DKR of Activated Esters

Figure 4.15 DKR of activated esters using a base for racemization.

Previously, the use of activated esters such as enol esters, especially VinOAc, has been shown for the classical KR of alcohols. Nevertheless, since the leaving acetaldehyde can react in the DKR with the racemization catalyst, other acyl donors must be considered, like IPA ( PrOAc) or p-chlorophenyl acetate (PCPA), the structures of which are shown in Figure 9.10. IPA is a very interesting acyl donor as its byproduct in acylation reactions is acetone, which is a less reactive carbonyl compound that usually does not caused biocatalyst deactivation, its lower atom economy being the only drawback for synthetic purposes. 

Oxazolones (azlactones) are a form of activated lactones, so they are included in this section. CAL-B is an effective catalyst for the DKR of various racemic four-substituted-5 (4H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters as illustrated in Figure 6.24 [40]. Enantioselective biotransformations of lactides [72,73] and thiolactones ]74] have also been reported. 

In this section, dynamic kinetic resolution of substrates having a proton with low pKa is discussed. Racemization occurs by performing the DKR in the presence of a weak base. Enzyme- and base-catalyzed DKRs are categorized, according to the nature of the substrates, as being thioesters, -activated esters, oxazolones, hydan-toins or acyloins. 

An alternative approach to the DKR of phenyl oxazolinones is represented by alcoholysis in organic solvents. The Hpase from Pseudomonas cepacia was used for this purpose. In organic solvent with low water activity non-enzymatic hydrolysis proceeds very slowly but the rate of enoHzation of the C-4 proton is sufficiently rapid so that 100% of the substrate is converted into product By using methanol as the nucleophile, methanolysis of oxazolones proceeded at a useful rate to furnish methyl esters of N-benzoyl-t-a-amino acids. The optical purity of the products ranged from 66 to 98% e.e. [41]. 

A widely-reported method for the DKR of secondary alcohols and a- and p-hydroxy acid esters involves ruthenium catalysed hydrogenation. No additional base is required as a cocatalyst (and consequently base-catalysed transesterification can be avoided) because one of the ligand s oxygen atoms can act as a basic centre. A robust ruthenium complex (named Shvo s catalyst) along with a p-chlorophenylacetate was developed by the BackvaU group. The metal catalyst must be used in combination with thermostable enzymes because it is activated by heat (Scheme 4.26). This system (with CALB) has been successfully used for the DKR of many secondary alcohols and diols (Scheme 4.27) [52, 63, 64]. 

In 2006, Kragl s group developed the DKR of a-amino acid esters (e.g. phenylalanine ethyl ester) in a water/acetonitrile mixture, leading to the corresponding optically active a-amino acids in good yields and optical purities (Scheme 3.45). The Alcalase catalysed hydrolysis of the ester was combined with an in situ racemisation catalysed by 3,5-dinitrosalicylaldehyde. 

It has been demonstrated that the combination of metal-catalysed racemisation and enzymatic kinetic resolution is a powerful method for the synthesis of optically active compounds from racemic alcohols and amines. There are many metal complexes active for racemisation, but the conditions for enzymatic acylation often limit the application of the metal complexes to DKR. In the case of DKR of alcohols, complementary catalyst systems are now available for the synthesis of both (R)- and (5)-esters. Thus, (R)-esters can be obtained by the combination of an R-selective lipase, such as CAL-B or LPS, and a racemisation catalyst, whereas the use of an A-selective protease, such as subtilisin, at room temperature provides (5)-esters. The DKR of alcohols can be achieved not only for simple alcohols but also for those bearing various additional functional groups. The DKR of alcohols has also been applied to the synthesis of chiral polymers and coupled to tandem reactions, producing various polycyclic compounds. 

In 2002, we reported that monomeric Ru catalyst 5 had a good racemization activity at room temperature and excellent compatibility with isopropenyl acetate [23]. We thus accomplished the first DKR of secondary alcohols, at room temperature by combining 5 with Novozym 435 or lipase PS-C in the presence of isopropenyl acetate (Scheme 5.15). A wide range of secondary alcohols including simple alcohols, allylic alcohols, alkynyl alcohols, diols, hydroxyl esters, and chlorohydrins were transformed to their acetates with good delds and excellent enantiomeric excesses in the DKR using 5 (Chart 5.12) [24]. 

Tetrahydroisoquinolines bearing a chiral center at the Cl position constitute a structural motif found in many biologically active compounds. For instance, (5)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 114 is a precursor of the natural product (5)-calycotomine (Scheme 57.31). Kanerva, Fiilbp, et al. have described the preparation of both enantiomers of 114 by enzymatic hydrolysis of the ethyl ester derivative rac-113. Considering this substrate undergoes spontaneous racemization in an aqueous medium, these authors carried out an exhaustive study of the reaction variables in order to find the optimal conditions and thus achieve the DKR of this substrate. Two enzymes with opposite enantiopreferences were used CAL-B and... 

Moreover, when these reactions were performed at higher temperatures ( rt), DKR could be achieved. This was first demonstrated for a-aryl UNCAs [192], but subsequently also for a-allcyl UNCAs [193]. Allyl alcohol was found to be the optimal nucleophile, allowing a variety of UNCAs to be resolved with high stereoselectivities (90-92% ee) and good yields (93-98%) [192]. The resulting allyl esters could be converted to the optically active a-amino acids via Pd-catalyzed deallylation (Table 8.12). 

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