Terpenoids

R.A.HILL
1 Introduction
The terpenoids constitute the largest class of natural products. The great
structural diversity of the terpenoids has been a challenge to the synthetic chemist and
will continue to be so as more skeletal types are found. The rate of discovery of new
terpenoids has increased over the last ten years largely as a result of the increase in the
sophistication of separation and analytical techniques. The use of two-dimensional
n.m.r. techniques, in particular, has helped the structural elucidation of new
terpenoids. Crystal structure determinations have assisted when n.m.r. has failed to
give an answer and many interesting new skeletons have been uncovered. This
chapter can only highlight a very small proportion of the advances in terpenoid
structure elucidation, synthesis and biosynthesis; however, references are given to
some key reviews that provide a more comprehensive coverage. A major catalogue of
natural terpenoids gives data and references to a large proportion of known terpenoids
arranged in groups of related structural types. This will aid the structure elucidation of
new terpenoids by providing an easy access to data on related compounds. The use of
substructure or data (e.g. melting point or molecular formula) searching of a natural
products computer database provides an efficient method of locating related or known
terpenoids.
Terpenoids are found in abundance in higher plants. The development of
techniques for growing plant tissue cultures to generate terpenoids has continued,
however yields of secondary metabolites are normally disappointingly low.
Phytoalexins produced by plants include a large number of antifungal terpenoids.
Fungi, themselves, produce a range of interesting terpenoids including trichothecanes,
the protoilludane group, cyathins, fussicoccanes and many triterpenoids. Recent
research into marine natural products has shown marine organisms are a prolific
source of unusual terpenoids. Detailed reviews of marine natural products appear
regularly and a comprehensive review of terpenoids of marine invertebrates
concentrates on their biological activity. Marine organisms continue to provide new
carbon skeletons. Many substituents that are rarely found in natural products occur in
marine terpenoids, for example bromo- and chloro-substituents in algal terpenoids and
isonitrile and isothiocyanate substituents in sponge terpenoids. The biosynthetic origin
of these isonitrile groups has prompted many studies. The biosynthesis of the
monoterpenoids, sesquiterpenoids and diterpenoids from all sources are covered in a
series of reviews. Terpenoids are found as insect pheromones and in insect defence
secretions particularly from termites. The synthesis of insect pheromones has been a
particularly active area recently.
Many terpenoids occur as glycosides or glycosyl esters, iridoid and triterpene
glycosides being the most abundant. The biological activity of terpenoid glycosides is
well established, many have been found in plants used in traditional medicine. With
the increase in the isolation of terpenoid compounds from plants, the terpenoid
content of a plant can be used as a taxonomic tool. Limonoids, quassinoids and
iridoids have been particularly useful in the field of chemosystematics.

2 Monoterpenoids
Comprehensive reviews concerning all aspects of monoterpenoids appear
regularly. There has been an upturn in interest in the area of monoterpenoids over the
past decade largely due to their economic importance. Volatile monoterpenoids
contribute to flavours and aromas in food and are important in perfumery. Microbial
transformations of monoterpenoids can produce compounds of use in the fragrance
industry and plant cell cultures can also be used to form and transform
monoterpenoids The importance of monoterpenoids in flavouring has renewed
interest in their biosynthesis and bioformation. The monoterpenoids and their
glycosides in grapes contribute to the aromas of wine and the analysis of the volatile
constituents has received a lot of attention. Gas chromatography and GC-MS
techniques are of particular importance in the analysis of these volatile components.
Plants produce large amounts of monoterpenoids. The distinctive aroma of
coniferous plantations is the result of the emission of volatile monoterpenes such as pinene(1) and Australian forests produce a high concentration of 1,8-cineole(2) from
eucalyptus trees. Attention has been turned to the fate of these volatile constituents. It
has been suggested that trees under attack by insects or other leaf predators may
produce certain.

(1)

(2)

4 Diterpenoids
Regular comprehensive reviews on the structures of new diterpenoids have
appeared and a catalogue of diterpenes has been published. The diterpenoid class has
one of the widest ranges of biological activity. The synthesis of diterpenoids, like
other classes of terpenoids, has become an increasingly important subject. An
excellent review covers the total synthesis of tricyclic and tetracyclic diterpenoids and
another review covers the biotransformations of diterpenoids.
Labdanes are one of the largest classes of diterpenoids and have generated much
synthetic interest; however, since the discovery that forskolin(86) possesses
interesting blood pressure lowering activity there has been a lot of chemistry directed
towards 86 and its derivatives. Originally 86 was isolated from Coleus forskohlii.
Independently coleonol was isolated from the same plant and assigned the same
structure as 86 apart from the opposite stereochemistry at C-7. Both structures were
assigned by X-ray crystallographic analyses. Subsequently they were shown to have
the same structure (86). The biosynthesis of 86 and related labdanes from Coleus
forskohlii has been studied.
Over 650 members of the clerodane class of diterpenoids had been isolated up

to 1991. They mainly possess the ent-clerodane skeleton (87). Confusion exists in the
literature over clerodane nomenclature. The first member of this class to be isolated
was clerodin (88). It was originally assigned a structure enantiomeric with 88 and
when the structure was revised the carbon skeleton (87) was designated as neoclerodane and those compounds enantiomeric to 87 as ent-neo-clerodanes. This is
contrary to the practice for the rest of the diterpene classes and there have been
several proposals to drop the neo-nomenclature. Thus neo-clerodanes should be
known as ent-clerodanes. The clerodanes have been isolated mainly from
dicotyledonous plants but also from monocotyledonous plants, liverworts, fungi and
bacteria. This widespread occurrence suggests independent evolution of the ability to
produce clerodanes. Teucrium species are a prolific source of highly oxygenated
clerodanes, teucvin (89) is typical. They all have the ent-clerodane skeleton,
oxygenation at C-6 and an equatorial methyl group at C-8.
O
OH

