Farnesol pyrophosphate

Farnesol pyrophosphate is an immediate precursor of squalene, the key intermediate in steroid and triterpenoid biogenesis, which arises from the coupling of two farnesol pyrophosphate molecules or of C,s units derived therefrom. The numerous types of sesquiter-penoid carbon skeletons represent various modes of cyclization of farnesol (sometimes with rearrangement) and it is probable that farnesol pyrophosphate is also the source of these compounds. 

The biosynthesis of the insect juvenile hormone (19) continues to present incorporation problems. The acid 10-epoxy-7-ethyl-3,ll-dimethyltrideca-2,6-dienoic acid (20) acts as a substrate for the hormone in the giant silk moth, Hyalopkora cecropia. L-Methionine gave the ester methyl group. However, it did not contribute to the carbon skeleton whilst farnesol, farnesol pyrophosphate, propionate, and mevalonate were apparently not utilized for the biosynthesis of the hormone under the conditions of these experiments. There was a very low incorporation of [2- C]acetate into juvenile hormone. 

Hydrolysis of the pyrophosphate ester group converts farnesyl pyrophosphate to the corresponding alcohol farnesol (see Figure 26 6 for the structure of farnesol)... 

The enzyme catalyzed reactions that lead to geraniol and farnesol (as their pyrophosphate esters) are mechanistically related to the acid catalyzed dimerization of alkenes discussed m Section 6 21 The reaction of an allylic pyrophosphate or a carbo cation with a source of rr electrons is a recurring theme m terpene biosynthesis and is invoked to explain the origin of more complicated structural types Consider for exam pie the formation of cyclic monoterpenes Neryl pyrophosphate formed by an enzyme catalyzed isomerization of the E double bond m geranyl pyrophosphate has the proper geometry to form a six membered ring via intramolecular attack of the double bond on the allylic pyrophosphate unit... 

The biosynthesis of the juvenile hormones is not yet fully known. Their similarity to famesol, an intermediate product in the biosynthesis of steroles in mammals, leads one to assume that their formation is analogous to that of farnesol. This obvious assumption seems to be supported by publications that have appeared in the early 1970s. Barnes and Goodfellow (1971) showed that isoprenoid biosynthesis in the larva of Sarcophaga bullata proceeds with the participation of mevalonate kinase. This enzyme regulates the formation of mevalonic acid pyrophosphate, an important intermediate product in steroid biosynthesis of mammals. Isopentenyl pyrophosphate, the C, unit of isoprenoid biosynthesis, is formed from mevalonic acid pyrophosphate by decarboxylation and, with the participation of ATP, by dehydration. 

As a general rule, natural products derived from isoprenoid units arise from head-to-tail reactions of that synthon. The majority of the structures of such products built up by condensation of IPP will as a result display a branched methyl on every fifth atom in the chain. Thus, reaction of IPP (1-5) with the isomer with the internal double bond (1-6) proceeds by head-to-tail coupling with expulsion of a pyrophosphate ion. The free alcohol from the product 2-1 (Scheme 2.2) is the fragrant terpene geraniol. Reaction of 2-1 with a second isoprene unit in this case again takes place by head-to-tail reaction to afford 2-2. The free alcohol from this 15-carbon triene is known as farnesol and is generally classed as a sesquiterpene (Latin sesqui-, one and a half). The molecule is displayed in the unlikely conformation 2-2b, in anticipation of the next reaction. 

Hydrolysis of geranyl pyrophosphate and farnesyl pyrophosphate produces the terpenes geraniol and farnesol, respectively (Fig. 12.74). 

Germacrene C 4.64) has been shown to derive from mevalonate and 2- raw5-farnesol 4.60). Its formation can be seen to be the result of displacement of pyrophosphate from C-1 of farnesyl pyrophosphate 4.63) by the distal double bond. Scheme 4.13. An oxygenated relative of 4.64), ageratriol has been shown to derive similarly via oxygenated intermediates [75, 76]. Further cyclization of the germacrene skeleton [as (4.64)] would afford compounds of type (4.4). On the other hand caryophyllene 4.66), known to be derived from mevalonate, is expected to derive from 2-m-farnesol (4.65) in a dif-... 

According to the biogenetic isoprene rule, sesquiterpenes arise from a linear precursor such as farnesol. There is considerable biosynthetic evidence to support this, and farnesyl pyrophosphate is considered as the immediate biosynthetic precursor of almost all sesquiterpenoids (110, 263). Conceptually, cyclization of farnesyl pyrophosphate can proceed from either the tail end (by ionization of the pyrophosphate moiety) or the head (by a or OH" attack on A ), Both... 

Open chain sesquiterpenes are relatively rare. Farnesol is an example and is an important component of the scent of lily of the valley and lime blossom. It is probably formed from farnesyl pyrophosphate by cleavage of the pyrophosphate group. We shall not give any further consideration to the cyclic sesquiterpenes either except to mention the phytohormone abscisic acid (page 210) as an example. 

LiAFH4 reduces a,)8-unsaturated aldehydes to the corresponding allylic alcohols in a 1,2-addition mode, as demonstrated with the synthesis of , -[l- H]farnesol (276, R = H), a precursor of ,/i-[l- H]farnesyl pyrophosphate (276, R = On the other... 

In a similar experiment, all-/ra .y-[l,5,9- H5,4,8,12- " C3]farnesyl pyrophosphate prepared enzymatically from [5- H2,2- " C]mevalonic acid was incubated with the cell-free preparation. From three isolated products, all-/ra .y-farnesol retained all six tritium atoms, whereas only five labels were present in 2-cw-6-rra 5-farnesol as well as in trichodiene (66). Thus, the isomerization and cyclization of all-/ra 5-farnesyl pyrophosphate takes place with the loss of one hydrogen atom. Bearing in mind the earlier... 

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