Enzymatic Hydrolysis and Selective Racemisation Reactions of α-Chloro Esters

Abstract

Esters E n z y m a t i c H y d r o l y s i s o f a-Chl o r o E s t e r sAbstract: The kinetic resolution of a-chloro esters was effected with good selectivity using CLEC (Cross-Linked Enzyme Crystals) enzymes. The selective racemisation of a-chloro esters in the presence of a-chloro acids enabled a successful dynamic kinetic resolution reaction to be performed.The use of enzymes to hydrolyse esters under kinetic resolution conditions is a widely used method for the preparation of enantiomerically enriched carboxylic acids. 1 Herein, we report on the use of enzymatic hydrolysis for a-chloro esters. Although not widely used as substrates, there is reasonable precedent for reactions of this type, 2 as well as for the corresponding resolution of a-bromo esters. 3 We were interested in the possibility of establishing a dynamic kinetic resolution, 4 according to Scheme 1. Scheme 1In order for this approach to be successful, it is necessary to find suitable conditions for a simple kinetic resolution of the a-chloro ester substrate, and to find conditions that facilitate racemisation of the a-chloro ester selectively in the presence of the a-chloro acid. Additionally, the dynamic resolution will only be effective if the enzyme and racemising agent do not interfere with each other. These points are addressed in turn.Firstly, the a-chloro esters 1a-c and 2 were prepared by conventional methodology. Starting materials 1a-c were prepared by the reaction of an appropriate alcohol with commercially available a-chlorophenylacetyl chloride (which could also be prepared by treatment of racemic mandelic acid with thionyl chloride). Starting material 2 was prepared by diazotisation of racemic norvaline with sodium nitrite in ethereal hydrochloric acid followed by acid-catalysed esterification in methanol. 5Various enzymes and reaction conditions were investigated for the hydrolysis of substrates 1a-c and 2 (Scheme 2). We found that commercially available CLEC's (CrossLinked Enzyme Crystals) were particularly reliable, and that conditions using phosphate buffer were the most satisfactory. Ethyl acetate was employed as a co-solvent, and the reactions stirred vigorously to ensure thorough mixing during the course of the reactions. The results of these kinetic resolution reactions afforded reasonable to good levels of enantioselectivity in the acid and recovered ester, as shown in Table 1. It is noteworthy that the Altus 17 and Altus 20 CLEC's (derived from Candida cylindracea lipase and Pseudomonas cepacia lipase, respectively) afford opposite selectivity to each other, although Altus 17 is generally more selective. Altus 20 did not catalyse the hydrolysis of ester 2. Similar results could be obtained using water in place of phosphate buffer, regulating the pH at 7-8 using an autotitrator. Scheme 2With good procedures in hand for the kinetic resolution of a-chloro esters, we turned our attention to the selective racemisation of a-chloro esters in the presence of a-chloro acids (as their carboxylate salts).

Catalytic Asymmetric α‐Chlorination of 3‐Acyloxazolidin‐2‐one with a Trinary Catalytic System

“…Negligible loss of optical purity during the hydrolysis was confirmed after conversion into methyl ester 6. The absolute configuration of 4a was determined to be R by comparing the retention times of both enantiomers of 6 on a chiral stationary phase with the reported data, [18,19] and this result is in accord with the sense of enantioselection observed in the previous fluorination reaction. [9] Under the optimized reaction conditions, we next examined the generality of the reaction by using various aryl acetic acid derivatives (Table 2).…”

Improvement of Yarrowia lipolytica Lipase Enantioselectivity by Using Mutagenesis Targeted to the Substrate Binding Site

“…[2][3][4][5] 2-halogeno-carboxylic acid esters are important intermediates found in the synthetic pathways of a number of drugs such as prostaglandin, prostacyclin, semisynthetic penicillin, and thiazolium salts. [6][7][8][9] In particular, 2-bromo-o-tolylacetic acid ethyl ester is used as a precursor for the synthesis of analgesics and nonpeptide angiotensin II-receptor antagonists. [10,11] Recently, we demonstrated that Lip2p lipase from Yarrowia lipolytica yeast was an efficient stereoselective enzyme for the resolution of 2-halogeno-arylacetic acid esters.…”

Chemoenzymatic and microbial dynamic kinetic resolutions

“…40 The (R)-a-chlorophenyl acetic acid (17) is a type of a-haloarylacetic acids which are known as important intermediates for synthesizing many drugs such as prostaglandin, prostacyclin, semi-synthetic penicillin, and thiazolium salts. [41][42][43] The DKR of (rac)-2,2,2-trifluoroethyl a-chlorophenyl acetate is shown in Scheme 6. The authors reported that the best hydrolysis reaction was catalysed by Lipase MY(I) at 358C and the racemisation was catalyzed by trioctylamine as the racemization agent.…”