Geranyl pyrophosphate cation

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 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... 

The previous view on the biosynthesis of monoterpenes is that the cyclization of the geranyl pyrophosphate proceeds via a common cationic precursor, which in turn is further transformed into the various monoterpenes, as shown in Fig. (2). 

Several groups +have examined the influence of divalent cations, such as Mg2 and Mn2, in catalyzing the solvolysis of allylic pyrophosphates such as geranyl pyrophosphate (58-60). The results strongly suggest that the role of the metal ion in enzymatic transformations of allylic pyrophosphates is to neutralize the negative charge of the pyrophosphate moiety and thus assist in the ionization of the substrate to produce the allylic cation. 

Two elements of the cyclization have yet to be addressed the isomerization of geranyl pyrophosphate to linalyl pyrophosphate (or the equivalent ion-pair) and the construction of bicyclic skeleta. Studies on the biosynthesis of linalool (61), and on the analogous nerolidyl system in the sesquiterpene series (52), have shown this allylic transposition to occur by a net suprafacial process, as expected. On the other hand, the chemical conversion of acyclic or monocyclic precursors to bicyclic monoterpenes, under relevant cationic cyclization conditions, has been rarely observed (47,62-65) and, thermodynamic considerations notwithstanding (66), bicyclizations remain poorly modeled. 

This allylic cation then reacts with 3-IPP to form geranyl pyrophosphate ... 

FIGURE 12.72 Loss of the pyrophosphate gives an aUyhc cation that can be attacked by a molecule of 3-methyl-3-buten-l-ol pyrophosphate to give a new cation. Deprotonation gives geranyl pyrophosphate. 

Assuming that geranyl pyrophosphate reacts like dimethylallyl pyrophosphate, the leaving group departs in an S l reaction. The electrons of the tt bond attack the aUyUc cation, forming the six-membered ring and a new carbocation. A base removes a proton to form the required double bond. 

In the first step, ionization of the allylic pyrophosphate gives an allylic cation. Attack by a molecule of 3-methyl-3-butenyl pyrophosphate, followed by proton loss, yields a dimer called geranyl pyrophosphate. Repetition of this process leads to natural rubber. 

Curiously, certain cyclases, notably (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase, are capable of cyclizing, at relatively slow rates, the 3S-linalyl pyrophosphate enantiomer to the respective antipodal products, (-)-bornyl pyrophosphate and (+)-endo-fenchol (74,75). Since both (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase produce the designated products in optically pure form from geranyl, neryl and 3R-linalyl pyrophosphate, the antipodal cyclizations of the 3S-linalyl enantiomer are clearly abnormal and indicate the inability to completely discriminate between the similar overall hydrophobic/hydrophilic profiles presented by the linalyl enantiomers in their approach from solution. The anomalous cyclization of the 3S-enantiomer by fenchol cyclase is accompanied by some loss of normal regiochemical control, since aberrant terminations at the acyclic, monocyclic and bicyclic stages of the cationic cyclization cascade are also observed (74). The absolute configurations of these abnormal co-products have yet to be examined. 

Mash, E. A., G. M. Gurria, and C. D. Poulter, Famesylpyrophos-phate synthetase. Evidence for a rigid geranyl cation-pyrophosphate anion pair, J. Am. Chem. Soc., 103, 3927-3929 (1981). 

Since both neryl pyrophosphate and linaloyl pyrophosphate (or some equivalent species) (34) have been seriously considered as likely acyclic precursors to this family of monoterpenes, it is appropriate to examine first the cationic reactions of these two compounds. A great many investigations have shown that, while geranyl derivatives undergo substitution reactions in a fashion typical of an allylic substrate, both neryl and, less efficiently, linaloyl derivatives lead to cyclic products such as a-terpineol, and its dehydrated relatives limonene, and terpinolene... 

---