Lecture n.

THE TERPENES part I

NATURAL PRODUCT CLASSIFICATION

The secondary metabolites can be classified according to different features and properties:

ü Molecular structure (alifatic, aromatic, heterocyclic, glycosilated, etc.)

ü Physical-chemical properties (acid, basic, ionic, volatile, not volatile, etc.)
ü Pharmacological and sensorial properties (cytotoxic, topical anesthetic, anti-
inflammatory, antibacterical, antiviral, bitter, spicy, odorous, etc.)
ü Ecological properties (attractive, repellant, etc.)
ü Biosynthetic origin
 Secondary Metabolism: The Building Blocks and Construction Mechanisms 9

NATURAL PRODUCT CLASSIFICATION GLYCOLYSIS

OH OH PENTOSE PHOSPHATE
OH OH CYCLE OH
O O
PO
HO PO O PHOTOSYNTHESIS
The main metabolic pathways are: OH
OH OH
OH
OH erythrose 4-P
D-glucose glucose 6-P

OHC OH
CO2H
1. Pathways of the terpenes (isoprenoids, sterols and NH2 PO
CO2H

glycine glyceraldehyde 3-P NH2

L-phenylalanine
steroids, saponins, essential oils) HO2C OH
CO2H
CO2H
CO2H CO2H
HS HO
NH2
2. Pathways of the alkaloids NH2
L-cysteine
NH2
L-serine
PO
3-phosphoglyceric acid
HO
OH
OH HO
L-tyrosine
CO2H
SHIKIMIC ACID
3. Pathway of the acetate (fatty acids and derivatives, CO2H
HO2C OP
NH2

NH
NH2 L-tryptophan
anthracenes and quinons) L-valine
phosphoenolpyruvate
OH OH

CO2H OP
HO2C O OP
4. Pathway of the shikimic acid (aromatic amino acids, NH2 O OH OH OH
L-alanine pyruvic acid deoxyxylulose 5-P METHYLERYTHRITOL 4-P
OH
phenylpropanoids and lignans) CO2H CoAS O
NH2 HO2C
L-leucine OH
5. Other pathways… ACETYL-CoA
MEVALONIC ACID

KREBS CYCLE
CO2H CO2H CO2H HO2C CO2H HO2C CO2H
HO2C HO2C
NH2 NH2 O O NH2
To the metabolites coming from these pathways, we should L-isoleucine L-aspartic acid oxaloacetic acid 2-oxoglutaric acid L-glutamic acid

NH

add the natural products from mixed biogenesis (eg. S CO2H H2N CO2H
H2N N
H
CO2H
H2N
CO2H

NH2 NH2 NH2 NH2

L-methionine L-lysine L-arginine L-ornithine
Flavonoids and tannins, steroidal alkaloids, etc.).
Figure 2.1
 had been established as a precursor of the animal sterol for the biosynthesis of pyridoxal phosphate (vitamin B6 ,
cholesterol, and the steps leading to and from MVA page 32) and thiamine (vitamin B1 , page 31).
THE TERPENES
The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 189
Mevalonic acid Methylerythritol
phosphate
OH
geraniol (C10)

Hemiterpenes (C5)
OH OPP OPP
farnesol (C15)
dimethylallyl PP isopentenyl PP
(DMAPP) (C5) (IPP) (C5)
OH
geranylgeraniol (C20)
C10 Monoterpenes (C10)
Iridoids
IPP
squalene (C30)
C15 Sesquiterpenes (C15)

IPP
phytoene (C40) ×2
C20 Diterpenes (C20)

IPP
×2
OH
C25 Sesterterpenes (C25)

188 Medicinal Natural bisabolene

menthol (C )
Products:
10 (C )
A Biosynthetic
taxadiene (C )
Approach. 3rd Edition
15 20

C30 Triterpenoids (C30)

