6. Terpenes: C5 to C20
RA Macahig
FM Dayrit
HO
CH3
3
1CO
_
2
5
OH
3-(R)-MVA
Introduction
• Terpenes make up very prominent and characteristic group of
plant secondary metabolites. Terpene metabolites range from
volatile compounds with 10 carbons to colored polyenes with
40 carbons.
• The word “terpene” comes from turpentine, the yellow to brown
thick oleoresin which is obtained as an exudate from the terebinth
tree (Pistacia terebinthus).
• Terpenes are historically, culturally and economically important:
• oleoresins, such as pine and eucalyptus oils; rubber (gutta percha)
• distillates of the resin yield solvents and thinners
• “essential oils” and perfumes, which are extracted from flowers
and leaves by pressing, alcohol extraction or steam distillation
• drugs and steroids
6. Terpenes: C5 to C20 (Dayrit)
2
Introduction
Some characteristic terpenes:
10
AcO
CH3
1
9
O
2
8
7
CH3
O
Ph
CH3
Ph
Camphor: monoterpene from
Cinamomum camphora.
21
CH3
1
10
3
HO
5
CH3
HO
24
20
18
CH3
CH3
O
OH
4
19
H3C
O
NH
26
23
O OH
CH3
H
H
AcO
O
PhCO2
Taxol: antitumor diterpene from
Pacific yew, Taxus species
25
27
13
11
17
14
9
8
6
Cholesterol: steroid originally
isolated from gallstones; component of
all cell membranes
Carotene: C40 terpene which is synthesized in
the chloroplast; important plant pigment; believed
to be one of the important natural anti-oxidants.
6. Terpenes: C5 to C20 (Dayrit)
3
Introduction
• In the late 19th century, Otto Wallach noted that upon chemical
degradation, many of the products obtained had chemical
formulas which were in multiples of 5 carbons. In the 1860s,
these C5 units were called “isoprene” units. This is the basis of
the “isoprene rule” which was formulated by Leopold Ruzicka.
Isoprene represents the basic skeletal structure of the C5 unit.
n
2
isoprene
n
natural rubber
limonene
The most prolific producer of isoprene-type
polymers is the rubber tree, Hevea brasiliensis.
6. Terpenes: C5 to C20 (Dayrit)
4
Overview of terpene biogenesis
• Isopentenyl diphosphate (IPP) is the
C5 precursor of all isoprenoids. In plants,
IPP is formed via two distinct
biosynthetic pathways:
• The mevalonic acid (MVA) pathway
operates in the cytoplasm and is
responsible for the smaller terpenes
and the phytosterols
• The methyl erythritol phosphate
(MEP) pathway is responsible for the
chloroplast isoprenoids (-carotene,
lutein, prenyl chains of chlorophylls
and plastoquinone-9).
6. Terpenes: C5 to C20 (Dayrit)
OPP
HO
CH3
_
CO2
OH
HO CH3
OH
HO
OP
5
The Mevalonic Acid (MVA) pathway
• 3R-Mevalonic acid (MVA) is biosynthesized from three acetates.
O
O
+
H
O
oA
C
C S
H
3
H
C
O
H
3
O
3
3
A
o
C
C S
H
3
C
H
3
H
C
O
H
3
A
o
C
S
1
O
_
5
O
O
A
o
C
S
S
A
o
C
1
O
C
5
2
H
O
3-(R)
A
o
C
C S
H
2
Note: 3S-MVA is an unnatural stereoisomer. There is no evidence that it is incorporated into terpenes.
• MVA is converted to isopentenyl diphosphate (IPP) which is
converted to its isomer, dimethylallyl diphosphate (DMAPP).
H
O
C
H
3
H
O
C
H
3
P
O
C
H
3
-CO
3
2
ATP 3
2 ATP
IPP
_
_
4.1.1.33
O
P
P
1
1
C
O
5
1
C
O
2
2 5
5
O
H
O
P
P _
O O O
P
P
5.3.3.2
3-(R)-MVA
5-diphospho-(R)-MVA
3
DMAP
O
P
P
6. Terpenes: C5:to Diphosphomevalo
C20 (Dayrit)
6
4.1.1.33
5.3.3.2
: 
Isopentyl-diphosp
-isomerase
The Mevalonic Acid (MVA) pathway
MVA pathway for isoprenoid biosynthesis with labeling pattern
from [1-13C]glucose metabolized via glycolysis. (Rohmer, Pure Appl
Chem 2003)
6. Terpenes: C5 to C20 (Dayrit)
7
The Methyl Erythritol Phosphate (MEP) pathway
• Glyceraldehyde-3phosphate (GAP) and
phosphoenolpyruvate (PEP)
are formed from glucose.
O
H
H
H
O
C
2
O
H
Glycera
3-phosp
)
3
C
H
O
P
O
O
O
H
O
H
O
O
H
Glucose
H
C
3
Phosph
C
O
H
pyruvat
)
2
3
• GAP condenses with PEP to form MEP. MEP is converted to
IPP which forms its isomer DMAPP.
O
H
P
O
C
H
O
H
OC
H
3
Glyceraldehyde-3-phosphate
)
(C
3
O
H
O
IPP
O
P
P
H
O
O
P
H
C
3
C
O
H
2
Methylerythritol phospha
) (MEP)
(C
Phosphoenol
)
pyruvate
(C
5
3
DMAP
O
P
P
6. Terpenes: C5 to C20 (Dayrit)
8
The Methyl Erythritol Phosphate (MEP) pathway
MEP pathway for the biosynthesis of isoprenoids with labeling
pattern from [1-13C]glucose metabolized via glycolysis. (Rohmer,
Pure Appl Chem 2003)
6. Terpenes: C5 to C20 (Dayrit)
9
Evolution of the MVA and MEP pathways
• The MVA pathway was originally thought to be the
obligatory intermediate for all terpenes. (This is the pathway
assumed in pre-2000 literature.)
• The MEP pathway was first found in eubacteria and green
algae, and was later shown to operate in the plant’s
chloroplast. It is hypothesized that the MEP evolved first, and
was incorporated into plants from cyanobacteria.
• Some fungi and yeasts have been shown to use the MVA
pathway. Because the plant cytosol uses the MVA pathway, it
is believed that the higher evolved organisms (fungi and
yeast) may be the source of the plant’s nuclear DNA.
• The co-occurrence of two distinct major metabolic pathways
in plant cells is unique for isoprenoid formation in plant cells.
6. Terpenes: C5 to C20 (Dayrit)
10
“Isoprenoid biosynthesis: The evolution of two ancient and
distinct pathways across genomes” (Lange et al., PNAS, 97(24):
13172–13177, Nov 21, 2000) (p 1)
• IPP is “the central intermediate in the biosynthesis of isoprenoids, the
most ancient* and diverse class of natural products. Two distinct routes
of IPP biosynthesis occur in nature: the MVA pathway and the recently
discovered DXP** pathway.”
