Squalene precursor

Interest in presqualene pyrophosphate continues and it is claimed that the structure (88) assigned to a squalene precursor is incorrect. Presqualene pyrophosphate has been shown to contain a cyclopropyl ring (89), and both (89) and its parent alcohol have been synthesised. -Mechanisms for the conversion of (89) into squalene have been pub-lished. -... 

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). ... 

Squalene precursor of cholesterol See Carotenoids in this chapter. 

Steroids are derived from the same squalene precursor and have an oxygen-dependent biosynthetic pathway beginning with the formation of the first intermediate, 2,3-oxidosqualene (for details, see Sect. 5.1). Sterols, also known as steroid alcohols, are a subclass of steroids and may be found either as fi ee sterols, acylated, alkylated, sulfated, or linked to a glycoside moiety which can be itself acylated. Sterol biosynthesis is nearly ubiquitous among eukaryotes but almost completely absent in prokaryotes. As a result, the presence of diverse steranes (saturated four-cycle skeleton) in ancient rocks has been considered as evidence for over 2.7 billion years of eukaryotic evolution. Cholesterol is the most well-known sterol found in animal cell membranes (for establishing proper membrane permeability and fluidity) and red blood cells. 

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). 

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). 

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

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). 

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]... 

Squalene is also an intermediate in the synthesis of cholesterol. StmcturaHy, chemically, and biogeneticaHy, many of the triterpenes have much in common with steroids (203). It has been verified experimentally that squalene is the precursor in the biosynthesis of all triterpenes through a series of cyclization and rearrangement reactions (203,204). Squalene is not used much in cosmetics and perfumery formulations because of its light, heat, and oxidative instabiUty however, its hydrogenated derivative, squalane, has a wide use as a fixative, a skin lubricant, and a carrier of Hpid-soluble dmgs. 

The most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

In a variation of these reactions, Grieco and Masaki used p-toluenesulfonyl groups to direct alkylation reactions in the formation of carbon chains and then cleaved the sulphones with lithium in ethylamine. This type of synthetic construction involving the use of sulphur-containing molecules has become a typical sequence in organic syntheses. In this case, the reactions formed part of successful syntheses of squalene and sesquifenchene and were carried out without any migration or loss of stereochemical integrity of the double bonds. Similar sequences have been reported by Trost (prenylation reactions) and Marshall (synthesis of a cembranoid precursor). 

The last acyclic precursor of cholesterol biosynthesis is squalene, consisting of a linear polyalkene chain of 30 carbons. 

From squalene, lanosterol, the first cyclic precursor, is created by a remarkable set of enzyme-catalyzed addition reactions and rearrangements that create four fused rings and seven stereocenters. 

Sea cucumbers (Holothuroidea, Echinodermata) appear to be unique in their mode of squalene oxide (37) cyclization. Tritium-labeled lanosterol (33), cycloartenol (32) and parkeol (38) were individually administered to the sea cucumber Holothuria arenicola. While the former two triterpenes were not metabolized [22], parkeol was efficiently transformed into 14x-methyl-5a-cho-lest-9(l l)-en-3/ -ol (39) (Scheme 3). Other A1 sterols present in H. arenicola were not found to be radioactive and were thus assumed to be of dietary origin. The intermediacy of parkeol was confirmed by the feeding of labeled mevalonate (23) and squalene (26) to the sea cucumber Stichopus californicus [15]. Both precursors were transformed into parkeol, but not lanosterol nor cycloartenol, aqd to 4,14a-dimethyl-5a-cholest-9(ll)-en-3/J-ol (40) and 14a-methyl-5a-cholest-9(ll)-en-3/ -ol. Thus, while all other eukaryotes produce either cycloartenol or lanosterol, parkeol is the intermediate between triterpenes and the 14-methyl sterols in sea cucumbers. 

Squalene had been isolated from shark s liver by Channon in 1929. He, Heilbron, and Robinson all postulated it was a potential precursor of cholesterol. In 1952, Bloch and his colleagues established the differential origins of the carbon atoms in the cholesterol side chain from the methyl or carboxyl carbon atom of acetate ... 

Other molecules in which the presence of a C2 axis of symmetry also simplifies the syntheses are squalene (5) rmd P-carotene (6). Notice that in such cases the simplification derives from the fact that the syntheses are convergent and reflexive i.e., syntheses which start from identical precursors [5]. In practice, the synthesis of these two substances may be carried out not only by dimerisation of two identical moieties [10] [11] -which may lead to a mixture of isomers-, but preferentially by addition of two identical fragments to a central bifunctional unit according to the scheme -1- + C. = Cjj (squalene Cji -t-Cg + Cj] = 30 [12] p-carotene ... 

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