Famesyl diphosphate, cyclization

Propose a mechanism for the biosynthesis of the sesquiterpene trichodiene from famesyl diphosphate. The process involves cyclization to give an intermediate secondary carbocation, followed by several carbocation rearrangements. 

Most of the compounds shown in Figure 22-4 are derived from the C15 famesyl diphosphate. There are more than 300 known cyclic structures among these sesquiterpenes, and many sesquiterpene synthases have been characterized.91/91a Aristolochene is formed by the action of a 38-kDa cyclase that has been isolated from species of Penicillium and Aspergillus,92"4 Notice that the synthesis must involve two cyclization steps and migration of a methyl group. Three-dimensional structures are known for at least two terpene synthases,95 96 and comparison of gene sequences suggests that many others have similar structures. 

Figure 10.8 Famesyl diphosphate (FPP) can be cyclized in many different ways by sesquiterpene synthases giving rise to different classes of sesquiterpenes. The eremophilane class of sesquiterpenes has received considerable attention because the genes coding for the corresponding synthase enzymes were the first to be isolated. 25...

Draw famesyl diphosphate in the configuration that resembles the product, then draw its allylic isomer (the mechanism for the formation of the isomer is shown in Problem 27.7). In this reaction, a cyclization, followed by loss of a proton to form the double bond, gives helminthogermacrene. 

Modification of enzymes involved in the synthesis from universal precursors of other secondary metabolites has also been demonstrated. The sesquiterpene synthases are a large family of enzymes that act by a common mechanism and catalyze the cyclization of famesyl diphosphate, each to form a distinct sesquiterpene. The active site of the synthase that produces trichodiene, the... 

Sesquiterpenes are formed from three C5 units where a further molecule IPP reacts with GPP to form famesyl diphosphate (famesyl pyrophosphate, FPP). FPP is further converted to linear or cyclic products. By cleaving the diphosphate group, an allylic cation is produced that underlies an electrophilic attack on the central or distal double bond leading to cyclization. Due to the increased chain length and an additional double bond, a huge number of structures can be built up. Sesquiterpene cyclase enzymes typically produce a major product accompanied by a range of related structures [44]. 

Biosynthesis of the sesquiterpene antibiotic albaflavenone in Streptomyces codicolor A3(2) was studied in detail. The mechanism and stereochemistry of the enzymatic formation of epi-isozizaene by multistep cyclization of famesyl diphosphate was investigated [101] and a P450 (CYP170A1) was identified to carry out two sequential allylic oxidations to convert epi-isozizaene to an epimeric mixture of albaflavenols and thence to albaflavenone [102],... 

Analogous processes involving cyclizations and rearrangements of carbocations derived from famesyl diphosphate produce a rich variety of structural types in the sesquiterpene series. We will have more to say about the chemistry of higher terpenes, especially the triterpenes, later in this chapter. For the moment, however, let s return to smaller molecules to complete the picture of how isoprenoid compounds arise from acetate. 

The next series of steps involves the combination of IPP units to form geranyl diphosphate, famesyl diphosphate, and geranylgeranyl diphosphate, which serve as the precursors of the mono-, sesqui- and diterpene families, respectively [Figure 4.9]. In effect, all of the other members of these families arise from the cyclization or secondary modification of these three precursors. 

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