Farnesyl cation

A quantum chemical investigation of the biosynthesis of farnesyl pyrophosphate through the condensation of isopentenyl pyrophosphate and dimethylallyl pyrophosphate suggests that the mechanism is concerted, although the transition state has carbocationic character.164 Quantum chemical calculations were performed on the cyclization of the farnesyl cation to the sesquiterpene pentalenene.165 Two distinct pathways with similar activation barriers were identified, each differing from previous proposed mechanisms, and each involving unusual carbocationic intermediates. Mechanisms previously proposed for enzyme-catalysed formation of the sesquiterpene trichodiene involve carbocation intermediates with a 1,4-hydride transfer as the key step, e.g. (89) -> (90) - (91).166 Quantum chemical calculations, however, show a... 

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. 

An exactly analogous process can then occur, in which geranyl diphosphate provides the allylic cation, and a further molecule of isopentenyl diphosphate adds on, giving farnesyl diphosphate this can subsequently yield geranylgeranyl diphosphate. 

The compounds geranyl diphosphate, farnesyl diphosphate, and geranylgeranyl diphosphate are biochemical precursors of monoterpenes, sesquiterpenes, and diterpenes respectively, and virtually all subsequent modifications of these precursors involve initial formation of an allylic cation through loss of diphosphate as the leaving group. 

A.2.2 Destabilization of Cationic Intermediates The electronegative character of a fluorinated substituent can be used to inhibit the development of the positive charge in a biological process when this latter involves a positively charged transition state. This approach has been used to perform mechanistic studies on the enzymatic farnesyl transfer involved in the synthesis of isoprenoids. The presence of fluorine atoms significantly decreases the transfer rates of the isopentenyl pyrophosphate catalyzed by the diphosphate famesyltransferase (FPPase) or by the farnesyl-transferase protein (FTPase). ... 

Prenylation, the key step in terpene biosynthesis, is catalyzed by prenyltransferases. These enzymes are responsible for the condensation of isopentenyl pyrophosphate (IPP) with an allyl pyrophosphate, thus yielding isoprenoids. Numerous studies have been performed with fluorinated substrates in order to determine the mechanism of the reactions that involve these enzymes prenyltransferases, farnesyl diphosphate synthase (FDPSase), famesyltransferase (PFTase), and IPP isomerase. These studies are based on the potential ability of fluorine atoms to destabilize cationic intermediates, and then slow down S l type processes in these reactions. 

In the sesquiterpene series, similar cyclizations lead to an amazing variety of products. After the initial unfavourable allylic rearrangement of the pyrophosphate group, farnesyl pyrophosphate can give a six-membered ring cation known as the bisabolyl cation. 

Studies of the precursor-product relationship in various biogenetically related humulene-derived metabolites have led to a unified scheme (equation 5) in which intramolecular cyclization of trans,trans-farnesyl pyrophosphate (73) generates humulene (74) by the attack at C(ll) of the distal double bond and loss of a proton from C(9) reprotonation at C( 10) of the key intermediate initiates further cyclization to a cyclobutyl-containing protoilludyl cation (75). Subsequent bond migration accompanied by contraction of the cyclobutane ring to the cyclopropane as shown, would then yield illudins. In accordance with the postulated pathway of illudin formation, C(l), C(14) and one of the... 

A variety of substrate analogs have been tested with microsomal squalene synthetase, and these have served to determine some of the specificity parameters for binding and reacting in this system. The requirement for the pyrophosphate moiety is absolute since farnesyl monophosphate does not participate in the reaction. It is not known if the divalent cation requirement is for binding and/or catalysis [67]. 

The essential oil of Echinops giganteus var. lelyi, a culinary herb from Cameroon, contains many sesquiterpenoids. The most abundant (26.9% of the oil) is silphiperfol-6-ene, (P24.1). The biogenesis of this material from farnesyl pyrophosphate is enzyme mediated but the chemistry of the enzymatic reactions follows the basic principles of carbocation mechanisms (Figure P24). Initial cyclisation of farnesyl pyrophosphate gives the cation (P24.2). Suggest a sequence of cationic reactions which could lead from (P24.2) to (P24.1). This is a particularly difficult problem. If you would like a hint (without having to look at the solution) one will be found at the end of the problems section. 

Of the carbocyclic sesquiterpenes found in Eremophila, the most elaborate are the tetracyclic enr-zizaenes (89,90,92,93). One possible sequence for the assembly of such a nucleus is given in Scheme 24. Cyclization of 2E,6Z-farnesyl pyrophosphate between the 1 and 6 position would generate the bisabolonium cation equivalent which, after a hydride shift, could further cyclize to a spiro carbocation. The tricyclic ring system can then be assembled by invoking alkylation of the cyclohexene double bond. The tertiary carbocation generated incorporates a bicyclo[3.2.1]octane system which can rearrange in two ways leading to the tricyclic sesquiterpenes metabolites found in Eremophila. 

Biosynthesis Farnesyl diphosphate is converted to trails- fi-hergamotene by cyclization of an intermediate bisabolyl cation. Oxidative ring opening followed by three specific oxidation reactions leads to O.. ... 

The taU-to-tail coupling of two farnesyl diphosphate molecules leads via a cyclopropane intermediate to squalene. The primary cyclopropane derivative, presqualene diphosphate, cleaves off the diphosphate residue, and the resulting cyclopropylmethyl carbocation opens the ring again. The aUyl cation is reduced by NADPH to squalene. 

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