CHM 3204

ORGANIC CHEMISTRY IV
TERPENES ( BIOSYNTHESIS AND TOTAL SYNTHESIS)

GROUP MEMBERS :
NIK MUHAMMAD IRFAN HAKIMI BIN MOHD SAUFI 175388
SITI NORHANNAH BT MUHAMAD RADZUAN 181130
WAN NUR HAFIZA BT WAN ZAINOL 176409
SYAZWWANI BT HAMZAH 173475
INTRODUCTION
Terpenes, a large and diverse class of organic compounds. They found in a variety of
plants, and contribute to their flavour, scent and colour. They often have a strong odour and may
protect the plants that produce them by deterring herbivores and attracting predators and
parasites of herbivores.These substances are the building blocks for essential oils and plant
raisins, and often used in food additives, perfumery and aromatherapy. Some are even thought to
have medicinal properties, and to help in fighting bacteria, fungus and environmental stress.

Terpenes are any of a class of hydrocarbons that occurring widely in plants and animals
and empirically regarded as built up from isoprene, a hydrocarbon that consisting of five carbon
atoms attached to eight hydrogen atoms (C5H8). The term is often extended to the terpenoids,
which are oxygenated derivatives of these hydrocarbons. The difference between terpenes
and terpenoids is that terpenes are hydrocarbons, whereas terpenoids contain
additional functional groups.They are the major components of resin, and of turpentine produced
from resin. The name of "terpene" is derived from the word "turpentine". In addition to their
roles as end-products in many organisms, terpenes are major biosynthetic building blocks within
nearly every living creature. Steroids, for example, are derivatives of the
triterpene squalene.When terpenes are modified chemically, such as by oxidation or
rearrangement of the carbon skeleton, the resulting compounds are generally referred to
as terpenoids. Some authors will use the term terpene to include all terpenoids. Terpenoids are
also known as isoprenoids.

Terpenes and terpenoids are the primary constituents of the essential oils of many types
of plants and flowers. Essential oils are used widely as fragrances in perfumery, and
in medicine and alternative medicines such as aromatherapy. Synthetic variations and derivatives
of natural terpenes and terpenoids also greatly expand the variety of aromas used in perfumery
andflavors used in food additives.
Types of terpene

Hemiterpenes consist of a single isoprene unit. Isoprene itself is considered the only
hemiterpene, but oxygen-containing derivatives such as prenol and isovaleric acid are
hemiterpenoids.

Monoterpenes consist of two isoprene units and have the molecular formula C10H16.
Examples of monoterpenes and monoterpenoids
include geraniol, myrcene, linalool andIridoids derive from monoterpenes.

Sesquiterpenes consist of three isoprene units and have the molecular formula C15H24.
Examples of sesquiterpenes and sesquiterpenoids include humulene, farnesenes, farnesol.

Diterpenes are composed of four isoprene units and have the molecular formula C20H32.
They derive from geranylgeranyl pyrophosphate. Examples of diterpenes and diterpenoids
are cafestol, kahweol, cembrene and taxadiene (precursor of taxol). Diterpenes also form the
basis for biologically important compounds such as retinol, retinal, and phytol.

Triterpenes consist of six isoprene units and have the molecular formula C30H48. The linear
triterpene squalene, the major constituent of shark liver oil, is derived from the reductive
coupling of two molecules of farnesyl pyrophosphate. Squalene is then processed
biosynthetically to generate either lanosterol or cycloartenol, the structural precursors to all
the steroids.

Tetraterpenes contain eight isoprene units and have the molecular formula C40H64.
Biologically important tetraterpenoids include the acyclic lycopene, the monocyclic gamma-
carotene, and the bicyclic alpha- and beta-carotenes.
Example of terpene

Limonene, is a monocyclic monoterpenoid and one of two major compounds formed from
pinene. As the name suggests, varieties high in limonene have strong citrusy smells like oranges,
lemons and limes. Strains high in limonene promote a general uplift in mood and attitude. This
citrusy terpene is the major constituent in citrus fruit rinds, rosemary, juniper and peppermint, as
well as in several pine needle oils. Limonene is highly absorbed by inhalation and quickly
appears in the bloodstream. It assists in the absorption of other terpenes through the skin and
other body tissue. It is well documented that limonene suppresses the growth of many species of
fungi and bacteria, making it an ideal antifungal agent for ailments such as toenail fungus.
Limonene may be beneficial in protecting against various cancers, and orally administered
limonene is currently undergoing clinical trials in the treatment of breast cancer. Limonene has
been found to even help promote weight-loss.Plants use limonene as a natural insecticide to ward
off predators. Limonene was primarily used in food and perfumes until a couple of decades ago,
when it became better known as the main active ingredient in citrus cleaner. It has very low
toxicity and adverse effects are rarely associated with it.

