Omar Parve

Preparation of highly enantiopure stereoisomers of 1-(2,6-dimethylphenoxy)-2-aminopropane (mexiletine)

Abstract Mexiletine [1-(2,6-dimethylphenoxy)-2-aminopropane], an orally effective antiarrhythmic agent, exhibits enantioselective pharmacokinetics and pharmacodynamics during mexiletine therapy. The purpose of this paper is to emphasize the advantage of tetrahydropyranyl-protected mandelic acid (THPMA) in the resolution of mexiletine enantiomers. Both enantiomers of mexiletine were obtained in 99% enantiomeric excess. Judging by the differential shielding effects in the 1 H and 13 C NMR analyses, we have observed the opposite predominant conformation for the mexiletine mandelates in comparison with the O -methylmandelates.

Switched enantiopreference of Humicola lipase for 2-phenoxyalkanoic acid ester homologs can be rationalized by different substrate binding modes

Humicola lanuginosa lipase was used for enantioselective hydrolyses of a series of homologous 2-phenoxyalkanoic acid ethyl esters. The enantioselectivity (E-value) of the enzyme changed from an (R) ...

The tetrahydropyranyl-protected mandelic acid: a novel versatile chiral derivatising agent

Abstract A simple synthesis of (2R)-2-phenyl-2-[(2S)-tetrahydro-2-pyranyloxy]ethanoic acid, a versatile chiral derivatising agent (CDA), is proposed. The derivatisation of secondary alcohols aimed at the absolute configurational assignment, determination of enantiomeric purity as well as semipreparative resolution is described.

Lipase-catalysed acylation of prostanoids.

Natural prostaglandins (PG) F2alpha and E1 as well as (+)-cloprostenol were regioselectively 11-acylated using Novozym 435 as a catalyst and vinyl acetate as an acyl donor. Unlike the above compounds the 15-OH group of PGE2 was also acylated with a significant velocity under the same conditions. The enantiospecificity of the lipase-catalysed 11-acetylation of cloprostenol was established by separate treatment of(+)- and (-)-cloprostenols.

Lipase action on some non-triglyceride substrates

Approaches for improving methodologies of kinetic resolution of enantiomers as well as of regioselective protection of functional groups of complex chiral molecules involving lipase-catalytic reactions are highlighted. Decyclization of hemiacetals by lipase as well as exclusive pathways of lipase-catalyzed derivatization of prostanoids are brought out. Lipase-triggered cascade-reactions are noticed.

Chemical versus enzymatic acetylation of α-bromo-ω-hydroxyaldehydes: decyclization of hemiacetals by lipase

Abstract Lipase-catalyzed decyclization of hemiacetals of α-bromo-ω-hydroxyaldehydes followed by trapping upon acetylation was observed. Quantum chemical investigations were performed to explain the energetic background of the reactions. The stereocontrolled synthesis of enantiopure trans -(2 S ,3 S )-2-methoxy-tetrahydropyran-3-ol was elaborated.

Short Synthesis of Novel 9,11-Secosterols

Abstract Starting from ergosterol two novel 9,11-secosterols with modified side chains (1a) and (1c) were synthesized via eight main transformations.

Lipase-catalysed enantioselective hydrolysis of bicyclo[3.2.0]heptanol esters in supercritical carbon dioxide

Abstract The esters derived from 2-exo-bromo-3-endo-hydroxybicyclo[3.2.0]heptan-6-one were treated with Lipolase under hydrolytic conditions in supercritical carbon dioxide (SCCO2). All the esters tested gave access to optically active material (e.e. 50–90%). The esters with an additional keto or hydroxy group were hydrolysed to 35–40% conversion while nonpolar lipophilic substrates gave poor conversions (3–5%) under the same conditions.

Lipase-catalysed enantioselective hydrolysis: Interpretation of the kinetic results in terms of frontier orbital localisation

Abstract The initial velocities of the enantioselective hydrolysis of the esters derived from mono- and bicyclic alcohols and hemiacetals catalysed by Lipolase™ in water have been determined. The differences in hydrolysis rates within groups of sterically similar substrates have been interpreted in terms of frontier orbital localisation.

Synthesis and Quantitative Analysis of Diastereomeric Linked Ester Conjugates With Remote Stereocenters Using High-Field NMR and Chiral HPLC

A stereochemically safe high-yielding procedure for linking unprotected as well as protected hydroxycarboxylic acids to chiral secondary alcohols via glycolic acid linker is proposed. L-menthol has been linked with both enantiomers of mandelic, malic, and methoxyphenylacetic acid using bromo- or iodoacetyl group as a precursor of the glycolic acid linker. High-field nuclear magnetic resonance (NMR) and chiral high-performance liquid chromatography (HPLC) determination of high diastereomeric ratio (dr) (>99%) of the products bearing remote stereocenters was explored. Chiral HPLC allowed quantitation of the diastereomers up to dr 99.9/0.1. High-field NMR quantitation of the diastereomeric and parent alcoholic impurities in esters was demonstrated at the molar 0.3% and 0.03% levels, respectively. These analyses were done via comparison of integral intensities from major component (13)C satellites in (1)H or even in (13)C spectra to the (1)H or (13C signals of impurities. Despite lower sensitivity, the last option generally has much better selectivity. In this way the dynamic resolution is brought down by two orders.