“The evolutionary history of the enzymes
involved in both routes and the phylogenetic
distribution of their genes across genomes
suggest that:
 the MVA pathway is germane to
archaebacteria,
 that the DXP pathway is germane to

eubacteria, and that eukaryotes have inherited MVA
their genes for IPP biosynthesis from
prokaryotes.”
* In evolutionary terms, the fats are
probablyC5
thetoolder
group!
6. Terpenes:
C20 (Dayrit)
** DXP (deoxyxylulose 5-phosphate) pathway = MEP pathway

DXP (MEP)
11
“Isoprenoid biosynthesis: The evolution of two ancient and
distinct pathways across genomes” (Lange et al., PNAS, 97(24):
13172–13177, Nov 21, 2000) (p 2)
“The occurrence of genes specific to the DXP pathway is restricted to
plastid-bearing eukaryotes, indicating that these genes were acquired from
the cyanobacterial ancestor of plastids.
“However, the individual phylogenies of
these genes, with only one exception, do not
provide evidence for a specific affinity
between the plant genes and their
cyanobacterial homologues. The results
suggest that:
 lateral gene transfer between eubacteria
subsequent to the origin of plastids has
played a major role in the evolution of this
pathway.”



MVA
6. Terpenes: C5 to C20 (Dayrit)
DXP (MEP)
12
The MVA and MEP pathways: taxonomic distribution
Organism
Pathways
Bacteria
Archaea
MVA or MEP
MVA
Green Algae
Fungi
Plants
Animals
MEP
MVA
MVA and MEP
MVA
6. Terpenes: C5 to C20 (Dayrit)
13
The MVA and MEP pathways: practical implications
• The mevalonate-independent methylerythritol phosphate
(MEP) pathway is present in many bacteria and in the
chloroplasts of all phototrophic organisms. It represents an
alternative to the well-known MVA pathway, which is present
in animals, fungi, plant cytoplasm, archaebacteria, and some
eubacteria.
• The MEP pathway in these bacteria represents a novel
selective target for antibacterial and antiparasitic drugs.
• The MEP pathway is also present in nonphototrophic
eukaryotes, but belonging to phyla related to phototrophic
unicellular eukaryotes, such as the parasite responsible for
malaria, Plasmodium falciparum. This presents a potential
target for a new class of antibacterial and antiparasitic drugs.
6. Terpenes: C5 to C20 (Dayrit)
14
DXS, 1-deoxy-d-xylulose-5-phosphate synthase
The MVA and MEP pathways:
practical implications
DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase
HMGR, 3-hydroxy-3-methylglutaryl coenzyme A
reductase
IDI, isopentenyl diphosphate isomerase
HDS, hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase
IDS, isopentenyl diphosphate dimethylallyl diphosphate synthase
Roberts, Nature Chemical Biology, 2007.
IDI, isopentenyl diphosphate isomerase
Compartmentalized biosynthesis of IPP and DMAPP via the
cytosolic MVA and the plastidic MEP pathways.
6. Terpenes: C5 to C20 (Dayrit)
15
Hemiterpenes (rare)
OPP
DMAPP, C5
OPP
The terpene family is
formed by
condensation of C5
(IPP) units:
• C10, monoterpenes
OPP
Monoterpenes
geranyl pyrophosphate, C10
OPP
• C15, sesquiterpenes
• C20, diterpenes.
OPP
Sesquiterpenes
farnesyl pyrophosphate, C15
OPP
OPP
Diterpenes
geranylgeranyl pyrophosphate, C20
6. Terpenes: C5 to C20 (Dayrit)
16
Terpene chains are produced by condensation of DMAPP with
IPP in “head-to-tail” manner. DMAPP is the “starter unit” while
IPP is the nucleophile which lengthens the terpene chain.
:B
a
s
e
IP
P
D
M
A
P
P
H
P
P
O
P
P -O
O
P
P
O
P
P
_
X
X
E
n
z
E
n
z
_
-E
n
z
-X
O
P
P
O
P
P
g
e
ra
n
y
lp
y
ro
p
h
o
s
p
h
a
te
fa
rn
e
s
y
lp
y
ro
p
h
o
s
p
h
a
te
O
P
P
O
P
P
IP
P
e
tc
.
_
X
E
n
z
6. Terpenes: C5 to C20 (Dayrit)
17
C30 terpenes are formed by head-to-head dimerization of C15
sesquiterpenes. This leads to the triterpenes, steroids, and carotenes.
OPP + PPO
(farnesyl pyrophosphate, C15) x 2
squalene, C30
Triterpenes, C30
OP P
+
Steroids
PPO
(geranylgeranyl pyrophosphate, C20) x 2
C40
Carotenes, C40
18
Overview of
Terpene
Biosynthesis
in Plants
Plastids
HOCH2
Cytosol
O
OH
OH
HO
CoA-SCOCH
3
H3C
OP
OH
OH
Glucose
PO
CO2H
PEP
CHO
GAP
OH
HO CH3
OH
MVA
HO2C
R
OPP
DMAPP, C5
Prenyl
side-chain
Monoterpenes
HO
OPP
OPP
MEP
OP
OPP
OPP
IPP, C5
DMAPP, C5
OPP
geranyl pyrophosphate, C10
IPP, C5
OPP
geranyl pyrophosphate, C10
Monoterpene
IPP, C5
IPP, C5
Sesquiterpenes
farnesyl pyrophosphate, C15
farnesyl pyrophosphate, C15
IPP, C5
Head-to-head
dimerization
Diterpenes
Sesquiterpen
OPP
OPP
H Polyprenyl
side-chain
R
n
OPP
geranylgeranyl pyrophosphate, C20
Diterpene
OPP
geranylgeranyl pyrophosphate, C20
Head-to-head dimerization
Triterpenes &
Steroids
squalene, C30
6. Terpenes: C5 to C20 (Dayrit)
19
Carotenoids
, C40
Estimates of number of structural groups and compounds
known for each of the major types of terpenes. (Devon and
Scott, 1972; Dictionary of Terpenoids, 1991)
Main terpene group
Number of structural types
Approx. number of known
compounds (1991)
Monoterpene
8
850
Sesquiterpene
88
2,800
Diterpene
53
2,500
Triterpene
25
1,500
Phytosteroid
19
800
6. Terpenes: C5 to C20 (Dayrit)
20
Phylogenetics and natural products:
Evolution of MVA biosynthesis in plants
A
c
e
ta
te
M
e
va
lo
n
a
te
Scutellaria
Plumeria spp.
Jasmine
C
1
0
Irid
o
id
s
(L
ab
iatae)
In
d
o
lea
lk
a
lo
id
s
(A
p
o
cy
naceae)
C
1
5
S
e
s
q
u
ite
rp
e
n
e
s
(M
y
rtaceae)
S
e
s
q
u
ite
rp
e
n
ela
c
to
n
e
s
(C
o
m
p
o
sitae)
C
2
0
D
ite
rp
e
n
e
s
(E
u
p
ho
rb
iaceae)
D
ite
rp
e
n
ea
c
id
s
(L
eg
u
m
ino
sae)
C
3
0
S
te
ro
id
a
la
lk
a
lo
id
s
(S
o
lan
aceae)
Tomato
6. Terpenes: C5 to C20 (Dayrit)
Daisy
Lima bean
21
Common transformations of the terpenes.
