Allylic pyrophosphate

Geranyl pyrophosphate is an allylic pyrophosphate and like dimethylallyl pyrophosphate can act as an alkylating agent toward a molecule of isopentenyl pyrophosphate A 15 carbon carbocation is formed which on deprotonation gives/ar nesyl pyrophosphate... 

The enzyme catalyzed reactions that lead to geraniol and farnesol (as their pyrophosphate esters) are mechanistically related to the acid catalyzed dimerization of alkenes discussed m Section 6 21 The reaction of an allylic pyrophosphate or a carbo cation with a source of rr electrons is a recurring theme m terpene biosynthesis and is invoked to explain the origin of more complicated structural types Consider for exam pie the formation of cyclic monoterpenes Neryl pyrophosphate formed by an enzyme catalyzed isomerization of the E double bond m geranyl pyrophosphate has the proper geometry to form a six membered ring via intramolecular attack of the double bond on the allylic pyrophosphate unit... 

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. 

Prenyl transferase, which catalyses the addition of an allylic pyrophosphate to iso-pentenyl pyrophosphate, also catalyses the hydrolysis of geranyl pyrophosphate.104 Inorganic pyrophosphate stimulates this hydrolysis, and the C—O bond is broken in... 

Prenylation, the key step in terpene biosynthesis, is catalyzed by prenyltransferases. These enzymes are responsible for the condensation of isopentenyl pyrophosphate (IPP) with an allyl pyrophosphate, thus yielding isoprenoids. Numerous studies have been performed with fluorinated substrates in order to determine the mechanism of the reactions that involve these enzymes prenyltransferases, farnesyl diphosphate synthase (FDPSase), famesyltransferase (PFTase), and IPP isomerase. These studies are based on the potential ability of fluorine atoms to destabilize cationic intermediates, and then slow down S l type processes in these reactions. 

Rubber is synthesized and sequestered on cytsolic vesicles known as rubber particles. Rubber transferase is localized to the surface of the rubber particles, and biosynthesis is initiated through the binding of an allylic pyrophosphate (APP, a pyrophosphate, produced by soluble trans- rtnyl transferases) primer. Progressive additions of IPP molecules ultimately result in the formation of high molecular weight cjT-l,4-polyisoprene. The rubber transferase also requires a divalent cation, such as Mg + or Mn +, as cofactor. 

Enantioselective (enzymatic) cyclization of 1 could lead to either enantiomer 2 a or 3 a, depending on which face of the internal double bond is attacked at C-6 by the cation derived from the allylic pyrophosphate unit. Re- or Si-face cyclization (see the detailed discussion in Section 4.3.4.1.2.1., p 442 of 1 b would, however, lead to the diastereomers 2b and 3b. respectively. A thorough analysis of the NMR spectrum of the cyclization product of 1 b definitely showed that 2b was formed thus proving the absolute configuration of (-)-fl-irans-berga-motene to be 2a185. 

ALLYLIC PYROPHOSPHATES Tris-(tetra-n-butylammonium)hydrogcn pyrophosphate. 

All natural 2,2-dialky lehr omenes are believed65 to be derived in vivo from alkylation of a phenol or a suitable precursor with an allyl pyrophosphate [Eq. (2)]. Surprisingly, no biosynthetic work has been... 

Allylic pyrophosphate esters.1 Allylic chlorides react with 1 in acetonitrile to provide allylic pyrophosphate esters typically in yields of 60-90% after ion-pair chromatographic purification. 

The biosynthesis of monoterpenoids and camphor has been described by several authors (108-llU). Ruzicka (115,116) proposed a unified biogenetic scheme for terpenes. The biosynthetic building blocks for these terpenes are iso-prene units. The biosynthetically active isoprene units are isopentenyl pyrophosphate [l] and dimethyl allyl pyrophosphate [2] the compounds that are derived from acetate via mevalonic acid (Scheme V). Geranyl pyrophosphate [3] is the C-10 precursor for the terpenes (117). Banthorpe and Baxendale (ll8) confirmed the biosynthetic pathway of (iamphor via acetate mevalonate by conducting degradation study of camphor, biosynthesized from l c labelled mevalonic acid. The biosynthesis of camphor is summarised in Scheme VI. 

