The putative oxidative cleavage mechanism of cholesterol double bond undergoes Hock rearrangement in presence of singlet O2 and acid. However, in vivo studies involving trametes hirsuta fungal enzyme reveal the requirement of two equivalents of O2 in the oxidative mechanism process. In light of this, a density functional theory study was carried out to elucidate the origin of cholesterol reactivity with two dioxygens, as the secosterol product is linked to disease plaque formation leading to Alzheimer, Atherosclerosis and dementia. We find that, upon O2 addition to the alkenyl double bond, ground state triplet O2 forms a triplet biradical peroxo intermediate that is incapable of abstracting an allylic hydrogen compared to singlet O2 addition. The subsequent complexation with another triplet O2 (overall quintet) lowers the energy landscape but the spin crossing from quintet to triplet state highly stabilizes to a diperoxo intermediate with new C-O bond formed. To realize C-C bond scission, reduction of the diperoxo to trioxo intermediate is required and the Me2S mimicking methionine is the most likely species to abstract an O atom. The C-C bond cleavage process yields a product with an aldehyde and carbonyl oxide group highly similar to the ozonolysis process of primary ozonide. The recombination and subsequent further reduction of this product yields the final cholesterol secosterol aldehyde, a chief component or precursor in biological plaque formation.

Mechanistic implications in oxidative cleavage of cholesterol C=C bond by dual triplet O<sub>2</sub> activation and sulfide reduction to secosterol aldehyde

248th National Meeting (2014)

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Mechanistic implications in oxidative cleavage of cholesterol C=C bond by dual triplet O2 activation and sulfide reduction to secosterol aldehyde

Mechanistic implications in oxidative cleavage of cholesterol C=C bond by dual triplet O₂ activation and sulfide reduction to secosterol aldehyde