Medicinal plant research in africa pharmacology and chemistry

1 Monoterpenes and Related
Compounds from the Medicinal
Plants of Africa
Michel Kenne Tchimenea, Christopher O. Okunjia,c,
Maurice Mmaduakolam Iwua and Victor Kueteb
a

International Centre for Ethnomedicine and Drug Development, Nsukka,
Nigeria, bDepartment of Biochemistry, University of Dschang, Dschang,
Cameroon, cUSP Headquarter, Rockville, MD

1.1

Introduction

Monoterpenes are a class of terpenes that consist of two isoprene units and have
the molecular formula C10H16. They are predominantly products of the secondary
metabolism of plants, although specialized classes occur in some animals and
microorganisms, and are usually isolated from the oils obtained by steam distillation or solvent extraction of leaves, fruits, some heartwoods, and, rarely, roots, and
bark [1]. In favorable cases they occur to the extent of several percent of the wet
weight of the tissue. Conjugated nondistillable forms, e.g., terpene-β-D-glucoside,
are also frequently found, especially in the floral organs. They are the most representative molecules, constituting 90% of the essential oils, and have a great variety
of structures. Monoterpenes may be linear (acyclic) or they may contain rings.
Biochemical modifications such as oxidation or rearrangement produce the related
monoterpenoids. They are known for their many biological activities such as antimicrobial, hypotensive, antiinflammatory, antipruritic, antigerminative, antiplasmodial, antiesophageal cancer, and anticandidal. The compounds are inexpensive and
have been widely used in flavoring and fragrances since the beginning of the nineteenth century. More recently, they have played a great role in the pharmaceutical
industry because of their potential. Monoterpenes are also included in the category
of nutraceuticals, which represent an industry in excess of US$75.5 billion with
prospects of growing to US$167 billion by 2010 [1].

1.2

Biosynthesis and Structural Diversity

Modern methods of separation and structure determination, as well as the advent of
radioisotope techniques, have led to a very rapid advance in knowledge of the route
of biosynthesis of this class and the other types of terpenoids over the last 30 years.
Medicinal Plant Research in Africa. DOI: />© 2013 Elsevier Inc. All rights reserved.


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Medicinal Plant Research in Africa

Several reviews, of differing completeness, have outlined the routes to terpenoids
and steroids [2À8] in general and monoterpenes in particular [9,10]. One important
conclusion that emerges is the accuracy with which chemical theory can predict
the course of the biochemical processes. Enzymes exploit the innate reactivity of
their substances, and the biosynthetic routes can be dissected into unit steps such
as elimination, electrophilic addition, and WagnerÀMeerwein rearrangement that
are controlled by the stereoelectronic factor known to operate in nonbiological
systems. Even the reactivity of apparently nonactivated atoms can usually be
rationalized in terms of conformational and electronic changes imposed by
postulated substrateÀenzyme or substrateÀcofactor linkages. The well-established
patterns found can be used to asses feasible structures for novel terpenoids and to
design biogenetic-type synthesis.

1.2.1

Biosynthetic Pathways

1.2.1.1 Isoprene Rule
The earliest attempt to rationalize the pattern of structures of the monoterpenes was
the rule proposed by Wallach in 1887, who envisaged such compounds as being
constructed from an isoprene unit (1) (Figure 1.1). Thirty years later, Robinson
extended this isoprene rule by pointing out that in monoterpenes, and such higher
terpenes as were then known, the units were almost invariably linked in a headto-tail fashion, as shown for limone (2) and camphor (3). However, many higher
terpenes and a few monoterpenes were later found not to obey this amended rule,
and Ruzicka and his collaborators [11,12] proposed a biogenetic isoprene rule. This
generalization, which is now universally accepted, states that naturally occurring
terpenoids are derived either directly or by way of predictable stereospecific cyclization, rearrangement, and dimerizations form acyclic C-10, C-15, C-20, and C-30
precursors geraniol, farnesol, geranylgeraniol, and squalene, respectively. This rule
implies a common pathway of biosynthesis for the whole family and any proposal
for irregular biogenetic routes must be treated with reservations.
Although isoprene has been formed on pyrolytic decomposition of some monoterpenes, it is not found in plants, and much speculation has occurred around the
nature of the active isoprene of the condensing unit, ranging from apiose to tiglic
acid. The C-5 unit was also postulated to arise from degradation of carbohydrates,
proteins, amino acids, and many other classes of plant metabolites or by elaboration
of acetic acid, ethyl acetoacetate, or acetone. These early views have been well

Figure 1.1 Chemical structure of isoprene unit (1),
limone (2), and camphor (3).
O

1

2

3

Monoterpenes and Related Compounds from the Medicinal Plants of Africa

3

summarized [13,14]. Many C-10 compounds have been implicated as progenitors
of monoterpenes including citral [15], geraniol [16], nerol [17], limonene [18],
linalool [19], ocimene [20], and others [21À24]. None of these speculations were
backed by experimental evidence of any kind.

1.2.1.2 Acyclic Compounds and Cyclohexane Derivatives
1.2.1.2.1 Hypotheses
The proposals of Ruzicka and his coworkers [11] for the pattern of monoterpene biogenesis are outlined in Figure 1.2. Several of the intermediates are formally represented as carbonium ions, but structurally equivalent species such as alcohols,
phosphate esters, terpene glycosides, or sulfonium salts, either free or bonded to proteins, may be the reactants in vivo. The scheme is extremely attractive; the formation

OPP
OH

4

5

6

OPP

7

9

8

OH

OH 10

Borane
skeleton

Pinane
skeleton

11
Carane
skeleton

Thujane
skeleton

Figure 1.2 Formation of acyclic monoterpene: myrcene (4), ctronellol (5), cis-ocimene (6),
α-terpineol (10), and terpinen-4-ol (11).


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Medicinal Plant Research in Africa

of acyclics such as myrcene (4), citronellol (5), or cis-ocimene (6) from geranyl
pyrophosphate (GPP) has many in vitro analogies, and monocyclization of the ion (7)
formed from neryl pyrophosphate (NPP) to give α-terpineol (10), or terpinen-4-ol (11)
is also chemically reasonable, although the biochemical details are open to conjecture.

