Squalene synthesis

Sponge sesquiterpenes H NMR, 4, 560 Squalene synthesis, 1, 469 Squalene oxide occurrence, 7, 119 Squamalone... 

Farnesylamine (123) (Fig. 20), a sesquiterpene alkaloid, was recently detected in whole extracts of Monomorium fieldi [129]. This compound had already be prepared by synthesis and found to display a whole range of biological activities. Among others, it inhibits arthropod molting, squalene synthesis, and the growth of malignant tumor cells, modulates human T cells and has anti-osteo-porosis activity [129]. 

Rl. Rilling, H. C., The effect of sterol carrier protein on squalene synthesis. Biochem. Biophys. Res. Commun. 46, 470-475 (1972). 

FPP is necessary for the synthesis of both sterols and longer chain nonsterol isoprenoids. The first committed step in sterol synthesis is catalyzed by the enzyme squalene synthesis and involves the head-to-head condensation of two FPP molecules to form squalene [15]. This is followed by cyclization steps, leading to sterol synthesis. The addition of IPP to FPP via the enzyme GGPP synthase yields the 20-carbon GGPP [16]. FPP and GGPP are substrates in the prenylation reactions catalyzed by the enzymes farnesyl transferase (FTase) and geranylgeranyl transferase (GGTase) I and II [17-20]. 

BertoUno A, Altman LJ, Vasak J, Rilling HC. Polyisoprenoid amphiphiUc compounds as inhibitors of squalene synthesis and other microsomal enzymes. Biochem. Biophys. Acta -Lipids and Lipid Metab. 1978 530 17-23. 

Figure 26.10. Squalene Synthesis. One molecule of dimethyallyl pyrophosphate and two molecules of isopentenyl pyrophosphate condense to form famesyl pyrophosphate. The tail-to-tail coupling of two molecules of famesyl pyrophosphate yields squalene.

Allylic sulfides can be coupled with allylic bromides in a process which was first described by Biellmann and applied to the squalene synthesis. Famesyl sulfide was prepared from 2,4-dinitrophenylfar-nesyl oxide and benzenethiolate. Finally, the allylic thiocarbanion was coupled with famesyl bromide to give, in 82% yield, squalene sulfide, easily transformed to squalene with Li tNH2 (Scheme 32). 

The addition of a carbene or benzyne to a sulfide, and to a lesser extent to an amine, provides a direct route to ylides. Enormous progress has been realized with this approach, mainly as a result of the efforts of Ando and Doyle. Most noteworthy amongst examples using benzyne is die squalene synthesis reported by Ollis, in which the sulfide (55) was transformed by a 3,2-rearrangement into the squalene precursor (58) and eventually into squalene itself (Scheme The stereospecific rearrangement of cjco-methylenecyclohexane derivatives discovered by Evans employed dichlorocarbene, generated under phase transfer conditions (Scheme 15). ... 

One of the landmarks in the early use of the 3,2-rearrangement of sulfur ylides is the squalene synthesis reported by Ollis and already discussed in Section 3.10.4. This approach used benzyne to generate the ylidic intermediate. Frequently, however, benzyne produces a mixture of products (Scheme 38). The sulfide (168) may be formally regarded as the expected 3,2-sigmatropic rearrangement product, whereas (169) results from a competitive 1,4-rearrangement. Use of carbenes instead of benzyne gener-... 

Nicolaides, N., and Rothman, S., The site of sterol and squalene synthesis in the human skin. J. Invest. Dermatol. 24, 125-129 (1955). 

Presqualene pyrophosphate (32), a compound whose structure has caused considerable controversy in the past, has been isolated from intact rat liver and a yeast microsomal system. Previously, (32) had been detected only in systems which have been starved of NADH and hence the new findings demonstrate that (32) is not an artefact. Despite earlier evidence that lycopersene is a precursor of phytoene, a recent stereochemical analysis of phytoene synthesis makes this appear to be unlikely, and a mechanism has been proposed for the synthesis of cis- and tmnj -phytoene directly from pre-phytoene pyrophosphate (33) (Scheme 7). This mechanism is similar to one proposed for squalene synthesis. ... 

One protein is required for squalene synthesis, but two catalytic sites may be involved one for the synthesis of pre-squalene pyrophosphate and one for the reduction of this compound to squalene (Sasiak and Rilling, 1988). Although the enzyme is membrane bound by the carboxyl terminal domain, the catalytic domain apparently is free in the cytosol (Zhang et al., 1993). Squalene synthase isolated by detergent treatment from daffodil microsomal membranes was activated after the first step of purification by liposomes of phosphatidylcholine (Berlingheri et al., 1991). 

The first steps of the [ C]squalene synthesis resemble the pathway selected for the synthesis on [3 - C]coenzyme QIO 13061 (Figure 6.84). In this case alkylation with solanesyl bromide (3011 and subsequent hydrolysis and decarboxylation of the ester function converted ethyl [3- C]acetoacetate into [2- C]solanesylacetone 302. Chain extension of 302 in a Homer-Wadsworth-Emmons reaction, reduction of the resulting a,/3-unsatu-rated ester 303 and coupling of the resulting alcohol ([3- C]decaprenol, 3041 to 2-methyl-5,6-dimethoxy-1,4-hydroquinone (3051 provided the coenzyme in an overall radiochemical yield of 8% after oxidation. Methodologically comparable pathways have also been published for the synthesis of [5- C]farnesylacetic acid and [3 - C]menaquinone . 

---