemic substrates into a single enantiomer of the product hy dynamic kinetic resolution (DKR) via racemization of the substrates has been a formidable challenge in asymmetric synthesis. Recently, DKR has been receiving increasing attention since it can overcome the limitations... 

When a reverse procedure was applied, i.e. enzymatic acetylation of racemic 3, formed in situ from the appropriate aldehydes and thiols, the reaction proceeded under the conditions of dynamic kinetic resolution and gave enantiomerically enriched acetates 2 with 65-90% yields and with ees up to 95% (Equation 2). It must be mentioned that the addition of silica proved crucial, as in its absence no racemization of the initially formed substrates 3 occurred and the reaction stopped at the 50% conversion. 

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

Interestingly, for the transformation of both the racemic 1-hydroxyalkanephosphonates 41 and 2-hydroxyalkanephosphonates 43 into almost enantiopure acetyl derivatives 42 and 44, respectively, a dynamic kinetic resolution procedure was applied. Pamies and BackvalP used the enzymatic kinetic resolution in combination with a ruthenium-catalysed alcohol racemization and obtained the appropriate O-acetyl derivatives in high yields and with almost full stereoselectivity (Equation 25, Table 5). It should be mentioned that lowering... 

In carrying out kinetic resolution, these in the standard approach are limited to 50% yield regarding the racemate. However, different approaches were developed [28] to overcome this limitation. The classical standard solution is to reracemize the unconverted enantiomer. A more advanced solution is the establishment of a dynamic kinetic resolution that has considerably expanded the synthetic scope of chemical processes. Here, the unconverted enantiomer is, in contrast to the latter method, racemized in situ. A great number of novel enzymatic methods have been developed [29]. Within this chapter, process solutions for enzymatic resolutions of racemic mixtures will be highlighted. 

Limited yield by racemic dynamic kinetic resolution separation by extraction... 

An efficient dynamic kinetic resolution is observed when an a-bromo- or a-acetylamino-/3-keto phosphate is subjected to the hydrogenation with an Ru-BINAP catalyst under suitable conditions. With RuC12[(A)-BINAP](DMF) (0.18 mM) as the catalyst, a racemic a-bromo-/3-keto phosphonate is hydrogenated at 25 °G under... 

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