Squalene

By means of experiments utilizing stereospecifically deuterated and tritiated precursors, it has been established that two molecules of trans, trans-fsLYYiQsyl pyrophosphate (112b) are incorporated into squalene in an unsymmetrical fashion. Thus, a pro (S) hydrogen from Ci of one farnesyl component is removed in the reaction and replaced with a 

The biosynthesis of phytoene (296c), the parent of the carotene family, also proceeds via a cyclopropane intermediate referred to as prephytoene pyrophosphate (113c) (772, 379). Phytoene is derived from (113c) by the same rearrangement sequence, the termination step being proton elimination instead of hydride transfer. 

It is relevant to discuss briefly at this point the stereochemistry and mechanism of the cyclopropylcarbinyl-cyclobutyl-homoallyl rearrangements. Solvolysis of cyclopropylcarbinyl, cyclobutyl, and homoallyl derivatives bearing stereospecific labels or substituents lead to rearranged products in which the stereochemical relationships in the starting material are retained (74—76). The stereochemistry is illustrated below with the hydrolysis of specifically deuterated cyclopropylcarbinyl methanesulfonate 

302-OMs which affords the c4-products shown with 97+4% stereospecificity ( 90% specificity in the case of the 4-butenols) (75).  

It is significant that trans-cyc obuty tosylate 298-OTs is much more reactive in solvolysis than its cis isomer (k trans l ds = 250) (380, 381) as is commonly the case with 3-substituted cyclobutyl sulfonates (76). The 

Mevalonate kinase [E.C.2.7.1.36 (5) - (6)] preparations from several plants are inhibited by geranyl, geranylgeranyl, farnesyl, and phytyl pyrophosphates, the most potent inhibitors being the latter two compounds.This enzyme may, therefore, be a control point of isoprenoid biosynthesis in plants. A cell-free system for conversion of mevalonic acid (5) into mevalonic acid S-pyro-phosphate (7) has been prepared from the sapogenin-producing plant Agave americana.  

Hemming, in Natural Substances Formed Biolt ically Irom Mevalonic Acid. Biochemical Society Symposium No. 29, ed. T. W. Goodwin, Academic Press, London and New York, 1970 p. lOS R Bentley, Molecular Asymmetry in Biology , Academic Press, New York, 1970, vol. 2, p. 316. 

Jedlicki, G. Jacob, F. Faini, and O. Cori, Arch. Biochem. Biophys., 1972,1S2, 590. 

Specificity of farnesyl pyrophosphate synthetase from pumpkin fruit with regard to the allylic pyrophosphate revealed that disubstitution at C-3 is 

The intermediacy of presqualene pyrophosphate (24) in the conversion of farnesyl pyrophosphate (11) into squalene (12) has been established in yeast and rat liver. Formation of (24) from mevalonic acid by a cell-free system from 

Molecular formula C30H50 Molecular weight 410.72 CAS Registry No 111-02-4 Merck Index 13,8847 

Sample preparation Centrifuge cell culture at 2772 g at 4° for 20 min, extract the supernatant with diethyl ether. Evaporate the extracts to dryness, reconstitute the residue with n-propanol, inject an aliquot. 

HPLC VARIABLES Column Nucleosil-100 C18 Mobile phase n-Propanol Flow rate 0.5 

Berekaa, M.M. Steinbtlchel, A. Microbial degradation of the multiply branched alkane 2,6,10,15,19,23-hexamethyltetracosane (squalane) by Mycobacterium fortuitum and Mycobacterium raUsbonense, Appl.Environ.Microbiol., 2000, 66, 4462-4467. 

Sample preparation Mix 500 mg solid food or milk powder, 5 g liquid milk, or 

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Farnesol pyrophosphate is an immediate precursor of squalene, the key intermediate in steroid and triterpenoid biogenesis, which arises from the coupling of two farnesol pyrophosphate molecules or of C,s units derived therefrom. The numerous types of sesquiter-penoid carbon skeletons represent various modes of cyclization of farnesol (sometimes with rearrangement) and it is probable that farnesol pyrophosphate is also the source of these compounds. 

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). 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

A prominent example of such a reaction is the biological epoxidation of the poly ene squalene... 

The reactivity of epoxides toward nucleophilic ring opening is responsible for one of the biological roles they play Squalene 2 3 epoxide for example is the biological... 

Tail to tail linkages of isoprene units sometimes occur especially m the higher terpenes The C(12)—C(13) bond of squalene unites two C15 units m a tail to tail man ner Notice however that isoprene units are joined head to tail within each C15 unit of squalene... 

FIGURE 26 10 The biosyn thetic conversion of squa lene to cholesterol proceeds through lanosterol Lano sterol IS formed by enzyme catalyzed cyclization of the 2 3 epoxide of squalene... 

Section 26 11 The triterpene squalene is the biosynthetic precursor to cholesterol by the pathway shown in Figure 26 10... 

Fritting From squalene Frontal Frontal chromatography Frontalin [28401-39-0] Froth Froth ers... 

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

The trimer famesyl pyrophosphate (35), in addition to serving as a pregenitor of steroids via squalene (114), is also the pregenitor of the compounds known as sesquiterpenes. It has been suggested that famesyl pyrophosphate (88) similarly serves as the carbon backbone of alkaloids such as deoxynuphatidine (120) ftom Nupharjapomcum (Nymphaceae) (water hhes) and dendrobine (121) Dendrobium nobikl indl. (Orchidaceae) (Table 11). 

Whereas dimerization of two famesyl pyrophosphates (35) generates squalene (114) on the path to steroids (89), the addition of one more C unit, as isopentenyl pyrophosphate (31) or its isomer, 3,3-dimethyl ally pyrophosphate (32), to the C compound famesyl pyrophosphate produces the C2Q diterpene precursor geranylgeranyl pyrophosphate [6699-20-3] (122). 

The path from squalene (114) to the corresponding oxide and thence to lanosterol [79-63-0] (126), C qH qO, cholesterol [57-88-5] (127), and cycloartenol [469-38-5] (128) (Fig. 6) has been demonstrated in nonphotosynthetic organisms. It has not yet been demonstrated that there is an obligatory path paralleling the one known for generation of plant sterols despite the obvious stmctural relationships of, for example, cycloartenol (128), C qH qO, to cyclobuxine-D (129), C25H42N2O. The latter, obtained from the leaves of Buxus sempervirens E., has apparentiy found use medicinally for many disorders, from skin and venereal diseases to treatment of malaria and tuberculosis. In addition to cyclobuxine-D [2241-90-9] (129) from the Buxaceae, steroidal alkaloids are also found in the Solanaceae, Apocynaceae, and LiUaceae. 

IPP react with each other, releasiag pyrophosphate to form another allyl pyrophosphate containing 10 carbon atoms. The chain can successively build up by five-carbon units to yield polyisoprenes by head-to-tad condensations alternatively, tad-to-tad condensations of two units can yield squalene, a precursor of sterols. Similar condensation of two C2Q units yields phytoene, a precursor of carotenoids. This information is expected to help ia the development of genetic methods to control the hydrocarbon stmctures and yields. 

Mice fed a diet containing the hexaisoprenoid cholesterol precursor squalene [111-02-4]... 

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