Pristanic acid synthesis

The synthesis of optically pure 2-methylacyl-CoA allowed us to investigate the stereospecificity of the acyl-CoA oxidases. Rat pristanoyl-CoA oxidase and THCCox (and most likely BRCACox) desaturate only the 2S-forms. Naturally occurring pristanic acid is racemic at position 2. To degrade the 2R-isomer, it needs to be transformed to the 2S-isomer and this happens at the level of the CoA ester. The responsible enzyme is 2-methylacyl-CoA racemase. It is present in mitochondria and in peroxisomes, both in rat and man. Presumably, the mitochondrial racemase activity is required for the racemisation of the shortened pristanic acid metabolites formed by peroxisomal P-oxidation and that contain 2R-methyl branches. Mitochondrial oxidation of branched fatty acids, like the peroxisomal one, is stereospecific for the 2S-isomers. ... 

Figure 8.11 Acid-catalyzed dehydration of an allylic alcohol and its application in pristane synthesis...

When the reaction was performed on a 100 mg scale, the diene was obtained in 55% yield as a mixture of ( )- and (Z)-stereoisomers. However, when the scale was increased to lOOg, various by-products, such as cyclized products or alkyl group-migrated compounds, were produced presumably because of acid-catalyzed reactions of the diene. The formation of such by-products can be reduced using a microflow system composed of a micromixer and a microtube reactor. Thus, a solution of the allylic alcohol in tetrahydrofuran (THF) was mixed with a solution of p-toluenesulfonic acid (p-TsOH) in THF/toluene at 90 °C. After the reaction mixture was allowed to flow for 47 s, the reaction was quenched with a saturated NaHCOs solution at room temperature. In this case the desired diene was obtained in 80% yield. It is noteworthy that the acid-mediated by-products were not detected. This process was applied to the synthesis of pristane, a biologically important natural product that is widely used as an adjuvant for monoclonal antibody production. 

Tanaka et al. recently demonstrated the application of methodology developed for the dehydration of p-hydroxy-ketones to the synthesis of the natural product pristane 50. Employing p-TsOH 51 as the acid catalyst, the authors synthesized the target compound 50 at a rate of 5 kg per week, which is sufficient to meet the current market demands for the immunoactivating agent (Scheme 6.27). 

---