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Lipase Catalysed Kinetic Resolutions of 3-Aryl Alkanoic Acids Tetrahedron

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Lipase Catalysed Kinetic Resolutions of 3-Aryl Alkanoic Acids Tetrahedron Tetrahedron: Asymmetry 22 (2011) 47–61 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy Lipase catalysed kinetic resolutions of 3-aryl alkanoic acids ⇑ Rebecca E. Deasy a, Maude Brossat b, Thomas S. Moody b, Anita R. Maguire c, a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland b Biocatalysis Group, Almac Sciences, David Keir Building, Stranmillis Road, Belfast, BT9 5AG, United Kingdom c Department of Chemistry & School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland article info abstract Article history: Hydrolase catalysed kinetic resolutions leading to a series of 3-aryl alkanoic acids ( P94% ee) are Received 16 November 2010 described. Hydrolysis of the ethyl esters with a series of hydrolases was undertaken to identify biocata- Accepted 22 December 2010 lysts that yield the corresponding acids with excellent enantiopurity in each case. Steric and electronic Available online 2 February 2011 effects on the efficiency and enantioselectivity of the biocatalytic transformation were also explored. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction naturally occurring d-lactone of algae origin, 23 curcumene and cur- cuphenol, biological important bisabolene sesquiterpenes 24 and in Lipases (triacylglycerol ester hydrolases, EC 3.1.1.3) are ubiqui- the synthesis of amino acids b-methyl phenylalanaine 25 and b- tous enzymes belonging to the family of serine hydrolases and are methyl tyrosine. 26 Within our own group, 3-aryl alkanoic acids unequivocally, the most utilized enzymes in biocatalysis, providing are utilised in the synthesis of diazoketone derivatives, which in one of the most advantageous and versatile biocatalytic methods turn have been employed in Buchner cyclization reactions demon- in asymmetric synthesis. 1–11 Hydrolases are excellent biocatalysts, strating excellent diastereoselectivity. 27,28 This key transformation combining wide substrate specificity with high regio- and enanti- is currently under investigation in the efficient asymmetric synthe- oselectivity enabling the resolution of organic substrates with effi- sis of the bicyclo[5.3.0]decane skeleton, characteristic of the cient efficiency and selectivity. 12–14 Further advantages are that aucane sesquiterpenoids. hydrolases do not require the use of labile co-factors, can be recy- Hydrolase catalysed non-aqueous enantioselective esterifica- cled, can be used in both free or immobilised form and are effective tion of acids (±)- 1a , (±)- 1b , (±)- 1c and (±)- 1d , ( Fig. 1 ) has previously under mild, environmentally benign conditions and are biodegrad- been reported, however substrate acids (±)- 1a and (±)- 1b were able. These attributes make these catalysts especially attractive for esterified with a modest to slow rate resulting in very low E values the pharmaceutical and agrochemical industries, where the inter- (E <2) and no ester was observed under any conditions for acids est in enantiomerically pure and specifically functionalized com- (±)- 1c and (±)- 1d .29 Traditional aqueous Burkholderia cepacia cata- pounds is growing continuously. 2,4–11 lysed ester hydrolysis has been described for the resolution of Hydrolase catalysed kinetic bioresolution is widely used to pro- 3-phenylbutanoic acid (±)- 1a (E >50), however this work has not vide highly enantioenriched chiral carboxylic acids, which are been expanded to include acid substrates (±)- 1b , (±)- 1c and (±)- valuable synthetic intermediates for the preparation of a variety 1d , encompassing more sterically hindered substituents at the ste- of compounds of biological interest. There have been many reports reogenic centre. 30 on the successful resolution of 2-aryl or 2-aryloxy-propionic acids; Herein, we wished to explore a wide range of hydrolases to the former are non-steroidal anti-inflammatory drugs and the establish if it was possible to generate the carboxylic acid latter an important class of herbicides. 15–20 Successful hydrolase (±)- 1a –i in enantiopure form through kinetic bioresolution. Acids catalysed resolution of alkanoic acids, with remotely located (±)- 1a –d, were selected for investigation to determine the impact methyl-branching has been reported, 21,22 however, the literature of steric effects at C3 on the efficiency of the kinetic resolution, has revealed only limited success on the hydrolase mediated while substrates (±)- 1e –i were designed to explore both steric kinetic resolution of 3-aryl alkanoic acids. Enantiomerically pure and electronic effects of substituents on the aromatic ring on the 3-aryl alkanoic acids are used as chiral synthons in the asymmetric biotransformations. In contrast to the limited reported success in synthesis of antibacterial agents, such as ( À)-malyngolide, a enantioselective esterification, this study focussed on enantioslec- tive hydrolysis and indeed it was found that through an appropri- ate choice of biocatalyst and reaction conditions, each of the ⇑ Corresponding author. Tel.: +353 21 4901693; fax: +353 21 4901770. carboxylic acids could be obtained in highly enantioenriched E-mail address: [email protected] (A.R. Maguire). form. 