For the latter process, either epoxides (which have been isolated from several essential
oils) [25] or sulfonium compounds formed with a thiol group of an enzyme [26] may
be involved as outlined in Eq. (1.1) and (1.2). Both of these types of intermediates are
known to be implicated in the formation of rings in higher terpenoids, and interesting
model systems for the synthesis of monoterpenes in vitro using sulfonium ylides have
been developed; the elucidation of the importance (if any) of such routes in the plant
must await the advent of suitable cell-free systems.
H

ð1:1Þ
O

OH

H

S

Enz

+

HS

ð1:2Þ

Enz

H
H

Bicyclic skeletons of the pinane and borane series are (according to Ruzicka’s
scheme) derived by internal additions of positive centers to double bonds within monocyclic frameworks in a direction governed either by electronic factors (Markovnikov
addition) or by steric factors. Hydride shift within the ion (8) followed by cyclization
of 9 gives rise to the thujane skeleton, and that of the caranes arises from an internal
electrophilic substitution at the allylic position of the former carbonium ion. This
latter reaction, as given, is biochemically improbable, and an internal displacement
(Figure 1.3) in an intermediate such as 12 (X 5 ester) or the intermediary of a nonclassical ion (13) has been suggested [27], but both proposals beg the question. A study of
the mechanism of decomposition of certain unsaturated epoxides suggests that Eq. (1.3)

X

12

13

Figure 1.3 Suggested internal displacement in an intermediate in monocyclic monoterpenes.


Monoterpenes and Related Compounds from the Medicinal Plants of Africa

5

is feasible and the mechanism could be modified to form other bicyclic monoterpenes
directly from acyclic precursors; cf. Eq. (1.4). The generation of the intermediate

OH

OH

O

ð1:3Þ

NADPH

EnzSH

ð1:4Þ

O
SEnz

SEnz

carbenes, or their formal equivalents, may be possible at the enzyme surface where
water and other potential scavengers may be locally excluded. No evidence is
available to assess these hypotheses.

1.2.1.3 Cyclopentane Derivatives
1.2.1.3.1 General
Iridoids (Figure 1.4) are a family of compounds based on carbon skeleton (14) that
can be regarded as being formed by cyclization of 15. They were originally isolated
from the defensive secretions of Iridomyrmex, a genus of ant [28,29], but are now
known to be widely distributed in higher plants, usually, but not invariably, as the
OH
CHO

O

O
CHO
HO

OR

c
o
O

MeO2C
OH
16

15

14
CHO

10

HO

OG

OG

O
HO
O

CO2Me

7 8

9

1 O
2
3
4
CO2Me
11

O

5

6

17
18

Figure 1.4 Structure of some iridoids.

HO
19
G=-β-D-glucose

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Medicinal Plant Research in Africa

β-D-glucosides. Several hundred iridoids and related compounds have been isolated
from leaf, seed, fruit, bark, and root tissue of dicotyledons. This widespread distribution in plant tissues may be a consequence of the water solubility endowed by the
sugar residue, and contrasts with the storage and retention in specialized oil glands
of the largely water-insoluble monoterpenes of the types considered previously.
Few systematic studies of chemotaxonomy have been made [30], although a simple
field test is available to detect iridoids.
A decade ago it was suggested [31,32] that tetrahydropyranmethycyclopentane
monoterpenes of this then unusual type were possible biogenetic precursors of the
indole alkaloids; similar proposals were made for the formation of oleuropeine (16)
and elenolide (17). More recent work has amply confirmed these speculations, and
there is little doubt that loganin, or a close-related compound, does fulfill these
roles. Most of the biosynthetic studies on the iridoids have been concerned with
their function as intermediates en route to indole alkaloids, and it is only recently
that these monoterpenes have begun to be studied in their own right.
Loganin is also an intermediate in the biosynthesis of other iridoids and of
secoiridoids formed by rearrangement and functionalization of the skeleton (14)
[33,34]. Its aglucone is unstable and the sugar moiety may play a solubilizing, transport-facilitating, and, very importantly, protective role; in particular, it may protect
the C1-linked hydroxyl group (for numbering of the ring see 18; alternative systems
are sometimes used) from oxidation until the appropriate stage in the biosynthetic
scheme, when the sugar residue is cleaved off.
The fused bicyclic system of loganin accounts for 8 of the 10 carbon atoms derived
from the acyclic monoterpene precursor. One of the remaining carbon is absent in some
compounds that cooccur with, and are undoubtedly related to, the iridoids, although
there is no formal biosynthetic demonstration for these relationships saved in the case
of aucubin (19) [35]. Unedoside (20) (Figure 1.5) [36] is the only compound so far
characterized that has lost both peripheral carbons; none have been reported which

have lost the C10 methyl group but not the C11 carboxyl group, whereas in contrast several families of compounds have lost the latter group but retained the former, e.g., aucubin (19) and catalposide (21); R 5 p-hydroxybenzol) [37,38]. Secoiridoids such as
gentiopicroside (22) [39] may be derived from loganin or a close-related compound by
cleavage of the C7ÀC8 bond yielding initially, in the case of loganin itself [40], secologanin (23) [41]. The isolation of compounds such as foliamenthin (24) [42], sweroside
(25) [43], and ipecoside (26) [44], as well as biosynthetic studies, provide further evidence that these groups of compounds are biogenetically related. Other relatives are the
alkaloids β-skytanthine (27) [45] and actinidine (28) [46]; most of these compounds
occur as their glucosides, but in addition to those described, genipin (29) and a few
others appear to be presenting plant tissues as their aglycones. A diglucoside and a
thioester are among interesting iridoids that have recently been characterized.
All the biosynthetic studies on this group of compounds have depended on
investigation of the fate in intact plant tissue of specifically labeled and carefully
chosen precursors, and these have often been supplemented by the isolation of
suspected intermediates from the tissue. Only a few plant species have been investigated, especially young shoots of Vinca rosea or Catharanthus roseus.


Monoterpenes and Related Compounds from the Medicinal Plants of Africa
OG

O

7
OG

OH OG

O

O

O

O

HO

RO

20

21

O

O

22
OG

OG
OH

O

O

OHC
CO2Me

CO

OG

O

23

O
O

O

O

G=β-D-glucose
25

O

24

OH OH
HO
N

N

NAc

HO

CO2Me

OG
MeO2C

O

27

28

29

26

Figure 1.5 Chemical structure of unedoside (20), captaposide (21), gentiopicroside (22),
secologanin (23), foliamenthin (24), sweroside (25), ipecoside (26), β-skytanthine (27),
actinidine (28), and genipin (29).

