Neryl diphosphate

The possibility of nucleophilic attack on different carbons in the resonance-stabilized carbocation facilitates another modification exploited by nature during terpenoid metabolism. This is a change in double-bond stereochemistry in the allylic system. The interconversions of geranyl diphosphate, linalyl diphosphate, and neryl diphosphate provide neat but satisfying examples of the chemistry of simple allylic carbocations. 

Before cyclization can occur, however, there has to be a change in stereochemistry at the 2,3-double bond, from E in geranyl diphosphate to Z, as in neryl diphosphate. It should be reasonably clear that geranyl diphosphate cannot possibly cyclize to a six-membered ring, since the carbon atoms that need to bond are not close enough to each other. The change in stereochemistry is achieved through allylic cations and linalyl diphosphate (see Box 6.4). 

The enzyme-catalyzed reactions that lead to geraniol and farnesol (as their diphosphate esters) are mechanistically related to the acid-catalyzed dimerization of alkenes discussed in Section 6.21. The reaction of an ally lie diphosphate or a carbocation with a source of 7T electrons is a recurring theme in terpene biosynthesis and is invoked to explain the origin of more complicated structural types. Consider, for example, the formation of cyclic monoterpenes. Neryl diphosphate, formed by an enzyme-catalyzed isomerization of the E double bond in geranyl diphosphate, has the proper geometry to form a six-membered ring via intramolecular attack of the double bond on the allylic diphosphate unit. 

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

In the next step, ohvetolic acid is condensed with geranyl diphosphate in the presence of a particular prenyltransferase. Olivetol itself is not active as a prenyl-acceptor. [128] Tracer experiments with C-labeUed glucose show that in hemp the terpene part of cannabinoids is constructed according to the newly-discovered deoxyxylulose phosphate pathway (the Rohmer route). Since can-nabinerolic acid is found as a second component, it appears likely that also neryl diphosphate is transformed by the same enzyme. 

Scheme 11.44. The formation of linalyl diphosphate from neryl diphosphate and geranyl-diphosphate. Both of the latter arise from coupling between dimethylallyl diphosphate and isopentenyl diphosphate. Both (31 )- and (35)-isomers form.

As shown in Scheme 11.47,isopentenyl diphosphate can (again in principle) attack geranyl diphosphate (or, indeed, in principle neryl diphosphate or linalyl diphosphate) and, in this way, account for the formation of farnesyl diphosphate. Indeed, under the influence of geranyltranxtransferase (EC 2.5.1.10), such a process occurs ... 

Mechanism 29.3 Isomerization of Geranyl Diphosphate to Neryl Diphosphate Steps [1]-[2] Isomerization of geranyl diphosphate to linalyl diphosphate... 

Steps [3]-[4] Isomerization of linalyl diphosphate to neryl diphosphate... 

Nucleophilic attack with diphosphate forms neryl diphosphate, a stereoisomer of geranyl diphosphate. The diphosphate leaving group of neryl diphosphate is now in closer proximity to the doubie bond at the other end of the chain, so that intramolecular cyclization can occur. 

In the synthesis of a-terpineol or limonene, for example, geranyl diphosphate isomerizes to form neryl diphosphate (Step [1] in the following reaction sequence). Neryl diphosphate 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. 

Draw a stepwise mechanism for the conversion of neryl diphosphate to a-pinene. a-Pinene is a component of pine oil and rosemary oil. 

Biological Formation of Geranyl Diphosphate 1135 Biological Formation of Famesyl Diphosphate 1136 Isomerization of Geranyl Diphosphate to Neryl Diphosphate Synthetic Polymers... 

The ( )-olefin GPP (3) can then be easily isomerized to the (Z)-configured neryl diphosphate (NPP 4). This isomerization most reasonably proceeds via carbocation formation and diphosphate addition to the tertiary carbon to give the conformationally flexible linalyl diphosphate (LPP, 5) (Scheme 6.2). In addition there are also enzymes known that... 

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