Molecules of biological importance, such as polyunsaturated fatty acids (PUFAs) and sterols are primary targets for the H-atom abstraction by a peroxyl radical. This process, known in biological sciences as lipid peroxidation, receives a considerate amount of research attention from multiple fields. There is a growing consensus that products of lipid peroxidation play a significant role in the pathophysiology of many human disorders. 7-Dehydrocholesterol (7-DHC) is a lipid that is the biosynthetic precursor to cholesterol and vitamin D3. This compound plays a crucial role in the human neurodevelopmental disorder, Smith—Lemli–Opitz Syndrome (SLOS). Characteristic to SLOS patients are increased levels of 7-DHC and lower than normal levels of cholesterol in the plasma. SLOS patients also suffer from congenital disabilities and delayed mental development. The rate constant of peroxidation of 7-DHC is 200 times higher than that of cholesterol contributing to the growing amount of evidence that links SLOS to peroxidation of 7-DHC. The overarching goal of our research is to better understand the relationship between the structure and oxidation rate in 7-DHC. Pyrocholecalciferol (1) and isopyrocholecalciferol (2) are C-9 and C-10 diastereomers of 7-DHC where the hydrogen atom that is attacked by the radical resides in the diametrically different steric environment. We developed a practical synthesis of pyrocholecalciferol (1) and isopyrocholecalciferol (2) by a thermal electrocyclic reaction of cholecalciferol (vitamin D3). The new protocol utilizing a microwave reactor significantly decreased the reaction time (from 12 h to 30 min) and reduced the amount of solvent used by 90%. Additionally, we observed almost undetectable levels of product decomposition despite high reaction temperature (200 °C). The results of optimization of reaction conditions, separation, and characterization of compounds 1 and 2 will be presented.

Towards understanding of peroxidation of mammalian sterols: Microwave-assisted synthesis of 7-dehydrocholesterol isomers

253rd National Meeting (2017)

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