The document discusses the mevalonate and methylerythritol phosphate pathways which are used by nature to synthesize terpenoids. Terpenoids are derived from isoprene units which can be joined in head-to-tail or head-to-head fashion, resulting in hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, and tetraterpenes. The mevalonate pathway is important for synthesizing steroids while the methylerythritol phosphate pathway may be more commonly used in most organisms. A variety of natural terpenoids derived from these pathways are then discussed, including their structures

1. Mevolinic Acid Pathway
Dr.Gurumeet C Wadhawa ,
Assistant Professor,
Department of Chemistry.
Rayat Shikshan sansthas Veer Wajekar ASC College,Phunde,Uran

2. The mevalonate and methylerythritol phosphate pathway
The mevalonate or the methylerythritol pathway are used by nature to
prepare dimethylallyl PP and isopentenyl PP as synthons for the
synthesis of terpenoids.
Terpenoids are derived from isoprene units which are joined in a head-to-
tail or head-to-head fashion.
C5
C10
C15
C20
C25
C30
C40
hemiterpenes
monoterpenes
sesquiterpenes
diterpenes
sesterterpenes
triterpenes
tetraterpenes
Huge variety of different structures; highly complex natural products because
of further skeletal rearrangements of metabolites. Furthermore, subunits of
terpenes are often derived from other metabolic pathways.

14. Mevalonate pathway is used for the
synthesis of important metabolic
products; most noteworthy steroids.
Inhibition of enzymes responsible
results in disruption of the steroid
biosynthesis
• Inhibition of HMG-CoA: statins
(used to lower cholesterol levels in
blood)
• Inhibition of FPPS: bisphosphonates
(used in the treatment of osteoporosis)

16. Labeling experiments (14C labeled glucose) gave interesting results which
could not be explained with the mevalonate pathway. These discrepancies
led o the discovery of the methylerythritol phosphate pathway.
The methylerythritol pathway might even be the more commonly used route
and is
predominant in most organisms.

18. Elucidation of the biosynthetic pathway for
glabrol

19. Hemiterpen
es
Isoprene is a volatile compound and only
few
Derivatives are used in nature:
preno
l
tiglic
acid
3-methyl-butanoic
acid
angelic
acid
Usually, these simple derivatives are glycosylated and serve as
pheromones.
Esters of angelic acid (angelates) are used in traditional herbal medicine
for the
treatment of fever and pain.
3-Methylbutanoic acid has a unpleasant smell of sweat – however, in
small conentrations, the acid and several esters have a pleasant smell
and deriviatives are used in perfume industry.

20. Many plants (especially trees in tropical regions) produce and release huge
amounts
of isoprene.
This release of isoprene into the atmosphere contributes to approximately
1/3 of hydrocarbon production (most important compound is methane
which is mainly produced by cattle).
The reason for the production and release of isoprene is not known. The gas
might serve as plant pheromone or protect the tree from O3.

21. Monoterpen
es
Monoterpenes are obtained by enzyme-catalyzed combination of
dimethylallyl
diphosphate (DMAPP) and isopentyl diphosphate (IPP)
 Formation of geranyl diphosphate

22. Geranyl diphosphate is the key intermediate in the biosynthesis of
terpenes.
Stabilization and rearrangement of the cationic intermediates explains
the vast number of different structures which can be obtained from this
intermediate.

24. Cyclization of
cations

26. Different carbon skeletons in
monoterpenes

28. Thujon
e
(+)--thujone (-)--thujone (+)--thujone (-)--thujone
Various members of the Artemisia plant family are
rich in bicyclic monoterpenes (mainly thujones).
Monethol odor; GABAA receptor antagonist
(causes spasms and convulsions);
Thujones are isolated from wormwood and
are ingredients of absinthe; believed to
cause halluzinations (could not be verified)

29. Camphor
White or transparent waxy solid with
strong odor. Can be isolated from
several plants; most noteworthy:
camphor laurel (Cinnamonum
camphora).
Has been known to many anient
cultures – name can be traced back to
a Sanskrit name.
Has been used in Arabian countries
and Europe since the 5th century for
flavouring of dishes and drinks.
Biosynthesis

30. Camphor can be used to treat swellings and inflammation.
Readily absorbed through skin  sensation of cooling; slight
anesthetic and
antimicrobial properties
Camphor used as chiral auxiliary in organic chemistry
Oppolzer sultam: one of the most important and often used
chiral auxiliaries in synthesis. Employed in asymmetric
dihydroxylations, DA-reactions, alkylations.
Asymmetric Thermal Reactions with Oppolzer‘s Camphor
Sultam.
Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293.

