KOE 221 Dr. Hasnah Osman Lecture 1

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KOE 221Dr. Hasnah OsmanLecture 1
Natural Products Chemistry
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Course synopsis

• Methods of plants analysis (extraction,
  isolation, separation methods, identification)
• Sugars (monosaccharides, disacccharides
  oligosaccharides, cellulose)
• Nitrogen compounds (amino acids, alkaloids)
• Phenolic compounds
• Organic acids and lipids
• Biogenesis and biosynthesis for terpene,
  alkaloid,
• poliketide and sikimic acid derivative

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• P. Y. Bruice, Organic Chemistry, 4th Edition,
  Prentice Hall, 2004
• P. M. Pewick, Medicinal Natural Product, A
  Biosynthetic Approach,
• 2nd Edition, Wiley Son, 2002.
• J. B. Harborne, Phytochemical Methods A Guide to
  Modern
• Techniques of Plant Analysis, London
  Chapman and Hall, 1973

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Final Exam 70 Assignment Test 30
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 What are Natural Products?
At the end of this lecture you should -appreciat
e what we mean by the term Natural Products
-be familiar with the kinds of organisms that
make them -appreciate why many Natural Products
are often more structurally complex that 
synthetic products ( human made) -appreciate
the main classes of Natural Product classes made
by plants
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-Plants -Marine (Sponge, Lichen) -Soil/
seamuds -insects
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Senduduk Scientific name Melastoma
malabathricum
http//www.forestexplorers.com/senduduk.html
(accessed on 26 Dec 2005)
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Height A shrub up to 2 meter. Distinguish
Features Attractive purple flowers. Dark
purplish edible fruit. Found On wasteland and
roadside. Commercial Unknown Use For
Piles1. Use roots of the shrub.2. Cut into
small pieces.3. Boil with water until 1/3.4.
Drink for about 3 times and you will see the
result.  Use For High blood pressue and
diabetes1. Eat the young shoot as ulam.
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Quercetin 3-O-?-L-rhamnosyl-(1
2)-?-D-galactoside
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Hypertensive principles have been isolated from
the leaves of Melastoma candidum
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http//www.tahitian-juice.com/public/xeronine.htm
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Latin Morinda citrifolia L.. Mengkudu / Pace
Small tree the root of which produces dyes /
morindaFamily Rubiaceae For Hawaiian, it is
known as Noni for Samoans and Tongans, Nonu for
Tahitians,Nono. In China it is called Ba ji tian,
in India, Indian mulberry. in Malaysia, it is
Mengkudu or Bengkudu. Science has dubbed it
Morinda citrifolia.
-can reach more than 20 feet in height -The
Mengkudu fruit is occasionally consumed as food,
nearly all parts of the Mengkudu plant have been
used in herbal presentations for thousands of
years
variety of health disorders such as diebetes,
high blood pressure, arthritis, poor digestion,
bruises, sprains, menstrual cramps, conditions of
aging and many more. It is considered a strong
blood purifier and cleanses the body of harmful
bacteria.
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Mengkudu contains only small amounts of
xeronine, it contains significant amounts of
proseronine and the enzyme that release xeronine
from proxeronine. According to various
studies,the Mengkudu fruit is rich with the
alkaloid. The body produces xeronine in order to
activate enzymes so that it can function properly
and alkoloid is influential in energising the
body.
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Misai Kuching (Orthosiphon Stamineus)
The family of Lamiaceae / Labiatae.
http//www.misaikucing.com/
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-for treating ailments of the kidney, bladder
stone, urinary tract infection,
liver and bladder problems, diabetes, rheumatism
,gout and is also used to reduce cholesterol and
blood pressure.
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Beta-caryophyllene, alpha-humulene,
caryophyllene-epoxide, eupatorin, sinensetin,
scutellarine tetramethyl ethers, salvigenin,
7,3',4-tri-O-methylluteolin, 5-hydroxy-6,
7,3',4-tetramethoxyflavone, ladanein,
6-hydroxy-5, 7,4'-trimethoxyflavone,
2,3-dicoffeoyltartrate, rosmaric acid,
2-caffeoyltartrate, terpenoids. diterpene ester,
http//content.nhiondemand.com/moh/media/monoHerb.
asp?objID101072ctypeherbmtyp1
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pegaga/Centella asiatica
http//www.borneofocus.com/saip/vaic/Natural_Wealt
h/pegaga.htm
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It is a relief for fever, bowel complaints,
rheumatism, ichthyosis, poultice for syphilitic
ulcers, uterine cancer, wounds, arthritis,
haemorrhoids, skin disease, respiratory tract
infection, venous sufficiency, tremors and
twitching muscles.
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Research studies show that pegaga contains active
ingredients such as Triterpenoid glycosides
(including asiaticoside), Vallerin, Tannins,
Alkaloid, Volatile oil and Pectin.
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• METHODS OF PLANT ANALYSIS
• Methods of extraction and isolations
• -The plant material
• Dried before extraction, control conditions to
  avoid too many chemical changes (contamination).
• -Extraction
• Macerated, Free of green colour can be assumed
  that all the low molecular weight compounds have
  been extracted, classical chemical procedure is
  by using Soxhlet apparatus with a range of
  solvents
• Examplepetroleum ether separate lipids and
  terpenoids
• Alcohol separate more polar compounds such as
  steroid
• The extract obtained is clarified by filtration
  through celite on a water pump and concentrated
  in vacuo at a temp. 30?-40?C

