Prephytoene alcohol

Full details have been given28 of the previously reported29 synthesis of ( )-prephytoene alcohol (47) by a route involving condensation of the Qo sulphone (48) with the C20 ester (49). Lycopersene 1,2-epoxide [1,2-epoxy-... 

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). 

Samples of (IK, 2R, 3R) and (IS, 25, 35) prephytoene alcohols have been chemically synthesized and only the (IK, 2K, 3K) enantiomer (91), as the pyrophosphate ester, is biologically active The absolute configuration of prephytoene pyrophosphate (89) is thus identical to that found for presqualene pyrophosphate (77) and the detailed stereochemistry of the formation of these compounds is probably identical. 

The resolution of synthetic presqualene and prephytoene alcohols via their etienic acid derivatives has been reported. This work confirmed that the active (-f-)-enantiomers in both series have the same absolute configuration [(li , 2/ , 3/ )]. It has been established, by use of Hn.m.r., that the proton (deuteron) introduced at C-3 during the cyclization of squalene to tetrahymanol by Tetrahymena pyriformis has the 3/8 configuration. Both antipodes of the trimethyldecalol (13) have been shown to be effective inhibitors of cholesterol biosynthesis in rat liver enzyme preparations and cultured mammalian cells. The accumulation of squalene 2,3-oxide and squalene 2,3 22,23-dioxide in the treated systems indicates that inhibition occurs at the cyclization stage. The inhibitor is metabolized to the diol (14). The results of other sterol inhibition... 

Acyclic Carotenoids. The etienate esters prepared by treatment of ( )-prephy-toene alcohol with 3/3-acetoxy-17/8-chloroformylandrost-5-ene have been resolved by h.p.l.c., and the prephytoene alcohol enantiomers obtained by... 

Full details have been described of the synthesis of prephytoene alcohol (29). The synthetic route from geranylgeraniol (69) is outlined in Scheme 3. 

Stereochemistry. It is well known that formation of the first C40 hydrocarbon in carotenoid biosynthesis proceeds via an intermediate, prephytoene pyrophosphate. It has now been shown that only the pyrophosphate of the (-1-)-(l/ ,2/ ,3i )-isomer of prephytoene alcohol is utilized for carotene production by Phycomyces blakesleeanus. Detailed mechanisms for the formation of (l/ ,2/ ,3/ )-prephytoene pyrophosphate (178) from geranylgeranyl pyrophosphate (177) have been proposed (Scheme 4). - ... 

The interesting formal parallel that exists between the rearrangements of the chrysanthemyl cation and the conversion of presqualene alcohol into squalene (and now of prephytoene alcohol into phytoene) has been further explored. Solvolyses ° of the cyclopropyl (65) and cyclobutyl (63) esters both afford head-to-head coupled Cio chains analogous to squalene. A versatile new method provides access to 9-substituted p-menthanes. This starts with natural limonene and proceeds via the anion (135) which retains chirality and leads to chiral products (see below). Skeletal rearrangements in the bicycloheptane series, an historic field in the study of organic reaction mechanisms, has received a fresh impetus from the extended work of Kirmse and his colleagues, - which is of preparative and mechanistic significance. 

Prephytoene alcohol pyrophosphate (22b) has been synthesized and identified as an intermediate in the biosynthesis of phytoene (24b). The reaction sequence shown (Scheme 2 b series) assumes that the absolute stereochemistry is the same as for presqualene alcohol. 

By a stereochemically controlled synthesis the C40 cyclopropane carotenoid precursor prephytoene alcohol [(57), as racemate] has been obtained (47). The total synthesis of azafrin [(6), as racemate] (175,176), of lutein [(14), as racemate] and 3 -epilutein [(58), as racemate] (176) and of 3,6(3, 6 )-cis (59) and 3,6(3, 6 )-trans ,e-carotene-3,3 -diol (60), both as racemates (176), have been announced in symposium reviews. Experimental details have not yet been published. The NMR data of racemic (6) were consistent with the threo structure of natural azafrin (6) that has been documented in other ways, while the H NMR properties of the models (59) and (60) were consistent with the previously established... 

A remarkably stereospecific elimination has been utilized in the synthesis of ( )-presqualene alcohol and ( )-prephytoene alcohol. The process is based on the addition of the anion derived from a Py-unsaturated phenylsulphone to an aP-unsaturated ester. The intermediate anion (24) cyclizes to give the truns-cyclopropane-carboxylic ester (25), the geometry about the double bond of the unsaturated sulphone... 

Michael addition of sulphonyl carbanions followed by 1,3-elimination of sulphinate anion provides a route to cyclopropanes utilized in the total synthesis of presqualene alcohol, prephytoene alcohol, and the preparation of the simple ketone (74). The palladium complex of an a-sulphonyl carbanion has been reported to add to isolated double bonds. 

First, we will take up cyclopropyl group formation by the rearrangement of carbon skeletons via cationic intermediates encountered in various mono- and sesquiterpenes, and also examine the illudin biosynthesis where contraction of a cyclobutyl cation to a cyclopropane has been invoked. We will then discuss the head-to-head condensation of isoprenoid alcohols at the C15 or C20 level to generate the cyclopropyl intermediates, presqualene pyrophosphate and prephytoene pyrophosphate, on the way to the C30 and C40 polyene hydrocarbons, squalene and phytoene respectively. Conversion of 2,3-oxidosqualene via common intermediate protosterol cation to cycloartenol or lanosterol represents an important pathway in which the angular methyl group participates in the three-membered ring formation. The cyclopropanation outcome of this process has been carefully studied. 

The crucial intermediacy of cyclopropylcarbinyl species in the biological synthesis of hundreds (thousands) of steroids, carotenoids, retinoids and derivatives is exemplified by the C30 presqualene pyrophosphate (77) and the C40 prephytoene pyrophosphate (89). In the biosynthetic construction of the key C(l)-C(l) carbon-carbon in head-to-head joining of Cl 5 or C20 alkyl alcohol pyrophosphate esters, the cyclopropylcarbinyl strategy via a formal insertion of C(l) of one monomer into the C(2)-C(3) double bond of the second monomer appears to be the central mechanistic solution in the biochemical inventory. The cyclopropylcarbinyl pyrophosphate forms as obligate intermediate whether the final... 

It is of interest that in some nonenzymatic studies, a small percentage of head-to-head condensation products are observed. Chrysanthemyl alcohol (92) is an analog of presqua-lene alcohol and prephytoene (see Chapters 23 and 26), but the fissions postulated to lead to the irregular monoterpenes have no counterparts for the higher classes (Charlwood and Chari wood, 1991a). 

Certain bacteria are able to form C3Q, C45, and CgQ-isoprenoids of the phytoene type in addition to phytoene by head-to-head condensation of appropriate precursor molecules. In higher plants certain monoterpenes probably are synthesized in a similar manner. Chrysanthemyl alcohol, occurring in Compositae, is an analog of presqualene and prephytoene. The C-skeletons given in Fig. 97 are derived from chrysanthemyl pyrophosphate. Chrysanthemum carboxylic acid is a constituent of the pyrethrins, compounds with marked insecticidal activity (E 5.5.3). 

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