Oxidosqualenes rearrangement

Tissue cultures of Isodon japonicus could biosynthesize oleanane- and ursane-type triterpenoids from [4-13C]MVA with sufficient incorporation of tracer to allow the elucidation of the labelling pattern by 13C n.m.r. spectroscopy.356 The results verify the hypothesis of Ruzicka involving cyclization of 2,3-oxidosqualene in a chair-chair-boat form, followed by specific 1,2-hydride shifts, and the rearrangement of... 

Figure 27.14 MECHANISM Mechanism of the conversion of 2,3-oxidosqualene to lanosterol. Four cationic cyclizations are followed by four rearrangements and final loss of H from C9. The steroid numbering system is used for referring to specific positions in the intermediates (Section 27.6). Individual steps are explained in the text.

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. 

Three distinct methods have been demonstrated for the cyclisation of squalene. Although most triterpenoids follow a similar route to lanosterol [(7)— (71)— (72) (73)] the 3-desoxytriterpenoids such as femene (98) are formed from squalene (7) not from 2,3-oxidosqualene (71). Presumably a proton-initiated cyclisation is followed by elimination of a hydrogen atom, with, or without, rearrangement of the carbonium ion . When [2- C,3R,4R- H]mevalonic acid... 

Fusidic acid (100) and helvolic acid (101) are interesting steroid-like triterpenoids derived from the carbonium ion (72) without rearrangement and subsequent loss of a 4-methyl group. As expected, [2- C,3R,4R- H]mevalonic acid only incorporated four tritium atoms [see (lOO)]. 2,3-Oxidosqualene (71)... 

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.

Brown and coworkers found use for the Meyer-Schuster rearrangement in their synthesis of quinuclidine inhibitors of 2,3-oxidosqualene cyclase/lanosterol synthase (OSC). The rearrangement was the last step in the synthesis of one such inhibitor, utilizing concentrated H2SO4 to carry out the transformation from 37. 

The biosynthesis of plant sterols and saponins proceeds via the isoprene pathway with the cyclization and subsequent rearrangement of a C30 2,3-oxidosqualene precursor, as discussed in reviews by Haralampidis et al. [107], Benveniste [108, 109], Kreis and Miiller-Uri [110], and Osbourn et al. [111]. Following cyclization of 2,3-oxidosqualene (in the chair-boat-chair conformation), the resultant... 

Triterpenes are synthesized via the MVA pathway from two molecules of FPP that are joined by tail-to-tail condensation to squalene. Cyclization of its metabolite 2,3-oxidosqualene followed by rearrangements and methyl shifts yields various structures, mostly tetra- or penta-cyclic. 2,3-Oxidosqualene is also the precursor of plant steroids. In this case, it is cyclized to the triterpene cycloartenol, which is then converted to the compound cholesterol with the loss of three methyl groups. The oxygen of 2,3-oxidosqualene is usually retained as hydroxy group at C-3 in both triterpenes and steroids. 

All steroids are biosynthesized from the triterpene squalene, which is converted to an epoxide by the enzyme squalene 2,3-epoxidase. In mammals, this is converted to lanosterol by 2,3-oxidosqualene-lanosterol cyclase. You should find the first step of the process fairly easy to follow, as it is simply a cascade of electrophilic additions to double bonds. The next step is a cascade of rearrangements— come back and look at that again, once you have studied rearrangements in Chapter 18, as at this point, it may seem a bit mysterious (Figure 16.9). There are 7 stereocenters in lanosterol, which gives a potential for 128 stereoisomers, but a single stereoisomer is produced by the enzymatic reaction. 

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