Whereas the broad outlines of the biosynthetic pathways have undoubtedly been
unveiled, some of the minor details may be species or even tissue specific. For example, differences in labeling patterns between the same compound found in the leaves
and flowers may occur. Generally the influence of this, and of other physiological parameters, on biosynthetic routes has been ignored, but studies on the formation
of verbenalin (30) (Figure 1.6), β-skytanthine (27), and nepetalactone (31) have demonstrated the critical importance of these factors may have on labeling patterns. The same
substrate may also be an effective precursor of a particular iridoid in one plant species
but not in another; for example, whole and sliced rhizomes of Menyanthes trifoliata
did not incorporate [2-14C]MVA into loganin, whereas in V. rosea the additive was an
efficient and specific precursor [47]. Data based on several different experimental
approaches or procedures are thus desirable for investigation of any one species.
Experiments using the 4R and 4S isomers of [2-14C, 4-3H1]MVA have confirmed
that the stereospecificity of formation of the two double bonds of geraniol used in
loganin formation is similar to that found in terpene synthesis in general, and that

direct condensation of isopentenyl pyrophosphate (IPP) with dimethyl allyl pyrophosphate (DMAPP) to give nerol rather than geraniol directly also does not occur in this
class of compounds. Geraniol, GPP, or some other derivative such as the enzymebound intermediate previously discussed, appears to be an obligatory precursor. The
use of (1R)- and (1S)-[2-14C,1-3H1]GPP has demonstrated that conversion of the C1
carbon into an aldehydic or equivalent oxidation level is also stereospecific, and the
hydrogens at rogens at C2 and C6 geraniol are retained during its transformation into


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Medicinal Plant Research in Africa

O

OG

OH
O

O

O

O

O
CO2Me
G= β-D-glucose

OG
O

31

30

CHO2Me
32
OH

N

O
MeO
33

N
HO

OCOMe
CO2Me

34

Figure 1.6 Chemical structure of verbenalin (30), nepetalactone (31), plumieride (32),
iridodial (33), and loganin (34).

loganin. However, if saturation of the C2/C3 double bond of geraniol is a prerequisite
for the formation of loganin, then both reduction and subsequent removal of the
added proton occur in a stereospecific fashion [48,49].
The occurrence of foliamenthin (24) and related compounds also suggests that

oxidation of the isopropylidene group in geraniol is essential for its conversion into
loganin. However, evidence from the incorporation of doubly labeled mevalonic acid
(MVA) into indole alkaloids suggests that incorporation of the intact propylidene
unit of geraniol takes place. Such findings are now reconciled by our knowledge that
oxidation occurs at both C9 and C10 of geraniol (Figure 1.7) and that equilibration
of these two carbons of geraniol occurs during the biosynthesis of loganin and related
compounds from geraniol. Thus early studies [50] on the biosynthesis of plumieride
(32) [51] proved that during its formation from geraniol the C9 and C10 atoms of the
latter became biosynthetically equivalent, for 25% of the label present was located at
the starred atoms in 32 when [2-14C]MVA was used as a precursor. A similar pattern
in loganin (18) was obtained with the same precursor and with [3-14C]MVA, and
analogous results have been reported for all the iridoids, secoiridoids, and indole
alkaloids that have been studied. To account for the pattern in plumieride, iridodial
(or irodial) (33) was proposed as an intermediate, but this compound is not a precursor of loganin or vindoline (34) in V. rosea [52]. The equilibration of carbon atoms
equivalent to C9 and C10 of geraniol may, however, not always be complete and can
vary with the physiological condition of the plant used. However, the point was
made that asymmetric labeling of the part of the molecule derived from IPP, common for the monoterpenes described in the previous section, is not as widespread a
phenomenon for these cyclopentane derivatives. 10-Hydroxygeraniol (35) and
10-hydroxynerol (36) (using the accepted numbering) have recently been shown to
be precursors of loganin and of the indole alkaloid, and a reasonable route for loganin biosynthesis can be summarized in Figure 1.7. Complete randomization of 14C
label from C9 and C10 of 35 was observed. Several related monoterpenes—linalool,


Monoterpenes and Related Compounds from the Medicinal Plants of Africa
HO

CH3

HOH2C

CO2H

H

H
5

4
3

HD

HA

HC

HB

9

8

9

1
CH2OH
2
HB

10

CH2OH

(Hc, HD)

OH
a

OH

OH

OHC

35

a

b
OH

CHO

OH

OH

37

b

a

HO
H 7
C

OG
HB
O
H(Hc, HD)
H
B Co2R
18

H
H

H
7
41

CHO

36

OG
CHO
O
CHO

H
38 CO2R

b

OH
CHO

Co2R

G=β-D-glucose
HA, HB, HC, and HD refer to the 4S, 4R, 2R, and 2S hydrogens, respectively of MVA

Figure 1.7 Formation of cyclopentane derivatives.

citronellol, and citral—were not significantly incorporated. These results suggest that
a further step after 35 and 36 in the biosynthesis of iridoids involves attack on C9
of 35 or 36 (or of the corresponding aldehydes) to give a hypothetical species such
as 37 (route a, Figure 1.7). It is not known whether C5 or C10 is oxidized first, or
if indeed there is a specific order. 10-Hydroxynerol was a more efficient precursor
than its isomer, and this suggests that the immediate precursors of the iridoids and
indole alkaloids [53] have the cis double bond at C2 and C3 that is expected on
stereochemical grounds. The rate of isomerization of this double bond may play an
important role in diverting GPP from its alternative function as a precursor of higher
terpenoids. It is also possible that cyclization may proceed prior to further oxidation
at C9 of 10-hydroxynerol (route b, Figure 1.7). The only other intermediates that
have been demonstrated between geraniol and loganin or loganic acid are deoxyloganin and deoxyloganic acid, respectively ((38), R 5 Me, H), and both have been
shown to be specific precursors of loganin [54]. Deoxyloganin occurs together with
loganin in V. rosea and Strychnos nux-vomica [55]. Neither the aglucone of deoxyloganin nor the isomers with the double bonds at the C6/C7 or C7/C8 positions were

incorporated into the final product. The final stage of loganin [56] biosynthesis is
therefore envisaged as hydroxylation of deoxyloganin at C7, which data on loganic
acid biosynthesis suggest is stereospecific, like other biological hydroxylations. Both


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Medicinal Plant Research in Africa

deoxyloganin and loganic acid occur in V. rosea, and a cell-free system from this
plant can convert the acid into loganin; thus a dual pathway is suggested in which
methylation can occur at different points (Figure 1.8). Similar and more complicated
metabolic grids have been observed in the biosynthesis of other terpenoids, especially
carotenoids, and others will be mentioned shortly.
Recent work on loganic acid and gentiopicroside [57À59] biosynthesized
from 14C and 3H doubly labeled isomers of MVA and geraniol has confirmed the
formation of geraniol and hence of the cyclopentane derivatives from MVA. The
stoichiometry of both the decarboxylation of MVAPP to give IPP and of the addition of IPP to DMAPP to give GPP is similar to that reported previously for other
terpenoids and steroids. Deviations from the expected 14C/3H ratio of activities
of C7 of loganic acid were found that were similar to those reported in steroid
synthesis. Such results have been accounted for by the relatively slow rate of
removal of DMAPP by prenyl transferase as compared to the rate of establishing
the equilibrium between IPP and DMAPP by IPP isomerase. Conversion of
DMAPP into IPP in the latter equilibration would result in a partial loss of asymmetry of the 3H/1H pair at C2 of IPP.
No preferential labeling of the two isoprene units of loganic acid was observed.
However, such patterns can occur at the monoterpene level; formation of menthiafolin, a hydroxylated isomer of 24, from [2-14C]geraniol gave a product in which
the two C-10 moieties were labeled in the ratio of 3:1. This finding suggests that
either the monoterpene or its constituent units may be synthesized in different
pools, which may correspond to intra- and extrachloroplastic sites of synthesis
(both of which sites contain terpene synthesizing enzymes). The pools may be