Figure 5.3

Three molecules of acetyl-coenzyme A are used to
form MVA. Two molecules combine initially in a Claisen
condensation to give acetoacetyl-CoA, and a third is
incorporated via a stereospecific aldol addition giving the
C5 isoprene unit
branched-chain ester 3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) (Figure 5.4). Two of the acetyl-CoA
molecules appear to be bound to the enzyme via a
Figure 5.1
thiol group. One linkage is broken during the Claisen
reaction and the second is subsequently hydrolysed to
The enzyme thus achieves what is a less favourable were gradually detailed in a series of painstakingly
reaction. The conversion of HMG-CoA into (3R)-MVA Steroids (C18−C30)
executed experiments. For many years, the early
involves a two-step reduction of the thioester group to
a primary alcohol via the aldehyde, and provides an
isoprene
essentially
parts of the
irreversible and rate-limiting transformation.
C40 mevalonate pathway were Tetraterpenes
believed(C40to) be
Carotenoids
Drug-mediated inhibition of this enzyme (HMG-CoA
reductase) is an important means of regulating the
common to the whole range of natural terpenoid
Figure 5.2steroid
derivatives in all organisms. However, after detailed
biosynthesis of mevalonate and ultimately
cholesterol (see statins, page 98).
of the
 The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 191

THE TERPENES CO2H

nucleophilic attack of
enamine onto aldehyde O
H
H
OH OH
O
H3C OH H3 C
190 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition O CO2 OP OP OP
pyruvic acid OH R1 OH O OH
R1
E1 N S D-glyceraldehyde E1 N S E1 1-deoxy-D-xylulose 5-P
thiamine PP 3-P
enzyme-bound (TPP) see Figure 2.16
acetyl group R2 R2 R1
stereospecific aldol reaction; N S TPP anion
Claisen H also involves hydrolysis of TPP/pyruvate-derived regenerated
O O H enamine
EnzSH reaction acetyl–enzyme linkage R2
O O OH
OH O
SCoA E1 SEnz N P
HO2C + EnzSH reduction of aldehyde to alcohol;
acetyl-CoA E1 SCoA E2 SCoA the aldehyde intermediate
O fosmidomycin
SCoA acetoacetyl-CoA remains enzyme-bound
acetyl-CoA 3-hydroxy-3-methylglutaryl-CoA reverse aldol aldol O
(HMG-CoA) OH reaction OH reaction OH OH
O SEnz NADPH
EnzSH
OP OP OP ≡ OP OP
acetyl-CoA enzyme-bound E2 HO E2
E2 O O O O O OH O OH OH OH
acetyl group H H
E3 NADPH 1-deoxy- 2-C-methyl-
D-xylulose 5-P D-erythritol 4-P
reduction of reduction of thioester
aldehyde to alcohol to aldehyde via nucleophilic attack of phosphate compare formation E3 CTP
6 hemithioacetal hydroxyl on diphosphate; of UDPglucose,
1 OH NADPH OH OH OH O formation of phosphoanhydride NH2 Figure 2.28
5 NH2
HO2C HO2C HO2C P
3 OH O E3 SCoA O OH O N N
2 4 E3 H OH O
OH
O O