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If single substances is present, the crystal can
be purified by Recrystallization-material
available for further analysis. Sometimes,
mixtures of solvents will be present in the
crystals Then be necessary to redissolve them up
in a suitable solvent and Separate the
constituets by chromatography Many compound
remain in mother liquor and these will also be
subjected to chromatographic fractionation Toluene
can be added to prevent fungal growth before
stored in refri.
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ii) Method of separation -Paper chromatography
(applicable to the water soluble plant
constituents (carbohydrates, amino acids, organic
acids and phenolic compounds) -TLC, 0.10-0.25 mm
(lipids, steroids, carotenoids, simple quinones
and chlorophylls) GLC-volatile compounds, fatty
acids, terpenes and hydrocarbons HPLC-high
molecular weight of compounds -Combination
methods such as PC and TLC, TLC and GLC may be
the best approach for separating a particular
class of plant compound. -For the preparative
work, TLC (1.0 mm) is carried out on thick layers
of adsorbent and PC on thicks sheets of filter
paper. Column Chromatography-Larger scale which
will yield purified components in gram amounts
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ii) Method of identification To determine the
class of compound and which particular
substance it is within that class once after
isolated and purified -UV spectroscopy Aromatic
compound -Infrared Spectroscopy Functional
group -Mass Spectroscopy Ion fraction - Nuclear
Magnetic Resonance Spectroscopy Proton and
cabon-13
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Carbohydrate

• Glucose
• The structure and configuration of glucose
• Anomeric forms of monosaccharides
• glycoside
• disacccharides
• polysacccharides

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• Why study carbohydrate chemistry?
• Important biomolecules, important constituents of
  all living organisms
• Powerhouse that provides energy to drive
  biochemical processes that keep us functioning
• Provide structural rigidity to materials. For
  example, chitin forms the exo-skeleton of many
  insects and crustaceans.
• Implicated in intercellular recognition, fine
  tuning of protein structure.
• Provide leads for drug development.

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What exactly is a carbohydrate?

• The name implies an empirical formula C.H2O or
  CH2O
• C6H12O6 being most common
• Water solubility implied the presence of OH
  groups.
• There was evidence for carbonyl groups (aldehydes
  and ketones)
• polyhydroxy-aldehydes and ketones
• It was recognised very early that larger
  molecules could be converted to the smaller more
  common units
• monosaccharides from polysaccharides.