31. Geraniol and related monoterpenes
Important monoterpenes used in food industry and perfumes.
Common ingredients in various fruits (citrus and other species)

32. -Pinene and -
pinene
Common ingredient in pine-resin where it can easily be isolated from;
pinenes are found in conifers and non-coniferous plants.
Upon heating, pinene can be converted to myrcene
which serves as pheromone to the bark beetle.

33. Verbenol: attracts bark
beetles;
Verbenol and verbenon are synthesized from
pinene
Verbenon: serves as repellant; also present in
rosemary; used in cough medicine

34. Menthol
Obtained from peppermint / mint extracts or synthetically prepared.
Waxy, crystalline substance with a melting point close to room
temperature
Menthol acts as local anesthetic; counterirritant properties.
The terpene interacts with cold-sensitive TRPM8 receptors in the skin

35. Menthol (and other substances) interact with the TRPM8 receptor in
the skin
 Cooling sensation
Capsaicin interacts with the TRPV1 receptor
 Sensation of heat

36. Different isomers of
menthol

37. Stability of menthol can be explained by all-equatorial positiions of
substituents

38. Biosynthesis of
menthol

39. Pulegone
Intermediate in the biosynthesis of menthol
Odor similar to peppermint and camphor. Used in
flavouring
agents and perfumery.
Important starting material for enantioselectivetotal
syntheses.
Extremely popular in the 1980‘s, still used today

40. Irregular
monoterpenes

41. Pyrethrins
Isolated from pyrethrum flowers;
important insecticidal compounds.
Synthetic derivatives shown below.

42. Iridoids
Iridoids are found in many medicinal plants and these compounds possess a
wide range of biological properties: cardiovascular, analgesic, anti-
inflammatory, antiviral , antitumor …
Produced by plants mainly as defense agents against insects and
microorganisms.
Important intermediates in the biosynthesis of various indol alkaloids.

45. Cantharidin
Produced by some insects, escpecially members of the family of blister
beetles (most noteable: Spanish fly).
Poisonous compound; can be used as topical medication: removal of
warts and small tattoos
One of the world‘s oldest aphrodisiacs; used by ancient Romans, Marquis
de
Sade, many famous artists…
Frequetly used as poison (Medici in
1500) Used in love charms…

46. Sesquiterpenes
Sesquiterpenes are synthesiszed from
geranyl
PP and isopentenyl PP.
 Farnesyl PP
Sesquiterpenes are commonly derived
from the mevalonate pathway.
In a similar fashion as monoterpenes, the
great diversity of sesquiterpenes can be
explained via rearrangement of
carbocations.

47. Farnesyl PP can isomerize to E,Z-isomer or form nerolidyl PP with
tertiar diphosphate moiety

48. A great variety of structurally complex sesquiterpenes are generated from
farnesyl PP

50. Humulene derived
sesquiterpenes

51. Artemisinin
Important natural product with unusual strucutral features (peroxide linkage)
Isolated from sweet wormwood (Artemisia annua) – originally native to temperate
Asia, But naturalized throughout the world.
Sweet womrwood was used in traditional Chinese medicine to treat fever and
malaria – artemisinin was identified as biologically active ingredient

52. Artemisini
n

53. Artemisia annum contains up to 1.4% artemisinin, but generally the yield is
much lower (0.05-0.2%).. The concentration of artemisinic acid is much
higher and the anti-malaria drug can be semisynthetically prepared.
Genes responsible for the encoding the enzymes required for the
biosynthesis of artemmisinic acid have been cloned in S. cerevisiae. Today,
artmeinisin is prepared semisynthetically from biotechnologically derived
artemisinic acid.

