Sterols are particularly prone to undergo radical chain oxidation, and evidence suggests that this process, known as lipid peroxidation, occurs in vivo under a variety of conditions that are the result of oxidative stress. One of those conditions is Smith�Lemli�Opitz syndrome (SLOS), an autosomal recessive metabolic disorder characterized by multiple congenital malformations, developmental delay, cognitive impairment, and behavior problems. At the molecular level, the syndrome is caused by toxic oxidation products (oxysterols) of 7-dehydrocholesterol (7-DHC) that accumulates when cholesterol biosynthesis is disrupted due to sterol ?7-reductase deficiency. Previous work established that 7-DHC is one of the most oxidizable lipids known�rate of H-atom transfer to peroxyl radicals is over 200 times larger than for cholesterol. The high rate of oxidation and theoretical calculations suggest that quantum tunneling may be involved, since the transformation occurs with minimal reorganization of the molecule. This work provides experimental support for tunneling in H-atom transfer from 7-DHC to peroxyl radicals. We describe a concise total synthesis of deuterium-reinforced previtamin D3 from (+)-carvone and Grundmann's ketone, and its light-induced electrocyclization to 7-DHC-d2. The kinetic isotope effect in tocopherol-mediated oxidation of 7-DHC-d2 was measured by co-oxidation with its H-analog and HPLC/MS analysis. Our results show that D-atom transfer is at least 26 times slower than H-atom transfer for 7-DHC in the free radical process mediated by tocopherol.

Kinetic isotope effect of deuterium-reinforced 7-dehydrocholesterol in tocopherol-mediated free radical chain oxidation

247th National Meeting (2014)

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