1.
Sn2-type
attack
of
c
on
a
carbon
electro
PP
):
(-O
-O
PP
O
P
P
O
P
P
_
IPP
DMAPP
X
E
nz
2.
3.
4.
O
P
P
X
E
nz
:Base
E2-type
elimination
H
formation
of
double
O
P
P
O
P
P
X
E
n
z
C
H
P
P
3O
1,3-Allyl
PP
):
shift
R
1
1
3
R
2
O
P
P gro
H
C
of
X
3
R
1
1
3
R
2
C
H
C
H
3
3
Epoxidation
of olefin:
[O]
R
R
R
R
1
2
1
2
O
6. Terpenes: C5 to C20 (Dayrit)
22
Common transformations of the terpenes.
C
H
3
+
5. Electrophilic attack
on
E
R
R
double bond
or epoxide
1
R
2
1
to produce carbocation
is usually H
):
+(E +
C
H
3
R
1
R
2
C
H
3
R
2
+
E
C
H
3
+
H
R
1
+
R
2
O
O
H
6.
C
H
3
C
H
Formation
of
3
H cyclop
C
H
+
3
E
group
from
olefin:
R
+
1
3
1
-H
R
1 3
1 +
R
R
1 1 3
2 2
2R
2
R
2
2
E
E
6. Terpenes: C5 to C20 (Dayrit)
23
Common transformations of the terpenes.
7. Cationic rearrangements:
C
H
3
a. 1,2-Shift of methyl or
hydrogen:
2
2 + R
R
1
R
1
1
C
H
3
b. 1,3-Shift of hydrogen:
+
3
R
1
H
1
+
2
C
H
3
R
2
1
H
C H
3
R
2
R
1 3
+
1
R
2
+
c. Acid-catalyzed cationic
cyclization:
+
H
R
+
6. Terpenes: C5 to C20 (Dayrit)
R
R
24
Common transformations of the terpenes.
O
P
P
O
H
8. Alkylation of alcohol and alkyl O
groups with isopentenyl group
(prenylation); analogous
to
O-alkylation
methylation:
O
H
O
H
C-alkylation
P
P
O
6. Terpenes: C5 to C20 (Dayrit)
25
Hemiterpenes, C5
• The true C5 terpenes are known as hemiterpenes.
However, there is a large number of C5 compounds that
are degradation products of larger compounds and these
are not considered as true terpenes.
• Prenylation is an alkylation process which adds C5 units
to a substrate by attack of a carbon nucleophile or alcohol
on the C5 diphosphate (C5H9-OPP). The reaction takes
place by nucleophilic displacement of diphosphate. If the
substrate is a non-terpene compound, a mixed metabolite
compound is produced.
6. Terpenes: C5 to C20 (Dayrit)
26
A . Tru e he m it e rp e n e s
CHO
C O 2H
is o va le ra ld e h y d e
F o un d in o ra n ge s , le m o n , p e p pe rm int ,
e u c a ly p tu s an d m a n y o t h e r vo la t ile oils .
It is a c o m p o n e n t o f fla vo rs a n d p e rfum e s .
Various aspects
of C5 terpene
chemistry:
B . F a ls e he m it e rp e n e s
C. examples of
prenylation.
H O 2C
CO 2H
CO 2H
s in e c io ic a c id
a ng e lic a c id
t ig lic ac id
A. true
hemiterpenes,
B. false
hemiterpenes,
and
is o vale ric a c id
F ou n d in h o p s a n d t o b a c c o .
C . E x a m p le s o f p ren y la t io n
1. [O ]
HO
O
O
HO
2.
O
O
O
OPP
O
HO
O
O
O
fu s c in
H+
HO
H+
O
O
OPP
HO
O
O
O
OCH3
O
OCH3
OCH3
a n is o fla vo n o id
O CH3
O
O
O
ro t e no n e
O
O CH3
OCH3
27
Monoterpenes, C10
Monoterpenes are characteristic plant natural products, in
particular, in the flowers. These are important materials for
perfumes and food flavors. The monotepenes are classified
structurally into the following: acyclic, monocyclic, bicyclic and
tricyclic.
Biosynthetically, the monoterpenes can be grouped into the
following: acyclic, cyclic, iridoid, and irregular.
Geranyl diphosphate (C10H17-OPP)
is the starting point for the
monoterpenes.
OPP
6. Terpenes: C5 to C20 (Dayrit)
28
OPP
Acyclic
monoterpenes
GPP
OH
geraniol
OPP
CHO
CHO
citral A (geranial)
citronellal
OH
linalyl pyrophosphate
linalool
OPP
OH
nerol
neryl pyrophosphate
Other common open chain terpenes
CHO
citral B (neral)
:
myrcene
6. Terpenes: C5 to C20 (Dayrit)
cis -ocimene
29
Cyclic monoterpenes
• In order to form the cyclic monoterpenes, it is postulated that
GPP isomerizes to neryl or linalyl diphosphate. Cyclization
produces a 1-methyl 4-isopropyl cyclohexane ring system.
This is the basis for limonene-type structures. Ring formation
can occur via three cyclization routes which produces bicyclic
structures.
• Ring formation produces optically active cyclic
monoterpenes. Both (+) and (-) enantiomers have been found
for many of the cyclic monoterpenes; these enantiomers can
be found in different plants but sometimes both enantiomers
can be found in the same plant.
6. Terpenes: C5 to C20 (Dayrit)
30
OPP
OPP
Route to the
various monoand bicyclic
monoterpenes.
OPP
GPP
linalyl pyrophosphate
neryl pyrophosphate
-OPP
-OPP
a
b
e
a
+
c
1,2-H shift
+
bornane
skeleton
b
+
c
+
d
-H+
+
OH
pinene
skeleton
limonene
borneol
[O]
4-carene
O
-pinene
camphor
-pinene
OH
-terpineol terpinolene
thujane
Cyclization of monoterpenes can occur with opposite conformations
giving rise to enantiomers.
D-Limonene:
L-Limonene:
P
P
O
P
P
O
H
displacement
from below
H
displacement
from above
H
P
P
O
H
equatorial
P
P
O
6. Terpenes: C5 to C20 (Dayrit)
H
equatorial
H
32
Labeling studies for the conversion of MVA into cyclic monoterpenes.
HO
o
_
O2C
OPP
OPP
o
OPP
o
o:
full label
: half-label
o
o
o
OPP
o
OPP
o
OPP
o
o
sabinene
+
99%
o
50%
each
o
o
o
+
o
o
o
o
o
thujone
O
90-99%
camphor
o
O
80%
o
50%
each
50%
each
o
o
o
o
33
+
WagnerMeerwein
rearrangement
of cationic
intermediates
in cyclic
monoterpenes.
+
H
H
+
+
+
+
+
+
+
+
+
+
+
+
+
-H +
HO
HO
fenchol
camphene
Iridoids
• Iridoids are rearranged monoterpenes which have a characteristic
fused 5/6-membered ring structure. The 6-membered ring contains
an acetal carbon where one oxygen forms part of the ring as a C-OC bond, and the other oxygen is usually glycosylated.
