Kinetic resolution examples

S)-14 (98% ee) was formed in the 38C2-catalyzed forward-aldol reaction (Table 6.1). The recovered aldols were highly enantiomerically enriched by the aldolase antibody-catalyzed kinetic resolution examples include secondary aldols 14, 17, 21, and 32-35, and tertiary aldols 36-40 (Tables 6.2 and 6.3). Kinetic resolution with antibody 38C2 usually afforded higher enantiomeric excess for the recovered aldols than the forward aldol reactions, because one enantiomer was completely consumed in the resolution. For example, (S)-32 was obtained in >99% ee by 38C2-catalyzed kinetic resolution after 67% conversion whereas in the 38C2-catalyzed forward aldol reaction (R)-32 was obtained in 58% ee. 

Sharpless epoxidations can also be used to separate enantiomers of chiral allylic alcohols by kinetic resolution (V.S. Martin, 1981 K.B. Sharpless, 1983 B). In this procedure the epoxidation of the allylic alcohol is stopped at 50% conversion, and the desired alcohol is either enriched in the epoxide fraction or in the non-reacted allylic alcohol fraction. Examples are given in section 4.8.3. 

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

As was the case for kinetic resolution of enantiomers, enzymes typically exhibit a high degree of selectivity toward enantiotopic reaction sites. Selective reactions of enaiitiotopic groups provide enantiomerically enriched products. Thus, the treatment of an achiral material containing two enantiotopic functional groups is a means of obtaining enantiomerically enriched material. Most successful examples reported to date have involved hydrolysis. Several examples are outlined in Scheme 2.11. 

The AE reaction has been applied to a large number of diverse allylic alcohols. Illustration of the synthetic utility of substrates with a primary alcohol is presented by substitution pattern on the olefin and will follow the format used in previous reviews by Sharpless but with more current examples. Epoxidation of substrates bearing a chiral secondary alcohol is presented in the context of a kinetic resolution or a match versus mismatch with the chiral ligand. Epoxidation of substrates bearing a tertiary alcohol is not presented, as this class of substrate reacts extremely slowly. 

Both reactions were carried out under two-phase conditions with the help of an additional organic solvent (such as iPrOH). The catalyst could be reused with the same activity and enantioselectivity after decantation of the hydrogenation products. A more recent example, again by de Souza and Dupont, has been reported. They made a detailed study of the asymmetric hydrogenation of a-acetamidocin-namic acid and the kinetic resolution of methyl ( )-3-hydroxy-2-methylenebu-tanoate with chiral Rh(I) and Ru(II) complexes in [BMIM][BF4] and [BMIM][PFg] [55]. The authors described the remarkable effects of the molecular hydrogen concentration in the ionic catalyst layer on the conversion and enantioselectivity of these reactions. The solubility of hydrogen in [BMIM][BF4] was found to be almost four times higher than in [BMIM][PFg]. 

Figure 6.4 Some successful examples of kinetic resolution of allylic alcohols by enantioselective epoxidation [21, 27].

Numerous reactions of racemic sulfoxides with chiral reagents have been accomplished2,12. These examples of kinetic resolution usually lead to sulfoxides of low enantiomeric purity, but there are some exceptions. 

The hydrolysis of seven alkyl arenesulfinylalkanoates by the bacterium Corynebacterium equi IFO 3730 studied by Ohta and coworkers34 are recent examples of kinetic resolutions which give sulfoxides of high enantiomeric purity and in reasonable yield. Compounds 16a, 16b and 16c were recovered in 30 to 43% yield and in 90 to 97% e.e. The S enantiomers underwent hydrolysis more rapidly than the R isomers. Sulfoxide 17 was isolated in 22% yield and 96% e.e., but sulfoxide 18 was completely metabolized. Esters other than methyl gave inferior results. The acids formed upon hydrolysis, although detected, were for the most part further metabolized by the bacterium. 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

Finally, as an old example of kinetic resolution of racemic mixtures, mention must be made on the report of Kise and Tomiuchi on the significant effect of acetonitrile on the enantioselectivity of different proteases toward the kinetic resolution of aromatic amino acid ethyl esters (5-8). For instance, (l)-DOPA (8) was obtained with 99% ee in the presence of 90% v/v acetonitrile [9]. 