54. Synthesis of artemisinin from artemisinic
acid

57. Malaria
• Anopheles mosquito
– Plasmodium falciparum
• Course of disease
– Incubation periode 10-30 days
– Symptoms
• Headache
• Lassitude
• Vague pain in bones and joints
• Fever (~40°C)
• Cramps
– Cyclic pattern (paroxysm) of chill-fever -relative normalcy
in an interval of 36 hours
– Coma (P. faciparum breached the blood-brain-barrier)
– Death (if untreated)

58. http://www.youtube.com/watch?feature=pla
y
er_detailpage&v=859YQcqYPko
Plasmodium life
cycle

59. Malaria – The Plasmodial Life
Circle

60. Malari
a
• Epidemiology
– estimated 200 million global cases
– mortality of more than one million
people/year

61. Historically important pesticide: DDT
(dichlorodiphenyltrichloroethane)
First synthesized in 1874 but insecticidal properties not discovered until
1939. Most
importatn insecticide during World War II.
The compound is extremely stable and shows low biodegradability;
accumulates in fatty tissue; might causes birth defects in humans; extremely
toxic to certain animals

62. Gossypol
Phenolic natural product derived from cotton plants (genus Gossypium). Yellow
pigment. Gossypol was responsible for low fertility in male plantation workers; has
been evaluated as male oral contraceptive; however, some patients suffered
permanent infertility.
Binds to calmodulin (Ca-binding messenger proteins); antimalarial and
anti-HIV properties

64. Protoilludanes
Protoilludanes can be isolated from various mushrooms and fungi.
Some protoilludanes possess moderate antibacterial and insecticidal
properties – compounds act as defense mechanism for these mushrooms.

65. Hirsutane skeleton –
hirsutene
Member of the triquinane family of natural products. Hirsutene and
derivatives are isolated from various fungi (hirsutic acid: Sternum
hirsutum)
Hirsutene has served as playground for organic chemists. More than 25
syntheses of hirsutene have been reported so far.
Pirrung, M. C.; Morehead, A. T.; Young, B. T. in The Total Synthesis of Natural
Products, Wiley New York, 2000, Vol. 112, pp. 275-357.

66. Banwell’s synthesis of
hirsutene

67. List’s synthesis of
hirsutene

68. Diterpenes

69. Some important members of the diterpene
family

70. Taxol
Extremely important anticancer drug (lung, ovarian, breast cancer) isolated
from the bark of the Pacific yew tree (Taxus brevifolia); produced by
endophytic fungi in the bark of the tree).
Stabilizes mictotubuli and prevents cell division.
Today prepared by semisynthesis

71. Biosynthesis of taxol

73. Steviol
Steviol was first isolated in 1931 from Stevia rebaudiana, endemic to tropical
and
subtropical regions in America. The plant has been cultivated for ist sweet
leaves.
Steviol extracts up to 300 times sweeter than sugar and is now used as a
substitute
for sugar (low calories, can be consumed by patients with diabetes mellitus.
The incorporation to the markest took several years and is still controversial
(sugar
industry).

76. Ginkgo biloba
Ancient plant; ony survivor of the Ginkgoaceae plant
family;
All other members are extinct.
Ginkgo extracts are used to treat cerebral vascular
disease. Terpenoids present in ginkgo extracts
improve peripheral and cerebrovascular circulation.
Thus, ginkgo extracts are also used to treat
symptoms such as vertigo, tinnitus and hearing loss
(these symptoms can arise from blood circulation
problems).
Ginkgo extracts also act as radical scavengers
(high flavonoid content).
However, some of these phenols are allergenic and
might induce contact dermatitis.

79. Forskolin and related diterpenes
Labdane diterpene; isolated from the Indian Coleus
plant
(Coleus forskolii, also known as Plectranthus
barbatus)
The plant has a long history in traditional folk
medicine.
Forskolin raises the level of cyclic AMP, an important
second messenger, responsible for signal transduction
as some hormones (glucagon, adrenalin) cannot pass
through cell membranes.
• Inhibition of colon cancer cell growth
• Potential as vasodilator (widening of blood vessels)
• Increases rsistance of skin towards UV-irradiation
(topical application in tanning solution)
• Treatment of urinary tract infections

81. Cascade cyclization to form bicyclic and poylcyclic natural products.
Trans-decalin systems are favored because of low sterical hindrance of
substituents.