• About 600 iridoids are known. However, these are mostly
glycosides; only about 100 non-glycosidic iridoids are known
• Iridoids are generally plant terpenes. The name, however, comes
from iridomyrmecin, a compound isolated from ants of the genus
Iridomyrmex. Iridoid monoterpenes also are known from other
O-Glu
O-Glu
insects, such as aphids.
CH3
H
O
• Loganin is a typical iridoid.
O
O
HO
Secologanin is a rearranged
H
H
iridoid which retains only the
CO2CH3
CO2CH3
Loganin
Secologanin
6-membered ring.
6. Terpenes: C5 to C20 (Dayrit)
35
_
HO
H
o
o
_
NADPH
o
CHO
OH
OPP
CH3
CHO
o
[O]
O2C
H
OH
o
o
o:
full label
o: half-label
o
nerol
OGlu
CH3
[O],
[CH3 ]
OHC
O
H
H
OGlu
CH3
O
HO
OHC
Glu,
[O]
O
o
CH3
OH
H
O
CH3 O
H
o
o
o
O
o
o
o
o
CO2H
CO2CH3
CHO
o
o
o
[O]
CH2
OGlu
OGlu
O
H-O
CHO
o
loganin
HO
H
o
o
CO2CH3
o
O
OHC
o
o
CO2CH3
o
secologanin
Iridoids are rearranged
monoterpenes. Loganin is a
typical example of an
iridoid. Opening of the
cyclopentane ring yields
secologanin. Secologanin is
incorporated into numerous
indole alkaloids.
Iridoids
• Because the biosynthesis is relatively long and involves steps not
commonly seen in other pathways, it would not be expected to
have arisen often in the course of evolution.
• The iridoids are produced by plants primarily as a defense
against herbivores or against infection by microorganisms.
Iridoids are often characterized by a deterrent bitter taste.
• Iridoids are found in many medicinal plants and may be
responsible for the some of their pharmaceutical activities.
Isolated and purified, iridoids exhibit a wide range of bioactivity
including cardiovascular, antiheptatoxic, chlorectic,
hypoglycemic, anti-inflammatory, antispasmodic, antitumor,
antiviral, immunomodulator and purgative activities.
• Iridoids are incorporated into the large family of indole
alkaloids.
6. Terpenes: C5 to C20 (Dayrit)
37
Irregular monoterpenes
The irregular monoterpenes are a miscellaneous group that
include the following types of compounds:
1. compounds that are formed from ring expansion;
2. compounds that are degraded so that the resulting
compound has less than 10 carbons; and
3. compounds that are formed via a head-to-head
condensation of DMAPP. A well-known group is the
pyrethrins which have the characteristic cyclopropyl ring
system.
6. Terpenes: C5 to C20 (Dayrit)
38
1. Irregular monoterpenes that are formed from ring expansion.
CO2H
CO2H
CO2H
[O]
sonanic acid
thujic acid
[O]
H
O
OH
O
H-O
O
HO
O
4-carene
O
OH
O
O
HO
O
-thujaplicin
O
HO
-thujaplicin
6. Terpenes: C5 to C20 (Dayrit)
-thujaplicin
39
2. Irregular monoterpenes that are degraded so that the resulting
compound has less than 10 carbons.
O
OH
O
[O]
[O]
geraniol
-phellandrene
6. Terpenes: C5 to C20 (Dayrit)
cryptone
40
3. Irregular monoterpenes that are formed via head-to-head
condensation of DMAPP: chrysanthemic acid. The cyclopropyl
group is characteristic of the pyrethroids, which is a well-known
insecticide which has low mammalian toxicity.
H
OPP
o
PPO
o
o
o
o
o
X-Enz
HO
o
HO
o
X-Enz
o
: full C-label
o
: half C-label
[O]
O
o
O
O
o
chrysanthemic acid
N
O
o
CO2H
Tetramethrin
(an active ingredient in Raid insect spray)
6. Terpenes: C5 to C20 (Dayrit)
41
Sesquiterpenes, C15
Sesquiterpenes (sesqui = “one and a half”) are derived from C15
farnesyl diphosphate (FPP). The sesquiterpenes comprise a very
large group of over 1,000 individual compounds with over 100
skeletal types. The great variety of structures arises from the
following types of transformation:
1. There are 3 double bonds in FPP; two of these double bonds
can isomerize into cis  trans configurations. This gives 4
double-bond geometric isomers: all-trans; 2-cis,6-trans; 2trans,6-cis; and 2-cis,6-cis isomers. The most important
geometric isomers are the all-trans and 2-cis,6-trans isomers.
Each double bond isomer gives rise to a different branch of the
sesquiterpene family.
10
6
2
6. Terpenes: C5 to C20 (Dayrit)
OPP
42
Many sesquiterpenes, however, are derived from either the
all-trans isomer, 1, or the 2-cis, 6-trans isomer, 2.
E
E
6
10
OPP
2
all-trans, 1
Z
E
10
6
2-cis, 6-trans, 2
2
Z
OPP
10
6
Z
10
Z
6
2
2-trans, 6-cis, 3
OPP
2-cis, 6-cis, 4
E
2
OPP
6. Terpenes: C5 to C20 (Dayrit)
43
2. When FPP cycles, the position of initial cyclization is the
second major source of variation. There are several ways in
which FPP can fold leading to a number of cyclization modes.
Cyclization can involve either nucleophilic displacement of
OPP by any of the -orbitals of the double bonds, or
nucleophilic attack of the double bond (usually the terminal
double bond) on a proton or other electrophile.
Two main groups arise from cyclization of:
• all-trans FPP
• 2-cis, 6-trans FPP
10
6
2
OPP
10
6
2
OPP
6. Terpenes: C5 to C20 (Dayrit)
44
E
E
Z
E
OPP
6
10
2
6
10
all-trans, 1
2-cis, 6-trans, 2
2
OPP
Figure 7.18
Skeletal types
obtained from
all-trans FPP.
a
b
OPP
b
a
humulane skeleton
+
illudanes and protoilludanes
+
+
germacrane skeleton
eudesmanes, valeranes
guaianes, pseudoguaiananes
45
3. Farnesyl diphosphate is achiral. However, as in the case of
geranyl diphosphate, it can fold up into two conformational
forms which give rise to enantiomers; the conformational
isomers are pro-chiral. Further modification of thse
enantiomers leads to diastereomers which are now chemically
distinct compounds.
O
P
P
-
-O
PP
+
H
H
-
-O
PP
+
O
P
P
6. Terpenes: C5 to C20 (Dayrit)
46
4. The remaining double bonds can react forming more C-C
bonds leading to bicyclic systems. The stereochemistry of the
second cyclization and the conformation of folding gives rise to
further types of isomers. From the all-trans FPP arises the
germacrane subgroup.
A. Simple germacrane metabolites:
O
+
germacrone
germacrane
_
B. Overview of three secondary cyclization modes, X
Mode A:
X
_
Mode B:
+
_
nucleophile is usually OH .
