Arto Liljeblad

Preparation of highly enantiopure β-amino esters by Candida antarctica lipase A

Abstract The enantioselectivities for the reactions of aliphatic β-substituted β-amino esters [RCH(NH 2 )CH 2 CO 2 Et with R=Me, Et, n -Pr, i -Pr, CHEt 2 , cyclohexyl and Ph] with butyl butanoate in neat butyl butanoate and with 2,2,2-trifluoroethyl butanoate in diisopropyl ether were studied in the presence of Candida antarctica lipase A. Enantioselectivities ranging from good ( E =70–100) to excellent ( E >100) were commonly observed, allowing gram-scale resolution of the substrates.

Enantioselective lipase-catalyzed reactions of methyl pipecolinate: transesterification and N-acylation

Abstract The present research introduces the highly ( S )-selective ( E >>100) acylation at the secondary ring nitrogen of methyl pipecolinate as a novel resolution method with Candida antarctica lipase A. Catalysis by lipase B leads to reactions at the methyl ester function of the substrate in an almost non-enantioselective manner.

Preparation of the enantiomers of 1-phenylethan-1,2-diol. Regio- and enantioselectivity of acylase I and Candida antarctica lipases A and B

Abstract Acylase I and Candida antarctica lipases A (CAL-A) and B (CAL-B) were evaluated for the preparation of the enantiomers of 1-phenylethan-1,2-diol. In the presence of CAL-B, the sequential one-pot methanolysis of the diacetate in acetonitrile allowed the preparation of ( S )-diol (e.e. 97%) and ( R )-1-acetoxy-1-phenylethanol (e.e. 94%). Base-catalyzed methanolysis of the monoacetate resulted in the corresponding ( R )-diol. When one of the diol enantiomers was subjected to Mitsunobu esterification, inversion of configuration occurred, allowing transformation of the initially racemic mixture to one enantiomer. Acylase I-catalysis led to the chemo- and enantioselective formation of ( S )-1-acetoxy-1-phenylethanol (e.e. 97%) in the presence of the primary hydroxyl function through acetylation of the secondary hydroxyl group. The low chemical yield (ca. 25%) was due to the moderate enzymatic regioselectivity. CAL-A behaved in a similar way to acylase I.

Biocatalysis in the Preparation of the Statin Side Chain

Statins used in the treatment of dyslipidemias are top-selling drugs in the world. Economical production of statins in industrial scale is challenging, because the side chain of statins is a 3,5-dihydroxyacid derivative consisting of two asymmetric centers. The most prominent methods for the preparation of the side chain are based on biocatalysis and surveyed in this review.

Sequential resolution of ethyl 3-aminobutyrate with carboxylic acid esters by Candida antarctica lipase B

Abstract The reactions of ethyl 3-aminobutyrate 1 with carboxylic acid esters, catalyzed by lipases from Candida antarctica , Pseudomonas cepacia and Pseudomonas fluorescens , have been studied. The reactions take place on the amino and ester functions of the substrate provided that the alkyl group of the achiral ester differs from ethyl. This property has been exploited for the Candida antarctica lipase B-catalyzed resolution of 1 in butyl butyrate, leading to the unreacted enantiomer ( S )- 1 and butyl 3-aminobutyrate, and to the butanamide of butyl ( R )-3-aminobutyrate.

Enzymatic methods for the preparation of enantiopure malic and aspartic acid derivatives in organic solvents

Abstract The kinetic resolution of malic and aspartic acid diesters as well as of its N -butanoyl dimethyl ester by highly regioselective lipases and acylase I enzymes were studied. Candida antarctica lipase A on Celite catalyzed the enantioselective acylation of the hydroxyl and amino groups. Acylase I from Aspergillus melleus and Candida antarctica lipase B catalyzed the enantioselective alcoholyses of the ester groups at the α- and β-positions, respectively.

Lipase-catalysed kinetic resolution in organic solvents: An approach to enantiopure α-methyl-β-alanine esters

Abstract The Candida antarctica lipase A (CAL-A) and B (CAL-B)-catalysed resolutions of α-methyl-β-alanine ethyl ester 1 with neat ethyl and butyl butanoates and with 2,2,2-trifluoroethyl butanoate in organic solvents were studied, as were the alcoholyses in neat butanol and with methanol (0.8 M) in diisopropyl ether. The two enzymes, which display opposite (S for CAL-A and R for CAL-B) and low enantioselectivities (E=7–10), allowed the preparation of the two enantiomers in a two-step resolution protocol. The R enantiomer (ee=97%) was first separated as its Boc-protected derivative from the CAL-A-catalysed resolution mixture of (R)-1 and the enantiomerically enriched N-butanoylated counterpart. The enantiopurification of the latter gave the S enantiomer (ee=96%) in the following CAL-B-catalysed ‘interesterification’ in butyl butanoate.

Use of enantio-, chemo- and regioselectivity of acylase I. Resolution of polycarboxylic acid esters

Abstract Acylase I was used to catalyze the enantioselective butanolysis of trimethyl 2-[(carboxymethyl)oxy]succinate ( E =30) and N -carboxymethylaspartate ( E =9) exclusively at the most sterically hindered of the three ester groups (the position α to the asymmetric centre). Gram-scale resolution allowed the preparation of the less reactive trimethyl ( S )-2-[(carboxymethyl)oxy]succinate (96% e.e.), that of the ( R )-butyldimethyl regioisomer (78% e.e.) at 55% conversion and finally the preparation of the corresponding trisodium carboxylate by saponification. Acylase I was shown to transform (±)-methyl N -acetylmethionine and (±)-valine to the corresponding ( S )-amino acids through ester hydrolysis- N -acetyl transfer sequence with absolute chemo- and enantioselectivity. Butanolysis of methyl N -acetylmethionine stopped in the formation of the butyl ester ( E =12), the valine derivative being totally unreactive.

Acylase I in the alcoholysis of α-substituted dicarboxylic acid esters and derivatives: enantio- and regioselectivity

Abstract Enantio- and regioselective butanolyses of α-substituted dimethyl succinates (substituents: Me, MeO 2 CCH 2 , NH 2 , AcHN, PrCOHN, HO, MeO, PrO, AcO, PrCO 2 , HepCO 2 , Cl and Br) and glutarates (substituents: PrCONH and CbzNH) and that of methyl pyroglutamate with acylase I enzymes have been studied. Acylase I-catalyzed reactions were totally regioselective proceeding exclusively at the sterically more hindered methyl ester group α to the substituent. High enantioselectivities ( E from 50 to ≫100) were observed only for the substrates containing CONH functionality in the substituent although the CN bond was unreactive. The nature of the substituent influenced which of the two enantiomers reacted faster.

Dynamic Kinetic Resolution of rac-2-Hydroxy-1-indanone by using a Heterogeneous Ru(OH)3/Al2O3 Racemization Catalyst and Lipase

Kinetic resolution and dynamic kinetic resolution, in particular, provide practical tools for synthesis of enantiomerically pure compounds. In the present work, the resolution of rac‐2‐hydroxy‐1‐indanone and racemization of (S)‐2‐hydroxy‐1‐indanone were investigated. Immobilized lipase AK (Pseudomonas fluorescens) was found as the best enzyme catalyst for kinetic resolution and ruthenium supported on Al2O3 as a potential heterogeneous catalyst for racemization of the starting material. By combining the two reactions, a simple dynamic kinetic resolution of rac‐2‐hydroxy‐1‐indanone producing (R)‐1‐oxo‐indan‐2‐yl butanoate was developed. Under optimal conditions, the product was obtained in 92 % ee at approximately 90 % conversion.