OH

OAc
OH
(86)

(87)

O
H

O
H

H
8

CH2OAc

OAc

O
O

(88)

(89)

Most perhydrophenanthrene-based diterpenoids have trans-anti- trans-ring

fusions as in 90. A small number including the momilactones such as momilactone
A(91) possess a 9,10-syn stereochemistry. The momilactones are phytoalexins from
the rice plant Oryza sativa and they have generated some synthetic and biosynthetic
interest. Aphidicolin (92) has also received attention regarding its biosynthesis.

H
H

H
(90)

H
O

H
O
(91)

OH
CH2OH

OAc
OAc

OH

OAc

CH2OH

(92)

(93)

AcO

O
OH

OH

H
(94)

OAc

OH

OH
(95)

Leaves of Rabdosia japonica are used as a common household medicine in

Japan for gastrointestinal disorders. The drug is called enmei-so which means grass
effective for prolongation of human life. Many bitter compounds have been isolated
from Rabdosia species. The constituents include ent-kauranes such as shikodokaurin
B (93), ent-6, 7-secokauranes such as enmein (94) and ent-8, 9-secokauranes, e.g.
shikodomedin (95). The Rabdosia diterpenoids have been shown to possess
antibacterial and antitumour activity and there has been much effort to investigate the
structures and chemical transformations of these highly oxygenated kauranes.
The gibberellins such as gibberellin A1 (96) are plant growth hormones and they
arise biosynthetically by ring contraction of the ent-karane ring system. The
nomenclature of the gibberellin family is well regulated and they are numbered in
order of discovery. The synthesis and chemistry of the gibberellins have been expertly
reviewed.
The tobacco plant (Nicotiana tabacum) has been extensively studied because of
its economic importance and the health factors associated with its use. One of the
major groups of compounds found in tobacco are the cembranoids such as 97. The
tobacco cembranoids have a close biogenetic relationship; they all possess the 1Sstereochemistry and normally have a 2E-double bond and oxygenation at C-4.
Cembranoids are also found in the oleoresins of conifers and the resin coatings of the
leaves of Eremophila species. The frankincense-producing Boswellia carteri produces
cembranoids containing 1,12-oxygen bridges such as incensole (98) Cembrene A(99)
is a trail pheromone of Nasutitermes and Trivervitermes termite species. Termites also
produce defensive substances that include trinervitanes such as trinerviol (100) and
kempanes such as kempene 1(101) and it is plausible that cembranes are biosynthetic
intermediates for those compounds. Cembranoids are also widespread in marine
organisms where they are probably biosynthetic precursors of the dolabellanes such as
102 and the dolastanes such as amijiol (103). The synthesis of cembranoids has been

recently reviewed.
OH
OH

OH

OC

OH

H CO H
2
(97)

(96)

OH

(98)

(99)

OH

H
OAc

(100)

H
H

OAc

(101)

OH

H
OH

OH
OH

(102)

(103)

The plant families Euphorbiaceae and Thymelaeaceae contain many tumour

promoting and irritant diterpenoids. These compounds can all be considered as
biogenetically arising from the casbane skeleton (104) as in Scheme 14. The lathyrane
skeleton (105) can be formed by cyclisation of 104 and ring opening of the
cyclopropane ring would lead to the jatrophane skeleton (106). Further cyclisation of
105 leads to the tigliane skeleton (107) which can undergo cyclopropane ring opening
or rearrangement to give the daphnane skeleton (108) and the ingenane skeleton
(109), respectively. Esters of ingol(110), a lathyrane and phorbol(111), a tigliane
possess potent biological activities. The promising antitumour activity of taxol (112)
has stimulated studies on its total synthesis, semi-synthesis and chemistry.

(106)

(104)

(105)

(107)

(108)

(109)

HO

OH

OH

H
O

OH

HO

OH

OH

OH

CH2OH

(111)

(110)

AcO

O OH

O
OC
HNOCPh

OH

HO

Ph

O
(112)

H
PhCO

OAc

5 Sesterterpenoids
Sesterterpenoids are a small group of natural products that occur mainly in
marine organisms, but some are found in terrestrial life. There are only about 200
natural sesterterpenoids known but they contain a diverse array of about thirty carbon
frameworks. Although they are strictly C25 compounds, there are a large number of
nor-and alkylated- sesterterpenoids.

OH

(113)

O
CO2H
(114)

Sumber: http://202.119.189.236:8087/ec3.0/C54/en/Terpenoids-1.doc