Squalene, epoxidation

Squalene epoxidation Squaraine Square 50 Square 80 Square permalloy Square Permalloy 80 Squaric acid [2892-51-5]... 

Squalene epoxidase, a key enzyme in the biosynthesis of cholesterol (9), epoxidizes one face of one of the three different olefins in squalene (7) to give squalene epoxide (8), which then cyclizes eventually to give cholesterol (9) (Scheme 1). The AD of squalene (7)... 

All 27 carbon atoms of cholesterol are derived from acetyl Co A. First acetyl CoA and acetoacetyl CoA combine to form HMG CoA which, in turn, is reduced to mevalonate by HMG CoA reductase. Mevalonate is converted into the five-carbon isoprene compounds 3-isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate. These two compounds condense to form the CIO geranyl pyrophosphate, which is elongated to the C15 farnesyl pyrophosphate by the addition of another molecule of isopentenyl pyrophosphate. Two molecules of farnesyl pyrophosphate condense to form the C30 squalene, which is then converted via squalene epoxide and lanosterol to cholesterol. 

Squalene is then converted into squalene epoxide in a reaction that uses 02 and NADPH (Fig. 2b). The squalene epoxide cyclizes to form lanosterol, and finally cholesterol is formed from lanosterol by the removal of three methyl groups, the reduction of one double bond by NADPH, and the migration of the other double bond (Fig. 2b). 

In polyenes even tandem additions are possible. The best known and the most impressive example is the biosynthesis of steroid structures from squalene or squalene epoxide (Figures 14.12 and 14.13). The corresponding biomimetic syntheses of the steroid structure are simply beautiful. 

Cyclization of squalene epoxide begins with the acid-catalyzed opening of the epoxide. Each additional cyclization step forms another carbocation. 

Figure 1.7 illustrates the synthesis of sterols in yeasts. Basically, sterols are synthesised by the mevalonate pathway. The key stage in this pathway is, without any doubt, the reaction catalysed by squalene monooxygenase. This reaction, which uses oxygen as substrate, transforms squalene into squalene 2,3, epoxide. Later, squalene epoxide lanosterol cyclase catalyses the synthesis of the first sterol of the pathway. 

Squalene oxidases enantiospecifically and regiospecifically epoxidize the terminal double bond of squalene 1 to give (31S )-squalene epoxide 258. This, in turn, is the precursor of triterpenes and sterols (e.g., 3) in both plants and animals. Squalene oxidases are found in higher forms of life with the probable exception of insects and terrestrial annelids. They are also present in algae and other lower forms with the possible exception of some bacteria. The enzyme system requires molecular oxygen, NADPH and FAD as well as supernatant protein and phospholipids. There is no evidence for the participation of cytochromes P-450. 

Figure 26.11. Squalene Cyclization. The formation of the steroid nucleus from squalene begins with the formation of squalene epoxide. This intermediate is protonated to form a carbocation that cyclizes to form a tetracyclic structure, which rearranges to form lanosterol.

Although cycloartenol (44) belongs to the tetracyclic triterpenoids as the parent compound, it is implicated as an important biosynthetic intermediate both in that class and in plant steroids and is thus a relevant introduction to the latter group which have been so significant in semi-synthetic applications. Following the enzyme-catalysed cyclisation of squalene epoxide, it is the first intermediary compound encountered and in the plant series it has a comparable position to lanosterol (45) in the animal... 

A comparison of the efficiency of the 2,3-oxidosqualene cyclase from human placenta microsomes with that from rat liver microsomes has led to the conclusion that in human placenta the conversion of squalene into lanosterol is limited by the rate of squalene epoxidation. Tracer from [l- C]-2,3-oxidosqualene was incorporated into cycloartenol (1% yield) by a cell-free system from Alnus glutinosa but none of the triterpenoid glutinone was synthesized from the labelled precursor. When 2,3-oxidosqualene was incubated with cell-free extracts from corn embryos the only product was cycloartenol, whereas when l-trarts-T-nor-2,3-oxidosqualene (9) was the substrate both 31-norcycloartenol and 31-norlanosterol were formed " l-c/s-T-nor-2,3-oxidosqualene (10) gave rise to no detectable cyclization products... 

Although Pt-alkene complexes are normally not as reactive as the corresponding Pd complexes toward nucleophilic addition, platinum can serve usefully as a catalyst in these reactions.59 The following cyclization was mediated by a Pt-PPP-pincer complex 22, demonstrating Markovnikov addition at each step of the cyclization (equation 8.42).60 The reaction is stereoselective and mimics the cyclization of squalene epoxide to lanosterol, a key step in the biosynthesis of cholesterol. 

The ergosterol (45) biosynthesis in fungi and leishmania utilizes squalene (41) as starting material, which is obtained from long chain precursors like farnesyl pyrophosphate (39) and presqualene pyrophosphate (40). Epoxidation of squalene in the presence of squalene epoxidase furnishes squalene epoxide (42), which is succes-... 

Since ergosterol is used in the formation of the leishmanial cell membrane, inhibition of ergosterol biosynthesis has been considered as a useful target for chemotherapeutic attack. Allylamines (eg. terbinafine) and imidazole antifungals (eg. ketoconazole) have been found to interfere with different steps in the biosynthetic pathway of C28 sterols in leishmania and fungi. Allylamines inhibit the microsomal squalene 2,3-epoxidase and, therefore, inhibit the synthesis of squalene epoxide, the precursor of lanosterol. Imidazoles, on other hand, inhibit cytochrome P-450 dependent C-14 demethylation of lanosterol leading to decreased or no synthesis of ergosterol [30]. 

The final stage of cholesterol biosynthesis starts with the cyclization of squalene (Figure 26.11). Squalene is first activated by conversion into squalene epoxide (2,3-oxi-dosqualene) in a reaction that uses O2 and NADPH. Squalene epoxide is then cyclized to lanosterol by oxi-dosqualene cyclase. This remarkable transformation proceeds in a concerted fashion. The enzyme holds squalene epoxide in an appropriate conformation and initiates the reaction by protonating the epoxide oxygen. The carbocation formed spontaneously rearranges to produce lanosterol. Lanosterol is converted into cholesterol in a... 

---