Hydrolysis, enantiomer-selective

Micelle-forming copper complexes were found to effectively discriminate between enantiomers in the hydrolysis of a-amino esters (257). Hydrolysis of (.V)-phenylalanine p-nitrophenyl ester is 14-fold faster than its enantiomer, Eq. 223. Leucine affords 10-fold faster hydrolysis. The authors note that the micellar nature of these systems is extremely important for both rate of hydrolysis and selectivity (258). For example, the /V-mcthyl-dcrivcd ligand 419b leads to inhibition of the hydrolysis process, relative to catalysis by Cu(II) ion alone. 

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

The result, upon removal of the chiral auxiliary by hydrolysis, favors selection of the E-enantiomer in this case. There are several examples of use of Method 4 in the chemical literature,6 but the technique does suffer from one disadvantage— one reaction is required to add the chiral auxiliary and another to remove it. 

At first, a protocol similar to that developed by the discovery group was adopted in order to determine whether (R,S)-9 would undergo enantioselective hydrolysis. A mixture of (R,S)-9 and Amano PS-30 lipase was stirred overnight in dimethyl sulfoxide (DMSO) in phosphate buffer at 38—40°C. Analysis by chiral HPLC indicated that hydrolysis was selective for the (f )-enantiomer. 

A large number of mono- and bicyclic lactones (73-91) have been obtained by using pig liver esterase in combination with horse liver esterase for the enantiomer-differentiating hydrolysis of the corresponding racemic lactones. Interestingly, in the series of methyl-substituted lactones (85-89), both enzymes show toward the seven-membered lactone (86) the opposite enantiomer selectivity as compared to the other lactones. 

Lipases are available and applied as lyophilized powders, in covalently and non-covalently immobilized form on inorganic or organic carriers, in sol-gel material 120 121 and as CLECs S4e 122l Most mammalian lipases exhibit pH optima ranging from 8 to 9 and most microbial lipases from 5.6 to 8.5. The temperature range for optimal activity is between 30 and 50 °C. In the case of labile substrates or insufficient enantiomer selectivity, hydrolysis may be carried out in water-saturated water-immiscible organic solvent such as diisopropyl ether, hexane or cyclohexane. 

A broad structural range of racemic secondary mono-, bi- and tricyclic acylated alcohols are substrates in lipase-catalyzed enantiomer-differentiating hydrolysis as the examples 1-90 of Table 11.1-16 reveal. A large number of cis- and trans-cycloalkanols bearing a functional group in 2-position (1-20, 25, 26, 58-62) is thereby available in enantiomerically pure form. Enantiomer selectivity in the case of cyclic allylic alcohols where the double bond bears no other substituent in the exposition is frequently low. Through a temporary substrate modification such as mono- or dibromination, enantiomerically pure cyclic allylic alcohols may also be obtained in these cases (51, 52). 

Table 11.1-21 lists cyclic secondary alcohols that have been synthesized by lipase-catalyzed enantiomer-differentiating acylation (1-129). The compounds that have been obtained by the alternative route of hydrolysis are listed in Table 11.1-16. The complementary nature of the two routes is obvious. For the series of the glycals 9-15, Pseudomonas cepacia lipase-catalyzed acylation works with good to high enantiomer selectivity and yield. myo-Inositol derivatives 17 and 18 may be prepared enantiomer-...

Some examples of DKR based on racemization of secondary alkyl amine via Shiff base were shown in Scheme 5.9. Schiffbase formation of a-amino carboxylic esters significantly increases the acidity of the a-proton in comparison to that of the parent amino acid, thus enabling enantiomer-selective hydrolysis and ammonoly-sis through DKR [23]. For example, chymotrypsin catalyses the hydrolysis of a Schiff base of phenylalanine ethyl ester and an aromatic aldehyde (Scheme 5.9, Equation 5.6) [23b]. In this particular case, natural phenylalanine precipitates, leaving the aldehyde and unhydrolysed enantiomeric ester in solution. Addition of l,4-diazabicyclo[2.2.2]octane (DABCO) (as the Bronsted base) allows DKR to take place by promoting racemization of the Schiffbase. Similarly, Novozym 435... 

For example, the enantiomer selective hydrolysis of racemic 3-methylthietan-2-one was performed in organic media in PER filled with Pseudomonas cepacia lipase (PcL) immobilized on Celite to produce enantiopure (R)-3-mercapto-2-methylpropanoic acid [86]. The product inhibition was successfully overcome by incorporating an aqueous extraction unit to give the product in 40% yield with 99% ee. 

