DKR

For an efficient enzymatic DKR the following requirements must be fulfilled (i) the KR must be very selective ( > 20) (ii) the racemization must be fast (at least 10 times faster than the enzyme-catalyzed transformation of the slow reacting enantiomer, krac >10 kent-s) (hi) the racemization catalyst must not react with the product of the reaction (iv) the KR and the racemization must be compatible under the same reaction conditions. 

In an ideal DKR, where the substrate stays racemic throughout the reaction process, the optical purity depends only on the enantiomeric ratio (E) (ee =(E— 1)/ (E +1)), and is independent of the extent of conversion. The enantiomeric excess of the product formed under racemizing conditions is equal to the initial enantiomeric... 

In this chapter, DKRs will be categorized according to the racemization method employed, as being catalyzed by (i) a metal, (ii) a base, (hi) an acid, (iv) an aldehyde, or (v) an enzyme. Also racemizations that take place through continuous cleavage/ formation of the substrate, or through 5 2 displacement, among other methods, will be discussed. In most cases, the racemization method of choice depends on the structure of the substrate. In all cases, the KR is catalyzed by an enzyme. 

A novel approach was developed very recently by Kita et al. [15]. DKR of allylic alcohols was performed by combining a lipase-catalyzed acylation with a racemization through the formation of allyl vanadate intermediates. Excellent yields and enantioselectivities were obtained. An example is shown in Figure 4.4. A limitation with this approach for the substrates shown in Figure 4.4 is that the allylic alcohol must be equally disubstituted in the allylic position (R = R ) since C—C single bond rotation is required in the tertiary alkoxy intermediate. Alternatively, R or R can be H if the two allylic alcohols formed by migration of the hydroxyl group are enantiomers (e.g. cyclic allylic acetates). 

The research groups of Williams [19] and Backvall [20] were the first to report the combination of enzymes and transition metals for DKR of sec-alcohols. 

Williams employed complexes of Al, Rh, or Ir in combination with Pseudomonas Jluorescens lipase (PFL) for the DKR of 1-phenylethanol. The best results were obtained using Rh2(OAc)4 as the catalyst for the racemization, and 60% conversion of the alcohol to give 1-phenylethyl acetate in 98% ee was obtained (Figure 4.6) [19]. At higher conversion, the enantiomeric excess dropped and 76% conversion gave 80% ee. 

The research group of Backvall employed the Shvo s ruthenium complex (1) [21] for the racemization. This complex is activated by heat. For the KR they used p-chlorophenyl acetate as the acyl donor in combination with thermostable enzymes, such as CALB [20] (Figure 4.7). This was the first practical chemoenzymatic DKR affording acetylated sec-alcohols in high yields and excellent enantioselectivities. In the best case 100% conversion (92% isolated yield) with 99% ee was obtained. This method was subsequently applied to a variety of different substrates and it is employed (with a different ruthenium complex) by the Dutch company DSM for the large-scale production of (R)-phenylethanol [22]. 

Figure 4.7 DKR of se< alcohols using CALB and Shvo s complex (1).

Figure 4.8 DKR of seoalcohols catalyzed by a lipase and Ru complexes at ambient temperature.

Very recently the Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reaction has been exploited for the racemization of alcohols using inexpensive aluminum-based catalysts. Combination of these complexes with a lipase (CALB) results in an efficient DKR of sec-alcohols at ambient temperature. To increase the reactivity of the aluminum complexes, a bidentate ligand, such as binol, is required. Also, specific acyl donors need to be used for each substrate [31] (Eigure 4.9). 

Kita et al. have made use of the structure of the acyl donor to develop a domino transformation, a DKR followed by an intramolecular Diels-Alder reaction [32]. They... 

Figure 4.9 DKR of sec-alcohols using a lipase and inexpensive Al complexes.

Figure 4.10 Tandem DKR-intramolecular Diels-Alder reaction.

More recently, Heise and coworkers have shown that DKR can be combined with enzymatic polymerization for the synthesis of chiral polyesters from racemic secondary diols in one pot [34] (Figure 4.12). 