connected at the monoterpene-glucoside level as these compounds are water
soluble. However, the stage at which glucose is coupled to a monoterpene remains
unknown; present evidence suggests that it is not the final step in loganin or iridoid
biosynthesis. The earlier findings indicate that iridoids may pass through several
intra- and extracellular compartments during biosynthesis, and the distribution of
iridoids in all types of plant tissues may provide further evidence for such tortuous
pathways. The changes in labeling pattern at C3 and C11 of certain iridoids and
related compounds dependent on the age of the plant material may also be related
to the need for the biosynthetic scheme to occur at several distinct sites. Indeed,
the observed 14C/3H isotope ratios of activities of C7 of loganic acid biosynthesized
from 4R and 4S isomers of [2-14C,-4-3H1]MVA that have been discussed earlier
may be the result of incomplete randomization at the two positions, since the
OG
O
O
CO2Me
G=β-D-glucose
41

Figure 1.8 Chemical structure of loganin derivative.


Monoterpenes and Related Compounds from the Medicinal Plants of Africa

11

expected isotope ratios were calculated on the assumption of the complete biosynthetic equivalence of these two positions. However, the pattern of randomization
between C3 and C11 of loganic acid formed from [2-14C]MVA did not vary with
the age of the V. rosea specimen that was used.

1.2.1.3.2 Other Iridoids and Related Compounds
The biosynthesis of some members of one family of iridoids, most of which have been
mentioned in the preceding discussion, is outlined in Figure 1.9. Deoxyloganic acid
(38) (R 5 H) is an efficient precursor for asperuloside (39) [60], aucubin (29), and verbenalin (40), as well as loganin. Early work showed that [2-14C]MVA was a specific
precursor of verbenalin in Verbena officinalis but not of aucubin in Verbascum thapsus. The incorporation of tracer into the latter was very low and was randomly distributed, with appreciable radioactivity appearing in the glucose moiety. Similar labeling
of the sugar occurred on biosynthesis of plumieride from [2-14C]MVA and of loganic
acid from HMG, and such observations emphasize the imperative need for determination of specific labeling patterns when presumed precursors are fed and compounds
possibly derived from them are isolated. Verbenalin may be biosynthesized directly
from 7-deoxyloganin, but it is usually found that 41 or a close relative is a parent
of both verbenalin and aucubin, as shown in Figure 1.9, although the biochemical
details are wanting. [2-14C]MVA was found to be a specific precursor of verbenalin in
V. officinalis, and differences occurred in the labeling of the product after feeding
1À2- or 4-month-old plants; in the young plants, complete randomization of label
between C3 and C11 had occurred (27% of total in C3 and 23% in C11 of the expected
total in these two positions of 50% of that incorporated). In older plants, little randomization took place (42% in C3 and 8% in C11). These differences, as mentioned
before, have implications for all work on terpene biosynthesis and may either reflect
differences in pool sizes or may indicate that the actual pathway of biosynthesis varies
with age. The actual patterns of randomization here, and in similar experiments on the
formation of β-skytanthine, although varying in extent, are similar to those found in
the biosynthesis of loganin and indole alkaloids from [2-14C]MVA.
Another pattern of biosynthesis is shown in Figure 1.5. MVA, deoxyloganin, and
both loganin and loganic acid are precursors of the secoiridoid gentiopicroside (22),
which may be more immediately derived from secologanin (23). Sweroside (25) is
also a known precursor of gentiopicroside, as detailed by feeding experiments, and
is itself probably formed from secologanin by an intramolecular transesterification
either before or after reduction of the aldehyde group. Further work on the biosynthesis of ipecoside (26) demonstrated that cleavage of loganin (19) to secologanin (23)
occurs via a mechanism which leaves the proton at C9 unaffected. As expected,
disacetyl ipecoside (but not its isomer), the condensation product of dopamine with
secologanin, is also a precursor of ipecoside.
The biosynthesis of β-skytanthine (27) from MVA has been studied in detail, and it

was confirmed that this compound is biogenetically related to the iridoids, as is also the
pyridine alkaloid actinidine (28). The labeling pattern of nepetalactone (31) biosynthesized from [2-14C]MVA by Nepeta cataria suggests that some randomization of label
occurs at the C-5 (IPP-DMAPP) as well as at the C-10 (monoterpene) stage of


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Medicinal Plant Research in Africa

OG
O
38
CO2R

OG
HO

O
18

HO

CO2Me

O

HO

CO2Me

O

O

O

40

OG

HO

OG

OG

(H,OH)
HO

CO2Me

CO2Me

OHOG

HO

O

O

(OH,H)

HO

CO2Me

19 CO2Me

O
HO

OG

OG
O

O

OG
O

CO2Me
O

O

OH OG

OH OG

HO

O

O
RO

O
39

CO2Me

21
51

Figure 1.9 Formation of catalposide (21), deoxyloganic acid (38), and asperuloside (39).

biosynthesis. The work confirms the suggested monoterpene nature of the compound,
which was indicated by preliminary tracer studies [61]. The observed labeling pattern
would not be in accord with the proposed mechanism of IPP isomerase, which certainly
applies in the biosynthesis of loganin and loganic acid. Evidence for the catabolism of
MVA was obtained in these experiments on N. cataria, and the observed randomization


Monoterpenes and Related Compounds from the Medicinal Plants of Africa

13

of label may result from this effect, which was probably brought into prominence by
the prolonged periods of incubation that were used in the feeding procedures.

Various biogenetic schemes for β-skytanthine, actinidine, and nepetalactone
have been outlined and pathways to other iridoids have been proposed. In all these
schemes, iridodial is thought to be a key intermediate, but the recent demonstration
that the C8 and C10 atoms of nerol must be oxidized at an early stage en route to
these compounds may rule this out. Furthermore, iridodial is not a precursor for
loganin or vindoline.
Figure 1.10, which is based on recent detailed discussions, summarizes most
of the speculations made in this section and includes many steps for which there is
evidence from feeding experiments. The major problems of the mechanism of the
closure of the cyclopentane ring and of the order in which the oxidation steps occur
are still uncertain.