82. General Information on
Euphorbiaceae
•One of the largest family of flowering plants
with approximately 2000 species.
• Worldwide distribution with huge variation of the different
members
•Economically important members: Hevea brasiliensis
(natural rubber), Croton tiglium (source of croton oil) and
Manihot esculenta (among top ten food crops).
• Plants for gardening, for example Euphorbia
pulcherrima
(poinsettia)
•Some members of this family have irritant lattices or seed
oil with a high content of terpene-based natural products

84. lathyran
e
daphnan
e
rhamnopholan
e
crotopholan
e
jatrophatrione-
type
presegetan
e
myrsinan
e
euphactin
e
Structural Diversity in Euphorbiaceae Natural Products:
Tricyclic Diterpenes

85. tiglian
e
ingenan
e
jatropholan
e
euphoractine-
type
segetan
e
cyclomyrsinan
e
euphoreppine-
type
paralian
e
euphoractine-
type
Structural Diversity in Euphorbiaceae Natural Products: Tetracyclic
Diterpenes

86. Euphorbiaceae as Source of Structurally
Challenging, Biologically Active Natural
Products
O CH3
H3C
AcO
AcO
AcO OAc
CH3
CH3
OAc
H
AcO O H
H
AcO
CH2
O CH3
CH2
H3C
AcO
AcO AcO
AcO
CH3
CH3
O
AcO
H
OAc
CH2
AcO
H3C
AcO
AcO
O
H
AcO
CH3
CH3
OAc
O
OH
OAc
O
H3C
O
CH3
CH3 CH3
CH3
O
O
H3C
3
H C
CH3
H
OAc
OAc
OH H
H
CH3
CH3
O
H3C
HO H O
H
AcO
OH
H
OH
HO HO
HO
H
H
H
O

87. Multidrug Resistance Effect
(MDR) 1
• Chemotherapy can fail
due to the development
of tumor cell resistance
to multiple drugs.
• The most important
mechanism of MDR is
the overexpression of
active drug efflux pumps
in the membranes of
cancer cells.

88. Multidrug Resistance Effect
(MDR) 2
• The efflux pump proteins belong to the ATP-Binding Cassette
(ABC) superfamily of proteins.
• The members of this family mediate a variety of transport processes in
healthy
procaryotic and eucaryotic cells.
Transmembrane efflux
pump
A: X-ray crystal structure of a
bacterial multidrug efflux
pump B: cryoelectron
microscope structure of
mammalian Pgp

89. Multidrug Resistance Effect
(MDR) 3
• 15 ABC proteins have been identified to export chemotherapeutics in in vitro
experiments.
• Only 3 transporters have been implicated as major contributors to MDR in
cancer
(Pgp, MRP1, ABCG2).
• A variety of compounds were identified as inhibitors that can reverse
MDR. As a result, cytotoxicity is restored and the cell is killed.
• Several structurally diverse diterpenes of the jatrophane skeleton, among
those Pl-3 and Pl-4, were found to be highly active MDR modulators.

90. Biologically most active Euphorbiaceae
diterpenes

91. Sesterterpenes

92. Triterpene
s

93. Triterpenes are not accessed from geranylfarnesyl PP but obtained from
two
molecules of farnesyl PP – head-to-tail coupling.
Squalene serves as starting material for the biosynthesis of steroids and
related
natural products

96. Lanosterol is converted into cholesterol and
steroids.

98. Conversion of lanosterol to cholesterol proceeds via loss of three
carbons

102. Cholester
ol
Cholesterol serves multiple purposes and is a key intermediate in the synthesis of
steroids
• Substrate for the synthesis of vitamin D
• Biosynthesis of mammalian sex hormones
• Production of bile – responsible for the digestion of lipids

103. Cholesterol is produced in all cells, but 20-25% are produced by
liver cells; transported through the body with special proteins in the
blood.
Only minor amounts of chlesterol is obtained from dietry
sources (main sources in food: cheese, egg, beef, poultry,
fish)
An average 70 kg person produces approximately 1 g of cholesterol per
day; total cholesterol level: 35g
Cholesterol is insoluble in water (blood): Different transporter proteins are
used HDL: high density lipoprotein
LDL: low density lipoprotein
Huge proteins with up to 1500 molecules of cholesterol bound; mass of 3
million Dalton
Distinct correlation of blood cholesterol level and cardiovascular problems.

