Geranyl diphosphate carbocation

Following this initial SN1 reaction, loss of the pro-R hydrogen gives geranyl diphosphate, itself an allylic diphosphate that dissociates a second time. Reaction of the geranyl carbocation with water in a second S>jl reaction, followed by loss of a proton, then yields geraniol. 

Geranyl diphosphate and farnesyl diphosphate are analogues of dimethylallyl diphosphate that contain two and three C5 subunits respectively they can undergo exactly the same SnI reactions as does dimethylallyl diphosphate. In all cases, a carbocation mechanism is favoured by the resonance stabilization of the allylic carbocation. Dimethylallyl diphosphate, geranyl diphosphate, and farnesyl diphosphate are precursors for natural terpenoids and steroids. 

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. 

Figure 5.6 Proposed mechanism for the cyclization of geranyl diphosphate to sabinene and sabinene hydrate under catalysis by monoterpene synthases the reaction begins with the hydrolysis of the diphosphate moiety to generate a resonance-stabilized carbocation (1) the carbocation then isomerizes to an intermediate capable of cyclization by return of the diphosphate (2) and rotation around a single bond (3) after a second diphosphate hydrolysis (4) the resulting carbocation undergoes a cyclization (5) a hydride shift (6) and a second cyclization (7) before the reaction terminates by deprotonation (8) or capture of the cation by water (9). Cyclizations, hydride shifts and a variety of other rearrangements of carbocationic intermediates are a characteristic of the mechanisms of terpene synthases. No known terpene synthase actually produces both sabinene and sabinene hydrate these are shown to indicate the possibilities for reaction termination. PP indicates a diphosphate moiety.

The ten-carbon carbocation that results is the same regardless of whether it is formed in one step or two. Once formed it can react in several different ways, all of which are familiar to us as typical carbocation processes. One is deprotonation to give the carbon-carbon double bond of geranyl diphosphate. 

Geranyl diphosphate is an allylic diphosphate and, like dimethylallyl diphosphate, can react with isopentenyl diphosphate. A 15-carbon carbocation is formed, which on deprotonation gives farnesyl diphosphate. Hydrolysis of farnesyl diphosphate gives the sesquiterpene farnesol. 

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. 

In a subsequent step, the allylic carbocation condenses with isopentenyl diphosphate, forming a new carbocation, which then loses the Hr (this chapter) proton to form the product. Alternatively, geranyl diphosphate can form if (as shown in the figure) proton loss is concomitant with condensation. 

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. 

The further conversion of geranyl diphosphate into monoterpenoids typically involves carbocation intermediates and multistep reaction pathways that are catalyzed by terpene cyclases. Monoterpene cyclases function by first isom-erizing geranyl diphosphate to its allylic isomer linalyl diphosphate (LPP), a process that occurs by spontaneous S>jl-like dissociation to an allylic carbocation, followed by recombination. The effect of this isomerization is to convert the C2-C3 double bond of GPP into a single bond, thereby making cyclization possible and allowing EjZ isomerization of the double bond. 

All other terpenes are biologically derived from geranyl and farnesyl diphosphates by a series of reactions. Cyclic compounds are formed by intramolecular reactions involving nucleophilic attack of n bonds on intermediate carbocations. To form some cyclic compounds, the E... 

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