mevalonic acid mevaldic acid mevaldic acid P P ATP P P

O O CH2 N O O CH2 N O
O O O
(MVA) hemithioacetal OH O OH OH O
OH OH OH E4 OH OH

E4 2-phospho-4-(CDP)- HO OH 4-(CDP)-2-C-methyl- HO OH
2 × ATP E5 2-C-methyl-D-erythritol D-erythritol
sequential O
phosphorylation of E5 CMP
the primary alcohol HO P O ADP stereospecific allylic
to a diphosphate ATP 5 isomerization O OH
OPP
O OH OH –CO2 H 1
OPP
3 O O O isopentenyl PP
2 P (IPP) +
H OPP P H+ H
O OPP E6 4 E7 OPP O OH OPP E7
E8
HR H S OH H OH
E6
OH
ATP facilitates the OPP OPP
decarboxylation–elimination; isopentenyl PP dimethylallyl PP 2-C-methyl-D-erythritol- 4-hydroxy-3-methyl-
2,4-cyclophosphate but-2-enyl diphosphate OPP H H H
phosphorylation of the tertiary (IPP) (DMAPP) minor
major
alcohol to make a better leaving dimethylallyl PP product product
(DMAPP)
group is apparently not involved
E1: 1-deoxy-D-xylulose 5-phosphate synthase (DXP synthase) E5: 2-C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF)
E1: acetoacetyl-CoA synthase E5: phosphomevalonate kinase E2: 2-C-methyl-D-erythritol 4-phosphate synthase; E6: 4-hydroxy-3-methylbut-2-enyl diphosphate synthase (IspG)
E2: 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) E6: mevalonate 5-diphosphate decarboxylase 1-deoxy-D-xylulose 5-phosphate reductoisomerase (IspC) E7: 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH)
E3: 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) E7: isopentenyl diphosphate isomerase (IPP isomerase) E3: 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (IspD) E8: isopentenyl diphosphate isomerase (IPP isomerase)
E4: 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE)
E4: mevalonate kinase
Figure 5.6
Figure 5.4
EP pathway OPP [1-13C]-D-glucose
HO via
OPP MVA pathway
194 Medicinal Natural Products: A Biosynthetic Approach.single
3rd Edition
bond in LPP
HO OH allows rotation
OPP
THE TERPENES
labelling of IPP
– hemiterpenes and monoterpenes OH
labelling of IPP E OPP
single bond in LPP
allows rotation
OPP
Z
via MEP pathway [1-13C]-D-glucose via MVA pathway OPP OPP OPP
OPP OPP
E ≡ Z OPP
OPP
ure 5.7 OPP
≡ OPP
geranyl PP linalyl PP neryl PP
– H+ (GPP) (LPP) (NPP)

H – H+ geranyl PP linalyl PP neryl PP

H (GPP) (LPP) (NPP)
E1 E1 E1 E1
allylic cation
allylic cation isoprene isoprene
OPP
OPP E2
+ H2O resonance-stabilized allylic cation resonance-stabilized allylic cation
DMAPP + H2O
HO (geranyl cation) (neryl cation)
DMAPP E2 E2 HO
Figureresonance-stabilized
5.10 allylic cation resonance-stabilized allylic cation
allylic cation E2
2-methyl-3-buten-2-ol (geranyl cation) (neryl cation)
E1: isoprene synthase
E2: methylbutenol synthase allylic Figure 5.10
cation 2-methyl-3-buten-2-ol OPP

ure 5.8 E1: isoprene synthase OPP

E1: geraniol synthase OPP
E2: methylbutenol synthase E2: geraniol dehydrogenase OPP
E3: linalool synthase OPP
E4: myrcene
E1: geraniol synthase synthase
electrophilic addition (GPPdehydrogenase
E2: geraniol is substrate for E1, E3, E4) GPP LPP OPP
NPP
giving tertiary cation E3: linalool synthase
E4: myrcene synthase
(GPP is substrate for E1, E3, E4) GPP LPP NPP
OPP E1 OPP
OH
OPP
DMAPP OH OH H O H 2O H2O
allylic cation HR HS HR H S 2
electrophilic addition stereospecific reduction E1 OH E3 OH
giving tertiary cation E1 loss of proton OH OH H O
2 H 2O H2O
E
citronellol geraniol geranyl cation nerol
OH neryl cation
E3 linalool
OPP reduction
(rose oil) (geranium oil)E1 (rose oil) (coriander oil)
OPP E1 OPP ≡ OPP
citronellol OPP
O NADP+ E2
geraniol geranyl cation
NADP+
nerol
E2 − H+ E4
neryl cation linalool
CH3COSCoA
E1: geranyl diphosphate synthase
PP allylic cation HR HS
geranyl PP
HR H S
(rose oil) (geranium oil) (rose oil) (coriander oil)
OAc
(GPP) +
O NADP
O E2 O NADP+ E2 − H+ E4 CH3COSCoA
stereospecific
ure 5.9 E1 loss of proton
reduction tautomerism O OAc
E O O via dienol?

