Oxidosqualene cyclizations

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. 

The principle underlying the ring-closure reaction and the structure of 47 is reminiscent of the natural biosynthetic pathway for steroids.16 In the latter case 2n3-oxidosqualene cyclizes under enzymatic control to lanosLerof a tetracyclic precursor of cholesterol. 

Scheme 31 2,3-Oxidosqualene cyclization catalyzed by a mutated enzyme [108]...

The 2,3-oxidosqualene cyclization reaction is one of particular Interest as a fungicide target since it is quite complicated and involves more than one TS or HE intermediate. It is surprising that more Inhibitors of the enzyme catalyzing this reaction have not been synthesized. A point of interest is the unusual overlap of specificity of 1-dodecyclimidazole (Figure 2) a an inhibitor of sterol C-14 demethylation and 2,3-oxidosqualene cyclization (12.323. The simple aliphatic substituent of this Imidazole may allow the compound to act as a TS analogue of 2,3-oxldosqualene and also to bind to the sterol C-14 demethylase and interact with the heme iron. A similar overlap of specificity... 

Questions of Evolution and Mechanistic Enzymology. The diversity and complexity of oxidosqualene cyclization reactions inspire a series of questions related to molecular evolution and mechanistic enzymology ... 

Figure 3. Johnson model for oxidosqualene cyclization. Shown are the proposed chair-boat-chair conformation of the substrate in the enzyme active site, the general acid initiating residue (AH ) and axial negative point charges (arrows).

The second part of lanosterol biosynthesis is catalyzed by oxidosqualene lanosterol cyclase and occurs as shown in Figure 27.14. Squalene is folded by the enzyme into a conformation that aligns the various double bonds for undergoing a cascade of successive intramolecular electrophilic additions, followed by a series of hydride and methyl migrations. Except for the initial epoxide protonation/cyclization, the process is probably stepwise and appears to involve discrete carbocation intermediates that are stabilized by electrostatic interactions with electron-rich aromatic amino acids in the enzyme. 

Despite the broad medical potentials reported so far, the total synthesis of triterpene QMs is yet to be reported. On the contrary, the biosynthesis of triterpene QMs has recently been validated as from the oxidosqualene 88 (Scheme 8.16) in the plants including Maytenus aquifolium and Salacia campestris.10S With the assistance of HPLC analysis and isotopic labeling, it was found that triterpene QMs 90 were formed only in the root of these plants from friedelin 89 and similar cyclized intermediates, which were synthesized in the leaves from oxidosqualene by cyclase. 

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.

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. 

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