Neryl 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... 

The product of the combination of two units of the pyrophosphate, 9, through this sequence is geranyl pyrophosphate if, as shown, the proton is lost to give a trans double bond. Formation of a cis double bond would give neryl pyrophosphate (Section 30-3B). 

Continuation of the head-to-tail addition of five-carbon units to geranyl (or neryl) pyrophosphate can proceed in the same way to farnesyl pyrophosphate and so to gutta-percha (or natural rubber). At some stage, a new process must be involved because, although many isoprenoid compounds are head-to-tail type polymers of isoprene, others, such as squalene, lycopene, and /3- and y-carotene (Table 30-1), are formed differently. Squalene, for example, has a structure formed from head-to-head reductive coupling of two farnesyl pyrophosphates ... 

Isomerization of the double bond of geranyl pyrophosphate from to 7 produces neryl pyrophosphate. As shown in Figure 28.3, the carbocation that is formed from neryl pyrophosphate can cyclize to a new carbocation that contains a six-membered ring. Nucleophilic addition of water to this carbocation produces a-terpenol, whereas loss of a proton produces limonene, a monoterpene with a lemonlike odor that occurs in citrus fruits. Further transformations lead to other monoterpenes, such as menthol,... 

Terpinen-4-ol is also produced from neryl pyrophosphate. Suggest a mechanism for its formation. 

Explain the regiochemistry of the cyclization of the initial carbocation formed from neryl pyrophosphate. 

Show a mechanism for the formation of thujene from neryl pyrophosphate. 

The metabolism of 7-endo-fenchol to ci-fenchone in fennel has been studied in quite some detail by Croteau and co-workers (Croteau and Felton, 1980). Croteau et al. (1980a) later reported a soluble enzyme preparation from the leaves of fennel which catalysed the cation-dependent cyclization of both geranyl pyrophosphate and neryl pyrophosphate to the bicyclic rearranged monoterpene 1-enc/o-fenchol. Croteau et al. (1980b) found that (+)-(lS)-fenchone, an irregular bicyclic monoterpene ketone thought to be derived... 

Croteau, R., Felton, M. and Ronald, R.C. (1980a) Biosynthesis of monoterpenes conversion of the acyclic precursors geranyl pyrophosphate and neryl pyrophosphate to the rearranged monoterpenes fenchol and fenchone by a soluble enzyme preparation from fennel (Foeniculum vulgare). Archives of Biochemistry and Biophysics 200(2), 524-533. 

As soon as we start to make typical cyclic mo no terpenes from geranyl pyrophosphate we run into a snag. We cannot cyclize geranyl pyrophosphate because it has a trans double bondf We could cyclize the as compound (neryl pyrophosphate), and it used to be thought that this was formed from the trans compound as an intermediate. 

In the synthesis of a-terpineol or limonene, for example, geranyl pyrophosphate isomerizes at one double bond to form neiyl pyrophosphate, a stereoisomer (Step [1] in the following reaction sequence). Neryl pyrophosphate then cyclizes to a 3° carbocation by intramolecular attack (Steps [2]-[3]). Nucleophilic attack of water on this carbocation yields a-terpineol (Step [4]) or loss of a proton yields limonene (Step [5]). Both products are cyclic monoterpenes. 

Figure 5. Stereochemistry at Cl of geranyl pyrophosphate and neryl pyrophosphate in the cyclization, via linalyl pyrophosphate, to bornyl pyrophosphate. "Reproduced with permission from Ref. 76. Copyright 1985, Journal of Biological Chemistry".

In the Figures, GPP indicates geranyl pyrophosphate, NPP indicates neryl pyrophosphate, LPP indicates linalyl pyrophosphate, and BPP indicates bornyl pyrophosphate. 

FIGURE 26.7 Two of the reaction pathways available to the Cio bicyclic carbocation formed from neryl pyrophosphate. The same carbocation can lead to monoterpenes based on either the bicyclo[3.1.1] or the bicyclo[2.2.1] carbon skeleton. 

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