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi: 10.1016/j.tetasy.2010.12.019 48 R. E. Deasy et al. / Tetrahedron: Asymmetry 22 (2011) 47–61 O O O O O OH OH OH OH OH R1 (±)- 1a (±)- 1b (±)- 1c (±)- 1d (±)- 1e-i 1 (±)- 1e R =p-CH 3 1 (±)- 1f R =m-CH 3 1 (±)- 1g R =o-CH 3 (±)- 1h R 1=p-OMe (±)- 1i R 1=p-F Figure 1. 2. Results and discussion which both enantiomers of the ester and acid could be seen on a single trace ( Fig. 2 ). With a single injection, ready monitoring of 2.1. Synthesis of ethyl 3-aryl alkanoates both the efficiency and stereoselectivity of each of the hydrolase mediated transformations could be performed. Racemic ester (±)- 3a was obtained via a simple Fischer esterifi- cation reaction from commercial 3-phenylbutanoic acid (±)- 1a 2.1.1. Hydrolase catalysed kinetic resolution of (±)-3- (Scheme 1 ). The 3-aryl alkanoic esters (±)- 3b –h were synthesized phenylbutanoic acid (±)-1a in a three step synthesis. Acids (±)- 1b –d were synthesised by the In total, 21 lipases and 1 esterase were screened in resolving conjugate addition of an alkyl Grignard to cinnamic acid, while racemic 3-phenylbutanoic acid (±)- 1a . All of the hydrolases inves- acids (±)- 1e –h were similarly prepared by the conjugate addition tigated resulted in the hydrolysis of ethyl 3-phenylbutanoate of the appropriate aryl Grignard to crotonic acid. 31 When the direct (±)- 3a to a certain extent and the screening results are summarised esterification of the crude carboxylic acid was attempted, it was in Table 1 . Pseudomonas cepacia , Alcaligenes spp . and Pseudomonas found that it was simpler to obtain the ethyl esters in analytically fluorescens , entries 6, 11 and 15, respectively, exhibited excellent pure form by first transforming the carboxylic acid (±)- 1b –h iso- enantioselection in the hydrolysis of substrate (±)- 3a . Burholderia lated from Grignard additions directly to the analogous acid chlo- cepacia hydrolysis of the methyl ester of (±)- 1a had previously ride, which was readily purified by vacuum distillation. Treatment been reported ( E >50) providing access to the acid ( S)- 1a with of the pure acid chloride with ethanol in the presence of triethyl- 89% ee. 30 Herein, Alcaligenes spp. yielded the acid ( S)- 1a with excel- amine led to an analytically pure ester ( Scheme 1 ). An alternative lent improved enantioselectivity of 97% ee ( E >200) by hydrolysis route via a Wadsworth–Emmons reaction was employed in the of the corresponding ethyl ester (±)- 3a . Unreacted ( R)- 3a was synthesis of ethyl 3-(4-fluorophenyl)butanoate (±)- 3i (Scheme 2 ). 32 recovered in 98% ee providing access to both enantiomeric series Acids 1a –e and 1h have been previously reported in the literature in a single resolution. in enantioenriched form and therefore the assignment of the abso- From Table 1 , it is evident that certain hydrolases preferentially lute stereochemistry for each of these compounds was made by hydrolysed the ( R)-enantiomer of substrate (±)- 3a , providing comparison of specific rotation data. Acids 1f –g and 1i have not access to the complementary enantiomer ( R)- 1a . Candida antarctica been previously reported in enantiopure form and the absolute ste- lipase B hydrolysis of (±)- 3a had previously been reported to yield reochemistry was determined in each case through crystallogra- (R)- 1a , ( E = 9), 33 while in this work, ( Table 1 , entry 16) it is clear phy studies. that the ( R) ester is selectively hydrolysed albeit with very low With racemic samples of both the esters and acids in hand, chi- enantioselectivity. The less common pathway involving selective ral HPLC conditions were developed for each ester hydrolysis in hydrolysis of the ( R)-ester has been successfully extended in this O OH (±)- 1a (v) O OH (i) R2 O R2 O R2 O (iii) (iv) OH Cl OEt R1 R1 R1 MgBr O R1 (ii) OH 1 2 1 2 1 2 (±)- 1b R =H, R =CH 2CH 3 (±)- 2b R =H, R =CH 2CH 3 (±)- 3a R =H, R =CH 3 1 2 1 2 1 2 (±)- 1c R =H, R =CH(CH 3)2 (±)- 2c R =H, R =CH(CH 3)2 (±)- 3b R =H, R =CH 2CH 3 1 2 1 2 1 2 (±)- 1d R =H, R =C(CH 3)3 (±)- 2d R =H, R =C(CH 3)3 (±)- 3c R =H, R =CH(CH 3)2 1 2 1 2 1 2 (±)- 1e R =p-CH 3, R =CH 3 (±)- 2e R =p-CH 3, R =CH 3 (±)- 3d R =H, R =C(CH 3)3 1 2 1 2 1 2 (±)- 1f R =m-CH 3, R =CH 3 (±)- 2f R =m-CH 3, R =CH 3 (±)- 3e R =p-CH 3, R =CH 3 1 2 1 2 1 2 (±)- 1g R =o-CH 3, R =CH 3 (±)- 2g R =o-CH 3, R =CH 3 (±)- 3f R =m-CH 3, R =CH 3 1 2 1 2 1 2 (±)- 1h R =p-OMe, R =CH 3 (±)- 2h R =p-OMe, R =CH 3 (±)- 3g R =o-CH 3, R =CH 3 1 2 (±)- 3h R =p-OMe, R =CH 3 2 Scheme 1.
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