Enantioselective hydrolysis with Candida cylindracea

Optically pure a-hydrojq -y-lactones. The a-hydro gr-y-lactones obtained by Lubineau were racemic mixtures many groups have worked in the aim to develop an asymmetric version of the synthesis or to develop efficient methods for their resolution. Most of the time, the syntheses used the enzymatic resolution described by Roberts in 1994. Thus ot-hydro)y-y-lactones could be resolved by an enantioselective acetylation using Candida cylindracea lipase or Pseudomonas Fluorescens lipase. In a large scale (>2kg), the enzymatic hydrolysis of the racemic butyrate ester was preferred because the reaction is faster and leads to a purer compound with a best yield (Scheme 6). 

The enantioselective hydrolysis of the racemic 2-acetoxy-l-silacyclohexane rac-78 represents a further example of an enzymatic kinetic racemate resolution (Scheme 15). Hydrolysis of this compound in the presence of porcine liver esterase (PLE E.C. 3.1.1.1) yielded the optically active 1-silacyclohexan-2-ol (S)-43 which was isolated with an enantiomeric purity of 93% ee7. Similar results were obtained when using a crude lipase preparation from Candida cylindracea (CCL E.C. 3.1.1.3) as the biocatalyst... 

Lipases have been used to effect the enantioselective esterification of cyanohydrins or the enantioselective hydrolysis of cyanohydrin esters. This works for aldehyde cyanohydrins. Selective (S)-cyanohydrin esterification is effected by the enzyme from Pseudomonas sp. [11], There is also an example of selective (R)-cyanohydrin esterification by Candida cylindracea lipase [12]. Effenberger has shown the feasibility of this approach in principle to produce a number of enantiopure cyanohydrins derived from aldehydes. In situ derivatization with racemization as shown in Fig. 7 is possible, resulting in theoretically 100% yield of the desired enantiomer [13]. Ketone cyanohydrins, which are tertiary alcohols, do not easily undergo this reaction. 

A limited number of acyclic and cyclic prochiral dicarboxylic acid diesters were found to be good substrates for hydrolysis catalyzed by lipases (Table 11.1-12). Notable examples which give a good illustration of the potential of hydrolases as well as of the trial and error approach one relies on to a certain extent are the dithio acetal derivative 9 and the fluoro alkyl malonates 1-8. The dithio monoester 9 is obtained with different lipases with high enantioselectivities and yields despite its remote chiral center. Candida cylindracea lipase is the enzyme of choice for the synthesis of fluoro alkyl malonates with small alkyl groups. An astonishing observation was... 

Prochiral diketones or racemic ketones, like enol esters, are also amenable to a hydrolase-catalyzed asymmetric transformation. The enol acetates and ketones 63 and 64, respectively, may be obtained by Pseudomonas cepacia lipase-catalyzed and Candida cylindracea lipase-catalyzed hydrolysis of the corresponding racemic enol esters or prochiral bis enol ester, respectively, with high enantioselectivity and yield. 

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). 

Naproxen, (S)-2-(6-methoxy-2-naphthyl)propanoic acid 126 is a nonsteroidal anti-inflammatory and analgesic agent first developed by Syntex [220,221]. Biologically active desired S-naproxen has been prepared by enantioselective hydrolysis of the methyl ester of naproxen by esterase derived from Bacillus subtilis Thai 1-8 [222]. The esterase was subsequently clone in Escherichia coli with over 800-fold ipcrease in activity of enzyme. The resolution of racemic naproxen amide and ketoprofen amides has been demonstrated by amidases from Rhodococcus erythropolis MP50 and Rhodococcus sp. C311 (223-226). 5-Naproxen 126 and 5-ketoprofen 127 (Fig. 44) were obtained in 40% yields (theoretical maximum yield is 50%) and 97% e.e. Recently, the enantioselective esterification of naproxen has been demonstrated using lipase from Candida cylindraceae in isooctane as solvent and trimethylsilyl as alcohol. The undesired isomer of naproxen was esterified leaving desired S isomer unreacted [227]. 

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