C–C Bonds in Biosynthesis: Squalene and the Sterol Biosynthetic Pathway

Abstract

The C30 hexa-olefinic hydrocarbon squalene is an iconic molecular scaffold in the isoprenoid biosynthetic pathway to cholesterol and its many downstream oxygenated steroid hormones. The biosynthetic pathway from 18 acetyl CoA starter molecules to C27 cholesterol is a clear story in how chemical logic and mechanism changes as complexity is built into the growing hydrocarbon and carbacyclic scaffolds. The pathway starts with three acetyl CoA molecules condensing to hydroxymethylglutary CoA, switches to allyl cation capture by olefin π-electrons as carbon nucleophiles, in head to tail alkylations before switching to head to head alkylations of two farnesyl-PP chains to generate squalene. Squalene is then epoxidized and cyclized to the tetracyclic framework of lanosterol. From lanosterol to cholesterol and all the way to the female steroid sex hormones, estrone and estradiol, the logic changes from carbocation-driven chemistry to carbon radical interemdiates. All told 19 O2 are reduced by 7 oxygenases on the way from lanosterol to estrone, suggesting 19 carbon radicals in the process.