Linalyl diphosphate

Problem 11.14 j Review the mechanism of geraniol biosynthesis shown in Figure 11.15, and then propose a mechanism for the biosynthesis of limonene from linalyl 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-catalysed cyclization of (R)-[9-2Hi,3 Hi]geranyl diphosphate to (4.S )-limonene has been found to terminate predominately by re-facial, anti proton elimination at the cis methyl group of the intermediate (35)-linalyl diphosphate.80... 

Strategy Redraw linalyl diphosphate so that has the same orientation as limonene. 

The mechanism follows the usual path cyclization of linalyl diphosphate, followed by attack of the n electrons of the second double bond, produce an intermediate carbocation. A carbocation rearrangement occurs, and the resulting carbocation reacts with water to form an alcohol that is oxidized to give a-fenchone. 

A mixture of (3/ )-[8,9- C]linalyl diphosphate and (l ,3/ 5)-[l- Hi]linalyl diphosphate was incubated with the two cyclase preparations. The bomeol from the Tanacetum... 

S)-linalyl diphosphate (3S)-linalyl diphosphate (transoid) (cisoid)... 

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 ... 

Besides a simple ionization-deprotonation process to the acyclic monoterpenes, GPP can also undergo cyclization reactions. The direct Markovnikov-type 1,6-cyclization of the ( )-configured geranyl cation by attack of the C6-C7 double bond at the cationic center is impossible since this would give a hypothetical ( )-cyclohexene product. Therefore, the isomerization of GPP via the geranyl cation to linalyl diphosphate (LPP) prior to cyclization is required (Scheme 87.15). The possible free rotation of the vinyl group into a cisoid conformation privileges... 

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