_
X
Mode C:
+
X
_
+
i. chair conformation, base attack from -face:
H+
Metabolites
from alltrans FPP:
germacrane
skeleton and
cyclization
mode A:
overview.
+
+
H
OH
HO
_
OH
H
H
OH
OH
OH
 -eudesmol
-eudesmol
(ovicidal compound from
Vitex negundo)
-eudesmol
+
ii. chair conformation, base attack from -face:
+
H
H
_
OH
+
+
HO
HO
+
H
[O[
valeranone
H-O
O
OH
iii. boat conformation, base attack from -face:
H+
_
OH
+
HO
+
HO
occidentalol
H
OH
H
+
i. chair conformation, base attack from -face:
H+
+
+
H
OH
HO
_
OH
H
H
OH
OH
-eudesmol
(ovicidal compound from
Vitex negundo)
-eudesmol
+
OH
 -eudesmol
ii. chair conformation, base attack from -face:
Metabolites
from all-trans FPP: germacrane skeleton and cyclization mode A:
i. chairH+ conformation, base attack fromH -face.
_
ii.OH
chair conformation, base attack from -face.
+
iii. boat conformation, base
+ attack from -face.
HO
HO
+
H
[O[
ii. chair conformation, base attack from -face:
+
H
H
_
OH
+
+
HO
HO
+
H
[O[
valeranone
H-O
O
OH
iii. boat conformation, base attack from -face:
Metabolites
from all-trans FPP: germacrane skeleton and cyclization mode A:
i. chair conformation,
base attack from -face.
H+
ii. chair
conformation, base attack from -face.
_
OH
HO
iii. boat conformation, +base attack from -face. +
HO
occidentalol
H
OH
H
+
iii. boat conformation, base attack from -face:
H+
_
OH
+
HO
+
HO
H
+
occidentalol
H
OH
Metabolites from all-trans FPP: germacrane skeleton and cyclization mode A:
i. chair conformation, base attack from -face.
ii. chair conformation, base attack from -face.
iii. boat conformation, base attack from -face.
Metabolites from all-trans FPP: germacrane skeleton and cyclization
mode B.
_
OH
H
OH
OH
+
+
H
H
H+
H
+
H
H
H
O
OH
bulnesol
OH
patchoulenone
6. Terpenes: C5 to C20 (Dayrit)
52
E
E
10
6
2
Z
E
OPP
all-trans, 1
2
6
10
2-cis, 6-trans, 2
OPP
Figure 7.17
a
b
Skeletal types
obtained from
2-cis, 6-trans
FPP (1)
c
d
d
OPP
a
c
b
+
+
+
bisabolene skeleton
caryophyllenes,
+
longifolanes,
longibornanes
carotane skeleton
begamotanes,
cadinanes, copaenes,
ylanganes, sativanes
santalanes, cedranes,
chamigranes, cupranes
Skeletal types
obtained from
2-cis, 6-trans
FPP (2)
Part of a biogenetic map for sesquiterpenes
showing all structural types found in the oils from
Toona ciliata, Cedrela odorata, and C. fissilis.
(modified from:
http://www.scielo.br/img/fbpe/jbchs/v11n6/3595f3.gif)
Sesquiterpenes, C15
5. Various skeletal rearrangements may occur through a number
of mechanisms, such as 1,2- and 1,3-H shifts, 1,2-methyl
shifts, double-bond migration (this generally occurs via H
migration), and Wagner-Meerwein type rearrangement.
6. Other modifications such as oxidation, reduction, etc.
The sesquiterpenes serve as plant defense compounds (e.g.,
polygodial, -eudesmol), sensory attractants or fragrance odors
(e.g., ylanganes, patchoulenone). The structures displayed by
these compounds attest to the rich chemistry that is found in
plants.
6. Terpenes: C5 to C20 (Dayrit)
55
The major
skeletal types
which contain the
-methylene-lactone
functionality
belong to the
germacrane
group.
germacrane skeleton
O
O
elemanolide
O
O
psuedoguaianolide
O
O
eudesmanolide
O
O
germacrenolide
O
O
guaianolide
O
eremophilanolide
O
6. Terpenes: C5 to C20 (Dayrit)
O
xanthanolide
56
O
Sesquiterpene -methylene--lactones
• The -methylene--lactone group is derived by oxidation and
cyclization of the isopropyl side chain of the cyclized
sesquiterpene.
[O]
O
H
[O]
Germacrane
skeleton
O

O



-methy

-lact
• The -methylene--lactone functionality is characteristic of
sesquiterpenes, and is found most widely in the Compositae
family.
6. Terpenes: C5 to C20 (Dayrit)
57
• This distinctive structural feature is accompanied by the
observation that many of these compounds show antimutagenic
properties which are attributed to the electrophilic exocyclic
methylene group which can react rapidly with nucleophilic
moieties, such as the nucleophilic 8-carbon of adenine and
guanine in DNA.
Reaction scheme for attack by nucleophile, OX:
O
O
N
O
O
NH2
O
O
P
O
N
5'
O
-
O
X
-
N
N
3'
O
X
6. Terpenes: C5 to C20 (Dayrit)
58
Examples of sesquiterpene -methylene--lactones.
O
OH
H
O
O
OH
O
O
O
O
HO
O
O
OH
O
HO
Hyporadiolide O
(guaianolide)
Tagitenin A
(germacrenolide)
Miloanokrypten
(guaianolide)
R1
O
H
R2
OR2
CH3
O
1
O
O
OH
Helenalin
OR1
H
O
C
CH3
O
O
CH3
O
2
H
Blumealactones
from Blumea balsamifera (sambong)
(Fujimoto, et al., Phytochem., 27, 1109 (1988).)
6. Terpenes: C5 to C20 (Dayrit)
O
C
CH3
O
3
Ac
H
59
Terminal cyclohexyl ring formation: Abscisic acid
• A terminal cyclohexyl group is readily formed from 2-trans, 6trans farnesyl diphosphate by electrophilic attack. This
relatively simple cyclization mode is surprisingly not common
among the sesquiterpenes. The best representative of this group
is abscisic acid.
• Abscisic acid (“abscission”  shedding of leaves, fruits or
flowers) is a very important plant growth regulator. In
particular, abscisic acid (commonly called ABA), as its name
suggests, is the plant hormone responsible for dormancy of
leaves and the abscission of leaves, flowers and fruit (the
natural process of removal, cutting, or falling off). Thus, ABA
plays an important role in normal plant development. In tissue
cultures, ABA has also been shown to inhibit plant cell
elongation.
6. Terpenes: C5 to C20 (Dayrit)
60
Terminal cyclohexyl ring formation leads to the biosynthesis of the
important plant growth regulator, abscisic acid.
E
H+
E
OPP
OPP
+
OH
CO2H
O
Abscisic acid
6. Terpenes: C5 to C20 (Dayrit)
61
Sesquiterpenes from cascading “linear” cyclization:
Polygodial
• 2-Trans, 6-trans farnesyl diphosphate can cyclize in a
cascading “linear” conformation to form a trans-decalin
structure. This process is initiated by attack of an electrophile at
the terminal double bond, formation of a cyclohexyl ring
followed by a second cyclization to form the fused transdecalin structure.