ONOTERPENES (C10 ) OPP

indeed, the two reaction mechanisms are essentially reduction
the
(citronella oil)
citronellal
(lemon oil)
geranial (E-citral )
tautomerism neral O
(Z-citral)
(lemon oil)
β-myrcene
(hops)
linalyl acetate
(lavender oil)

≡ a proton and the other a carbocation.

via dienol?
same, one involving
yme-catalysed combination of DMAPP and IPP yields Figure OPP
citronellal 5.11 geranial (E-citral ) neral (Z-citral) β-myrcene linalyl acetate
This produces a monoterpene diphosphate, geranyl
(citronellaPP,
oil) in (lemon oil) (lemon oil) (hops) (lavender oil)
 isocamphane type
carane type thujane type
THE TERPENES
Figure 5.12
– hemiterpenes and monoterpenes
LPP is preferred substrate
electrophilic
addition giving
OPP tertiary cation
OPP
OPP

OPP

GPP LPP NPP delocalized allylic cation− menthyl/α-terpinyl

196 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition diphosphate ion-pair cation

Figure 5.13 cyclopropane

ring formation electrophilic addition electrophilic addition
creates 4-membered creates 5-membered The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 197
GPP ring and tertiary ring and secondary
has been demonstrated that the reactions proceed through
H
cyclase
carbocation enzymes are able to accept all three diphosphates,
carbocation Artemisia absinthium
the carbocation intermediates. Thus, geraniol is the result with linalyl PP being the best substrate, and it appears
of addition of water to the geranyl cation, and is not they have the ability to isomerize the substrates initially
formedmenthyl/α-terpinyl
by hydrolysis of GPP. + as well as to cyclize them. It is convenient, therefore, to
cation –H E4 H
The range of monoterpenes encountered is 1,2-shift creates
extended secondary
consider the species involved 1,2-shift creates
in the cyclization as the de- H
H 2O – H+ cation, but reduces ring strain tertiary cation W–M = Wagner–Meerwein
considerably
E1 byE2cyclization reactions, and monocyclic or localized allylic cation tightly bound to the diphosphate rearrangement
W–Manion, and bond formation follows W–M due to the proximity menthyl/α-terpinyl
bicyclic systems can be created. Some of the more im- 1,2-alkyl 1,2-alkyl cation although the menthyl cation 1,2-shift produces a W–M
W–M is tertiary, the 1,3-shift new tertiary cation 1,2-hydride
portant examples of these ring systems are shown inshift of the π-electrons of the double shift bond (Figure 5.13). 1,3-hydride creates a resonance- shift
Figure 5.12. A considerable amount of information about In Chapter 2, the possible fates of carbocations were shift stabilized allylic cation
the enzymes (terpene cyclases), genes, and cyclization discussed. These include quenching with nucleophiles
mechanisms
OH pinyl
is now available, providing a satisfactory fenchylwater), loss
(especially of a proton, isocamphyl
bornyl cyclization, and
cation cation cation cation
and detailed picture of these car-3-ene
natural products.
+
Cycliza- +
the possibility that Wagner–Meerwein rearrangements
α-terpineol – H – H
tions would notlimonene
be expected to occur with theE5precursor E5 might
H2Ooccur E6 (see page −
PPO 15). E7 All of these – Hfeature
+ strongly
GPP,
H+ the E stereochemistry of the double bond being un- in terpenoid biosynthesis, and examples are shown in terpinen-4-yl thujyl
favourable for ring formation (Figure 5.13). Neryl PP or Figures 5.14 and 5.15. The newly generated menthyl phellandryl cation cation cation
OH OPP – H+
linalyl PP, however, do have favourable stereochemistry, cation could be quenched by attack of water, in which case – H+
– H+ H2O
– H+ E3
– H+ E1
E2
and either or both of these would be more immediate the alcohol α-terpineol would be formed, or it could lose
precursors E3of the monocyclic menthane system, forma- a proton to give limonene (Figure 5.14). Alternatively,
α-pinene β-pinene fenchol
tion ofOHwhich could be O
represented as shown, generating folding the cationic bornyl PP
side-chain towardscamphene
the double bond O
a carbocation (termed menthyl or α-terpinyl) that has the (via the surface O characteristics
E8 of the enzyme) would al-
oxidation
menthane skeleton. It has been found
cineole W–M that monoterpene low a repeat of the cyclization mechanism and produce
= Wagner–Meerwein
OH +
rearrangement reduction
O OH O
E1: α-terpineol synthase E6: fenchol synthase O
E2: limonene synthase α-phellandrene β-phellandrene α-terpinene γ-terpinene terpinen-4-ol sabinene thujone
E7: bornyl diphosphate synthase
E3: 1,8-cineole synthase E8: bornyl diphosphate phosphohydrolase E9
E4: 3-carene synthase E9: borneol dehydrogenase E1: β-phellandrene synthase E3: sabinene synthase
E5: pinene synthase (GPP is substrate for E1−E7) fenchone borneol camphor E2: γ-terpinene synthase (GPP is substrate for all enzymes)

