Anders Mattson

Kinetic resolutions of amine and thiol analogues of secondary alcohols catalyzed by the Candida antarctica lipase B

Abstract Chiral amine and thiol analogues of secondary alcohols were tested as substrates for the Candida antarctica lipase B with emphasis on lipase enantioselectivity and substrate reactivity. Although the apparent enantiomeric ratios were lower for the amines than for the corresponding alcohols, the amines 2-octylamine and 1-phenyl-ethylamine were produced with high optical purity (ee-93–99%) in a lipase-catalyzed acyl transfer reaction with ethyl octanoate as the acyl donor. The initial rates were lower and the reaction times longer for the amines than for the corresponding alcohols. The thiols 2-octanethiol and 1-phenylethanethiol did not yield any thiol ester product in the analogous lipase-catalyzed acyl transfer reaction. By preparing the thiooctanoate of 1-phenyl-ethanethiol and employing it as acyl donor in a lipase-catalyzed reaction with 1-phenylethanol as acyl acceptor, however, 1-phenylethanethiol could be resolved with high enantiomeric excess of the ( R )-enantiomer (ee-95%) and moderate enantiomeric excess of the ( S )-enantiomer (ee-75%).

Candida antarctica lipase B catalysed kinetic resolutions: Substrate structure requirements for the preparation of enantiomerically enriched secondary alcanols

Abstract The lipase B of the Candida antarctica yeast displays high enantioselectivity in transesterification reactions with chiral secondary alcohols in non-aqueous media. This was exploited to resolve a series of racemates structurally related to 2-octanol, namely 3-hydroxy-1-undecyne, 3-hydroxy-1-nonene, 3-nonanol, 1-chloro-2-octanol, 2-methyl-3-nonanol, 2,2-dimethyl-3-nonanol. The substrates were designed to probe the alcohol binding part of the active site of the lipase. The first four racemates could be resolved to produce compounds of high enantiomeric purity. A lipase catalysed transesterification of 1-chloro-2-octanol was observed. 2-Methyl-3-nonanol and 2,2-dimethyl-3-nonanol did not form any detectable amounts of product ester. The kinetic resolutions of the alcohols were performed with S-ethyl thiooctanoate as the acyl donor.

Resolution of diols with C2-symmetry by lipase catalysed transesterification

Abstract S-Ethyl thiooctanoate was used as acyl donor in the transesterification of 2,3-butanediol ( 1 ), 2,4-pentanediol ( 2 ), and 2,5-hexanediol ( 3 ), catalysed by a lipase from Candida antarctica . Mixtures of all stereoisomers were used as substrates in each case. 2,5-Hexanediol was transesterified with high stereoselectivity and the (2 S ,5 S )-2,5-hexanediol was isolated in good yield with >99 % ee. The diester of (2 R ,5 R )-2,5-hexanediol was formed in good yield and was hydrolysed to yield the (2 R ,5 R )-2,5-hexanediol of high enantiomeric excess (>99% ee). Similar results were obtained for 2,4-pentanediol with >99% ee for both enantiomers. The stereoselectivity for 2,3-butanediol was lower than for 2 and 3 , giving 89% ee for the R,R -enantiomer and 34% ee for the S,S -enantiomer.

Molecular Modelling of Chymotrypsin-Substrate Interactions: Calculation of Enantioselectivity

A method has been developed for the calculation of the enantioselectivity of chymotrypsin catalysed hydrolytic reactions using molecular mechanics and molecular dynamics. Nine different ester substrates, which are hydrolysed by the enzyme over a wide range of reaction rates have been studied. Models of the transition state of the ester hydrolysis were built using computer aided molecular modelling. The energies of the transition state models were calculated by molecular mechanics and molecular dynamics methods. The point charges of the substrates were modelled from known force field parameters and by semiempirical methods. The difference in free energy of activation between the enantiomers of each substrate were compared with experimental values. The calculations approximated the experimental results. The calculated structure of the transition state model of the chymotrypsin catalysed hydrolysis of acetyl-phenylalanine ester was virtually the same as the published crystal structure of a chymotrypsin-trifl...

