Cyclization farnesyl diphosphate

By far the most impressive example of electrophilic addition in natural prodnct formation is in the biosynthesis of steroids. The snbstrate sqnalene oxide is cyclized to lanosterol in a process catalysed by a single enzyme. Lanosterol is then converted into the primary animal-steroid cholesterol. Sqnalene oxide comes from sqnalene, which is itself formed throngh a combination of two molecules of farnesyl diphosphate. 

A descriptor for an enzyme active site that permits binding of a family of related compounds (e.g., mimics of the reaction intermediate) that can be derived from the initial binding and conformational changes in the substrate. This concept arose from the observation that a number of monoterpene cyclases were incapable of discriminating between enantiomers of the reaction intermediate, even though the enzyme catalyzes the synthesis of an enantiomerically pure product from an achiral substrate. An example is trichodiene synthase which catalyzes the cyclization of farnesyl diphosphate to trichodiene. 

Sesquiterpenoids (Sq) are Cj5 compounds formed by the assembly of three isoprenoid units. They are found in many living systems but particularly in higher plants. There are a large number of sesquiterpenoid carbon skeletons, which arise from the common precursor, farnesyl diphosphate, by various modes cyclization followed, in many cases, by skeletal rearrangement. 

The genetic engineering of qinghao (4. annua) has also been paid great attention recently some preliminary results about the early stage of qinghaosu biosynthesis have been reported. For example, amorpha-4,11-diene synthase, an enzyme responsible for the cyclization of farnesyl diphosphate into ring sesquiterpene, has been expressed in Escherichia coli and production of amorpha-4,11-diene (122) was identified. °... 

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

The first step taken in the biosynthetic pathway of artemisinin was the cyclization of the general mevalonate pathway originated sesquiterpenoid precursor farnesyl diphosphate (FPP) into IS, 6R, 7R, i0it)-amorpha-4,ll-diene by amorpha-4,11-diene synthase (AMDS) (Fig. 4) [6-8]. The crystal structure of this sesquiterpene synthase is not known. From aU plant... 

The isomerization of farnesyl diphosphate (5.10) to nerolidol diphosphate (5.11) has been examined in a cell-free system from Gibberella fujikuroi. The cyclization of nerolidol diphosphate to cyclonerodiol (5.12) and the conversion of the latter into cyclonerotriol (5.13) have been observed in Fusarium culmorum. 

B. cinerea. In this experiment one of the plausible modes of cyclization and rearrangement of the multiply-labelled farnesyl diphosphate leads to bond formation and hence to coupling between carbon atoms that had their... 

The biosynthesis of the illudins from C-acetates and variously stereo-specifically labelled mevalonates has been studied. The results are in accord with the cyclization of farnesyl diphosphate set out in 5.59 5.65. 

Andibenin B (117) is a highly oxidized meroterpenoid produced by the fungus Aspergillus variecolor. On the basis of the biosynthetic study,it was proposed that a plausible intermediate 115 from Claisen rearrangement of 114 affords the adduct 116 via the intramolecular inverse-electron demand [4 - - 2] cycloaddition as shown in Scheme 19(b). In this case, an enzyme catalyzes the cyclization of the terpene part on intermediate 114 derived from farnesyl diphosphate, and benzoates might provide the reactive dienophile 116. 

Biosynthesis By cyclization of farnesyl diphosphate, rearrangement, and subsequent elimination. 

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.. ... 

Analogous processes involving cyclizations and rearrangements of carbocations derived from farnesyl 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 pattern of substitution of both P-eudesmol and a-santonin can be accounted for by assuming that the cyclization of farnesyl diphosphate, followed by (or preceded by) suitable oxidation changes at allylic positions, is as shown in Scheme 11.50. 

Scheme 11.50. A cartoon representation of the organization of farnesyl diphosphate that, on oxidation and cyclization (or cyclization and oxidation), produces both P-eudesmol and a-santonin.

Flexibilene is a terpene isolated from Sinulaha flexibilis, a soft coral found In the Indian Ocean. Draw a stepwise mechanism for the formation of flexibilene from farnesyl diphosphate and isopentenyl diphosphate. What is unusual about the cyclization that forms the 15-membered ring of flexibilene ... 

Farnesyl diphosphate is cyclized to sesquiterpene A, which is then converted to the bicyclic product epi-aristolochene. Write a stepwise mechanism for both reactions. 

FIGURE 7.4 Crystal structure of (a) bisabolene synthase active center bound to farnesyl diphosphate inhibitor (b) aristolochene synthase cocrystallized with FDP (metal coordination and hydrogen bonds are shown as dashed lines magnesium anions and water molecules are shown as spheres) and the proposed catalytic mechanisms for each cyclization Images created with PyMOL. (See insert for color representation of the figure.)... 

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. 

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