1.2.1.3.3 Indole Alkaloid
Figure 1.11 summarizes our present knowledge of the formation of the indole
alkaloids from loganin and later precursors. The terpenoid moieties in the alkaloids
are outlined with heavier lines. The indole part of these compounds was shown
to be derived from tryptophan or tryptamine [62À65]; first experiments designed to
confirm the suggestion that the remaining 9 or 10 carbon atoms were of terpenoid
origin were inconclusive. However, recent work has clearly that 14C-labeled MVA,
geraniol, and loganin are efficient precursors of the nontryptophan part of the molecule in many members of this class. As with the iridoids, current ideas on the
routes involved are based almost entirely on experiments which trace the metabolic
fate of added presumed precursors. In most cases, the postulated intermediate has
also been isolated from the plants under investigation. The presence of structurally
related compounds such as ipecoside (26), foliamenthin (25), vincoside (42), and
its isomer isovincoside (or strictoside) derivatives of secamine and many others provide indirect evidence for the accepted pathways, although the secamines may be
artifacts of isolation [66].
The nature of the postulated monoterpenoid precursor was demonstrated by
the incorporation of 0-[3H]methylloganin into representatives of the three main
structural types of indole alkaloids: ajmalicine (44) and corynantheine (43)
(Corynantheine type), catharanthine (49) (Figure 1.12) (Iboga type), and vindoline

(34) (Aspidosperma type). The related iridoids monotropeine methyl ester (51),
verbenalin (29), and genipin (28) were not incorporated. The incorporation results
with loganin could not, therefore, be attributed to transfer of the O-methyl group.
[8-14C]- or [2-14C]loganin, as well as various tritiated forms of this compound, was
also specifically incorporated.
The next established precursor of the class was secologanin (24). The route of formation of this compound from loganin is at present obscure, although it is generally
believed that 10-hydroxyloganin may be an intermediate as outlined in Figure 1.11
the isolation of many 10-hydroxylated compounds such as genipin (28) demonstrates that the C10 methyl group can be hydroxylated in vivo 10-Hydroxyloganin
should readily be cleaved to secologanin, particularly if the exocyclic hydroxyl was


14

Medicinal Plant Research in Africa

OH
OH
R''H2C

CHO

CH2R'
42
N

N

OG
HO

O
28
19

27

CO2Me
OH

O

O

O

OG
O
OHC

31

34

CO2Me

23

OG

OG

N
O

O

O
O
25

O

O

O

O

22
G=β-D-glucose

Figure 1.10 Formation of gentiopicroside (22), secologanin (23), sweroside (25), ipecoside (26),
β-skytanthine (27), actinidine (28), nepetalactone (31), loganin (34), and vincoside (42).

first converted into a good leaving group such as phosphate or pyrophosphate.
Secologanin has been shown to condense in vitro with tryptamine to form vincoside
(42) and isomeric compounds, and the reaction also occurs in vivo [67].
Sweroside (25), which is closely related to secologanin, is also an excellent
precursor of vindoline and is incorporated in 11% yield, but recent evidence

Monoterpenes and Related Compounds from the Medicinal Plants of Africa

H

HO

H

CO2Me

CO2Me

O

O

15

H

CO2Me

OHC
HO

O
H

OG

OG

19

OG

23

50

N
H

NH
H
OG

HO

H

HO

N
H

NAc
OG
H

O

MeO2C

H

42

O

MeO2C
26
N

N
H H

N
H H
H

45

O

MeO2C

H
43

H
44

N

N
H H

N

MeO2C

MeO2C

OH

OMe

N

N
N
H

N
H
MeO2C
49

MeO2C

OH
46

N

HO

N
OH
34

N

OAc
CO2Me

N
N
H

N
CO2Me
48

47

Figure 1.11 Formation of secologanin (23), loganin (34), ajmalicine (44), stemmadenine (46),
and catharanthine (49). Note: G 5 glucose.

suggests that this and its hydroxy derivative swertiamarin are probably on a branch
of the biosynthetic pathway leading from secologanin but not proceeding directly
to the indole alkaloids. Gentiopicroside cannot be a direct precursor of the indole
alkaloids since it loses a C5 hydrogen when biosynthesized from loganin, whereas


16

Medicinal Plant Research in Africa

the indole alkaloids lose a C5 hydrogen. Vincoside (42) seems to be the precursor
of most indole alkaloids, being initially converted into geissoschizine (41) and
corynantheine aldehyde (42), and present evidence suggests that the rearrangement
of the 2À10 monoterpene skeleton to give the three classes of indole alkaloids
takes place after formation of this parent compound. Isovincoside does not appear
to be a natural precursor [68].
Current investigation suggests that the three main classes of indole alkaloid
are formed in the order: Corynantheine, Aspidosperma, and Iboga types. A novel
approach to the problem has been introduced by following the formation of
different alkaloids during the germination of seeds of V. rosea. Saturation of the
nonindolic bond of vincoside destroyed its ability to act as a precursor of the
class; furthermore the hydrogen at C5 of vincoside is retained in all three classes
of alkaloid. Geissoschizine may also be a precursor of all classes and has been
isolated from V. rosea, whereas corynantheine aldehyde is not, and is only a
precursor compound of its own class, e.g., corynantheine (42). In feeding experiments, geissoschizine is specifically incorporated into catharanthine (47), coronaridine (a dihydro derivative of 47, vindoline (34), and also the strychnos group
alkaloid akuammicine. An isomer of stemmadenine (46) was also isolated, which
was converted by base into akuammicine [69].
Stemmadenine (46) may be related to the intermediates, the secamines (47),
and tabersonine (48), which rearrange to give Iboga- and Aspidosperma-type

compounds. 16, 17-Dihydrosecodin-17-01 that is isolated from Rhazya orientalis,
similar secodines, and also an alkaloid isolated from Tabernamontana cumminsii
may also be related to this intermediate. In V. rosea, tabersonine (48) is a precursor
of catharanthine (49) and vindoline (34) [70].
Further evidence for the pathway in Figure 1.11 is provided by the location in
the alkaloids of the tritium from C7 of loganin (18), which is incorporated without
loss. No migration of hydrogen occurs from the carbon corresponding to Ci of
loganin and Cs of vincoside (42)—the C3 of the alkaloids—during all the subsequent rearrangements.
OH

N
N
N
H

N

N

51

N
H

OH

Me

53

52
MeO

N
N

MeO

OMe

MeO

N
H

N
N

OH
HN

54

MeO2C

55

O

O

O

56

Figure 1.12 Chemical structure of appraising (51), uleine (52), and related compounds
(53À56).