Figure 5.14 Figure 5.15

The menthyl cation, although it is a tertiary, may be substrate molecule and, thus, define the stereochemistry
THE TERPENES – hemiterpenes and monoterpenes The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 199
198 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition
oxidation
allylic HO O
NAD+
GPP can be folded in two different ways, thus hydroxylation
allowing generation of enantiomeric LPP molecules O2 E2
NADPH
OPP PPO
E1 (–)-trans-carveol (–)-carvone reduction O
OPP PPO E3 oxidation allylic
isomerization NADPH
O2 NAD+ (–)-piperitone
NADPH E6
GPP GPP (–)-limonene
OH E4 O E5 O NADPH
allylic
hydroxylation E6
OPP OPP OPP OPP (–)-trans- (–)-isopiperitenone piperitenone
isopiperitenol reduction O

OH
(+)-piperitone
NADPH E7 reduction

E1: (−)-limonene 6-hydroxylase reduction NADPH (+)-neomenthol

(–)-(3R)-LPP (+)-(3S)-LPP E2: (−)-trans-carveol dehydrogenase
E3: (−)-limonene 3-hydroxylase E8
E4: (−)-trans-isopiperitenol dehydrogenase NADPH
E5: (+)-cis-isopulegone isomerase reduction
E6: (+)-pulegone reductase allylic E9
E7: (−)-isopiperitenone reductase NADPH O OH
isomerization
− H+ − H+ E8: (−)-menthone:(+)-neomenthol reductase reduction
E9: (−)-menthone:(−)-menthol reductase E6
E10: (+)-menthofuran synthase (–)-menthone (–)-menthol
E5 (levomenthol)
O O NADPH
α-terpinyl α-terpinyl E6
reduction
cation (+)-(R)-limonene (–)-(S)-limonene cation (+)-cis- (+)-pulegone NADPH
isopulegone reduction
O E8 OH
E10 O2
allylic NADPH
hydroxylation (+)-isomenthol
(+)-isomenthone
− H+ − H+
E9
hemiketal NADPH
formation
− H2O
reduction
OH
pinyl (+)-α-pinene (–)-α-pinene pinyl O O O OH
cation cation OH

(+)-menthofuran (+)-neoisomenthol
Figure 5.16
Figure 5.17

α-pinene are illustrated in Figure 5.16. This shows reflecting the common carbocation chemistry involved
the precursor GPP being folded in two mirror-image in these biosyntheses. This suggests that the enzyme (+)-neoisomenthol,
is covering four of the possible eight specificity. The pathway also exemplifies that oxygen
THE TERPENES – hemiterpenes and monoterpenes
The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 205
The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 205

