Isopentenyl diphosphate double bond

Two SN1 reactions occur during the biosynthesis of geraniol, a fragrant alcohol found in roses and used in perfumery. Geraniol biosynthesis begins with dissociation of dimethylallyl diphosphate to give an allylic carbocation, which reacts with isopentenyl diphosphate (Figure IT 15). From the viewpoint of isopentenyl diphosphate, the reaction is an electrophilic alkene addition, but from tile viewpoint of dimethylallyl diphosphate, the process in an Sjjl reaction in which the carbocation intermediate reacts with a double bond as the nucleophile. 

The isomerization of isopentenyl diphosphate to dimethylally diphos phate is catalyzed by JPP isomerase and occurs through a carbocation pathway Protonation of the IPP double bond by a hydrogen-bonded cysteine residue ir the enzyme gives a tertiary carbocation intermediate, which is deprotonated b a glutamate residue as base to yield DMAPP. X-ray structural studies on the enzyme show that it holds the substrate in an unusually deep, well-protectec pocket to shield the highly reactive carbocation from reaction with solvent 01 other external substances. 

Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl diphosphate, then condensed with another molecule of isopentenyl diphosphate to form the ten-carbon intermediate ger-anyl diphosphate (Figure 26-2). A further condensation with isopentenyl diphosphate forms farnesyl diphosphate. Two molecules of farnesyl diphosphate condense at the diphosphate end to form squalene. Initially, inorganic pyrophosphate is eliminated, forming presqualene diphosphate, which is then reduced by NADPH with elimination of a further inorganic pyrophosphate molecule. 

In the presence of the enzyme isopentenyl diphosphate isomerase, isopentenyl diphosphate is converted to dimethylallyl diphosphate. The isomerization involves two successive proton transfers one from an acidic site of the enzyme (Enz—H) to the double bond to give a tertiary carbocation the other is deprotonation of the carbocation by a basic site of the enzyme to generate the double bond of dimethylallyl diphosphate. 

Isopentenyl diphosphate and dimethylallyl diphosphate are structurally similar—both contain a double bond and a diphosphate ester unit—but the chemical reactivity expressed by each is different. The principal site of reaction in dimethylallyl diphosphate is the carbon that bears the diphosphate group. Diphosphate is a reasonably good leaving group in nucleophilic substitution reactions, especially when, as in dimethylallyl diphosphate, it is located at an allylic carbon. Isopentenyl diphosphate, on the other hand, does not have its leaving group attached to an allylic carbon and is far less reactive than dimethylallyl diphosphate toward nucleophilic reagents. The principal site of reaction in isopentenyl diphosphate is the carbon-carbon double bond, which, like the double bonds of simple alkenes, is reactive toward electrophiles. 

In keeping with its biogenetic origin in three molecules of acetic acid, mevalonic acid has six carbon atoms. The conversion of mevalonate to isopentenyl diphosphate involves loss of the extra carbon as carbon dioxide. First, the alcohol hydroxyl groups of mevalonate are converted to phosphate ester functions—they are enzymatically phosphorylated, with introduction of a simple phosphate at the tertiary site and a diphosphate at the primary site. Decarboxylation, in concert with loss of the tertiary phosphate, introduces a carbon-carbon double bond and gives isopentenyl diphosphate, the fundamental building block for formation of isoprenoid natural products. 

Mechanistie studies of the IspH (HMB-PP reduetase, 4-hydroxy-3-methylbut-2-enyl diphosphate reduetase) eatalysed reduetive dehydroxy-lation of 4-hydroxy-3-methyl-2-( )-l-diphosphate (130) to isopentenyl diphosphate (131) and rearranged dimethylallyl diphosphate (132), suggested that both the 4-OH group and the double bond of (130), may eon-tribute to the formation of a substrate-IspH complex (Scheme 34). ... 

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