Farnesyl cyclization

Analogous processes involving cyclizations and rearrangements of carbocations derived from farnesyl pyrophosphate produce a rich variety of structural types m the... 

Bark beetles primarily utilize isoprenoid derived pheromones [100,101] and have been the most studied regarding their biosynthesis [8,98]. Earlier work indicated that the isoprenoid pheromones could be produced by the beetle altering host derived isoprenoids however more recent work indicates that for the most part bark beetles are producing pheromones de novo. The production of isoprenoids follows a pathway outlined in Fig. 4 which is similar to the isoprenoid pathway as it occurs in cholesterol synthesis in mammals. Insects cannot synthesize cholesterol but can synthesize farnesyl pyrophosphate. Insects apparently do not have the ability to cyclize the longer chain isoprenoid compounds into steroids. The key enzymes in the early steps of the isoprenoid... 

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. 

A detailed account of the chemical and spectroscopic evidence for the structures of cochlioquinone-A (18a) and -B (18b) has been published. These compounds are metabolites of Cochliobolus miyabeanus, a parasitic mould which grows on rice, and their unusual cyclofarnesane structure is probably derived in nature by introduction of a farnesyl unit into an aromatic precursor followed by cyclization of an intermediate bis-epoxide. 

A recent X-ray crystallographic study has resulted in a revised structure (98) for nidifocene, a minor metabolite of the Hawaiian marine alga Laurencia nidifica. In the previous structure (Vol. 7, p. 69) the positions of chlorine and bromine were reversed. An extension of previous work on the non-enzymic biogenetic cyclization of geranyl and farnesyl diphenylphosphates has shown that (Z)-monocyclo-farnesyl diethylphosphate (99) can be converted into ( )-a-chamigrene (100) in... 

In green plants, which contain little or no cholesterol, cydoartenol is the key intermediate in sterol biosynthesis.161-1623 As indicated in Fig. 22-6, step c, cydoartenol can be formed if the proton at C-9 is shifted (as a hydride ion) to displace the methyl group from C-8. A proton is lost from the adjacent methyl group to close the cyclopropane ring. There are still other ways in which squalene is cyclized,162/163/1633 including some that incorporate nitrogen atoms and form alkaloids.1631 One pathway leads to the hop-anoids. These triterpene derivatives function in bacterial membranes, probably much as cholesterol does in our membranes. The three-dimensional structure of a bacterial hopene synthase is known.164 1643 Like glucoamylase (Fig. 2-29) and farnesyl transferase, the enzyme has an (a,a)6-barrel structure in one domain and a somewhat similar barrel in a second domain. 

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... 

If sterol content and conformation are so important for membrane stability, we should study the biosynthesis of sterols (Figure 3). The first enzyme in terpenoid biosynthesis is the 3-Hydroxy-3-Methyl-Glutary1-Coenzyme A-reductase (HMG-CoA-reductase) that catalyzes the synthesis of mevalonate. Two phosphorylations and decarboxylation of mevalonate lead to isopentenylpyrophosphate, the basic C -unit in sterol synthesis. Isopentenylpyrophosphate reacts with its isomer, the dimethylally1-pyrophosphate, in a head/tail-reaction to geranyl-pyrophosphate reaction with another C -unit leads to farnesyl-pyro-phosphate, that dimerizes in a tail/tail-reaction to squalene. After expoxidation of its A -double bond, squalene cyclizes to lano-... 

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. 

Alternative Cyclization of Farnesyl Pyrophosphate Section 28.3 Figure 28.5... 

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. 

Classified into the chemical group sesquiterpenes, trichothecene skeleton is constructed from farnesyl pyrophosphate (FPP) with two rounds of cyclization237-239 Isotrichodiol (ITdiol)240 is a branching-point intermediate of Fusarium trichothecenes and non-Fusarium trichothecenes that precedes the second cyclization. In this section, we summarize outlines of trichothecene biosynthesis focusing on those of Fusarium species. 

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. °... 

FPP is necessary for the synthesis of both sterols and longer chain nonsterol isoprenoids. The first committed step in sterol synthesis is catalyzed by the enzyme squalene synthesis and involves the head-to-head condensation of two FPP molecules to form squalene [15]. This is followed by cyclization steps, leading to sterol synthesis. The addition of IPP to FPP via the enzyme GGPP synthase yields the 20-carbon GGPP [16]. FPP and GGPP are substrates in the prenylation reactions catalyzed by the enzymes farnesyl transferase (FTase) and geranylgeranyl transferase (GGTase) I and II [17-20]. 

Further biosynthetic studies by Cane et have shown that the conversion of farnesyl pyrophosphate (15) into nerolidyl pyrophosphate (16) proceeds by a net syn (suprafacial) process and that the subsequent cyclization to cyclonerodiol (17) occurs in a trans manner (Scheme 4). This careful piece of work was achieved by incorporation studies with doubly labelled nerolidol and mevalonate precursors and then by ascertaining the chirality of the acetate derived by Kuhn-Roth oxidation through enzymatic conversion (malate synthase/fumarase incubation) into labelled malate. In a subsequent series of experiments with labelled precursors, Cane et have confirmed that (i) only the C-7 hydroxy-group in cyclonerodiol is derived from water whereas the C-3 hydroxy-group is derived... 

The potent biological activity (insect antifeedant, antitumour, antifungal) of warburganal (35) has stimulated considerable synthetic interest in this compound. Three total syntheses of this compound have been recorded in the period under review. " The synthesis by Tanis and Nakanishi has additional flexibility since the key intermediate diol (34) can be used in the syntheses of cinnamolide (36), drimenin (37), and polygodial (38). Both norisoambreinolide (39 R = O) and isoambrox (39 R = H2) have been synthesized from (40), the product of the stannic chloride-catalysed cyclization of farnesyl phenyl sulphone. Yahazunol (41), a bicyclofarnesyl hydroquinone, has been identified in the brown seaweed... 

Chromazonarol, a minor constituent of the brown Pacific seaweed, has been synthesized using LBA-promoted enantiose-lective cyclization. The cyclization of 4-benzy loxyphenyl farnesyl ether with (5)-LBA gives the desired tetracyclic compound as the major diastereomer in 44% ee (eq 13). 

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

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... 

C(2) of mevalonic acid (56a) as well as the known absolute configuration of illudol, the stereochemical outcomes of the early steps can be inferred (equation 7) farnesyl pyrophosphate (73) cyclization has occurred exclusively on the si face of the distal double bond the humulene (74) cyclization must have occurred from the RSR-CT conformation and protonation at C(10) has taken place at the re face of the 9,10-double bond ... 

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