204 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition

O
CO2H CO2H O
CO2H CO 2H
R2
MeO2C R1 O R 2
chrysanthemic acid pyrethric acid HO
MeO2C R1 O
chrysanthemic acid pyrethric acid O
O regular monoterpene skeleton
OH R1 R2
HO HO HO R1Me R2CH=CH
HO HO HO pyrethrin I 2
pyrethrin I Me CH=CH2
cinerin I Me Me
p-cymene thymol
cinerin I MecarvacrolMe
O O O jasmolin I Me Et
Opyrethrolone Ocinerolone Ojasmolone jasmolin I Me Et
Figure 5.18 pyrethrin II CO2Me CH=CH2
pyrethrolone cinerolone jasmolone pyrethrin II CO2Me CH=CH2 irregular monoterpene skeletons
cinerin II CO2Me Me
cinerin II CO2Me Me
jasmolin II CO2Me Et Figure 5.19
further cytochrome P-450-dependent
jasmolin II oxidative
CO2Me modifica-
Et 204 Medicinal Natural Products: A Biosynthetic Approach
Figure 5.20 tion that leads to generation of a heterocyclic furan ring
Figure 5.20 via the hemiketal. Both pulegone and menthofuran are monoterpenes and seem to be limited almost exclusively
DMAPP electrophilic addition considered
loss of proton hepatotoxic. Pulegone is ofa phosphate
hydrolysis major constituent
ester; to members of the Compositae/Asteraceae HO plant family.
DMAPP giving tertiary cation lossofof oil
via of pennyroyal fromhydrolysis
cyclopropyl Menthaofpulegium,
oxidation of which
phosphatetoester;
alcohol acid has
electrophilic addition proton Allowing for possible rearrangements, the two isoprene
giving tertiary cation viaring formation
cyclopropyl oxidation of alcohol to
a folklore history as an abortifacient. Pulegone is me-acid
H ring formation units appear to have coupled in another manner, and this
OPP tabolized in humans first to menthofuran, by the same OH
H OPP is borne out by information available on their biosyn-
OPP OPP
DMAPP E1 OPP mechanism E1 as it is in the
OPP
plant pathway, and then CO to2H thesis, though this is far from complete. Thus, although
DMAPP E1 electrophilic
E1 metabolites that form adducts with cellu- CO2H DMAPP and IPP are utilized in their biosynthesis, GPP
chrysanthemyl PP chrysanthemic acid p-cymene thymol carvacrol
lar proteins (compare pyrrolizidine alkaloids, page 325). and neryl PP do not appear to be involved. Pre-eminent
E1: chrysanthemyl diphosphate synthase chrysanthemyl PP chrysanthemic acid
High menthofuran levels in peppermint oils are regarded amongst these structures are chrysanthemic acid and
(substrate
E1: DMAPP)
chrysanthemyl diphosphate synthase Figure 5.18
(substrate DMAPP) as undesirable. Peppermint plants transformed with an pyrethric acid (Figure 5.20), found in ester form as
Figure 5.21 antisense version of the menthofuran synthase gene pro- the pyrethrins (pyrethrins, cinerins, and jasmolins,
Figure 5.21 duce less than half the normal amounts of this metabo- Figure
further5.20), which are
cytochrome valuable insecticidal
P-450-dependent components
oxidative modifica-
radical oxidation and formation lite. intionpyrethrum flowers, the flower heads of Chrysan-
that leads to generation of a heterocyclic furan ring
of peroxide (compare Figure 3.23)
radical oxidation and formation
of peroxide (compare Figure 3.23)
p-Cymene and the phenol derivatives thymol and themum cinerariaefolium
via the hemiketal. (Compositae/Asteraceae)
Both pulegone and menthofuran are
 5 The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 207
7 9 1 HO HO
8 O2 O O
O
10 THE TERPENES – hemiterpenes and monoterpenes
H
OGlc
H
OGlc OGlc
OGlc GPP
cyclization formulated as initiated by electrophilic
addition utilizing the unsaturated carbonyl,
deoxyloganic acid 7-epi-loganin oleoside 11-methyl ether ligstroside terminated by addition of hydride; the imine-
assisted mechanism shown below is more realistic
E1 hemiacetal
H formation
O2 oxidations
H
is geraniol NADPH
NADPH H
OH OH O OH
ng CHO CHO
E2 E3 E4 H H H
o- H CO2H O HO OH
HO OH O H OH O
H − CO2 CHO
pe O
geraniol OH O iridodial iridodial iridodial
iridane iridoid secoiridoid
al- O O O O
