Cyclization of squalene

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

Pentacyclosqualene, the symmetrical hydropicene corresponding to squalene, has not been made by acid-induced cation-olefin cyclization of squalene, despite considerable experimental study. A simple, convergent synthesis of pentacyclosqualene using cation-olefin cyclization to generate ring C was developed. The Cjo-framework was constructed by radical coupling to a tetracyclic intermediate that was also used for the synthesis of onoceradiene. 

In 1953, Bloch, together with the eminent organic chemist R. B. Woodward, proposed a new scheme (see figure, part b) for the cyclization of squalene. (Together with Fyodor Lynen, Bloch received the Nobel Prize in medicine or physiology in 1964 for his work.) The picture was nearly complete, but one crucial question remained How could isoprene be the intermediate in the... 

Scheme 1, Enzyme-induced cyclizations of squalene oxide (2) (a) and the Stork-Eschenmoser hypothesis (b).

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

As described earlier, the dichotomy at the point of squalene (26) cyclization has been used as a distinguishing feature of photosynthetic and non-photosynthetic organisms [1], Cycloartenol (32) is the primary cyclization product in the former group, while in the latter, lanosterol (33) is initially produced (Scheme 2). Recent investigations into the cyclization of squalene in marine organisms have provided interesting results. 

As described above, the cyclization of squalene oxide is a biosynthetic branching point not only for phytosterols and triterpenes but also for dammarane- and oleanane-type ginsenosides. In ginseng, the enzyme... 

Synthesis takes place in four stages, as shown in Figure 21-33 (D condensation of three acetate units to form a six-carbon intermediate, mevalonate (2) conversion of mevalonate to activated isoprene units (3) polymerization of six 5-carbon isoprene units to form the 30-carbon linear squalene and ( ) cyclization of squalene to form the four rings of the steroid nucleus, with a further series of changes (oxidations, removal or migration of methyl groups) to produce cholesterol. 

Basic scheme for cholesterol biosynthesis proposed by Bloch in 1952 (left) and scheme proposed for the cyclization of squalene by Woodward and Bloch in 1953 (right). 

Cyclization of squalene is via the intermediate squalene-2,3-oxide (Figure 5.55), produced in a reaction catalysed by a flavoprotein requiring O2 and NADPH cofactors. If squalene oxide is suitably positioned and folded on the enzyme surface, the polycyclic triterpene structures formed can be rationalized in terms of a series of cycliza-tions, followed by a sequence of concerted Wag-ner-Meerwein migrations of methyls and hydrides... 

Abe I, Rohmer M and Prestwich GD (1993) Enzymatic cyclization of squalene and oxidosqualene to sterols and triterpenes. Chem Rev 93, 2189-2206. 

Next, follow the path of the 14C-enriched carbons in the cyclization of squalene 2,3-epoxide to lanosterol. 

The CYCLIZATION OF SQUALENE OXIDE TO LANOSTEROL. Test yourself on the concepts in this figure at OrganicChemistryNow. 

Cyclization of Squalene Oxide to Lanosterol Section 28.5 Figure 28.7... 

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

Although cyclization of squalene-2,3-epoxide is controlled by an enzyme, its mechanism is similar to the acid-catalyzed opening of other epoxides. The epoxide oxygen becomes protonated and is attacked by a nucleophile. In this case, the nucleophile is a pi bond. The initial result is a tertiary carbocation (Figure 14-7). 

The following reaction resembles the acid-catalyzed cyclization of squalene oxide. Propose a mechanism for this reaction. 

Figure 25-13 shows that cholesterol is a triterpenoid, formed from six isoprene units with loss of three carbon atoms. The six isoprene units are bonded head to tail, with the exception of one tail-to-tail linkage. The triterpene precursor of cholesterol is believed to be squalene. We can envision an acid-catalyzed cyclization of squalene to give an intermediate that is later converted to cholesterol with loss of three carbon atoms. Possible mechanisms are outlined in Figures 14-6 and 14-7 (pages 651-652). 

The final stage of the biosynthesis of cholesterol requires molecular oxygen, and the chain of squalene is cyclized to produce the primary steroid lanosterol, which is subsequently modified to cholesterol. The cyclization of squalene is shown in Fig. 13-23. 

The full details of the synthesis and resolution of presqualene and prephytoene alcohols and the stereochemistry of the non-oxidative cyclization of squalene to tetrahymanol by Tetrahymena pyriformis have appeared (see Vol. 9, p. 187). 

Cyclization of Squalene-like Substrates. Ultrasonically stimulated BY is a source of sterol cyclase, which catalyzes the cyclization of squalene oxide and squalenoid compounds to lanos-terol derivatives (eq 13). ... 

Cyclization of squalene oxide yields a carbocation, called the protosterol cation. This reaction results in the formation of four new C—C bonds and the tetracyclic ring system. 

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