Monoterpenes C10

Combination of DMAPP and IPP via the enzyme prenyl transferase yields geranyl diphosphate (GPP) (Figure 5.8). This is believed to involve ionization of DMAPP to the allylic cation, addition to the double bond of IPP, followed by loss of a proton. Stereochemically, the proton lost (HÄ) is analogous to that lost on the isomerization of IPP to DMAPP. This produces a monoterpene diphosphate, geranyl PP, in which the new double bond is trans (E). Linalyl PP and neryl PP are isomers of geranyl PP, and are likely to be formed from geranyl PP by ionization to the allylic cation, which can thus allow a change in attachment of the diphosphate group (to the tertiary carbon in linalyl n

DMAPP

electrophilic addition giving tertiary cation

stereospecific loss of proton geranyl PP (GPP)

Figure 5.8

Isomerized Gpp

geranyl PP (GPP)

geranyl PP (GPP)

resonance-stabilized allylic cation (geranyl cation)

single bond in LPP allows rotation

linalyl PP (LPP)

neryl PP (NPP)

neryl PP (NPP)

resonance-stabilized allylic cation (geranyl cation)

resonance-stabilized allylic cation (neryl cation)

Figure 5.9

PP) or a change in stereochemistry at the double bond (to Z in neryl PP) (Figure 5.9). These three compounds, by relatively modest changes, can give rise to a range of linear monoterpenes found as components of volatile oils used in flavouring and perfumery (Figure 5.10). The resulting compounds may be hydrocarbons, alcohols, aldehydes, or perhaps esters, especially acetates.

The range of monoterpenes encountered is extended considerably by cyclization reactions, and monocyclic or bicyclic systems can be created. Some of the more important examples of these ring systems are shown in Figure 5.11. Such cyclizations would not be expected to occur with the precursor geranyl diphosphate, the E stereochemistry of the double bond being unfavourable for ring formation (Figure 5.9). Neryl PP or linalyl PP, however, do have favourable stereochemistry, and either or both of these would seem more immediate precursors of the monocyclic menthane system, formation of which could be represented as shown in Figure 5.12, generating a carbocation (termed menthyl or a-terpinyl) having the menthane skeleton. It has been found that monoterpene cyclase enzymes are able to accept all three diphosphates, with linalyl PP being the best substrate, and it appears they have the ability to isomerize the substrates initially as well as to cyclize them. It is convenient therefore to consider the species involved in the cyclization as the delocalized allylic cation tightly bound to the diphosphate anion, and bond formation follows due to the proximity of the n-electrons of the double bond (Figure 5.12).

In Chapter 2, the possible fates of carbocations were discussed. These include quenching with nucleophiles (especially water), loss of a proton,

geranial (Z-citral ) (lemon oil)

citronellal (citronella oil)

geranial (Z-citral ) (lemon oil)

citronellal (citronella oil)

Enantiomer Citronellol

citronellol (rose oil)

geraniol (geranium oil)

P-myrcene (hops)

,OPP

citronellol (rose oil)

geraniol (geranium oil)

linalool (coriander oil)

Figure 5.10

pinane type camphane / bornane type neral (£-citral) (lemon oil)

nerol (rose oil)

nerol (rose oil)

menthane type isocamphane type camphane / bornane type

Cationic Cyclization Mechanism
carane type thujane type

MONOCYCLIC

BICYCLIC Figure 5.11

cyclization, and the possibility that Wagner -Meerwein rearrangements might occur (see page 15). All feature strongly in terpenoid biosynthesis. The newly generated menthyl cation could be quenched by attack of water, in which case the alcohol a-terpineol would be formed, or it could lose a proton to give limonene (Figure 5.13). Alternatively, folding the cationic side-chain towards the double bond (via the surface characteristics of the enzyme) would allow a repeat of the cyclization mechanism, and produce bicyclic bornyl and pinyl cations, according to which end of the double bond was involved in forming the new bonds (Figure 5.14). Borneol would result from quenching of the bornyl cation with water, and then oxidation of the secondary

.OPP

electrophilic addition giving tertiary cation delocalized allylic cation- menthyl / a-terpinyl cation diphosphate ion-pair

Figure 5.12

menthyl / a-terpinyl cation

limonene

cyclization

cyclization

,OH a-terpineol

cineole

"Y- TH although the menthyl cation is gl^X tertiary, the 1,3-shift creates a resonance-stabilized allylic cation

W-M 1,3-hydride phellandryl cation

a-phellandrene

W-M = Wagner-Meerwein rearrangement

ß-phellandrene shift

Figure 5.13

alcohol could generate the ketone camphor. As an alternative to discharging the positive charge by adding a nucleophile, loss of a proton would generate an alkene. Thus a-pinene and P-pinene arise by loss of different protons from the pinyl cation, producing the double bonds as cyclic or exocyclic respectively. A less common termination step involving loss of a proton is the formation of a cyclopropane ring as exemplified by 3-carene and generation of the carane skeleton.