O 10-hydroxygeraniol 10-oxogeranial (keto form) (enol form) (hemiacetal form)
dicinal Natural Products: A Biosynthetic Approach. HO 3rd Edition H
dly H H H OGlc
O
OH OGlc OGlc
nd (NADPH) H hemiacetal
8-epi-iridodial geraniol 8-epi-deoxyloganic acid harpagide harpagoside formation
he H
at-
igure 5.26 O O CHO
OH
CHO CHO H H
of H HO O O O
H H CO2Me OHC CHO OHC
her
oganin, to give secologanin,
iridoid
OH O representative O
of the
secoiridoid H
Nepetalactone from catmint Nepeta cataria (Labi- iridotrial iridotrial
ma- O ≡ (Figure
ecoiridoids H 5.24). This isH catalysed by≡ a atae/Lamiaceae),O a HO
powerful attractant and stimulant for HN H HN (keto form) (hemiacetal form)
Enz
In Figure
ytochrome 5.24 O O
P-450-dependent monooxygenase, and cats, H is produced from iridodial by simple oxidationO of
Enz
OH O
radical mechanism is proposed in Figure
iridodial 5.25. the hemiacetal to a lactone (Figure 5.26). Ligstroside
nepetalactone oxidation oxidation of
ecologanin now contains a free aldehyde group, and oleuropin are phenolic esters oleuropin OGlc oil
found in olive formation of alkene aldehyde to acid;
and ring cleavage Enz Fe leading to
radical glucosylation
ogether with further aldehyde and enol groups, with (see page 47) from Olea europea (Oleaceae), and are
H O H
hese
11 latter two210 Medicinal
fixed as an Natural
acetalProducts:
by the Apresence
Biosynthetic
ofApproach.
believed 3rd Edition
to contribute to the health benefits of this oil. HO HO HO HO
heCO glucose.
H As we shall see with COsomeMe of the complex These compounds are secoiridoids, butOare formed from H
2 2 HO2C CO2Me O O2
lkaloids,
4 these functionalities H be released again by
can
Box 5.3 (continued) Hthe 7-epimer of loganin; in this case, the stereochemistry
CO2Me H H H SAM H NADPH H
H OGlc OGlc OGlc OGlc OGlc
3
ydrolysing off the glucose and reopening the hemiacetal of 7-hydroxylation is different from the normal loganin H H H H
HO HO E6 E5 H
nkage.
1 O2 O O O O pathway.
O O Harpagide and harpagoside are examples of
CHO O O O O O
MeO2C MeO2C MeO2C HO2C HO2C
Well over a thousand different
O natural
H H O iridoids and sec-
O decarboxylated
H iridoids; these particular examplesO are
OGlc are known. Structural variation OGlc arises predom- formed OGlcO via 8-epi-iridodial, in which geraniol is cyclized loganin loganic acid deoxyloganic acid
iridoids CHO
O O OGlc glucosylation has
ganic
nantlyacid from hydroxylations, O 7-epi-loganin
esterifications,
O O oleoside
and changes O 11-methyl Oether
by aO stereochemically ligstroside Harpagoside
different mechanism.
Enz Fe O2 now transformed
n stereochemistry. Another O major change is the lossO of is O
the cinnamoyl ester ofbaldrinal
harpagide. These compounds are E7 NADPH the hemiacetal
valtrate isovaltrate OH
carbon atom by a decarboxylation mechanism. A few found in devil’s claw (Harpagophytum O procumbens;
O Ped- HO HO into an acetal
OH
xamples
niol showing their
OAc relationship to the intermediates
O O O aliaceae)
O and contribute to the anti-inflammatory
O and anal- CHO
H H – H2O H tryptamine terpenoid
f Figure 5.25 are presented in Figure 5.26. O
gesicH properties associatedH
with thishomobaldrinal
plant drug [Box 5.2]. OGlc OGlc OGlc indole
O H
O O alkaloids
H H H
H HO O O O
O CO2H
O O HO O O O OH MeO2C MeO2C MeO2C
H − CO2 OH
O acevaltrate O didrovaltrate O secologanin
CO2H O
O E1: geraniol synthase E4: monoterpene cyclase
O O O valerenic acid
O
valeranone
E2: geraniol 10-hydroxylase E5: 7-deoxyloganin 7-hydroxylase (also accepts acid as substrate)
HO H E3: 10-hydroxygeraniol oxidoreductase E6: loganic acid methyltransferase
Figure 5.28 H H OGlc (acyclic monoterpene primary alcohol dehydrogenase)
OH OGlc OGlc E7: secologanin synthase
idodial of 8-epi-deoxyloganic acid
valepotriates than V. officinalis, harpagide
e.g. V. mexicana contains up to about 8%. Some other species of Valeriana which contain
harpagoside
Figure 5.25