Amino esters enantioselective hydrolysis

Numerous other examples of enantioselective hydrolysis of esters have been reported. For example chymotrypsin, immobilised in a liquid membrane of kerosene or cydohexane, can be used for resolution of D,L-amino add esters in an emulsion type... 

A semi-synthetic metalloenzyme that catalyses the enantioselective hydrolysis of simple amino acid esters has been reported. Iodoacetamido-l,10-phenanthroline (238) was interacted with a cysteine residue in adipocyte lipid binding protein (ALBP) to produce the conjugate ALBP-Phen (239), which was converted into its Cu(II) complex. The ALBP-Phen-Cu(II) was found to catalyse the enantioselective... 

Proteases have also been successfully used in ionic liquids. Papain mediated the enantioselective hydrolysis of a number of amino acid esters in an 80 20 mixture of [BMIm][BF4] and water [68]. The reaction rate was approx. 50% of that in aqueous buffer and equal to that in aqueous mixtures containing 70- 80% of solvents such as acetonitrile or tert-butyl alcohol. 

Subtilisin is an endoprotease that has been used in the enantioselective hydrolysis of N-acylamino acid esters (Figure 10.16) into the corresponding (S)-amino acid derivatives. An organic solvent, such as acetonitrile, is often added to improve the solubility of the amino acid derivative, and this function can also be performed by an ionic liquid mixture [133, 134, 135]. 

Both enzymes catalyze the hydrolysis of the amino ester 30 enantioselectively (Scheme 6.15). At about 60% substrate conversion, the enantiomeric excess of recovered ester 32 from both reactions exceeds 98%. In addition, the acid product 31 (96-98% ee) was obtained by carrying the hydrolysis of the ester to 40%. The rates of hydrolysis become significantly slower when conversion approaches 50%, allowing a wide window for kinetic control of the resolution process. Both enzymes function well in a concentrated water/substrate (oil) two-phase system while maintaining high enantioselectivity, making this system very attractive for industrial processes. 

Enantioselective Hydrolysis of a-Amino Esters Catalyzed by Humicola Amino Esterase... 

Initial scale up of the enzymatic resolution for production of kilogram quantities of (R)-2-amino-2-ethylhexanoic acid was performed in a batch process. The oil of ethyl 2-amino-2-ethyl-hexanoate was suspended in an equal volume of water containing the enzyme. The enantioselective hydrolysis of the ester proceeded at room temperature with titration of the produced acid by NaOH through a pH stat (Figure 6.4). 

Hydrolyses. The presence of hydrolytic enzymes in BY is well documented. However, the use of the yeast for biocatalytic ester hydrolysis suffers because of the availability of commercially available purified hydrolases. Nonetheless, the hydrolytic ability of fermenting BY has been proposed for the resolution of various amino acid esters (eq 14). The BY-mediated enantioselective hydrolysis has also been applied to the resolution of acetates of hydroxyalkynes and a hydroxybutanolide. ... 

Although pig liver esterase (PLE) catalyzes the hydrolysis of all amino esters tested in this work, it was only enantioselective toward esters (30, R = ArCH2, or -Bu, = Et). This lack of correlation between enantioselectivity... 

Scheme 10.8 Enantioselective hydrolysis of A -acetyl amino acid esters (Reproduced from Ref. [90], with kind permission of Springer Verlag-Berlin)...

Typical commercial enzymes reported for resolution of amino acids were tested. Whole cell systems containing hydantoinase were found to produce only a-monosubstituted amino acids" the acylase-catalyzed resolution of Xacyl amino acids had extremely low rates toward a-dialkylated amino acids and the nitrilase system obtained from Novo Nordisk showed no activity toward the corresponding 2-amino-2-ethylhexanoic amide. Finally, a large-scale screening of hydrolytic enzymes for enantioselective hydrolysis of racemic amino esters was carried out. Of all the enzymes and microorganisms screened, pig hver esterase (PLE) and Humicola langinosa lipase (Lipase CE, Amano) were the only ones found to catalyze the hydrolysis of the substrate (Scheme 9.6). 

There are numerous examples of enantioselective hydrolyses of the types described in Schemes 3.2 and 3.3, catalysed by lipases and esterases. The selective hydrolysis of amino acid derivatives has been an important part of this field of study. For example, the hydrolase enzyme a-chymotrypsin catalyses the enantioselective hydrolysis of JV-acetyl-DL-phenylalanine methyl ester (5) to give optically pure (L)-acid (6) in 40% yield (Scheme 3.4). The lipase from the fungus Candida cylindracea (ccl) has been shown to hydrolyse octyl 2-chloropropionate (7) with high stereoselectivity on a large scale, giving the (/ )-acid (8) in 46% yield (96% e.e.) and the (S)-ester (45% yield) (Scheme 3.5). 

A considerable number of optically pure L-amino acids have been prepared using enzymatic methods. An elegant DKR process for a-amino acids made use of the esterase method, i.e. the enantioselective hydrolysis of a-amino acid esters catalysed by proteases. The remaining unhydrolysed o-enantiomer of the substrate was in situ racemised in the presence of pyridoxal 5-phosphate (Scheme 3.20). ... 

Conjugate addition of the lithium salt of a chiral amine to a -substituted a, 3-unsaturated ester leads to formation of a chiral, nonracemic amino acid. Addition of the chiral, nonracemic lithium amide 5.143 (contains a phenethyl auxiliary) to 5.142 gave the amino-ester.63 Catalytic hydrogenation removed both benzylic groups (the auxiliary and the benzyl group) and acid hydrolysis of the ester moiety led to 3-amino-3-(4-benzyloxyphenyl)-propanoic acid, 5.144. The initial Michael adduct was formed with >99% dr (dr is diastereomeric ratio), leading to high enantioselectivity in 5.144 after removal of the auxiliary. 

A method that has been successfully applied to the resolution of p-amino acids is N-acylation or N-acyl hydrolysis. Enantioselective N-acylation of p-amino esters in an organic solvent has been carried out using Candida antarctica lipase A (CAL-A) lipase, while enantioselective hydrolysis of N-acyl p-amino acids in aqueous medium has been catalyzed by aminoacylase (Scheme 14.2). 

A catalytic and enantioselective alkylation of Af,0-acetals, protected by the SES group, is an interesting method to prepare various chiral a-amino esters from a common precursor, the SES hydroxyglycine (21), which is easier to form and more resistant to hydrolysis than the corresponding imine (eq 21). A first equivalent of enol silyl ether reacts with iV,0-acetal (21) to form the imine intermediate in situ. Eventually, a second equivalent of enol silyl ether is necessary to perform the alkylation of the Cu(I) SES imine complex. 

A highly enantioselective PT-catalyzed alkylation mediated by Maruoka s catalyst was also successfully employed for the synthesis of the Parkinson therapeutics u-Dopa ester and its analogues [20f,62], Hereby, minute amounts of catalyst 105 were used to catalyze the alkylation of 14 with benzyl bromides 114 and 115 followed by hydrolysis to give the corresponding amino esters 116 and 117, respectively. The corresponding L-Dopa tcrt-butyl ester... 

Optically active 4-hydroxyalkanenitriles 115 are useful building blocks for asymmetrical synthesis as the cyano group is a functional precursor group of the amino and carbonyl groups. Lipase PS-30-catalyzed enantioselective hydrolysis of ester of 4-hydrox-yalkanenitriles 116 [Fig. 40] has been demonstrated by Takagi and Itoh [203]. The e.e. s of 80-98% were obtained depending on the compound used in the reaction mixture. 

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