Squalene cyclizations

Exercise 30-16 An ingenious and highly practical synthetic procedure for forming the steroid ring system has been developed by W. S. Johnson that closely mimics the squalene cyclization without the need for enzymes. The cyclizations occur by carbocationic intermediates under rather strictly defined conditions that are designed to prevent the reactants from being diverted to nucleophilic substitution or elimination... 

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-... 

How does squalene cyclize to lanosterol so that the very odd labelling pattern can be achieved ... 

In stage three, squalene cyclizes in an astounding reaction and the tetracyclic product is subsequently converted into cholesterol. 

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.

As shown by HV scan spectra, the only origin for this ion is the molecular ion. Under these conditions, the reverse of squalene cyclization in sterol biosynthesis could be produced and followed by the migration of H (17-OH) during decomposition, to yield the m/z 110, 162 and 231 ions, such as Figure 45 indicates. 

Squalene Cyclization.—Squalene epoxidase from rats needs a supernatant protein fraction for full activity. However, this fraction does not seem to correspond to the sterol carrier proteins mentioned above. It is a heat-labile molecule with a molecular weight of about 44 000. A 2,3-dioxetan derivative of squalene has been suggested as an intermediate in this oxidation. " ... 

Reaction of A with aqueous NaOH (1 equivalent, cold) gives B, CsHsO (no 3590-3650-cm infiared absorption). (See the squalene cyclization discussion in The Chemistry of... Cholesterol Biosynthesis in WileyPLUS for a hint.)... 

A, Formation of Cyclic 3 Deoxytriterpenes from Squalene, In some groups of procaryotes squalene cyclization begins with the enzyme-mediated addition of a proton to one of the terminal double bonds. In a concerted mechanism a C-21 cation is formed, which may stabilize through acquisition of a hydroxyl ion by formation of tetrahymanol ... 

A comprehensive rationale for structural and stereochemical outcome of squalene cyclization in terms of conformation dictated by the cyclase has been build up by the Zurich school. It provides a convenient basis for discussing various triterpene structures (263, 323). These conformations are described in terms of section-wise folding of the squalene chain into a chair (C), or boat (B) conformation or a part remaining unfolded (U). The following discussion of triterpenoids relevant to wood chemistry is based on these considerations. 

Triterpenes are synthesized via the MVA pathway from two molecules of FPP that are joined by tail-to-tail condensation to squalene. Cyclization of its metabolite 2,3-oxidosqualene followed by rearrangements and methyl shifts yields various structures, mostly tetra- or penta-cyclic. 2,3-Oxidosqualene is also the precursor of plant steroids. In this case, it is cyclized to the triterpene cycloartenol, which is then converted to the compound cholesterol with the loss of three methyl groups. The oxygen of 2,3-oxidosqualene is usually retained as hydroxy group at C-3 in both triterpenes and steroids. 

The use of inhibitors acting after squalene cyclization, such as triparanol, the azasterols mentioned above, and AY-9944 (an inhibitor of 7-dehydrocholesterol-A -reductase see Fig. 1) has no practical advantages the decreased cholesterol formation is accompanied by accumulation of steroidal precursors, which are believed to be as atherogenic as cholesterol itself. 

Squalene Cyclization. A bacterial squalene cydase has been firstly characterized in a cell-free system from an Acetobacter species (28). This enzymic activity has been reported later from several other bacteria (29). More recently the enzyme has been isolated from Alicyclobacillus acido-caldarius (30), Rhodopseudomonas palustris (31) and Zymomonas mobi-... 

AMO 1618 (Figure 4.9), an inhibitor of squalene cyclization and kaurene synthetase, is also an inhibitor of lycopene cyclization when used at high concentrations with the Aphanocapsa cell-free system. ... 

Mulheirn, T. j., and E. Caspi Mechanism of Squalene Cyclization. The Biosynthesis of Fusidic Acid. J. Biol. Chem. 246, 2494 (1971). 

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