Cyclization of oxidosqualene

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

CYCLIZATION OF 2,3-OXIDOSQUALENE - THE FIRST COMMITTED STEP IN TRITERPENOID BIOSYNTHESIS... 

Triterpenoid saponins are synthesized via the isoprenoid pathway.4 The first committed step in triterpenoid saponin biosynthesis involves the cyclization of 2,3-oxidosqualene to one of a number of different potential products (Fig. 5.1).4,8 Most plant triterpenoid saponins are derived from oleanane or dammarane skeletons although lupanes are also common 4 This cyclization event forms a branchpoint with the sterol biosynthetic pathway in which 2,3-oxidosqualene is cyclized to cycloartenol in plants, or to lanosterol in animals and fungi. 

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.

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. 

Cyclization of 2,3-Oxidosqualene - The First Committed Step in Triterpenoid Biosynthesis... 

Abe I, Rohmer M and Prestwich GD (1993) Enzymatic cyclization of squalene and oxidosqualene to sterols and triterpenes. Chem Rev 93, 2189-2206. 

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... 

The following syntheses of natural products were based on the use of substo-ichiometric quantities of Cp2TiCl to catalyze different cyclization processes initiated by homolytic epoxide opening. They have been classified according to the type of cyclization process employed. Section 4.4 has been reserved for the Cp2TiCl-catalyzed radical cyclization of 2,3-oxidosqualene due to the biological importance of this terpenoid and steroid precursor. 

In this context, Hoshino et al. have recently reported the cyclization of (3S)-2,3-oxidosqualene catalyzed by a Gly600-deletion mutant (AG600SHC) of the enzyme squalene-hopene cyclase (SHC) from Alicyclobacillus acidocal-darius (Scheme 31) [108]. The enzymatic biotransformation gave monocyclic (9) and tricyclic triterpenoids (38 and 44-47), but no detectable bicychc products [108]. Despite the authors biogenetic proposal of a conventional carbocationic pathway, the skeletal profile of products reported closely resembles that expected for a radical-type cyclization. 

Cyclization of Squalene.—Marked differences have been found between specir mens of the enzyme 2,3-oxidosqualene cyclase isolated from yeast and hog liver. In the former organism the enzyme was in the soluble fraction, whereas in the latter it was associated with the microsomes. Further studies of unnatural precursors showed that a preformed steroidal ring-D (65) gave in low yield the corresponding lanosterol analogue (68). Similarly, 6-demethyl-2,3-oxido-squalene (66) was efficiently used and gave 19-norlanosterol (69). ... 

The biosynthesis of triterpenes by photosynthetic organisms proceeds via cyclization of 2,3-oxidosqualene (92) to yield cycloartenol (93), in contrast to non-photosynthetic organisms where the cyclization product is lanosterol (94) The last step in this... 

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. 

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.

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