Monoterpenes and Related Compounds from the Medicinal Plants of Africa

17

These last steps in the biosynthesis (Figure 1.6) are supported by the reported
conversions in vitro of the Aspidosperma-type alkaloid tabersonine (48) into the
Iboga-type compound catharanthine (49) and of stemmadenine (46) into tabersonine
and catharanthine [71,72]; but other workers have, unfortunately, been unable to
repeat these experiments.
Recently, the biosynthesis of apparicine (51) and uleine (52) has been studied.
These are structurally unusual in having only a single carbon atom in the link between
the indole ring and the nonindolic nitrogen atom. The a-carbon atom of the side chain
of the precursor tryptophan is lost and the 3-carbon atom is retained. Tryptophan,
however, was only incorporated into apparicine. The fission of the side chain must
have occurred at a late biosynthetic stage as stemmadenine is incorporated.

1.2.1.3.4 Irregular Structures
Two classes of compounds can be grouped under this heading: first, degraded
monoterpenes that contain fewer than 10 carbon atoms; and, second, compounds
that apparently break the isoprene rule in its simpler statements [73], in containing
C-5 units that are not linked head to tail.

The first class presents no biogenetic problem. An early example was cryptone (57)
(Figure 1.13), which is almost certainly formed in vivo from 6-phellandrene (71) with
which it cooccurs [74]; others are the arthropod defensive substances (58À60), the origin of which can be reasonably deduced, although no tracer studies have been
carried out. Santene (61) is believed to be formed by Eq. (1.5), and all the presumed
intermediates have been identified as cooccurring in sandalwood. The oils of Pinus
jeffreyi and Pinus sabiniana consist predominantly (.95 w/w) of n-heptane, but as
[2-14C]HMG was not incorporated into this compound, it was concluded to be of
polyketide rather than of mevalonoid origin. Such conclusions are questionable in
view of the negligible incorporations of MVA and biogenetically related compounds
into many products that are of undoubted mevalonoid origin. In this context, it is
interesting that leucine was incorporated in over 80% yield into amyl alcohol and its
acetate in disks of banana fruit and in yeast, and this amino acid may be a precursor
of certain unusual “terpenoids.”

O

OH

OH

ð1:5Þ

CO2H

O
O
O

O
57

58

59

60

61

71

Figure 1.13 Chemical structure of cryptone (57), 5, 6-dimethylhept-5-2-one (58),
2-methylheptan-4-one (59), 4-methylhexan-2-one (60), santene (61), and 6-phellandrene (71).


18

Medicinal Plant Research in Africa

Some of the irregularly linked C-10 compounds of the second class are very
probably formed by well-established rearrangements of precursors biosynthesized
with conventional head-to-tail linking of the C-5 units, and thus come within
the province of the operation of the biogenetic isoprene rule. Examples are fenchane derivatives such as fenchol (64) derived from the ion (62) and isocamphane
derivatives such as camphene (65) (Figure 1.14), derived from 63 by a similar
WagnerÀMeerwein shift. A more unusual type of rearrangement gives carquejol (65)
(Figure 1.15), which occurs in the oil of the same name [75] and is the only known
naturally occurring α-menthane derivative. Another speculative proposal is the
derivation of 66 from thujone.
One of the most discussed compounds of this class is artemisia ketone (67)
(Figure 1.16). A novel route for its biosynthesis was implied by the discovery that

[2-14C]MVA was not detectably incorporated into the compound formed by
Santolina chamaecyparissus under conditions where the regularly constructed and
cooccurring monoterpenes were significantly labeled. These observations have
been confirmed, but the same precursor was found to be normally incorporated into
the artemisia ketone produced by Artemisia annua, such that the position of the
label allowed delineation of the route of synthesis. On degradation, about 92% of
the incorporated tracer was deduced to be at Ca and CIO and only about 8% was
located at C7 and CS (these pairs of atoms were not distinguished by the degradation scheme); thus asymmetric labeling occurred, although not to such an extreme
as in the monoterpenes previously discussed.

62

63

OH

64

Figure 1.14 Formation of fenchol (64) and camphene (65).

65


Monoterpenes and Related Compounds from the Medicinal Plants of Africa

19

A variety of mechanisms has been proposed, all unbacked by any experimental
evidence, for the biogenesis of this compound. These are (a) a ring opening of a
cyclopropane intermediate (68) derived from linalool fission of a carane skeleton (69),

(b) Stevens rearrangement of a sulfonium ylide derived from condensation of
two molecules of DMAPP, (c) condensation of two units of 1,1-dimethylallyl pyrophosphate, and (d) vague speculations about an origin from a cationic intermediate
common to linalool and menthol, the intermediary of the chrysanthemyl ion (70) or
its biogenetic equivalent [76].
The observed pattern of incorporation of tracer was inconsistent with routes (b),
(c), and (d); e.g., a direct condensation of two molecules of DMAPP would, unless
specific compartmentation effects were evoked, lead to an equal distribution
of tracer between C7, C8, C9, and C10 atoms. Also, when [2-14C]geraniol was fed
to A. annua, considerable scrambling of tracer resulted in artemisia ketone; each
carbon now contained at least 6% of the tracer, although C2 and C4 were by far
the most heavily labeled, accounting for over half of the total. This contrasts with
the smooth incorporation of [1-14C]GPP into cineole in an Eucalyptus species
with negligible scrambling. If routes (a) or (e) were operative, geraniol would reasonably be expected to be a more efficient precursor than MVA and would be
incorporated with less randomization, whereas route f would require the additive to
be degraded to C-1, C-2, or C-5 fragments that would be incorporated through formation of 70. The tracer results seem better in accord with the last route, especially
as the details of mechanisms (a) and (e) seem biochemically unlikely, but nothing
is known about the route to 70.

O
O
O

OH

65
66

Figure 1.15 Chemical structure of carquejol (65) and thujone derivative (66).

O

67

68

69

70

Figure 1.16 Chemical structure of artemisia ketone (67), cyclopropane intermediate (68),
carane skeleton (69), and chrysanthemyl ion (70).


