Protosterol cation

Cyclization of squalene oxide yields a carbocation, called the protosterol cation. This reaction results in the formation of four new C—C bonds and the tetracyclic ring system. 

First, we will take up cyclopropyl group formation by the rearrangement of carbon skeletons via cationic intermediates encountered in various mono- and sesquiterpenes, and also examine the illudin biosynthesis where contraction of a cyclobutyl cation to a cyclopropane has been invoked. We will then discuss the head-to-head condensation of isoprenoid alcohols at the C15 or C20 level to generate the cyclopropyl intermediates, presqualene pyrophosphate and prephytoene pyrophosphate, on the way to the C30 and C40 polyene hydrocarbons, squalene and phytoene respectively. Conversion of 2,3-oxidosqualene via common intermediate protosterol cation to cycloartenol or lanosterol represents an important pathway in which the angular methyl group participates in the three-membered ring formation. The cyclopropanation outcome of this process has been carefully studied. 

A group of fungicides that inhibit squalene epoxidation has been developed primarily for use against pathogenic fungi in medicine. Epoxidation of squalene is catalyzed by squalene epoxidase (a flavoprotein) that starts the complicated cyclization of squalene. The squalene-2,3-epoxide formed by this enzyme is further metabolized to a protosterol cation intermediate, which is transformed to either cycloartenol in plants (cycloartenol synthase) or lanosterol (lanosterol synthase). Cycloartenol is the precursor to plant sterols, whereas lanosterol is the precursor of cholesterol and the other sterols in animals, and to ergosterol in plants. 

Fig. 18. The cyclization of 2,3-oxidosqualene (b) to the protosterol cation (c) and its subsequent rearrangement to lanosterol by a series of 1-2 shifts.

Draw the individual 1,2-hydride and 1,2-methyl shifts responsible for conversion of the protosterol cation to lanosterol. How many hydride shifts are involved How many methyl shifts ... 

The biosynthesis of cholesterol from squalene was examined. Using model structures and intrinsic reaction coordinate calculations, evidence was reported for the asynchronous, concerted reaction of squalene oxide to the protosterol cation. 

Acid-catalyzed opening of the epoxide initiates a series of cyclizations resulting in the protosterol cation. 

Figure 7. Hy thctical model for involvement of aromatic amino acid sidechains in the cyclization of oxidosqualene to the protosterol cation.

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