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Carbohydrates
They have the molecular formulas Cn(H2O)n
Compounds that can be hydrolyzed to polyhydroxy
aldehydes or polyhydroxy ketones are also
classified as carbohydrates
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D-Glucose

• C6H12O6
• 5 x OH groups, 1 x CHO
• structure determined by Emil Fischer in 1891

Horizontal lines - coming towards us out of the
plane of the paper Vertical lines going away
from us behind the plane of the paper
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Two classes of carbohydrate Simple
(monosaccharides) Complex (disaccharides,
oligosaccharides, polysaccharides)
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Simple Carbohydrates Are Monosacharides

• Complex carbohydrates contain two or more sugar
  units
• linked together
• disaccharides
• oligosaccharides
• polysaccharides

Polyhydroxy aldehydes are aldoses Polyhydroxy
ketones are ketoses
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D and L notations are used to describe the
configurations of carbohydrates
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The smallest aldose, aldotriose. Common name,
glyceraldehyde
Isomer 21 2 isomers D and L like R and S and
Do not indicate whether the compound Rotates
polarized light to the right () or to the left
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• Absolute Configuration
• Compare the configuration of the highest numbered
  carbon of the standard Fischer projection with
  those of D- and L-glyceraldehyde
• If the OH is on the right then the configuration
  is D
• If left, the configuration is L

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D-erythrose
Configurations of the D-aldose
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Configurations of Aldoses
Aldotetroses have two asymmetric carbons and
four stereoisomers
Isomer 22 4 isomers Enantiomers ,diastereomers
and epimers (2 diastereomers that differ in
configuration at only One chirality center eg
D-ribose and D-arabinose
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A ketose has one less asysmmetric carbon than
aldoses, therefore they have fewer stereoisomers
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Reduction The carbonyl group of aldoses and
ketoses can be reduced By H2 Pd/C, NaBH4 The
product, polyalcohol, known as an alditol
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Redox Reactions of Monosaccharides
The carbonyl of aldoses and ketoses can be
reduced by the carbonyl-group reducing agents
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Oxidation By an oxidizing agent, HNO3
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Oxidation
The aldehyde groups can be oxidized by mild
oxidizing agent, Br2
Ketones and alcohols cannot be oxidized by Br2
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D-threose
D-erythrose
meso-tartaric acid
()-tartaric acid
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Osazone Formation
Aldoses and ketoses react with three equivalents
of phenylhydrazine
Yellow crystalline solid
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Acetals and Hemi-acetals

• Open-chain structures of the sugars explain some
  of their chemical properties
• Open chain forms exist in equilibrium with cyclic
  structures.These structures dominate the
  chemistry of carbohydrates.
• Need to recall hemi-acetal and acetal chemistry

SN1
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Cyclic Structure of Monosaccharides Hemiacetal
Formation
anomer
anomer
The specific rotation of pure a-D-glucose or
b-D-glucose changes over time to reach an
equilibrium (mutarotation)
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• Anomeric Configuration
• Compare the orientation of the substituents at
  the anomeric centre to that on the last ring
  carbon
• If cis then the anomer (isomer) of the sugar is ?
• If trans, then ?

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Note

• If an aldose can form a five- or six-membered
  ring, it will exist predominantly as a cyclic
  hemiacetal

• Six-membered rings are called pyranoses
• Five-membered rings are called furanoses

• A sugar with an aldehyde, a ketone, a
  hemiacetal, or
• a hemiacetal group is a reducing sugar