• This mode of cyclization is commonly observed in the longer
diterpenes and triterpenes, but is unusual in sesquiterpenes.
6. Terpenes: C5 to C20 (Dayrit)
62
Appropriate folding of all-trans farnesyl diphosphate and electrophilic
attack at the terminal double bond with sequential cyclization leads to a
trans-decalin structure. The -OPP- group is not displaced during the initial
cyclization. This mode of cyclization is very common for diterpenes and
triterpenes, and unusual in sesquiterpenes. Polygodial is an antipest
compound produced by plants.
OPP
OPP
CHO
2
E
H+
10
CHO
+
E
6
H
Polygodial
OPP
OPP
7
H+
E
E
+
2
11
H
6. Terpenes: C5 to C20 (Dayrit)
63
Sesquiterpenes from 2-cis, 6-cis-farnesyl diphosphate:
Gossypol
A few biologically important sesquiterpenes are formed from 2cis, 6-cis-farnesyl diphosphate. The best known metabolite from
this group is gossypol. Gossypol is an unusual sesquiterpene
since it is has a naphthalene structure and is dimerized. Although
gossypol can be easily mistaken for a polyketide, the isopropyl
group hints at its terpenoid origins. The final proof of biogenetic
origin comes from labeling studies which are consistent with its
being a sesquiterpene metabolite.
C
H
O O
H
O
H
C
H
O
H
O
O
H
H
O
O
H
Gossypol
6. Terpenes: C5 to C20 (Dayrit)
64
Gossypol is formed from 2-cis, 6-cis-farnesyl diphosphate. It is a
dimeric naphthalene. Gossypol has attracted interest because it is an
insecticidal defense compound found in the seeds of the cotton plant.
CHO OH
OPP
HO
Z
.
2
6
.
Z
.
.
HO
.
o
o
. = 14C label
o
[O]
= partially labeled
CHO OH
HO
OH
CHO
.
.
.
HO
o
o
6. Terpenes: C5 to C20 (Dayrit)
.
Gossypol
OH
OH
o
o
65
Propionic acid in starter unit: Insect juvenile hormones
Insect development is characterized by discrete stages in its life
cycle in going from larva to adult. Two types of hormones –
juvenile hormones (JH) and moulting hormones (MH) -- initiate
these changes. Juvenile hormones are required at the initial
metamorphosis from the 1st to 2nd stage larva, while molting
hormones are required at all stages of development:
MH/JH
MH
MH
1st stage Larva  2nd stage Larva  Pupa  Adult
Many juvenile hormones use propionyl CoA as the starting unit
to form homo-mevalonic acid. Juvenile hormones are linear
sesquiterpenes with various oxidized groups (epoxides,
alcohols). Moulting hormones, on the other hand, are steroidal
compounds.
6. Terpenes: C5 to C20 (Dayrit)
66
Juvenile hormones are linear sesquiterpenes which use a propionyl CoA as
the starting unit to make homo mevalonic acid.
Starter unit: propionyl CoA:
.
SCoA
O
-
O 2C
.
O
-
-CO 2
O
.
O
SCoA
O
SCoA
.
HO
-
O 2C
-
O
SCoA
OPP
homo-mevalonic acid
.
.
.
OH
3X
OPP
OPP
farnesyl pyrophosphate analogue
CO 2CH3
O
Neotenin
6. Terpenes:
to C20
(Dayrit)
Neotenin is C5
a juvenile
hormone
isolated from thousands
of male butterflies of the species
Hyalophora cecropia L.
67
Diterpenes, C20
Addition of another isopentenyl diphosphate (C5) group to
farnesyl diphosphate (C15) forms geranylgeranyl diphosphate
(GGPP, C20). GGPP is the starting point for the biogenesis of the
diterpenes. As in the case of the sesquiterpenes, there is a great
variety of structures that are formed due to five important
structural features of diterpenes :
1. GGPP has four double bonds. Three of the double bonds can
take the cis- or trans- configuration. This gives seven possible
double-bond geometric isomers.
• The largest group of diterpenes is formed from the all-trans
GGPP.
• A number of important diterpenes arise from the 2-trans,6cis,10-trans isomer.
6. Terpenes: C5 to C20 (Dayrit)
68
The majority of the diterpenes are cyclic compounds. However, some
unusual open-chain di-, tri- and tetraene diterpenes (along with
sesquiterpenes) have been isolated from the skin glands of alligators and
crocodiles. These terpenes are believed to act as pheromones. (The most
commonly-occurring open-chain terpene on the skin of many animals,
including humans, is squalene.) (Schultz, Krückert and Weldon, J. Nat Prod., 2003, 66, 34-38)
6. Terpenes: C5 to C20 (Dayrit)
69
Diterpenes, C20
2. Initial cyclization of GGPP can occur at different sites. As in
the case of FPP, the position of initial cyclization contributes to
structural variety. This includes the important consideration of
whether the cyclization involves the displacement of the -OPP
group or not.
• Cyclization in the all-trans mode does not displace -OPP,
while the other modes cause displacement of the -OPP group.
3. Further cyclization steps may occur using the remaining
double bonds to form additional smaller rings. The
stereochemistry of these cyclization steps depends on the
double-bond configurations and the conformation of the ring.
6. Terpenes: C5 to C20 (Dayrit)
70
GGPP cyclizes in
a variety of ways.
Theoretically,
there are seven
double-bond
geometric
isomers possible
from
geranylgeranyl
diphosphate. The
most important
diterpenes are
formed from the
all-trans GGPP
and 2-trans,6cis,10-trans
isomer.
+
Taxane
-OPP
all- trans
14
-
Cembrane
2-trans,
6-cis,
-OPP
10-trans
10
-OPP
6
2
-
Fusicoccin
OPP
Geranylgeranyl pyrophosphate, GGPP
all- trans
2-cis,6-trans,
-OPP
10-cis
-OPP
-
OPP
+
Artemisene
Labdane
6. Terpenes: C5 to C20 (Dayrit)
Pimarane
Kaurane
71
Gibberelane
Diterpenes
4. Skeletal modifications can occur via migration of hydrogen
and/or methyl, Wagner-Meerwein-type rearrangements, and
others.
5. Other modifications may occur, such as oxidation, reduction
of double bond (+2[H]), etc.
There are a number of well-known compounds which belong to
the diterpene group, in particular, the cembranes, pimaranes and
the gibberelanes. The cembrane structure is a recurring theme
among marine natural products. The pimaranes are major
constituents of pine oleoresin, which is heavily used in paper
sizing and other coating applications. The gibberellins are
important plant growth hormones. Taxol, the anticancer drug, is
also a diterpene.
