2,3-Oxidosqualene formation

An example of this type is the highly stereoselective formation of lanosterol (0-6) from (S)-2,3-oxidosqualene (0-5) in Nature, which seems not to follow a concerted mechanism (Scheme 0.2) [9],... 

Fig. 5.1 Cyclization of 2,3-oxidosqualene to sterols and triterpenoids. The 2,3-oxidosqualene cyclase enzymes that catalyse the formation of the different products are indicated LS, lanosterol synthase CS, cycloartenol synthase LuS, lupeol synthase PAS, P-amyrin synthase aAS, a-amyrin synthase.

KUSHIRO, T., SHIBUYA, M., EBIZUKA, Y P-Amyrin synthase. Cloning of oxidosqualene cyclase that catalyzes the formation of the most popular triterpene among higher plants, Eur. J. Biochem., 1998,256,238-244. 

Theoretical evidence [Hartree-Fock (RHF) calculations and density functional theory] has been obtained for a concerted mechanism of oxirane cleavage and A-ring formation in oxidosqualene cyclization. A common concerted mechanistic pathway has been demonstrated for the acid-catalysed cyclization of 5,6-unsaturated oxiranes in chemical and enzymic systems. For example, the conversion of (24) into (26) proceeds via (25) and not via a discrete carbocation (27). Kinetic studies and other evidence are presented for various systems. 

Comparison of the amino acid sequences of OSCs that generate sterols and triterpenoids reveals a number of residues in addition to the DCTAE and QW motifs that are highly conserved in all classes. These residues may be required to open up the epoxide ring of 2,3-oxidosqualene, a catalytic step that is common to all of these enzymes [46]. Amino acid residues that are conserved exclusively in sterol OSCs or in triterpenoid OSCs maybe required for formation of the pro-tosteryl or dammarenyl cations, respectively. 

Hasserodt, J., Janda, K.D., and Lerner, R.A. (2000) Anibodies mimic natural oxidosqualene-cyclase action in steroid ring A formation, J. Am. Chem. Soc. 122, 40-45. 

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. 

Investigations with tissue cultures of Isodon japonicus using [l,2- C]acetate have been extended to the study of the formation of ring E of ursolic acid. Ruzicka s hypothesis for the cyclization of 2,3-oxidosqualene appears to hold for the ursanes (103) and (104) as indicated in Scheme 17, and routes involving the carbonium ion (105) can be excluded. 

The conversion of oxidosqualene 50 to lanosterol 52, the so-called squalene folding in the biosynthesis of steroids has initiated much research efforts (Scheme 10) [23]. This process is catalyzed by the enzyme lanosterol synthase, which controls precisely the formation of four rings and six new stereocenters. According to the pioneering work by Eschen-moser and Stork the cyclization proceeds in a concerted fashion due to favorable orbital overlap [24, 25]. In contrast Nishizawa et al. were able to trap several cationic intermediates 55-57 from a related model system 54... 

Scheme 11.74. The formation of (5 )-2,3-oxidosqualene from squalene in the presence of FADH2 and squalene monoxygenase (EC 1.14.99.7). After McMurry, J. Begley, T. The Organic Chemistry of Biological Pathways, Roberts Co., Englewood, CO, 2005,148 ff.

Steroids are derived from the same squalene precursor and have an oxygen-dependent biosynthetic pathway beginning with the formation of the first intermediate, 2,3-oxidosqualene (for details, see Sect. 5.1). Sterols, also known as steroid alcohols, are a subclass of steroids and may be found either as fi ee sterols, acylated, alkylated, sulfated, or linked to a glycoside moiety which can be itself acylated. Sterol biosynthesis is nearly ubiquitous among eukaryotes but almost completely absent in prokaryotes. As a result, the presence of diverse steranes (saturated four-cycle skeleton) in ancient rocks has been considered as evidence for over 2.7 billion years of eukaryotic evolution. Cholesterol is the most well-known sterol found in animal cell membranes (for establishing proper membrane permeability and fluidity) and red blood cells. 

Xiong, Q., Wilson, WK, and Matsuda, S.P. 2006. An Arabidopsis oxidosqualene cyclase catalyzes iridal skeleton formation by Grob fragmentation. Angew Chem Int Ed Engl 45 1285-1288. 

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