20

1.3

Medicinal Plant Research in Africa

Monoterpenes Isolated from African Medicinal
Plants and Their Pharmacological Activities

Ajuga remota is the most frequently used medicinal herb for malaria treatment in
Kenya. Its two known isolates ajugarin-1 and ergosterol-5,8-endoperoxide and a
new isolate 8-O-acetylharpagide were evaluated for their in vitro antiplasmodial
activity. Ajugarin-1 was moderately active with an IC50 of 23.0 μM, as compared
to chloroquine (IC50 of 0.01 μM) against the chloroquine-sensitive (FCA20/GHA)
strain of Plasmodium falciparum. Ergosterol-5,8-endoperoxide was about threefold
as potent (IC50 of 8.2 μM) [77].
8-O-Acetylharpagide, isolated for the first time from the east African
A. remota, did not exhibit any antiplasmodial activity even at the highest concentration of about 500 μM used against the chloroquines-sensitive strain of

P. falciparium (FCA20/GHA). However, the compound exhibited in vitro cytotoxicity against the A431 human skin carcinoma cell line. It showed a
concentration-dependent inhibition of cell proliferation with an IC50 of 310 μM,
approximately sevenfold less active than the standard antineoplastic agent
(fluorouracil) [77].
Compounds from Plocamium suhrii were tested for their in vitro antiproliferative
effects against WHCO1 esophageal cancer cells using the MTT assay. (1E,3RÃ ,4SÃ ,5E,
7Z)-1-bromo-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene, (1E,3RÃ ,4SÃ ,5
E,7Z)-1-bromo-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene,
(1E,3RÃ ,
Ã
4R ,5E,7Z)-1-bromo-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene,
(3R Ã ,4S Ã ,5E,7Z)-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene,
(1E,3RÃ ,4RÃ ,5E,7Z)-1,8-dibromo-3,4-dichloro-3,7-dimethylocta-1,5,7-triene, and
(3RÃ ,4SÃ )-3,4,6,7-tetrachloro-3,7-dimethylocten-1-ene showed greater cytotoxicity
(IC50 of 6.6À9.9 μM) than the known cancer drug cisplatin (IC50 of 13 μM) in
the cancer cell line [78].
Furthermore, compounds from Plocamium cornutum were evaluated for their
antiplasmodial activity against the chloroquine-sensitive P. falciparum strain
(Figure 1.17). Although the compounds tested here were significantly less active
than the standard drug chloroquine (IC50 of 0.036 μM), it is interesting to note
that (3RÃ ,4SÃ ,5E,7Z)-3,4,-dichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene
and (3RÃ ,4SÃ ,5E,7Z)-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene
containing the 7-dichloromethyl moiety were the most active (IC50 of 16 and
17 μM, respectively) [79] (Table 1.1).

1.4

New Monoterpenes Isolated in African
Medicinal Plants

In this section, we report the new monoterpenes isolated from African medicinal
plants (Figure 1.18) without any reported pharmacological activity (Table 1.2).


HO HO

Cl

O
O

OAC
OAc

H

Cl

74

Cl

Cl
Cl

Cl

Cl

H

Cl

H

Cl
Cl

H
Cl

Oglc

73

72

Cl
Cl

Br

Cl
Cl

76

Cl

H

H

Cl

Br

Br

Cl

O
AcO

Cl
Cl

O

77

75
Cl

Cl
Br

Br

Cl

Br
Cl

Cl

Br

78
Cl

Cl

Cl

79

Cl

Cl

Cl

Cl

80

Cl
Cl

Cl

Cl

81

Cl

82

Figure 1.17 Some bioactive monoterpenes identified in African medicinal plants.

Table 1.1 Selected Bioactive Monoterpenes from African Medicinal Plants
Compounds

Plants (Family)

Activities with
Reference

Ajugarin-1 (72)
A. remota
Antiplasmodial [77]
(Lamiaceae)
8-O-Acetylharpagide (73)
(1Z,3RÃ ,4SÃ ,5E,7Z)-1-Bromo-3,4,8-trichloro-7P. suhrii
Anticancer activity
(dichloromethyl)-3-methylocta-1,5,7-triene (74)
(Plocamiaceae)
[78]
(1E,3RÃ ,4SÃ ,5E,7Z)-1-Bromo-3,4,8-trichloro-7(dichloromethyl)-3-methylocta-1,5,7-triene (75)
(1E,3RÃ ,4RÃ ,5E,7Z)-1-Bromo-3,4,8-trichloro-7(dichloromethyl)-3-methylocta-1,5,7-triene (76)

(3RÃ ,4SÃ ,5E,7Z)-3,4,8-Trichloro-7(dichloromethyl)-3-methylocta-1,5,7-triene (77)
(1E,3RÃ ,4RÃ ,5E,7Z)-1,8-Dibromo-3,4-dichloro3,7-dimethylocta-1,5,7-triene (78)
(1E,3RÃ ,4SÃ ,5E,7Z)-1,8-Dibromo-3,8-dichloro-7(dichloromethyl)-3-methylocta-1,5,7-triene (79)
(3RÃ ,4SÃ )-3,4,6,7-Tetrachloro-3,7dimethylocten-1-ene (80)
(3RÃ ,4SÃ ,5E,7Z)-3,4,-Dichloro-7P. cornutum
Antiplasmodial [79]
(dichloromethyl)-3-methylocta-1,5,7-triene (81)
(Plocamiaceae)
(3RÃ ,4SÃ ,5E,7Z)-3,4,8-Trichloro-7(dichloromethyl)-3-methylocta-1,5,7-triene (82)


22

Medicinal Plant Research in Africa
HO

OH

3'
1' 6'
10
H3C

Cl

Cl

HO

O

O

H

H3C

Cl

Cl

Cl

85

84

O

H

Cl

Cl

O

7 6
9
1 5 H CH3

4 O
O
OH 3
O
OH

HO

Cl

Br

Cl
Cl

83
Br

HO

Cl

Cl
Br
Br

Br

Cl

86

OH

7 9 5

3
1 O

AOc H H

87

Oglc

88
32 26
OMe
15 24

1 4b 5

27 MeO
19

3
20

4a O
OMe O

28

OH

AcO

17
25
13 13a
13b OMe
O
7 11 OMe
22
9
21
OMe
29
89

OH

AcO

O
AcO

O

H

AcO

Oglc

H

90

OH

OAc
O AcO

91

OH

HO

7

1

O

6

O
2

5

92

Br

9

Cl

CHO

8

10

Cl
Br

CHO

Cl

Br

95

4

94

93
CHO

3

O

HO
HO

HO

OH
OH

O

96

Cl

97

Figure 1.18 Newly isolated compounds identified in African plants: 7-caffeoylloganin
(83); (1Z,3RÃ ,4SÃ ,5E,7Z)-1-bromo-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7triene (84); (3RÃ ,4SÃ )-3,4,6,7-tetrachloro-3,7-dimethylocten-1-ene (85); (1Z,3E,5SÃ ,6SÃ )-1bromo-5,6-dichloro-2,6-dimethyl-octa-1,3,7-triene (86); (1Z,3E,5RÃ ,6SÃ )-1-bromo-5,6dichloro-2,6-dimethyl-octa-1,3,7-triene (87); 8-O-acetylharpagide (88); ( 6 )-Schefflone
(89); 6,8-diacetylharpagide (90); 6,8-diactyl-1-O-β-(30 ,40 -di-O-acetylglucoside) (91); (2)
(1R0 ,4S)-1,4-dihydroxy-p-menth-2-ene (92); (2)(1R0 ,2SÃ ,3SÃ ,4S)-1,2,3,4-tetrahydroxy-pmenthane (93); chenopanone (94); 4,6-dibromo-3,7-dimethylocta-2,7-dienal (95);
4,8-chloro-3,7-dimethylocta-2,4,6-trienal (96); 8-bromo-6,7-dichloro-3,7-dimethylocta2,4-dienal (97); 4-bromo-8-chloro-3,7-dimethylocta-2,6-dienal (98); 3-formyl-2,2,6trimethyl-3,5-cyclohexadienyl angelate (99); 3-formyl-2,2,4-trimethyl-3,5-cyclohexadienyl
angelate (100); 7-hydroxymyrthenal (101); 7-hydroxymyrtenol (102); (1)-quebrachitol