6. Terpenes: C5 to C20 (Dayrit)
72
Diterpenes from all-trans GGPP
• The largest group of diterpenes is produced from all-trans
GGPP which lead to the labdanes. The biosynthesis starts from
two conformations of chair-like folding of all-trans GGPP: one
conformation leads to the 10- series while the alternative
conformation leads to the 10- series. This is an example of a
very important phenomenon in generation of diversity in
natural products where the same starting compound produces
stereoisomeric products—in this case, diastereomers.
• Electrophilic attack at the terminal double bond accompanied
by two rapid ring-forming steps produces the two trans-decalin
stereoisomers with a stable tertiary cation intermediate. It
should be noted that initial cyclization retains the -OPP group
which is used in subsequent transformations.
6. Terpenes: C5 to C20 (Dayrit)
73
The largest group of diterpenes is produced from all-trans GGPP which
leads to the labdanes. The biosynthesis starts from two conformations of
chair-like folding of all-trans GGPP leading to the 10- /10- series.
-Series
14
X+
H1
3
6
1
10
H
X
OPP
4
9
10
5
OPP
8
+
OPP
11
1
10-Me 
3
10
5
4
X
9
8+
H
-Series
OPP
1 OPP
6
X+
14
1
X
3
10
10 9
4
8
+
5
H
OPP
11
1
10-Me 
6. Terpenes: C5 to C20
3 4
(Dayrit)
X
10
5
H
9
8+
74
Diterpenes from all-trans GGPP
The initially formed decalin cation subsequently undergoes
various transformations leading to sub-groups, as illustrated by
the following reactions. Examples from both the 10- and 10-
series are known in nature, but both are rarely found in the same
plant.
1. Loss of H+: Loss of H+ limits modifications of the ring to the
decalin system. This produces an exocyclic methylene group at
the 8-position of the decalin. Secondary modifications may take
place at the side chain. This group is exemplified by the
labdanes.
6. Terpenes: C5 to C20 (Dayrit)
75
OPP
Loss of H+ from
the intermediate
decalin produces
an exocyclic
methylene group
a the 8-position.
Secondary
modifications
may take place at
the side chain.
This leads to the
labdanes.
+
10-series
10-series
8
10
H
H3C CH2OH
Ozol
OH
13
10
OH
13
8
10
H
H3C CH2OH
8
H
18
Ent-18-hydroxy-13-epi-manool
(+)-Manool
OH
13
OH
10
H
H3C CH2OH
18
8
20
15
OH
10
8
20
15
H
6. Terpenes: C5 to C20 (Dayrit)
Enantio-labda-8(20)-en-15,18-diol
76
Labda-8(20)-13-dien-15-ol
Diterpenes from all-trans GGPP
2. Attack of nucleophile (e.g., OH-) at intermediate cation on 8position: Attack of hydroxide (OH-) at the cationic carbon at the
8-position is controlled by steric considerations. Because the
10- methyl blocks approach from the bottom side, the
hydroxide has the 8- configuration. Similarly, the 10- methyl
series gives rise to the 8- hydroxide configuration.
6. Terpenes: C5 to C20 (Dayrit)
77
Attack of hydroxide (OH-) at the cationic carbon at the 8-position is
controlled by steric considerations. The 10- methyl blocks nucleophilic
attack from the bottom, while the 10- methyl blocks attack from the top.
10-Series
H
OH
H
OH-
10
OH
8 R
steric
hindrance
CH3
10
+
8
H
OH-
10-Methyl- -labdane
10-Series
CH3
10
OH
steric
hindrance
OHR
10
8
8
OH
+
H
H
10-Methyl- -labdane
OH6. Terpenes: C5 to C20 (Dayrit)
78
Diterpenes from all-trans GGPP
3. Tricyclic diterpenes: The 8-methylene exocyclic group
participates in a nucleophilic attack on the -OPP group on the
side chain and forms the pimaryl tricyclic system. Two
stereoisomeric groups of pimaranes are formed from the 10-
and 10- methyl series.
H
H
6. Terpenes: C5 to C20 (Dayrit)
79
The 8-methylene
exocyclic group
participates in a
nucleophilic attack
on the -OPP group
on the side chain
and form the
pimaryl tricyclic
system. This figure
shows the
pimarane 10- and
10- series.
10-Series
H
H
H
H
OPP
OPP
+
1. -H+
2. OPP: 1,3-migration
-OPPH
H
+
H
H
H
CO 2H
OH
7-Hydroxypimara-8(14),15-diene
19-oic acid
6. Terpenes: C5 to C20 (Dayrit)
HO
H
CO 2H
Oblongifoliol
80
10-Series
The 8-methylene
exocyclic group
participates in a
nucleophilic attack
on the -OPP group
on the side chain
and form the
pimaryl tricyclic
system.
OPP
OPP
+
H
1. -H+
2. OPP: 1,3-migration
H
+
H
Isopimara-7,15-diene
H+
H+
H
CO 2H
Pimaric acid
CO 2H
1,2-methyl shift
6. Terpenes: C5 to C20 (Dayrit)
CO 2H
Abietic acid
81
Diterpenes from all-trans GGPP
4. Tetracyclic diterpenes: Further cyclization of the tricyclic
cationic intermediate leads to a tetracyclic cationic intermediate
known as the kaurenes. Two stereoisomeric groups are formed.
Many of the kaurenes display remarkable complexity of
structure.
H
H
6. Terpenes: C5 to C20 (Dayrit)
82
10-Series
Further
cyclization of
the tricyclic
cationic
intermediate
leads to a
tetracyclic
cationic
intermediate
known as the
kaurenes. This
figure features
the kaurane 10 series.
from
pimarane
H
10
H
H
H
H
12
+
+
17
14
H
+
13
15
path A
path B
H
H
H
12
H
H
17
+
13
15
1. 1,2-bond shift: (C13>C15)
2. -H+ (C17)
H
H
12
14
H
H
14
17
13
+ 15
1. 1,3-H shift: (C12>C15)
2. 1,2-bond shift: (C13>C12)
3. -H+ (C17)
H
H
H
H
H
H
(-) Kaurene
(Ent-kaurene)
Atisirene
10-Series
Further
cyclization of
the tricyclic
cationic
intermediate
leads to a
tetracyclic
cationic
intermediate
known as the
kaurenes. This
figure features
the kaurane 10-
series.
H
from
pimarane
10
H
+
+
+
H
H
H
-H+
1,2-bond shift
1,2-H shift
H
H
H
(+) Kaurene
((+) Phyllocladene)
H
H
+
+
H
H
H
+
H
H
-H+
1,2-bond shift
H
6. Terpenes: C5 to C20 (Dayrit)
H
84
H
Diterpenes from all-trans GGPP
5. Kaurene B-ring contraction: the gibberellins: From the 10–
kaurene series comes the important group of plant hormones,
the gibberellins. The gibberellins are synthesized in the
protoplasm of plants and increase the rate and amount of
growth. There are over 66 compounds which have been isolated
which belong to this structural group. Interestingly, gibberellic
acid was first isolated in a fungus, Gibberella.
H
H
CO2H CHO
6. Terpenes: C5 to C20 (Dayrit)
85
H H
Contraction of the
kaurene B-ring
leads to the
gibberellins. The
gibberellins are
plant growth
hormones which
increase the rate
and amount of
growth.
