SYNTHESIS OF POTENTIAL MECHANISM-BASED INACTIVATORS OF LANOSTEROL 14-ALPHA-METHYL DEMETHYLASE

Lanosterol 14a-methyl demethylase is a key enzyme in the degradation of lanosterol to cholesterol. This cytochrome P-450 monooxygenase catalyzes the oxidative removal of the methyl group at C-14 of lanosterol. Inhibitors of this enzyme may prove useful as cholesterol-lowering agents and as antimycotics. This paper describes the design and synthesis of seven potential mechanism-based inactivators (compounds 9—15) of lanosterol 14a-methyl demethylase. The appropriately protected aldehydes 20a and 20b were the key intermediates in the synthesis of compounds 9, 11, 12, 14, 15. A method was developed for the homologation of these aldehydes to give 25a and 25b, which were converted to lanosterol analogues 10 and 13. © 1990, American Chemical Society. All rights reserved.