Esters kinetic resolution

A few natural product syntheses feature the use of both acyclic and cyclic aldimines of either enantiomer of f-leucine f-butyl ester. Kinetic resolution of racemic aldehydes has also been achieved using L-f-leucine f-butyl ester. ... 

Kinetic resolutions. A chiral alcohol is obtained on. selective removal of one enantiomer by acetylation using a chiral analog 1 of DMAP, or by oxidation based on hydrogen transfer to acetone mediated by a Ru complex 2. Benzylic secondary alcohols are resolved by selective pivaloylation with optically activeA-pivaloyl-4-t-butylthiazolidine-2-thione. A kinetic resolution of sulfoxides is based on asymmetric oxidation with (i-PrO)4Ti-cumyl hydroperoxide in the presence of a tartrate ester. Kinetic resolution of 1,3-diarylallenes is realized by selective oxidation with NaClO catalyzed by a chiral (salen)manganese(III) complex, whereas asymmetric hydrolysis of terminal epoxides with the aid of a chiral (salen)cobalt(II) catalyst solves the problem of their accessibility. 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

In this case study, an enzymatic hydrolysis reaction, the racemic ibuprofen ester, i.e. (R)-and (S)-ibuprofen esters in equimolar mixture, undergoes a kinetic resolution in a biphasic enzymatic membrane reactor (EMR). In kinetic resolution, the two enantiomers react at different rates lipase originated from Candida rugosa shows a greater stereopreference towards the (S)-enantiomer. The membrane module consisted of multiple bundles of polymeric hydrophilic hollow fibre. The membrane separated the two immiscible phases, i.e. organic in the shell side and aqueous in the lumen. Racemic substrate in the organic phase reacted with immobilised enzyme on the membrane where the hydrolysis reaction took place, and the product (S)-ibuprofen acid was extracted into the aqueous phase. 

The plotting of Dixon plot and its slope re-plot (see 5.9.5.9) is a commonly used graphical method for verification of kinetics mechanisms in a particular enzymatic reaction.9 The proposed kinetic mechanism for the system is valid if the experimental data fit the rate equation given by (5.9.4.4). In this attempt, different sets of experimental data for kinetic resolution of racemic ibuprofen ester by immobilised lipase in EMR were fitted into the rate equation of (5.7.5.6). The Dixon plot is presented in Figure 5.22. 

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. 

The preparation of enantiomerically enriched a-ketosulphoxides 272 was also based on a kinetic resolution involving the reaction of the carbanion 273 derived from racemic aryl methyl sulphoxides with a deficiency of optically active carboxylic esters 274334, (equation 151). The degree of stereoselectivity in this reaction is strongly dependent on the nature of both the group R and the chiral residue R in 274. Thus, the a-ketosulphoxide formed in the reaction with menthyl esters had an optical yield of 1.3% for R = Et. In the... 

Enzyme-mediated hydrolysis of some racemic co-arenesulfinylalkanoic methyl esters, ArSO(CH2) COOMe, using Corynebacterium equi has led to a kinetic resolution in which the unreacted sulfinyl esters are enriched in one enantiomer at the sulfoxide center49. The enantiomeric purity of unreacted sulfinyl acetates and propionate ranges from 90 to 97%. 

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]. 

Figure 2.9 Schematic summary of the directed evolution of enantioselective lipase variants originating from the WT PAL used as catalysts in the hydrolytic kinetic resolution of ester rac-1. CMCM = Combinatorial multiple-cassette mutagenesis [8c,22],...

Efforts were also made to invert the sense of enantioselectivity in the hydrolytic kinetic resolution of ester (1) using PAL with preferential formation of (R)-2 [40,411-Using epPCR and DNA shuffling, an (R)-selective mutant showing an E value of 30 was evolved by screening about 45 000 clones for the (R) enantiomer. The best mutant is characterized by 11 mutations, which are different from those of the best (S)-selective variant X [41]. 

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... 

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]. 

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]. 

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. 

Scheme 9.23 Kinetic resolution of noncyclic ketones to chiral esters.

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

Thus, racemic acid 12 (R = H) was obtained by [3+2] cycloaddition in 90-95% yield (Scheme 5.9) [28]. Its resolution into enantiomers could be achieved either by chiral preparative HPLC, or by fractional crystallization of its cinchonidine salts. Better results were obtained upon enzymatic kinetic resolution of its iso-butyl ester 12 (R = i-Bu) [29]. However, further work showed that racemic thiolester 13, which... 

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. 

Searching for a method of synthesis of enantiopure lamivudine 1, the compound having a monothioacetal stereogenic centre, Rayner et al. investigated a lipase-catalysed hydrolysis of various racemic a-acetoxysulfides 2. They found out that the reaction was both chemoselective (only the acetate group was hydrolysed with no detectable hydrolysis of the other ester moieties) and stereoselective. As a result of the kinetic resolution, enantiomerically enriched unreacted starting compounds were obtained. However, the hydrolysis products 3 were lost due to decomposition." In this way, the product yields could not exceed 50% (Equation 1). The product 2 (R = CH2CH(OEt)2) was finally transformed into lamivudine 1 and its 4-epimer. ... 

Phosphotriesterase from P. diminuta (PTE) was found to exhibit high hydrolytic activity towards various types of tetracoordinated phosphorus acid esters. Apart from the phosphonothionate 92, phosphoric acid triesters 94 (Equation 45), °" benzenephosphonic acid diester 95 (Equation 46) ° and methyl-phenylphosphinic acid ester 96 (Equation 47) were also stereoselectively hydrolysed under kinetic resolution conditions. Of course, in the case of the latter three kinds of substrates, half of the reacting ester was irreversibly lost due to the formation of achiral phosphorus acids. 

The ability of enzymes to achieve the selective esterification of one enantiomer of an alcohol over the other has been exploited by coupling this process with the in situ metal-catalysed racemisation of the unreactive enantiomer. Marr and co-workers have used the rhodium and iridium NHC complexes 44 and 45 to racemise the unreacted enantiomer of substrate 7 [17]. In combination with a lipase enzyme (Novozyme 435), excellent enantioselectivities were obtained in the acetylation of alcohol 7 to give the ester product 43 (Scheme 11.11). A related dynamic kinetic resolution has been reported by Corberdn and Peris [18]. hi their chemistry, the aldehyde 46 is readily racemised and the iridium NHC catalyst 35 catalyses the reversible reduction of aldehyde 46 to give an alcohol which is acylated by an enzyme to give the ester 47 in reasonable enantiomeric excess. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

In another approach, the alcohol moiety, formed by an enzymatic hydrolysis of an ester, can act as a nucleophile. In their synthesis of pityol (8-37a), a pheromone of the elm bark beetle, Faber and coworkers [17] used an enzyme-triggered reaction of the diastereomeric mixture of ( )-epoxy ester 8-35 employing an immobilized enzyme preparation (Novo SP 409) or whole lyophilized cells of Rhodococcus erythro-polis NCIMB 11540 (Scheme 8.9). As an intermediate, the enantiopure alcohol 8-36 is formed via kinetic resolution as a mixture ofdiastereomers, which leads to the diastereomeric THF derivatives pityol (8-37a) and 8-37b as a separable mixture with a... 

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