(103); (1SÃ ,2SÃ ,4RÃ )-trihydroxy-p-menth-5-ene (104); (1SÃ ,2RÃ ,4RÃ )-trihydroxy-pmenth-5-ene (105); 50 -epi-isoethuliacoumarin B (106); 50 -epi-isoethuliacoumarin A (107);
ethuliaconyzophenone (108); ferulagol A (109); ferulagol B (110); plocoralide A (111);
plocoralide B (112); plocoralide C (113); shanzhisin methyl ester gentiobioside (114);
and djalonenol (115).


Monoterpenes and Related Compounds from the Medicinal Plants of Africa

H

CHO

Br

23
H

CHO

AngO

CHO

AngO

Br
H

98

HO

H

CH2OH

HO

H

H

H

99

100

H

OH

CHO

HO
HO

101

O

OH

102

OH

103
OH

OH
OH

8'
OH

OH

H
9

OH

104

6

105

7

9'

7' O

HO 6'
O 5' 4'
5 4 3 3'
2

1
O

8

10'
1'

O

106
9
5

6

OH
O 5'

8

O

10'

O

HO

4
1
OH

O

OH

8'

4' 5' 6' 7'
1'

2'

5

9'

O

3'

3

9'

8'

7'

9 O 2

1' O 7

4'

10
O

109

108

O

107
Cl
O

O

O

Br

Cl
Cl

HO

Cl

Br

110

Br

111
Cl

Cl

Br

112
CO2Me

HO

5
Br
Cl

Cl

113

Me

H
OH OR

114

O
6 1
4

O
2
3 CH2OH

8 CH2OH
10

7
9

115

Figure 1.18 (Continued)

1.5

Other Monoterpenes in African Medicinal Plants

Several other monoterpenes were identified as known compounds in African plants,
but no data were documented in regard to their biological activities. Some of them
were isolated as monoterpene coumarins. They are summarized in Figure 1.19 and
Table 1.3.


Table 1.2 Newly Isolated Monoterpenes from African Medicinal Plants
Name

Plant (Family)

Area of Plant Collection Physical Properties

7-Caffeoylloganin (83)
(1Z,3RÃ ,4SÃ ,5E,7Z)-1-Bromo-3,4,8-trichloro7-(dichloromethyl)-3-methylocta-1,5,7triene (84)
(3RÃ ,4SÃ )-3,4,6,7-Tetrachloro-3,7dimethylocten-1-ene (85)
(1Z,3E,5SÃ ,6SÃ )-1-Bromo-5,6-dichloro-2,6dimethyl-octa-1,3,7-triene (86)
(1Z,3E,5RÃ ,6SÃ )-1-Bromo-5,6-dichloro-2,6dimethyl-octa-1,3,7-triene (87)
8-O-Acetylharpagide (88)
(6)-Schefflone (89)
6,8-Diacetylharpagide (90)
6,8-Diactyl-1-O-β-(30 ,40 -di-Oacetylglucoside) (91)
(2)-(1R0 ,4S)-1,4-Dihydroxy-p-menth-2-ene (92)

(2)-(1R0 ,2SÃ ,3SÃ ,4S)-1,2,3,4-Tetrahydroxyp-menthane (93)
Chenopanone (94)
4,6-Dibromo-3,7-dimethylocta-2,7-dienal (95)
4,8-Chloro-3,7-dimethylocta-2,4,6-trienal (96)
8-Bromo-6,7-dichloro-3,7-dimethylocta-2,4dienal (97)

Cassinopsis madagascariensis [80]
P. suhrii [78]

Leaves
Aerial parts

mp 123À125 C; [α]D 229.3
[α]D 116.9
[α]D 28.8

P. cornutum [81]

Aerial parts

[α]D 15.0
[α]D 238.6

A. remota [82]
Uvaria scheffleri [83]
A. remota [77]

Aerial parts
Stem bark
Aerial parts

Aerial parts

À
mp 210 C, [α]D 6 0.0
mp 166À168 C, [α]D 165
mp 174À176 C, [α]D 192

Chenopodium ambrosioides [84]

Aerial parts

[α]D 22.6
[α]D 21.6

Plocamium corallorhiza [85]

Aerial parts

[α]D 27.5
[α]D 227
À
[α]D 268


4-Bromo-8-chloro-3,7-dimethylocta-2,6dienal (98)
3-Formyl-2,2,6-trimethyl-3,5-cyclohexadienyl
angelate (99)
3-Formyl-2,2,4-trimethyl-3,5-cyclohexadienyl
angelate (100)
7-Hydroxymyrthenal (101)

7-Hydroxymyrtenol (102)
(1)-Quebrachitol (103)
(2)-(1SÃ ,2SÃ ,4RÃ )-Trihydroxy-p-menth-5-ene
(104)
(1)-(1SÃ ,2RÃ ,4RÃ )-trihydroxy-p-menth-5-ene
(105)
50 -Epi-isoethuliacoumarin B (106)
50 -Epi-isoethuliacoumarin A (107)
Ethuliaconyzophenone (108)
Ferulagol A (109)
Ferulagol B (110)
Plocoralide A (111)
Plocoralide B (112)
Plocoralide C (113)
Shanzhisin methyl ester gentiobioside (114)
Djalonenol (115)

[α]D 224
Bupleurum gibraltaricum [86]

Leaves

[α]D 1196.6
[α]D 1194.2

Artemisia suksdorfii [87]

Aerial parts

[α]D

[α]D
[α]D
[α]D

25.1
115.6
120
224

[α]D 120
Ethulia conyzoides [88]

Aerial parts

Ferula ferulago [89]

Roots
Roots
Aerial parts
Aerial parts
Aerial parts
Stem bark
Stem, roots, leaves

P. corallorhiza [81]

Canthium subcordatum [90]
Anthocleista djalonensis [91]

À

À
À
À
À
À
[α]D 2 15
[α]D 243
[α]D 256
À