H
O
H
H
H 6
CO2H X
(-) Kaurene
7
O
HO 2C
X
H
1. -X2. 1,2-C migration (7>6)
3. -H+
H
H
H
OHC
HO 2C
H
CO2H CHO
C19 gibberellic acids
CHO
HO
[O]
H
[O]
C20 gibberellic acids
H
H
H
CO2H CO 2H
CO2H CO 2H
GA R
1. -CH2O
2. [O]
1. [O]
2. -CH2O
3. [O]
H
O
O
HO
H
OH
H
CO 2H
O
GA 1
O
H
CO 2H
-2H
GA 15
H
O
HO
O
OH
H
6. Terpenes: C5 to C20 (Dayrit)
CO 2H
GA 3
(Gibberellic Acid)
86
Diterpenes from 2-trans,6-cis,10-trans GGPP: Cembranes
Isomerization of the 6-double bond of all-trans GGPP to the cis
configuration allows nucleophilic attack of the terminal double
bond on the 1-position accompanied by displacement of -OPP
and formation of a 14-membered cembrane ring.
6. Terpenes: C5 to C20 (Dayrit)
87
Diterpenes from 2-trans,6-cis,10-trans GGPP: Cembranes
The name cembrane is taken from the simplest member of this
group, cembrene, which was isolated form the oleoresin of Pinus
sibirica.
The most interesting members of the cembrane group are found
in marine soft corals. The 14-carbon ring marine cembranes are
in many ways structurally analogous to the 10-carbon ring
sesquiterpenes. While the sesquiterpene germacranes form methylene--lactones, the diterpene cembranes form methylene--lactones. Like the sesquiterpene lactones, the
cembrane lactones also exhibit powerful cytotoxic and antitumor properties.
6. Terpenes: C5 to C20 (Dayrit)
88
Isomerization of the 6-double bond of all-trans GGPP to the cis configuration
allows nucleophilic attack of the terminal double bond on the 1-position
accompanied by displacement of –OPP- and formation of the cembrane ring.
E
Z
2
10
Z
6
E
PPO
Cembrene
Cembrene itself was isolated from the
oleoresin of Pinus sibirica .
-Methylene- -lactones in marine natural products:
O
OH
O
O
H
H
HO
OAc
Crassin acetate
from Psuedoplaxaura porosa
O
O
Sinulariolide
from Sinularia flexibilis
6. Terpenes: C5 to C20 (Dayrit)
89
Diterpenes from all-trans GGPP with loss of OPP: Taxanes
The biosynthetic pathway to the tricyclic taxoid skeleton involves
an alternative cyclization attack of C10 on C15, accompanied by
attack of C14 on C1 with displacement of -OPP. This forms a 6membered A ring, with an 8-membered B-ring.
1
12
11
4
H
5
H
6. Terpenes: C5 to C20 (Dayrit)
90
The taxoid skeleton is formed from all-trans GGPP. The initial
step involves attack of C14 on C1 with displacement of -OPP and
attack of C10 on the cationic center which forms on C15.
H
6
10
E
E
15
14
H
-OPP-
+
+
1
OPP
H
H
-H+
+
H
H
6. Terpenes: C5 to C20 (Dayrit)
H
H
91
Taxol is a well-known diterpenoid from the Pacific yew tree, Taxus
brevefolia. Over 350 compounds belonging to the taxoid group have
been isolated. In a short span of seven years from 1992-1999, over 250
taxoids were isolated and characterized. (Baloglu and Kingston, J. Nat.
Prod. 1999, 62, 1448-1472.)
O
AcO
Ph
NH
H3C
O
Ph
7
O
OH
O 19 OH
CH3
H3C
2
14
HO
Taxol
(Paclitaxel)
17
CH3
4
H
AcO
H
O
PhCO2
6. Terpenes: C5 to C20 (Dayrit)
92
Potential labeling patterns
of monoterpenes and the
sesquiterpene nerolidol by
[2H2]-DOX (A) and [2H2]MVL (B).
93
HO
trans-Nerolidol
Emission and in vivo labeling kinetics of nerolidol during feeding of
snapdragon flowers with [2H2]-MVL. Filled circles represent emission from
[2H2]-MVL-fed flowers, and open circles represent control flowers fed with
sucrose solution. Open triangles represent percent of unlabeled compounds,
and filled squares and triangles represent percent of nerolidol labeled by +4
amu; open squares represent percent of nerolidol labeled by +6 amu.
In the case of snapdragon petals, only one of the two pathways is operating in
the formation of volatiles isoprenoids. The MEP pathway, localized in the
plastids, provides IPP and DMAPP precursors for both monoterpene
biosynthesis (in plastids) and sesquiterpene biosynthesis (in the cytosol) and
determines their rhythmic emission.
6. Terpenes: C5 to C20 (Dayrit)
94
Summary
The following biosynthetic patterns among terpenes can be
observed:
1. The terpenes are readily recognizable from the characteristic
presence of 1,5-methyl substituents and the carbon number
which is a multiple of 5.
2. The key intermediates, geranyl diphosphate, farnesyl
diphosphate and geranylgeranyl diphosphate, have a -OPP
group at the C1 position and 1,5-diene groups.
3. Monoterpenes: There are three main types: linear, cyclic and
the iridoids.
4. Sesquiterpenes: This a very diverse group of over 100 skeletal
types. The initial source of diversity is the variation of the
cyclization step.
6. Terpenes: C5 to C20 (Dayrit)
95
Summary
5. Diterpenes: Diversity starts from the initial cyclization step
from the four double bonds in geranylgeranyl diphosphate.
The most prominent subgroups are the labdanes which arise
from cyclization of the all-trans GGPP, the cembranes which
come from cyclization of 2-trans,6-cis,10-trans GGPP, and the
taxanes which arise form cyclization of all-trans GGPP with
loss of -OPP.
Terpene chemistry is an exquisite example of diversity,
stereochemistry and biochemical control in natural products.
Despite the diversity of structure, however, the majority of
chemical reactions are actually limited to a few types: Sn2
displacement of -OPP by an olefinic group; E2 elimination to
yield an olefin; 1,3-allyl shift of -OPP; epoxidation; and
protonation of olefins followed by cationic rearrangement.
6. Terpenes: C5 to C20 (Dayrit)
96
Summary
6. MVA and MEP Pathways: The co-occurrence of two completely
distinct pathways for isoprenoid formation in plant cells is
remarkable because a similar situation does not hold for any other
major metabolic route. The plastidial pathway probably arose
from genes contained in a cyanobacterium-like symbiont that
served as the progenitor of modern chloroplasts. However, this
scenario still does not explain the persistence of both pathways in
contemporary plants. The answer may lie in the enormous variety
of isoprenoids formed by plants, which could require two
separate pathways composed of completely different enzymes
and different intermediates to facilitate separate regulation.
Further study of when and where the two pathways are active in
plants should shed further light on questions regarding their
evolutionary origin and maintenance. (Dudareva et al. PNAS 2005)
6. Terpenes: C5 to C20 (Dayrit)
97