Trans-squalene oxide

Squalene is also an intermediate in the synthesis of cholesterol. Structurally, chemically, and biogenetically, many of the triterpenes have much in common with steroids (203). It has been verified experimentally that trans-squalene is the precursor in the biosynthesis of all triterpenes through a series of cyclization and rearrangement reactions (203,204). Squalene is not used much in cosmetics and perfumery formulations because of its light, heat, and oxidative instability however, its hydrogenated derivative, squalane, has a wide use as a fixative, a skin lubricant, and a carrier of lipid-soluble drugs. 

The two remaining reactions in the biosynthesis of lanosterol are shown in figure 20.9. In the first of these reactions, squalene-2,3-oxide is formed from squalene. As can be seen in figure 20.8, squalene is a symmetrical molecule, hence the formation of squalene oxide can be initiated from either end of the molecule. The oxide is converted into lanosterol. The reaction can be formulated as proceeding by means of a protonated intermediate that undergoes a concerted series of trans-1,2 shifts of methyl groups and hydride ions to produce lanosterol (see fig. 20.9). 

Johnson et al. used their newly developed orthoester Claisen reaction to achieve a highly stereoselective total synthesis of aM-trans squalene (5)1 (Scheme 1.20. The diene diol 6 underwent Johnson-Claisen rearrangement when it was heated with ethyl orthoacetate in the presence of propionic acid for 3 h at 138 C. The diene dialdehyde 7, obtained by treatment of the resulting ester with lithium aluminum hydride followed by oxidation with Collins reagent, reacted with 2-propenyllithium to give the tetraene diol 8. The tetraene dialdehyde 9, which... 

The reaction was used for the oxidation of 2,7-dimethyl-2,6-octadiene (12) to 2,7-dimethyl-/ranj,trans-2,6-octadiene-l,8-dial (13). This is a tail-to-tail a -trans bifunctional isoprenoid synthetic unit and was used in a convenient synthesis of a -trans squalene.5... 

The enzyme-catalyzed polycyclization of squalene 135 produces dammaradienol 138, which is known to be the precursor of cholesterol. In the process, squalene oxide is the intermediate, which adopts the conformation as shown in 137, and rearranges, under acid catalysis, to 138 [20, 21]. Note that in the transformations 131 —> 133 and 137 —> 138, many SN2 reactions take place in tandem for the sole reason of stereoelectronically driven well-organized geometrical orientations of the reacting functional groups. Note that all the double bonds are trans, and also that two such consecutive bonds are 1,5-related to each other. 

Epoxidation of squalene afforded a mixture of squalene 2,3-oxide along with the two trans internal oxides shown above. Controlled acidic hydrolysis allowed selective opening of the terminal epoxide moiety to a diol from which the desired internal oxides were readily separated by thiourea clathrate formation. 

The isoprenoid polyenes famesyl acetate, geranyl acetate and squalene underwent oxidative poly cyclisation to bis-, tris- and penta-tetrahydrofurans with RuO /aq. Na(IO )/CH3CN-EtOAc [185]-[188]. This oxidative polycyclisation of squalene with RuO was shown to lead to the cis-threo-cis-threo-trans-threo-trans-threo-trans penta-tetrahydrofuranyl diol product, this configuration being determined by 2D-NMR (Fig. 3.14) [185]-[188] cf mech. Fig. 1.8 [185]. 

The first example of the synthesis of a natural product by non-enzymic cyclization of a squalene derivative has been provided by Sharpless. Picric acid-induced cyclization of eryt/iro-18,19-dihydroxysqualene-2,3-oxide (18) resulted in the formation of a mixture of products from which ( )-malabaricanediol (19) could be isolated in 7% yield. The crythro-dihydroxysqualene oxide (18) was synthesized from squalene via the internal trans-oxide (20) and erythro-dio (21). The formation of the bromo-ether (22) permitted selective epoxidation of the other terminal double bond. Zinc dust reduction of (22) followed by mild alkaline... 

Valuable minor components Fat degradation products Contaminants Tocopherols, sterols, squalene, oryzanol Trans-fatty acids, polymeric and oxidized triacylglycerols, cyclic fatty acids Pesticides, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, dioxins, furans ... 

Although most attention has focussed on a cationic mechanism in the oxidative cyclization of squalene [20]. Breslow was concerned with the possibility that nature utilizes a free-radical pathway [21]. and studied the addition of benzoyloxy radical to trans, trani-famesyl acetate [22]. The benzoyloxy radicals generated by CuCl-catalyzed thermal decomposition and copper(II) benzoate was added to provide a termination mechanism. Excluding any intervention of a carbocationic process, Breslow obtained a tran -decalin compound (20 30% yield) bearing an exomethylene moiety. As pointed out by Breslow, despite a limited biochemical interest , this work evidenced a new synthetic reaction of considerable potential . An application shortly followed with the first example of a triple cyclization by Julia [23]. Triene isomers 40 were treated by benzoylperoxide in benzene and alforded after saponification alcohol 41 in 12% yield as a single diastereomer (relative stereochemistry confirmed by an X-ray analysis) with a similar tra 5-decalin system (A and B rings. Scheme 14). 

A second new synthesis of squalene utilizes the observation that selenium dioxide oxidation of gem-dimethyl olefins or cis- and truns-allylic alcohols yields stereospecifically traus-aj3-unsaturated aldehydes. The olefin (4) or a mixture of cis- and truus-diols (5) were transformed by use of selenium dioxide, followed by reduction, into the truns-allylic diol (6). The corresponding bromide (7) was used to alkylate two moles of the ylide from trans-geranyltributylphosphonium bromide leading eventually to all-traus-squalene in 46% yield [from the diol (6)]. Protection of one of the p-alcohol groups of (6) as the tetrahydropyranyl ether opens the possibilities of unsymmetrical coupling and the introduction of specifically labelled fragments. 

Miscellaneous Reactions of Oxirans.—The first successful enzymatic cyclization of a non-natural squalene has been disclosed. (18Z)-Oxidosqualene (188), which does not possess the naturally occurring a -trans stereochemistry, was caused to cyclize, in the presence of 2,3-epoxysqualene sterol cyclase, to (205)-epinorlanosterol (189). The polyene oxide (190) underwent an uncommon tricyclization in CH2CI2 containing Bp3-OEt2 to form the cw-fused A/B-ring 18-nor-steroid (191) (25%) this compound was found to be identical with a material derived by treatment of a naturally occurring steroid with BF3. 

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