A continuous-flow closed-loop PER packed with Candida rugosa hpase (CrL) on Amberlite XAD-7 was applied for enantiomer selective hydrolysis of the racemic naproxen ethoxyethyl ester to enantiopure (S)-(-l-)-naproxen [87] on a kilogram scale. 

A recirculated PER filled with lactonase from Fusarium proUferatum adsorbed onto cotton cloth and cross-linked with glutaraldehyde was applied for enantiomer selective hydrolysis of racemic 2-hydroxy-Y-butyrolactone (HBL) [89]. The system was operated for 60 cycles with an average productivity of 2.48gl h and 90.0-96.4% ee. 

Porcine liver esterase (PLE) gives excellent enantioselectivity with both dimethyl 3-methylglutarate [19013-37-7] (lb) and malonate (2b) diester. It is apparent from Table 1 that the enzyme s selectivity strongly depends on the size of the alkyl group in the 2-position. The hydrolysis of ethyl derivative (2c) gives the S-enantiomer with 75% ee whereas the hydrolysis of heptyl derivative (2d) results in the R-monoester with 90% ee. Chymotrypsin [9004-07-3] (CT) does not discriminate glutarates that have small substituents in the 3-position well. However, when hydroxyl is replaced by the much bulkier benzyl derivative (Ic), enantioselectivity improves significantly. 

Optically Active Acids and Esters. Enantioselective hydrolysis of esters of simple alcohols is a common method for the production of pure enantiomers of esters or the corresponding acids. Several representative examples are summarized ia Table 4. Lipases, esterases, and proteases accept a wide variety of esters and convert them to the corresponding acids, often ia a highly enantioselective manner. For example, the hydrolysis of (R)-methyl hydratropate [34083-55-1] (40) catalyzed by Hpase P from Amano results ia the corresponding acid ia 50% yield and 95% ee (56). Various substituents on the a-carbon (41—44) are readily tolerated by both Upases and proteases without reduction ia selectivity (57—60). The enantioselectivity of many Upases is not significantly affected by changes ia the alcohol component. As a result, activated esters may be used as a means of enhancing the reaction rate. 

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. 

A similar case of enolatc-controlled stereochemistry is found in aldol additions of the chiral acetate 2-hydroxy-2.2-triphenylethyl acetate (HYTRA) when both enantiomers of double deprotonated (R)- and (S)-HYTRA are combined with an enantiomerically pure aldehyde, e.g., (7 )-3-benzyloxybutanal. As in the case of achiral aldehydes, the deprotonated (tf)-HYTRA also attacks (independent of the chirality of the substrate) mainly from the /te-side to give predominantly the t/nii-carboxylic acid after hydrolysis. On the other hand, the (S)-reagcnt attacks the (/ )-aldebyde preferably from the. S7-side to give. s wz-carboxylic acids with comparable selectivity 6... 

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

Thus, a series of racemic phosphinylacetates, " phosphonylacetates and phos-phorylacetates were resolved into enantiomers via their PLE-promoted hydrolysis to give products in high yields and with high ees (Equation 33). The most representative, selected examples are collected in Table 7. 

An enantio-selective enzymatic hydrolysis of meso( )-2,5-diacetoxy-3-hexene gives (+)-( )-(25 ,5/ )-5-acetoxy-3-hexen-2-ol in 77% yield (92% ee).97 The monoacetate with its two allylic groups offers possibilities for stereo-controlled introduction of nucleophiles via Pd(0) catalysis. Synthesis of both enantiomers of the Carpenter bee pheromone based on this strategy is presented in Scheme 5.14.98... 

Enzymes are known to show high enantio-selectivity, which is a parameter one wishes to install in the MIP as well. That this is possible was demonstrated in a recent paper on enantio-selective ester hydrolysis catalyzed by MIP. The MIP imprinted with the D-enantiomer preferentially hydrolyzed the D-ester with rate enhancements of up to three comp ared to the CP [117]. Although these findings may be far from outstanding, they represent remarkable results on the route towards the generation of competitive biomimetic catalysts. 

With a good route to the key meso diol 128 in hand, the authors turned their attention to desymmetrization, using the known asymmetric hydrolysis of meso diacetates by Lipase AK (Scheme 23). The meso diol 128 was first converted to diacetate 140, and then hydrolyzed with Lipase AK to cleave selectively one of the two acetates, producing chiral hydroxyester 141. Oxidation, cleavage of the acetate, and lactonization yielded the (3S,4.R) lactone 129. The corresponding lactol (3S,4 )-130 was found to be the enantiomer of the compound produced in the HLADH synthesis. 

Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

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