The chemistry of terpenoid formation is essentially based on the reactivity of carbocations, even though, in nature, these cations may not exist as such discrete species, but rather as tightly bound ion pairs with a counter-anion, e.g. diphosphate. The analogy with carbocation chemistry is justified, however, since a high proportion of natural terpenoids have skeletons which have suffered rearrangement processes. Rearrangements of the Wagner - Meerwein type (see page 15), in which carbons or hydride migrate to achieve enhanced stability for the cation via tertiary against secondary character, or by reduction of ring strain, give a mechanistic rationalization for the biosynthetic pathway. The menthyl cation, although it is a tertiary, may be converted by a 1,3-hydride shift into a favourable resonance-stabilized allylic cation (Figure 5.13). This allows the formation of a- and P-phellandrenes by loss of a proton from the phellandryl carbocation. The bicyclic pinyl cation, with a strained four-membered ring, rearranges to the less strained five-membered fenchyl cation (Figure 5.14), a change which presumably more than makes up for the unfavourable tertiary to secondary carbocation transformation. This produces the fenchane skeleton, exemplified by fenchol and fenchone. The isocamphyl tertiary carbocation is formed from the bornyl secondary carbocation by a Wagner - Meerwein rearrangement, and so leads to camphene. A hydride shift converting the menthyl cation into the terpinen-4-yl cation only changes one tertiary carbocation system for another, but allows formation of a-terpinene, y-terpinene, and the a-terpineol isomer, terpinen-4-ol. A further cyclization reaction on the terpinen-4-yl cation generates the thujane skeleton, e.g. sabinene and thujone. Terpinen-4-ol is the primary antibacterial component of tea tree oil from Melaleuca alternifolia (Myrtaceae); thujone has achieved notoriety as the neurotoxic agent in wormwood oil from Artemisia absinthium (Compositae/Asteraceae) used in preparation of the drink absinthe, now banned in most countries.

So far, little attention has been given to the stereochemical features of the resultant monoter-pene. Individual enzyme systems present in a particular organism will, of course, control the folding of the substrate molecule and thus define the stereochemistry of the final product. Most menthyl / a-terpinyl cation

1,2-shift creates pinyl secondary cation, but cation reduces ring strain

\W-M 1,2-alkyl shift

1,2-shift produces another tertiary cation

W-M 1,2-hydride shift formation of I @ cyclopropane 1 - H ring fenchyl cation a-pinene ß-pinene fenchyl cation fenchone

fenchol

fenchone fenchol

bornyl 1,2-shift creates cation tertiary cation

car-3-ene borneol

camphor camphene

terpinen-4-yl cation

isocamphyl cation

a-terpinene y-terpinene terpinen-4-ol thujyl cation

thujone

reduction thujyl cation

reduction

sabinene thujone sabinene

monoterpenes are optically active, and there are many examples known where enantiomeric forms of the same compound can be isolated from different sources, e.g. (+)-camphor in sage (Salvia officinalis; Labiatae/Lamiaceae) and (—)-camphor in tansy (Tanacetum vulgare; Com-positae/Asteraceae), or (+)-carvone in caraway (Carum carvi; Umbelliferae/Apiaceae) and (- )-carvone in spearmint (Mentha spicata; Labiatae/ Lamiaceae). There are also examples of compounds found in both enantiomeric forms in the same organism, examples being (+)- and (-)-limonene in peppermint (Mentha x piperita; Labiatae/Lamiaceae) and (+)- and (—)-a-pinene in pine (Pinus species; Pinaceae). The individual enantiomers can produce different biological responses, especially towards olfactory receptors in the nose. Thus the characteristic caraway odour is due to (+)-carvone whereas (—)-carvone smells of spearmint. (+)-Limonene smells of oranges whilst (—)-limonene resembles the smell of lemons. The origins of the different enantiomeric forms of limonene and a-pinene are illustrated in Figure 5.15. This shows the precursor geranyl PP being folded in two mirror image conformations, leading to formation of the separate enantiomers of linalyl PP. Analogous carbocation reactions will then explain production of the optically active monoterpenes. Where a single plant produces both enantiomers, it appears to contain two separate enzyme systems each capable of elaborating a single enantiomer. Furthermore, a single enzyme typically accepts geranyl PP as substrate, catalyses the isomerization to linalyl PP, and converts this into a final product without the release of free intermediates. Sometimes, multiple products in varying

GPP can be folded in two different ways, thus allowing generation of enantiomeric LPP molecules

cation

a-terpinyl

a-terpinyl cation

a-terpinyl cation cation rf

pinyl cation

pinyl cation amounts, e.g. limonene, myrcene, a-pinene, and P-pinene, are synthesized by a single enzyme, reflecting the common carbocation chemistry involved in these biosyntheses, and suggesting the enzyme is predominantly providing a suitable environment for the folding and cyclization of the substrate. Subsequent reactions such as oxidation of an alcohol to a ketone, e.g. borneol to camphor (Figure 5.14), or heterocyclic ring formation in the conversion of a-terpineol into cineole (Figure 5.13), require additional enzyme systems.

In other systems, a particular structure may be found as a mixture of diastereoisomers. Peppermint (Mentha x piperita ; Labiatae/Lamiaceae) typically produces (—)-menthol, with smaller amounts of the stereoisomers (+)-neomenthol, (+)-isomenthol, and (+)-neoisomenthol, covering four of the possible eight stereoisomers (Figure 5.16). Oils from various Mentha species also contain significant amounts of ketones, e.g. (—)-menthone, (+)-isomenthone, (—)-piperitone, or (+)-pulegone. The metabolic relationship of oxidation

allylic hydroxylation oxidation

(-)-limonene allylic hydroxylation

(-)-trans-carveol (-)-carvone oxidation

"OH

allylic isomerization

(-)-isopiperitenone allylic isomerization

^-cymene

(-)-trans-isopiperitenol

(-)-isopiperitenone reduction

Piperitone

piperitenone reduction

(+)-piperitone piperitenone reduction

(+)-piperitone reduction (+)-neomenth°l

(+)-cis-isopulegone allylic isomerization reduction

(+)-pulegone reduction reduction

reduction

(-)-menthol (levomenthol)

(-)-menthol (levomenthol)

(+)-cis-isopulegone

(+)-pulegone reduction ring formation

(-)-menthone reduction

reduction

thymol carvacrol thymol

(+)-menthofuran

(+)-isomenthone (+)-isomenthol

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Responses

  • Eemil
    Which step involves an electrophilic alkene addition geranyl diphosphate limonene?
    8 years ago

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