104. Bil
e
Cholic
acid
Chendodeoxycholic
acid
Taurocholic
acid
Glycholic
acid
Deoxycholic
acid
Lithocholic
acid

105. Bile is produced by liver cells and used for the digestion of lipids; emulsifies the fats
in food; The higher surface than helps to increase the efficiency of pancreatic
enzymes (lipases)
Liver cells with droplets of
bile
Gallstones are mainly insoluble derivatives of
cholesterol and cholesterol which is required for
the biosynthesis of bile

106. Vitamin D
Group of fat-soluble steroids which play a major role in the intestinal
absorption of calcium and phosphate.
Vitamin D differ from other vitamins as humans can produce it – we do not
solely depend on dietry sources. If exposed to sunlight, vitamin D is
prepared from cholesterol and related steroids in the skin.
Additional vitamin D is obtained from meat, fish, eggs…usually added to
milk and milk products to reduce risk of deficiency.
Deficiencies of vitamin D results in cardiovascular problems, multiple
sclerosis

107. Vitamin
D

110. Cardioactive
glycosids
Digitalis
purpurea
Bufo
toads

111. Several steroids are able to strengthen a weakened heart. The
number of heartbeats is reduced and the force of the heart muscle
is increased.
Cardioactive glycosides are mainly produced by plants – only a small
number of animals have been identified which produce these
compounds.

112. Cardioactive steroids are characterized by a cis-fused AB-decalin
system

113. Biosynthesis of cardioactive steroids starts with
cholesterol

116. The biological activity of cardiactive steroids (glycosids) strongly depends on
the
structure of the aglycone and the sugars attached to the steroid.
 Isolation of cardioactive drugs from plant sources is a highly delicate
process.
Levaes of the plants (mainly Digitalis purpurea) have to be dried at 60 °C
immediately after the harvest in order to prevent the cleavage of the
glycosidic bond.
 Concentration and glycosylation pattern varies in differernt batches. Every
extract
needs to be tested (usually on guinea pig)

117. Corticosteroi
ds

118. Corticosteroids
Biosynthesis takes place in the adrenal cortex (outer part of adrenal
glands) Two main activity groups:
 glucocorticoids: responsible for the synthesis of sugars from proteins and
glycogenformation / deposition in the liver
 mineralcorticoids: responsible for electrolyte balance (retention of Na+, Cl-,
K+)
Biosynthesis starts with cholesterol or progesterone and involves leavage of
the side
shain (compare to biosynthesis of cardioactive steroids)

119. Biosynthesis starts from
cholesterol

120. The medicinal use of corticosteroids started after the observation that
cortisone reduces symptoms of rheumatois arthritis.
Initially, cortisone was isolated from adrenal glands of cattle and later
prepared via a 30 step synthesis from deoxycholic acid (see chapter on
bile)
Cortisone is not the acive compound, the steroid is reduced in the
liver to hydrocortisone which is the active agent.
Cortisone has serious side effects if administered over a prolonged time
or in larger amounts. Several corticosteroids have been developed with
reduced side effects, a variety of different compounds is in use today.
Hydrocortisone reduces inflammation and is responsible for
immunosuppression.

123. Semisynthesis of
corticosteroids

124. Sex
hormones
Responsible for the development of sexual characteristics,
pregnancy…
Female sex hormones:
Progestogens: responsible for
preparing theuterus for pregnancy;
most important steroid: progesterone
Oestrogens: mainly produced
during pregnancy; responsible for
menstrual cycle

125. Sex hormones
Male sex hormones:
Testosteron: Development and maintenane of male sex characteristics;
stimulates growth of bones and muscles. (low levels of testosterone are also
prduced by females)

127. Tetraterpenes
Only one group of natural products is knows:
carotenoids

133. Vitamin A
Group of fat soluble vitamins; only found in animals (mainly eggs, dairy
products,
liver, kidneys).
Precursors (provitamins) are present in many plants, especially green
vegetables.
Provitamins are converted to vitamin A in the liver
Vitamin A is important vision (night vision), embryonic development, cell
differentiation, growth

135. Esterification of the vitamin creates a better leaving group in the isomerization
reaction

136. Higher terpenoids
Natural ruber and Gutta percha are the most important naturally
occuring
isoprenoid polymers

137. Natural
rubber

138. Natural rubber was used by indigenous people; natural rubber polymerizes
and can be used for tools…
In 1839, Goodyear invented the vulcanization process and initiated
polymer chemistry. Cross-linked polymers showed better properties and
rubber could be used for tires…