Displacement of the equilibrium in lipase catalysed transesterification in ethyl octanoate by continous evaporation of ethanol

SummaryA simple method to overcome low equilibrium conversion in lipase catalysed resolution of alcohols by transesterification was developed. Ethyl octanoate was used as acyl donor as well as solvent and the reaction equilibrium was shifted by applying reduced pressure, forcing the co-product ethanol to evaporate during the reaction. Using a lipase fromCandida antarctica 2-octanol, 1-phenyl ethanol, 1-cyclohexyl ethanol andtrans-2-methylcyclohexanol were resolved in good optical and chemical yields.

Preparation of 1-pyridinylethanols of high enantiomeric purity by lipase catalysed transesterifications

Abstract Component B lipase of the Candida antarctica yeast displays high enantioselectivity in catalysing transesterification reactions in non-aqeuous media with chiral secondary alcohols. This was exploited to resolve racemates of 1-(pyridinyl)-ethanols, 1- (6-bromopyridin-2-yl)ethanol, and 1-(6-bromopyridin-2-yl)-2,2-dimethylpropanol. The lipase esterified the ( R )-alcohols of the first four substrates in > -99% enantiomeric excess in less than three hours with 30–40% isolated yield. Remaining ( S )-enantiomers were isolated in similar yields and in 97–98% ee. 1-(6-Bromopyridin-2-yl)-2,2-dimethylpropanol did not form any detectable ester in one week.

Thioethyl-, Vinyl-, Ethyl Octanoate Esters and Octanoic Acid as Acyl Donors in Lipase Catalysed Acyl Transfer Reactions

S-Ethyl thiooctanoate, vinyl octanoate, ethyl octanoate and octanoic acid were studied as acyl donors in a lipase catalysed acyl transfer reaction with 2-octanol as acyl acceptor. The reaction conditions had a pronounced effect on the equilibrium displacement and the apparent enantioselectivity. The thioethyl and vinyl esters proved to be efficient acyl donors under atmospheric pressure and 39 d`C, affording a high apparent enantiomeric ratio. Under these reaction conditions the apparent enantioselectivity seemed to be enhanced by water, which was present in the reaction system and caused the production of octanoic acid, by hydrolysis of me acyl enzyme.

Enantiotopic Selectivity of-Pig Liver Esterase Isoenzymes

Pig liver esterase was separated into isoenzyme fractions with known subunit compositions. The fractions showed differences in enantiotopic ester group selectivity in hydrolysis of two substrates of synthetic value, benzylmethylpropanedioic acid dimethyl ester and cis-N-benzyl-2,5-bismethoxy-carbonylpyrrolidine. A difference in aliphatic chain length specificity between the isoenzyme fractions was also observed. The results indicate that pig liver esterase cannot be regarded as homogeneous when used in organic synthesis.

A Convenient Synthesis of 5-Hydroxymethyl-1-aza-3,7-dioxabicyclo[3.3.0]octane and Its β-Methoxyethoxymethyl Derivative

Abstract 5-(β-methoxyethoxymethyl)-1-aza-3,7-dioxabicyclo[3.3.0]-octane (1) was prepared in high yield by a reaction of tris-(hydroxymethyl)-aminomethane (TRIS) with β-methoxyethoxymethylchloride (MEMCl).

Enhanced stereoselectivity in pig liver esterase catalysed diester hydrolysis. The role of a competitive nucleophile

The enantioselectivity of pig liver esterase catalysed hydrolysis of cis-N-benzyl-2,5-bis(methoxy-carbonyl)pyrrolidine (1) has previously been shown to be very dependent on the reaction conditions. Hydrolysis performed in media buffered with tris(hydroxymethyl)aminomethane (Tris) afforded a monoester with much higher optical purity than hydrolysis in media without Tris. Detailed product studies in a Tris-buffered medium have been performed using NMR-techniques and a 13C-labelled ester. The NMR-studies revealed the presence of (2S,5R)-N-benzyl-2-methoxycarbonyl-5-[[[2-hydroxy-1,1- bis(hydroxymethyl)ethyl]amino]carbonyl]pyrrolidine (4) as an intermediate, which together with the isolated product (2S,5R)-N-benzyl-2-carboxy-5-[[[2-hydroxy-1,1-bis(hydroxymethyl) ethyl]amino]carbonyl]pyrrolidine (3) suggested Tris as a competitive nucleophile to water. The increased enantioselectivity seen in the produced (2R,5S)-N-benzyl-2-methoxy-carbonyl-5-carboxypyrrolidine (2) was explained by the preference of Tris to react faster with one of the diastereomeric acyl enzymes over the other.