Squalene Stability

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. 

Recently, nonionic ortho ester surfactants have been used as emulsifiers for squalene, a polar oil [65]. In this case a polymer is used together with the surfactant. The emulsification is made under acidic conditions, and the surfactant breaks down rapidly after the emulsion is formed, leaving a surfactant-free, polymer stabilized emulsion with reasonable stability. 

There are several reports for successfully prolonged release of short half-life drugs with squalene emulsions. Wang et al. (2008) reported that a squalene emulsion stabilized by phosphatidylethanolamine or pluronic F68 prolonged in vitro release of a morphine prodrug. Intravenous... 

In view of the synthetic applications, among carbanions stabilized by only one divalent sulfur atom, allylic thiocarbanions proved to be particularly valuable, as shown with Biellmann coupling of allylic groups, applied to an elegant synthesis of squalene from farnesyl bromide [301]. In this synthesis, the retention of the allylic double bond position and stereochemistry in both the metallation-alkylation and the desulfurization steps are noteworthy. However, the results are not always as clear-cut, and... 

The stabilized carbanion a to a sulfonyl group has been used mainly for carbon-carbon bond-forming purposes by reactions with electrophiles [109, 110, 386]. Their importance is based on the efficiency of their preparation, of their use particularly for alkylation procedures and on the elaboration of reliable methods for sulfonyl group elimination. One example is shown here, with a synthesis of fl//-trans-squalene [396] close to the Biellman synthesis (see Section 4.2.1.4). 

If sterol content and conformation are so important for membrane stability, we should study the biosynthesis of sterols (Figure 3). The first enzyme in terpenoid biosynthesis is the 3-Hydroxy-3-Methyl-Glutary1-Coenzyme A-reductase (HMG-CoA-reductase) that catalyzes the synthesis of mevalonate. Two phosphorylations and decarboxylation of mevalonate lead to isopentenylpyrophosphate, the basic C -unit in sterol synthesis. Isopentenylpyrophosphate reacts with its isomer, the dimethylally1-pyrophosphate, in a head/tail-reaction to geranyl-pyrophosphate reaction with another C -unit leads to farnesyl-pyro-phosphate, that dimerizes in a tail/tail-reaction to squalene. After expoxidation of its A -double bond, squalene cyclizes to lano-... 

Approximately 0.5% of crude coconut oil is not saponified by caustic treatment. The unsaponifiable matter consists mainly of tocopherols, sterols, squalene, color pigments, and carbohydrates. The odor and taste of coconut oil is largely due to 5- and y-lactones, which are present in trace quantities (24). Among the unsaponifi-ables, tocopherol contributes to the oxidative stability of crude coconut oil. A typical sample of crude coconut oil contained 55 ppm total tocopherols of which 40.7 ppm is cx-tocopherol (25). Most of the unsaponifiables are removed in the process of refining, bleaching, and deodorizing of crude coconut oil. 

Transformation products of 16b contribute to some extent to the antioxidant effect. The dimer 103 is a weak AO in squalene [106] and in fish oil [98], The nitroxide 108 stabilizes fish oil, if present at a relatively high concentration (0.1%) [105], Its effect is not significant at lower concentrations. QI 105 was a weak retarder in oxidized fish oil [98] and decane [103]. It may be anticipated that other QI arising from 16 contribute similarly to the stabilization effect. A transient formation of the respective hydroxylamines is theoretically possible after hydrogen abstraction from a donor by 108 according to Eq. (8) or after thermolysis of the respective O-alkylhydroxylamine (an analogy to the process shown in Scheme 7). Their contribution to the stabilization effect is certainly not important, as revealed by a model study with NOH derived from 16b. It is very unstable and disproportionates to the parent 16b and nitroxide 108 [5,101]. 

In order to achieve long term stability in society, industry should focus on renewable sources both as raw material and as process chemicals. Therefore, renewable raw material has been searched for to give a source of squalene, for example olive oil (5,6) and amaranth seed oil (7,8). Another component of interest in olive oil pomace is a-tocopherol, which is traditionally considered as the major antioxidant of olive oil. 

Squalene has been shown to possess moderate antioxidant properties (Manzi et al. 1998) but loss during storage of the oil in the dark is greater than that of (3-tocopherol. According to Psomiadou and Tsimidou (1999), squalene plays only a limited role in olive oil stability. 

The stationary phases used in reversed-phase chromatography, when it was first introduced, comprised of a non-polar substance (e.g. squalene) coated on to a silica-based support. These are now seldom used. The stability of such systems is low, because the forces holding, say, squalene to even a silylated silica are so weak that the stationary phase is easily washed from the column. A compromise reversed-phase packing material was developed, which had a polymeric hydrocarbon stationary phase on the support, but although quite successful it has now been superseded by a chemically bonded stationary phase of which some examples are discussed below. 

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