Presqualene alcohol

The use of chiral dirhodium carboxamidates has made possible the highly enantioselective synthesis of presqualene alcohol (4) from farnesyl diazoacetate (14) through cyclopropane 15 [9] (Eq. 1). Highly enantiomerically en-... 

Another polyprenyl compound formed by a head to head condensation is chrysanthemic acid. This monoterpene component of the pyrethrum insecticides is formed by chrysanthemums from two molecules of dimethyallyl-PP via an intermediate analogous to presqualene alcohol-PP.118a... 

The full details of one synthesis of presqualene alcohol have been published.7 The 13C resonances of a series of presqualene esters, related cyclopropanes, and acyclic precursors have been assigned.8 The stereochemistry of the biosynthesis of presqualene alcohol has been investigated.9... 

Unexpected results have come to light bearing on monoterpenoid biosynthesis (Chapter 1). Banthorpe s group have shown that in the formation of the thujane and camphor skeletons, activity from labelled mevalonic acid can appear predominantly in the C5 unit supposedly derived from isopentenyl pyrophosphate and only to a minor extent in the dimethylallyl pyrophosphate-derived portion. Banthorpe has also presented evidence for a chrysanthemyl intermediate, analogous to presqualene alcohol, in the biosynthesis of artemesia ketone. 

The structure of presqualene alcohol has been established beyond reasonable doubt by three independent rational syntheses (Chapter 4). " As the last isolable intermediate between acetate and squalene to be formulated, its structure has been a subject of controversy since its isolation in 1966, Its formulation therefore represents a major advanee which makes it possible to eonsider its mode of formation from famesol and its transformation into squalene. Enzymie... 

The structure (1) proposed by Rilling and Epstein for presqualene alcohol, the elusive biological intermediate between farnesol and squalene, has been confirmed by three independent rational syntheses. Altman et al selected the allylic diazo-compound (2) as starting material. Addition of this to trans,trans-farnesol in the presence of zinc iodide gave a 25 % yield of presqualene alcohol (1) and its isomer (3). 

The method used by Coates and Robinson" involved the copper-catalysed decomposition of trans,trans-farnesyl diazoacetate (4) to the cyclopropyl-lactone (5) having the stereochemistry shown. This was transformed into the cis-aldehyde-ester (6) by standard methods. Base epimerization gave the more stable transcompound (7). A Wittig reaction between the trans-aldehyde-ester (7) and the phosphorane (8), followed by lithium aluminium hydride reduction, yielded presqualene alcohol (1) as the major product accompanied by the minor isomer (9). 

The third synthesis, by Crombie et al., utilizes the base-catalysed condensation of the trans,trans-phenyl farnesyl sulphone (10) with trans,trans-Qthy farneso-ate to give the ester (11) as a major product via the intermediate (12). Lithium aluminium hydride reduction again yielded presqualene alcohol (1). In each case the labelled synthetic alcohol, as its pyrophosphate, was incorporated by yeast subcellular particles into squalene in ca. 68 % yield. The minor synthetic isomers were not incorporated. 

The relative stereochemistry of the substituents attached to the cyclopropane ring of presqualene alcohol received further confirmation by a synthesis of the triacetate (13), obtainable from (1) by ozonolysis, reduction, and acetylation. Treatment of 3-methyl-truns-hex-2-ene-l,6-diacetate (14) with ethyl diazoacetate in the presence of copper powder gave two isomers (15) and (16) whose stereochemistry was assigned by n.m.r. The triacetate derived from synthetic (15) by reduction and acetylation was identical in all respects with the triacetate (13) from natural presqualene alcohol. Presqualene alcohol has a c.d. curve similar to, but of opposite sign to, that of (li ,2i )-trans-chrysanthemyl alcohol (17). The mechanism for the stereospecific biosynthesis of squalene from farnesol via presqualene alcohol has received detailed comment. ... 

The controversy over presqualene alcohol has been resolved in favour of Rilling s second structure (5), rather than the diester proposed by Popjak or the acyclic formulation suggested by Lynen. In the biosynthesis from farnesyl pyrophosphate one hydrogen atom is lost to the medium from C-1, and when the presqualene alcohol pyrophosphate is further metabolized to squalene (6) no further hydrogen atoms are lost. Final proof of the structure came from its synthesis by three groups the indicated absolute stereochemistry was based on a correlation with trans-chrysanthemyl alcohol. This structure is now also accepted by Popjak and co-workers. Thus the conversion of farnesyl pyrophosphate into squalene may be rationalized as shown (see also ref 29). 

A series of analogues, (4) and (5), of the precursors of squalene, in which the carbinol oxygen is replaced by a methylene group, inhibited the formation of squalene from [2- C]- and [S- HaJ-MVA by rat liver squalene synthetase. These phosphonophosphates also inhibited the biosynthesis of kaurene from MVA in a cell-free system from Ricinus communis, but the corresponding phosphonates were only weakly inhibitory. The formation of labelled squalene from a mixture of [2- C]MVA and [l- H]presqualene alcohol pyrophosphate by the squalene synthetase preparation was completely inhibited by the addition of (5) to the incubation... 

The consistency of the high levels of enantiocontrol accessible in these diazoester cyclizations is underpinned by their growing applications in enantiose-lective synthesis of bioactive molecules containing cyclopropane units. Notable examples include the preparation of multifunctional cyclopropanes as peptide isosteres for renin inhibitors (Scheme 4) [42] presqualene alcohol from farnesyl diazoacetate (Scheme 5) [43] the GABA analogue 3-azabicyclo[3.1.0]hexan-2-one from N-allyldiazoacetamide, Eq. (26) [23] and precursors of lR,3S)-cis-chrysanthemic acid and the pheromone, E-(-)-dictyopterene C (Scheme 6) [44, 45],... 

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. 

Crombie and his colleagues have confirmedthe stereochemical assignments of their previously obtained synthetic presqualene alcohol isomers by use of lanthanide shift reagents (see Vol. 2, p. 156). 

Popjak and co-workers have published their confirmation of the structure of presqualene alcohol pyrophosphate (22a) in full. They showed that synthetic (racemic) material had half the activity of the natural product. The absolute configuration of the cyclopropane ring has been revised to RRR and this is more consistent with the known stereochemistry of the squalene produced (Scheme 2). 

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. 

Epstein, W. W. and C. C. Poultbr, A survey of some irregular monoterpenes and their biogenetic analogies to presqualene alcohol, Phytochemistry, 12, 737-747 (1973). 

In studies of the biosynthesis of presqualene alcohol with [l-0 ]famesyl pyrophosphate, exchange of oxygen did not occur. These observations indicate that the pyrophosphate group of one famesyl pyrophosphate molecule occurs in the product without change of configuration in presqualene pyrophosphate (Popjak et al., 1975). 

PopjAK, G., H. Ngan, and W. Agnew, Stereochemistry of the biosynthesis of presqualene alcohol, Bioorg. Chem., 4, 279-289 (1975). 

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... 

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