The isopentenyl pyrophosphate [l] derived from mevalonic acid isomerized into dimethyl allyl pyrophosphate [2] and... 

Geranyl pyrophosphate is the starting point for all the monoterpencs. It is still an allylic pyrophosphate and repeating the alkylation with another molecule of isopentenyl pyrophosphate gives farnesyl pyrophosphate, the starting point for the sesquiterpenes, and so on. 

Maybe ids not so obvious that this is more rational The first C-Cbond formation is quite straightforward. The alkene in the red molecule attacks the allylic pyrophosphate in the black molecule in a simple S]vj2 reaction. The product is a stable carbocation. Only one C-Cbond remains to be formed to close the three-membered ring and this occurs by the loss of a proton from the black molecule. 

The biosynthesis of the ergot alkaloids involves condensation of dimethyl-allyl pyrophosphate (derived from mevalonic acid) with tryptophan. Closure of the C- and D-rings of the alkaloid involves specific hydroxylations by cytochrome P450-dependent oxidases and rearrangements. Further modifications involve N-methylation in the presence of S-adenosyl methionine and/or condensation with amino acids and peptides. Coupling of lysergyl CoA with certain peptides forms the peptide alkaloids which are the most bioactive of the ergot alkaloids. 

Goodman, D.S., and Popjak, G. (1960). Studies on the biosynthesis of cholesterol Xll. Synthesis of allyl pyrophosphates from mevalonate and their conversion into squalene with liver enzymes. J Lipid Res 1 286-300. 

Terpene cyclase enzymes catalyze the cychzation of allylic pyrophosphate substrates to form carbocyclic products via car-bocation reaction intermediates. One well-studied example is pentalenene synthase (11, 12), which catalyzes the cychzation of farnesyl pyrophosphate to give pentalenene, whose reaction mechanism is shown in Fig. 15. Cychzation of farnesyl pyrophosphate is proposed to form an 11-membered intermediate, humulene, which is followed by a five-membered ring closure to form a bicychc tertiary carbocation. 1,2-Hydride migration followed by an additional five-membered ring closure gives a tricyclic carbocation, which gives pentalenene, at elimination. 

There are many possible approaches all involving O-aUcylation at one end, C-alkylation at the other, and cyclization. Here is one scheme you may have thought of others as good. The first step is electrophilic aromatic substitution (Chapter 22) on a reactive benzene ring (two OH groups) with a reactive allylic pyrophosphate. 

II is easy to draw a mechanism for the second cyclization as the nucleophilic end of the exomethylene alkene attacks the allylic pyrophosphate to form a new six-membered ring. 

Cyclization of an allylic pyrophosphate is a key step in the biosynthesis of most monoterpenes. Early hypotheses concerning the nature of the acyclic precursor and the cyclization process are first described, and chemical models for the cyclization presented. Following a review of several representative cyclase enzymes and the reactions that they catalyze, a series of stereochemical and mechanistic experiments with partially purified cyclases are reported. The results of these studies have allowed a detailed description of events at the active site and the formulation of a unified stereochemical scheme for the multistep isomerization-cyclization reaction by which the universal precursor geranyl pyrophosphate is transformed to cyclic monoterpenes. 

Several groups +have examined the influence of divalent cations, such as Mg2 and Mn2, in catalyzing the solvolysis of allylic pyrophosphates such as geranyl pyrophosphate (58-60). The results strongly suggest that the role of the metal ion in enzymatic transformations of allylic pyrophosphates is to neutralize the negative charge of the pyrophosphate moiety and thus assist in the ionization of the substrate to produce the allylic cation. 

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