Racemization of amines is difficult to achieve and usually requires harsh reaction conditions. Reetz et al. developed the first example of DKR of amines using palladium on carbon for the racemization and CALB for the enzymatic resolution [35]. This combination required long reaction times (8 days) to obtain 64% yield in the DKR of 1-phenylethylamine. More recently, Backvall et al. synthesized a novel Shvo-type ruthenium complex (S) that in combination with CALB made it possible to perform DKR of a variety of primary amines with excellent yields and enantioselectivities (Figure 4.13) [36]. 

In this chapter, DKR of substrates having a proton with low pKa will be discussed. Racemization occurs by performing the D KR in the presence of a weak base. Also in... 

In contrast to oxoesters, the a-protons of thioesters are sufficiently acidic to permit continuous racemization of the substrate by base-catalyzed deprotonation at the a-carbon. Drueckhammer et al. first demonstrated the feasibility of this approach by performing DKR of a propionate thioester bearing a phenylthiogroup, which also contributes to the acidity of the a-proton (Figure 4.14) [39a]. The enzymatic hydrolysis of the thioester was coupled with a racemization catalyzed by trioctylamine. Owing to the insolubility of the substrate and base in water, they employed a biphasic system (toluene/H2O). Using P. cepacia (Amano PS-30) as the enzyme and a catalytic amount of trioctylamine, they obtained a quantitative yield of the corresponding... 

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

DKR of esters bearing an electron-withdrawing group at the ot-carbon can be performed easily under mild reaction conditions due to the low pKa of the oc-proton. Tsai et al. have reported an efficient DKR of rac-2,2,2-trifluoroethyl ot-chorophenyl acetate in water-saturated isooctane [40]. They used lipase MY from C. rugosa for the KR and trioctylamine as the base for racemization. (R)-chlorophenylacetic acid was obtained in 93% yield and 89.5% ee (Figure 4.15). 

A very attractive and efficient method for the synthesis of L-aminoacids via DKR has been reported by Turner et al. [41a,b]. They employed enzyme-catalyzed ring opening of 5(4H)-oxazolones in combination with a catalytic amount of Et3N. The relatively low pKa of the C-4 proton (8.9) of oxazolones facilitates racemization. Hydrolysis of the ester obtained through DKR, followed by debenzoylation, yields L-aminoacids in excellent enantiomeric excess (99.5%) (Figure 4.16). In their initial studies, they employed Rhizomucor miehei lipase (Lipozyme) as the biocatalyst [41]. More recently, they have obtained excellent results employing CALB [41bj. This method has also been employed by Bevinakatti [41c,d] and Sih [41e,fj. 

Another approach for the synthesis of enantiopure amino acids or amino alcohols is the enantioselective enzyme-catalyzed hydrolysis of hydantoins. As discussed above, hydantoins are very easily racemized in weak alkaline solutions via keto enol tautomerism. Sugai et al. have reported the DKR of the hydantoin prepared from DL-phenylalanine. DKR took place smoothly by the use of D-hydantoinase at a pH of 9 employing a borate buffer (Figure 4.17) [42]. 

Ogasawara ef al. took advantage of the easy racemization of acyloins in the presence of a weak base for the DKR of ewdo-3-hydroxytricyco[4.2.1.0 ]non-7-en-4-one (Figure 4.18) [43]. Acylation of the hydroxyl group was catalyzed by a lipase, and racemization took place via a transient meso-enediol. 

In contrast to enzyme- and base-catalyzed DKRs, there are only a few reports of enzyme- and acid-catalyzed DKRs. A plausible explanation is that deactivation of the enzyme can occur under acidic conditions. Also, decomposition of the substrate has... 

Figure4.18 DKR of acyloins through meso-enediol intermediates.

Figure 4.19 DKR of sec-alcohols catalyzed by acid zeolites and a lipase.

Jacobs et al. employed an acidic zeolite catalyst for the racemization of sec-alcohols, which occurs through the formation of carbocations [44] (Figure 4.19). The KR is catalyzed by CALB in the presence of vinyl octanoate as acyl donor. DKR takes place successfully in a biphasic system (octane/H2O, 1 1) at 60 °C. 

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