Linalyl cation

Cyclization modes are even more diverse for the sesquiterpenes than for the discussed hemi- and monoterpenes (Scheme 87.18). Transoid sesquiterpene synthases catalyze the ionization of FPP to the farnesyl cation that can cyclize by attack of the ClO-Cll double bond. A 1,10-ring closure affords the tertiary ( , )-germacradienyl cation in a Markovnikov fashion. Alternatively, the less stable secondary ( , )-humulyl cation can be furnished via an anh-Markovnikov 1,11-ring closure that is, in contrast to the 1,7-cycUzation of the linalyl cation, a well-known reaction. Cisoid synthases encourage the reattack of the diphosphate at C3 of the farnesyl cation to give (/ )- or (S)-nerolidyl diphosphate (NPP). As in LPP this allows for rotation of the newly formed vinyl group into a cisoid conformation. 

The key prenyltransferase in the biosynthesis of monoterpenes is GPP synthase. To date, only a few GPP synthases have been fully characterized (Burke et al. 1999 Bouvier et al. 2000). Enzyme-catalysed isomerization of GPP via loss of pyrophosphate as a leaving group produces the allylic linalyl cation (16). Attack by an extraneous nucleophile can take place at either end of the allylic system and ultimately gives rise to linear monoterpenes such as geraniol (17), linalool (18) and linalyl acetate (19), all common components of a number of essential oils (Figure 3.9). 

The more complicated cyclic carbon skeletons of the bornanes, thujanes and pinanes are also derived from intramolecular cyclization of the linalyl cation. Members of all three families are present in the essential oil of cotrrmon sage (Salvia officinalis) which contains some 75 separate volatile compounds (Santos-Gomes and Fernandes-Ferreira... 

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). 

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. 

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. 

Figure 3.12 shows how the -electrons of the double bond of an allylic cation can move towards the carbon atom bearing the positive charge. This generates an isomeric allylic cation, with the positive charge on the opposite end of the 3-atom system. In free allylic cations, this exchange is so rapid that the two isomers are indistinguishable. In fact, in molecular orbital theory, we consider the system to consist of a single set of orbitals which stretches across all three atoms. Since there is single bond character in each of the bonds, rotation is possible and the three cations, viz. geranyl (3.22), neryl (3.21) and linalyl (3.23), become equivalent. This is often represented as a smear of electrons as shown in structure (3.24) at the foot of Figure 3.12. Therefore in reactions such as those of...

Apparent from Scheme 4 is the necessity of the ionization-isomerization step to the cisoid linalyl intermediate for cyclization to the a-terpinyl cation, a reaction not directly possible from the geranyl substrate because of the frans-C2,C3 bond. A notable feature of all monoterpene cyclases is the abUity to utilize LPP... 

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... 

The major difference between the IPPSs and the terpene cyclases lies in the fact that terpene cyclases do not bind IPP. The first step in the terpene cyclase-catalysed reaction is still in most cases the loss of the pyrophosphate group with the formation of a polyprenyl cation in the active site. This time, however, it is an electron-rich double bond elsewhere in the molecule which serves as an internal nucleophile, with the result being formation of a cychc structure. The active sites of terpene cyclase enzymes are tailored to fold the polyprenyl pyrophosphates into the optimum conformation for intramolecular attack to take place, with hydrophobic residues to force the prenyl chain into the desired conformation, and aromatic residues such as tyrosine to stabilize the positive charge on the intermediate carbocation (Starks etal.1997). Initial isomerization, for example to linalyl or nerohdyl pyrophosphate (vide infra), is often important to present the correct geometry at the electron-accepting end of the molecule to allow cychzation to occur (Bohhnann et al. 1998). 

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