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Whats in a name?
pyranose
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The structures of cyclic sugars are best
represented by the Haworth projections
Haworth projections allow us to see the
relative orientation of the OH groups in the ring
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Ketoses also exist predominantly in cyclic forms
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b-D-Glucose Is More Stable
b-D-glucose is the predominant form at equilibrium
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Eg.
2,3,5,6-Tetra-O-acetyl-?-D-galactopyranosyl
bromide
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The Anomeric Effect
Acetylation of the hydroxyl groups of glucose
gives rise to two products. Under basic
conditions
Under acidic conditions
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One would think that the ?-anomer would be the
more stable since all the large groups are
equatorial. However, equilibration of the anomers
occurs under acidic conditions.
The ?-anomer is the thermodynamic product
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How do we explain this?
The Anomeric effect Stabilises an axial
substiuent at the anomeric centre.
There are two descriptions of the anomeric
effect (a) DipoleDipole interactions.
Dipoles aligned destabilising
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(b) Molecular orbital explanation
n
Consider
The co-planar geometry allows orbital overlap and
back-donation of the non-bonding electrons.
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MO diagram
New MOs
?E is greater if ? and n are close in energy.
?E is greater if X is electron withdrawing
F, Cl, Br gt esters (OCOR) gt OR gt
OH 13 kJ mol-1 0 kJ mol-1
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What are the ramifications of this?
Thermodynamically controlled reactions tend to
give products with axial anomeric substituents if
they are electron withdrawing.
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Exo-Anomeric Effect
The exo-anomeric effect is responsible for
stabilising certain orientations of groups
glycosidically linked. It has some control over
the 2 structures of complex carbohydrates.
The exo-anomeric effect can be explained in the
same way as the anomeric effect. The n to ???
interaction is between the non-bonding orbitals
of the glycosidic oxygen and the antibonding
orbital of the C-1O-5 bond.
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Consider
n to ??? orbital mixing is stabilising.
View system along the C-1 exo-O bond Two
geometries are available for orbital overlap
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Studies directed to the protein bound GPI anchor
Tanaka et al.Tetrahedron 59 (2003) 4059
protein
membrane
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GPI anchored are membrane bound proteins found
throughout the animal kingdom. GPI (
Glycosylphosphatidylinisotol) Phosphoethanolamin
e
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Formation of Glycosides
The acetal (or ketal) of a sugar is called a
glycoside
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Mechanism of Glycoside Formation
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Determination of Ring Size Approach 1
The size of the ring can be determined from the
structure of the open-chain form
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Determination of Ring Size Approach 2
An acetal of the monosaccharide is oxidized with
excess HIO4
The a-hydroxyaldehyde formed from HIO4 oxidation
is further oxidized to formic acid and another
aldehyde
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Disaccharides
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Disaccharides
Composed of two monosaccharide subunits hooked
together by an acetal linkage
In a-maltose, the OH group bonded to the anomeric
carbon is axial
Maltose is a reducing sugar
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In cellobiose, the two subunits are hooked
together by a b-1,4-glycosidic linkage
Cellobiose is a reducing sugar
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In lactose, the two different subunits are joined
by a b-1,4-glycosidic linkage
Lactose is a reducing sugar
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The most common disaccharide is sucrose
Sucrose is not a reducing sugar
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Polysaccharides
The most common polysaccharides are starch and
cellulose
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Polysaccharides
Amylose is a component of starch
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Amylopectin is another polysaccharide component
of starch that has a branched structure
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An example of a naturally occurring product
derived from carbohydrates
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Cellulose is a linear polymer of
b-(14)-D-glucopyranose
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Drugs as Enzyme Inhibitors
Penicillin destroys bacteria by inhibiting the
enzyme that synthesizes bacterial cell walls
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Bacteria develop resistance to penicillin by
secreting penicillinase which destroys pencillin
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Peptides and proteins are polymers of amino acids
linked together by amide bonds
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Basic Amino Acids
lysine
arginine
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Aliphatic Side-Chain Amino Acids
glycine
alanine
valine
leucine
isoleucine
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Benzene-Containing Amino Acids
phenylalanine
tyrosine
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Heterocyclic Amino Acids
proline histidine tryptophan
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AcidBase Properties of Amino Acids
An amino acid can never exist as an uncharged
compound
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The isoelectric point (pI) of an amino acid is
the pH at which it has no net charge
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A mixture of amino acids can be separated by
electrophoresis on the basis of their pI values
Ninhydrin is used to detect the individual amino
acids
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A mixture of amino acids can also be separated on
the basis of polarity
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Ion-exchange chromatography can be used to
perform preparative separation of amino acids
Negatively charged resin binds selectively to
positively charged amino acids
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Ion-Exchange Chromatography

• Cations bind most strongly to cation-exchange
• resins

• Anions bind most strongly to anion-exchange
• resins

• An amino acid analyzer is an instrument that
  automates
• ion-exchange chromatography

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Formation of a Peptide
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Strategy for Making a Specific Peptide Bond
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Peptide Bond
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Because amino acids have two functional groups, a
problem arises when one attempts to make a
particular peptide