Synthesis of the Racemate and Both Enantiomers of Biologically Active 4-(2,6-Dimethylheptyl)Benzoic Acid and Their Effect on Cholesterol Accumulation in Aorta Cells

Abstract

A chemical and enzymatic approach to the synthesis of (S)-and (R)-3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols, convenient intermediates for the synthesis of both enantiomers of 4-(2,6-dimethylheptyl)benzoic acid, was described. The biological activity of (R)-and (S)-isomers of the racemic acid was studied. It was established that the (S)-configuration of its antipode in the racemate decreased the cholesterol level in aorta cells.Keywords: (R)-and (S)-4-(2,6-dimethylheptyl)benzoic acids, (S)-and (R)-3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols and their h 6 -chromiumtricarbonyl complexes, porcine pancreatic lipase (PPL), aorta cholesterol level.Racemic 4-(2,6-dimethylheptyl)benzoic acid [(RS)-I] reduces effectively the in vivo blood level of excessive cholesterol [1] and also suppresses cholesterol accumulation in human atherosclerotic aorta cells in culture [2] more strongly that standard Clofibrate ® . This makes it promising in the battle with atherosclerosis. However, the pharmacological properties of the pure enantiomers (R)-I and (S)-I have not been previously studied because the acids themselves were unknown.We developed previously [3] a stereo-divergent synthetic scheme in order to synthesize the undescribed acids (R)-I and (S)-I from the common precursor enal II [4] through racemic alcohol (RS)-III. The scheme included enzymatic kinetic separation of (RS)-III using porcine pancreatic lipase (PPL).The PPL-catalyzed kinetic separation of the (RS)-acetate of 3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanol produced the (R)-III and (S)-III enantiomers of the corresponding alcohol with 22 -27% optical purity. The enantiomeric excess (ee) could not be increased above 33% with repeated enzymatic hydrolysis of the "residual" acetate under the same conditions. Partial acylation [5] of (RS)-III alcohol using vinylacetate-Candida cylindracea (CCL) also did not give products with the required high enantiomeric purity.The limited choice of lipases with high enantiomeric selectivity for racemic substrate (RS)-III and the desire to synthesize pure enantiomers of (R)-III and (S)-III with an acceptable ee for synthesizing target acids (R)-I and (S)-I prompted us to seek new approaches for solving this problem.Examples where the selectivity of lipases was increased by adding chemical additives to the reaction mixture were reported. The addition of them could have a favorable effect on the enzyme microenvironment [6,7]. Amines, crown ethers, moistened sodium or lithium salts, and various combinations of enzymes with added Group IV -VII elements (Si, Cr, Ru) were used as such additives.We settled on a previously unused approach, i.e., a drastic change of the electronic and steric properties of the substrate by converting it into the corresponding racemic arene(tricarbonyl)chromium complex of alcohol (RS)-IV [5] and/or its acetate (RS)-IVa [8].