Myrcene is found in menthol, lemon grass and most varieties of marijuana, and is widely
used in the perfumery industry. It has anti-microbial and anti-septic properties, and acts as a
natural anti-depressant, anti-carcinogen and anti-inflammatory agent. It is a relaxing substance
and in marijuana-derived products, it increases the cell membrane permeability, and lowering the
resistance across the blood to brain barrier, allowing itself and many other chemicals to cross the
barrier easier and more quickly.

Pinene is a bicyclic monoterpenoid. Akin to its name, pinene has distinctive aromas of
pine and fir. There are two structural isomers of pinene found in nature: α-pinene and β-pinene.
Both forms are important components of pine resin. α-pinene is the most widely encountered
terpenoid in nature. Pinene is found in many other conifers, as well as in non-coniferous plants.
It is found mostly in balsamic resin, pine woods and some citrus fruits. The two isomers of
pinene constitute the main component of wood turpentine. Pinene is one of the principal
monoterpenes that is important physiologically in both plants and animals. It tends to react with
other chemicals, forming a variety of other terpenes (like limonene) and other compounds.Pinene
is used in medicine as an anti-inflammatory, expectorant, bronchodilator and local antiseptic. α-
pinene is a natural compound isolated from pine needle oil which has shown anti-cancer
activity and has been used as an anti-cancer agent in Traditional Chinese Medicine for many
years. It is also believed that the effects of THC may be lessened if mixed with pinene.

Geraniol produces a sweet, delightful smell similar to roses. This makes geraniol a popular
choice for many bath and body products. It is also known to be an effective mosquito repellant.
Medically, geraniol shows promise in the treatment of neuropathy.
DISCUSSION

1. Classification of Terpenes
Previously, it had been stated that terpenes are classified into many categories based on the
number of carbon atoms and isoprene residues present in their structure. Thus to summarize this :

(i) Monoterpenes. They consist of 10-C atoms or two isoprene residues.

(ii) Sesquiterpenes. These contain 15-C atoms or three isoprene residues.

iii) Diterpenes. These contain 20-C atoms or four isoprene residues.

(iv) Triterpenes. These consist of 30-C atoms or six isoprene units.

(v) Tetraterpenes. These consist of 40-C atoms or eight isoprene residues.

(vi) Polyterpenes. These consist of large number of isoprene residues.

2. Biosynthesis of Terpenes
Biosynthesis of terpenes may be in two parts:

(A) Synthesis of Activated 5-C units:

Isoprene unit is almost entirely synthesized from acetyl-CoA through mevalonic acid
pathway as shown in Fig. 24.2 Three acetyl-CoA molecules are joined together in a stepwise
manner to from a six-carbon intermediate, mevalonic acid. Mevalonic acid is then
pyrophosphorylated utilizing 2 ATP molecules to form mevalonic acid pyrophosphate (MVA-
PP).
 Decarboxylation and dehydration of MVA-PP result in the formation of activated 5-C
unit called as isopentenyl pyrophosphate (IPP). It can further be isomerized to another activated
5- C unit called as dimethylallyl pyrophosphate (DPP). Both these activated 5-C units are build-
ing blocks of terpenes in plants.
(B) Condensation of activated 5-C units IPP and DPP to form terpenes:

Terpenes are formed by condensation of activated 5-C units IPP and DPP as shown in
Fig. 24.3. Firstly, IPP and DPP unite to form 10-C geranyl phyrophosphate (GPP) which is
precursor of monoterpenes.GPP then unites with another molecule of IPP to give rise to 15-C
farnesyl pyrophosphate (FPP) which is precursor of sesquiterpenes.FPP unites with IPP to form
20-C compound geranylgeranyl pyrophosphate (GGPP) which is precursor of diterpenes.Next,
FPP dimerises to form 30-C compound which after elimination of two pyrophosphate groups
(2PP) gives rise to squalene. It is precursor for triterpenes and steroids.GGPP can dimerise to
form 40-C compound which after elimination of two pyrophosphate groups (2PP) gives rise to
phytoene. The latter is a precursor of tetraterpenes.In addition, polyterpenes are polymers
containing large number of isopentenyl units.
 3. Total synthesis of eudesmane sesqueterpenes