Esterases have a catalytic function and mechanism similar to those of lipases, but some structural aspects and the nature of substrates differ [4]. One can expect that the lessons learned from the directed evolution of lipases also apply to esterases. However, few efforts have been made in the directed evolution of enantioselective esterases, although previous work by Arnold had shown that the activity of esterases as catalysts in the hydrolysis of achiral esters can be enhanced [49]. An example regarding enantioselectivity involves the hydrolytic kinetic resolution of racemic esters catalyzed by Pseudomonasfluorescens esterase (PFE) [50]. Using a mutator strain and by screening very small libraries, low improvement in enantioselectivity was... 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

Despite its widespread application [31,32], the kinetic resolution has two major drawbacks (i) the maximum theoretical yield is 50% owing to the consumption of only one enantiomer, (ii) the separation of the product and the remaining starting material may be laborious. The separation is usually carried out by chromatography, which is inefficient on a large scale, and several alternative methods have been developed (Figure 6.2). For example, when a cyclic anhydride is the acyl donor in an esterification reaction, the water-soluble monoester monoacid is separable by extraction with an aqueous alkaline solution [33,34]. Also, fiuorous phase separation techniques have been combined with enzymatic kinetic resolutions [35]. To overcome the 50% yield limitation, one of the enantiomers may, in some cases, be racemized and resubmitted to the resolution procedure. 

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 a-alkyl-P-keto ester was conducted successfully using biocatalysts. For example, baker s yeast gave selectively syn(2R, 3S)-product [29a] and the selectivity was enhanced by using selective inhibitor [29b] or heat treatment of the yeast [29c]. Organic solvent was used for stereochemical control of G. candidum [29d]. Plant cell cultures were used for reduction of 2-methyl-3-oxobu-tanoate and afforded antialcohol with Marchantia [29e,f] and syn-isomer with Glycine max [29f]. 

Another example of dynamic kinetic resolution is the reduction of a sulfur-substituted ketone. Thus, yeast reduction of (R/S)-2-(4-methoxyphenyl)-l, 5-benzothiazepin-3,4(2H, 5H)-dione gave only (2S, 3S)-alcohol as a product out of four possible isomers as shown in Figure 8.39c [29kj. Only (S)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded... 

Other biocatalysts were also used to perform the dynamic kinetic resolution through reduction. For example, Thermoanaerobium brockii reduced the aldehyde with a moderate enantioselectivity [30b,c], and Candida humicola was found, as a result of screening from 107 microorganisms, to give the (Jl)-alcohol with 98.2% ee when ester group was methyl [30dj. 

Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is caUed chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (53) partially to resolve the racemic amine salt (54). " When an aqueous solution of 54 was... 

Stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on page 132. A method has been developed to evaluate the enantiomeric ratio of kinetic resolution using only the extent of substrate conversion. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane, since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as (56 with one... 

In the case of the ketone (12), a racemic mixture was converted to an optically active mixture (optical yield 46%) by treatment with the chiral base (13). This happened beeause 13 reacted with one enantiomer of 12 faster than with the other (an example of kinetic resolution). The enolate (14) must remain coordinated with the chiral amine, and it is the amine that reprotonates 14, not an added proton donor. 

The complex Pd-(-)-sparteine was also used as catalyst in an important reaction. Two groups have simultaneously and independently reported a closely related aerobic oxidative kinetic resolution of secondary alcohols. The oxidation of secondary alcohols is one of the most common and well-studied reactions in chemistry. Although excellent catalytic enantioselective methods exist for a variety of oxidation processes, such as epoxidation, dihydroxy-lation, and aziridination, there are relatively few catalytic enantioselective examples of alcohol oxidation. The two research teams were interested in the metal-catalyzed aerobic oxidation of alcohols to aldehydes and ketones and became involved in extending the scopes of these oxidations to asymmetric catalysis. 

Recently, an interesting example of the enzymatic kinetic resolution of a-acetoxyamide 8 was demonstrated using native wheat germ lipase and immobilized lipase PS (AMANO) (Scheme 5.6). 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

Kim and co-workers recently reported an excellent example of dynamic kinetic resolution (DKR) using lipase-ruthenium combo catalyst in an IE solvent system (Fig. 7). Applied to this protocol, the authors succeeded in preparing (R)-ester or (5 )-ester using lipase PS or subtilisin, respectively. An IE solvent system is truly appropriate for DKR because racemizafion takes place easily in a highly polar solvent. 

TKase can be used as a tool for the kinetic resolution of racemic a-hydroxy aldehydes. For example, D-glyceraldehydes shows 66% of the rate compared with... 

Scheme 12.53 Example of kinetic resolution of alkyl-aryl alcohols...

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