The eudesmane group of terpenes contained more than 1,000 members with assortments of
oxidation pattern expressed. In spite of having low sub-atomic weight, the unbending(rigid)
skeleton of eudesmane render them troublesome focuses for synthesis, particularly if huge
amounts are sought. Dihydrojunenol (4), one of the most minimal oxidized members, has been
arranged just once by a stereorandom semi-synthesis from santonin that continued in nine stages
(8% general yield) as a separable mixture of three stereoisomers. The gram-scale arrangement of
4 included a nine-stage sequences, five stages of which created C–C bonds and four of which set
key stereocentres. In this manner, an enantioselective intermolecular Michael response of 3-
methyl butyraldehyde and methyl vinyl ketone, catalyzed by prolinol 9, trailed by treatment with
base, prompted development of the cryptone (10) in 63% general yield and 89% enantiomeric
abundance. Iodination of 10 continued in almost quantitative respect bear the cost of the
iodoenone 11. Introduction of the side chain by Grignard expansion and resulting 1,3-carbonyl
transposition furnished intermediate12 (74% general yield). The decalin system of the
eudesmanes was forged using an intramolecular Heck cyclization under standard conditions to
convey diene 13 in 95% yield. The last carbon molecule was introduced by a regio-and
stereoselective 1,4-addition and couple isomerization to afford enone 14 in 56% yield (along
with recovered13). A two-stage vital reduction sequences set the three sequential steric centres
of 4 in 87% general yield as a solitary diastereomer. By this course, gram amounts of
enantiopure 4 were prepared (21% general yield).
Reagents and conditions are as follows:

a, Methyl vinyl ketone (1.5 equiv.), 3-methyl butyraldehyde (1.0 equiv.),prolinol catalyst (0.05 e
quiv.), ethyl 3,4-dihydroxybenzoate (0.20 equiv.), neat, 4 °C, 36 h, 89%. b, LiOH(0.1 equiv.), i-
PrOH, room temperature (RT, 23 °C), 24 h, 63% over two steps, 89% enantiomeric excess. c, I2(
1.2 equiv.), Pyr/DCM, RT, 12 h, 99%. d, (CH2CHCH2CH2CH2)MgBr (1.5 equiv.), toluene, -78
°C, 30 min; then0 °C, 30 min. e, PCC (1.2 equiv.), 3 Å MS, DCM, RT, 6 h, 74% over two steps.
f,
Pd(OAc)2(0.1equiv.),Ph3P(0.3 equiv.), Et3N (1.2 equiv.), Ag2CO3 (1.0 equiv.), CH3CN, 70 °C,
3 h, 95%. g, LiMe2Cu (1.5 equiv.), DCM,0 °C, 4 h, 56% (17% recovered starting material). h,
H2 (1 atm), Pd/C (0.1 equiv.), EtOAc, RT, 30 min. i, Na(5 equiv.), EtOH, RT, 30 min, 87% over
two steps. Et3N, triethylamine; DCM, dichloromethane; I2, iodine; Pyr,pyridine; PCC, pyridiniu
m chlorochromate; MS, molecular sieves; Ph3P, triphenylphosphine; CH3CN,acetonitrile; LiMe
2Cu, lithium dimethylcuprate; EtOAc, ethyl acetate.
CONCLUSION

As a summary, Terpenes have properties as chemicals in food, cosmetics, pharmaceutical

and biotechnology industries. Chemical synthesis of terpenes can be problematic because of their
complex structure, and plants produce small amounts of terpenes, making it difficult, time-
consuming and expensive to extract them directly from plants. The genomes of 17 plant species
contain genes that encode terpenoid synthase enzymes imparting terpenes with their basic
structure, and cytochrome P450s that modify this basic structure.

Research into terpenes has found that many of them possess qualities that make them
useful active ingredients as part of natural agricultural pesticides. Terpenes are used
by termites of the Nasutitermitinae family to attack enemy insects, through the use of a
specialized mechanism called a fontanellar gun.
REFERENCES

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2. Pichersky, E. (10 February 2006). "Biosynthesis of Plant Volatiles: Nature's Diversity
and Ingenuity". Science. 311 (5762): 808–811.
3. Andre CM+, Hausman JF, Guerriero G (2016). "Cannabis sativa: The Plant of the
Thousand and One Molecules". Front Plant Sci. 7: 19.
4. EberhardBreitmaier (2006). Terpenes: Flavors, Fragrances, Pharmaca, Pheromones.
John Wiley & Sons. pp. 1–13.
5. Khandelwal S. Terpenes: Classification and Biosynthesis (With Diagram) (2016).
Retrieved online : http://www.biologydiscussion.com/plant-physiology-2/stress-
physiology/terpenes-classification-and-biosynthesis-with-diagram/23682

6. Total synthesis of eudesmane terpenes by site-selective C–H oxidations

Ke Chen & Phil S. Baran Nature 459, 824-828(11 June 2009)
Retrieved online :
http://www.nature.com/nature/journal/v459/n7248/fig_tab/nature08043_F2.html