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422
Pharmaceutical Chemistry of Natural Products
Lanosterol and Euphol
OH
OH
Lanosterol
Euphol
Amyrins
HO
H
HO
␣-Amyrin
-Amyrin
Amyrins are isolated from oleoresin, which is isolated from numerous other resins and saps. Two
amyrins (α and β) are identifi ed. These two amyrins are stereoisomers which differ only in the
position of the methyl groups. Out of these two, β-amyrin is more important than α-amyrin.
TETRATERPENOIDS
Tetraterpenoids are compounds containing 40 carbons in their structure. The important compounds
belonging to this class include carotenoids. Carotenoids are coloured pigments generally yellow
or orange to red in colour. These are used as food colourants (pharmaceutical aids). Examples of
tetraterpenoids are β-carotene and luteolin.
Terpenoids
423
-Carotene
HO
OH
Luteolin
POLYTERPENOIDS
Polyterpenoids consist of many isoprene units. Rubber is a common example of polyterpenoid.
Pharmaceutically important polyterpenoid is gutta-percha (gutta-percha consists of many isoprene
units but less than rubber). It is a purifi ed and coagulated latex obtained from trees of the genera
Palaquium and Payena (Family: Sapotaceae). Its chloroform solution is used as a means of applying
drugs to the skin.
PROBABLE QUESTIONS
1. What are terpenes? Classify them with suitable examples and mention the importance of terpenes in pharmacy.
2. Write in detail about the general methods for the structural elucidation of terpenes.
3. How will you perform the structural elucidation of zingiberene?
4. Write in detail about isoprene rule and special isoprene rule.
5. Mention the name and structure of one from each of the following types of sesquiterpenes:
a. Open chain
b. Monocyclic
c. Bicyclic
d. Tricyclic
6. What are terpenes? How are they extracted from plants? Briefl y write about the constitution of camphor.
7. Enumerate the monoterpenes you have studied and write the structural elucidation of one of them.
8. How will you determine the structure of citral by degradative and synthetic reactions?
424
Pharmaceutical Chemistry of Natural Products
9. Outline the structural elucidation of geraniol.
10. Outline the structural elucidation of cineole.
11. Write notes on sesquiterpenoids.
12. How is the constitution of α-terpineol established by degradation and rational synthesis?
13. Outline the structural elucidation of menthol and menthone.
14. How will you perform the following conversions?
a. Citral-b to p-cymene
b. Citral to ionones
c. Geraniol to α-terpineol
15. Write the synthesis of citral and menthol.
16. How will you demonstrate the following in terpenes?
a. Unsaturation
b. Nature of oxygen
c. Isopropylidene grouping
d. Number of rings
e. Carbon framework
17. Write short notes on squalene.
18. How will you establish the structure of α-pinene?
19. What are di- and tri-terpenes? Draw the structure of abietic acid.
20. Describe the evidence in support of the accepted structure of camphor.
21. Write notes on ionones.
22. Enumerate the different types of monocyclic monoterpenoids and outline the structure of limonene.
23. Write the structural elucidation of citronellal.
SUGGESTED READINGS
Apsimon, J (ed) (1973). The Total Synthesis of Natural Products, Vol 2. Wiley-Interscience, pp. 1–640.
Budzikiewicz, H, Djerassi, C and Williams, DH (1964). Structure Elucidation of Natural Products by Mass Spectrometry,
Vol 2. Holden-Day, Inc., San Francisco.
Cane, DE (1999). Comprehensive Natural Products Chemistry, Vol 2. Elsevier, Amsterdam, pp. 155–200.
Coffey, S (ed) (1968). Rodd’s Chemistry of Carbon Compounds, Vol IIB, 2nd Ed. Elsevier. Amsterdam.
Coffey, S (ed) (1969). Rodd’s Chemistry of Carbon Compounds, Vol IIC, 2nd Ed. Elsevier, Amsterdam.
Connolly, JD and Hill, RA (2000). Triterpenoids. Nat Prod Rep 17: 463–482. (Earlier reviews: 1999, 16: 221–240; 1997, 14:
661–679.)
Florkin, M and Stotz, EH (1963). Comprehensive Biochemistry, Part B, Vol 9. Elsevier, Amsterdam.
Gilman, H (1943). Organic Chemistry: An Advanced Treatise, Vol 2. Wiley, New York, p. 1172.
Grayson, DH (2000). Monoterpenoids. Nat Prod Rep 17: 385–419. (Earlier reviews: 1998, 15: 439–475; 1997, 14: 477–522.)
Hanson, JR (2001). Diterpenoids. Nat Prod Rep 18: 88–94. (Earlier reviews: 2000, 17: 165–174; 1999, 16, 209–219.)
Terpenoids
425
Henne, AL and Perilstein, WL (1943). The preparation of aldehydes and ketones by ozone oxidation. J Am Chem Soc 65:
2183–2185.
Mahato, SB and Garai, S (1998). Triterpenoid saponins. Prog Chem Org Nat Prod 74: 1–196.
Massy-Westropp, RA, Reynolds, GD and Spotswood, TM (1966). Freelingyne, an acetylenic sesquiterpenoid. Tetrahedron Lett
7: 1939–1946.
Mayo, P (1959). Mono and Sesquiterpenoids, Vol I. Interscience, New York.
Mayo, P (ed) (1963). Molecular Rearrangements, Part I. Interscience, New York.
Mayo, P (ed) (1963). Molecular Rearrangements, Part II. Interscience, New York.
Mulheirn, LJ and Ramm, PJ (1972). The biosynthesis of sterols. Chem Soc Rev 1: 259.
Pinder, AR (1960). The Chemistry of Terpenes. Chapman and Hall.
Robinson, Sir Robert (1955). The Structural Relations of Natural Product. Clarendon Press: Oxford.
Robles M et al. (1995). Recent studies on the zoopharmacognosy, pharmacology and neurotoxicology of sesquiterpene
lactones. Planta Med 61: 199–203.
Ruzicka, L (1959). History of the isoprene rule: Faraday lecture. Proc Chem Soc, 341.
San Feliciano, A et al. (1993). Abietane acids: sources, biological activities, and therapeutic uses. Planta Med 59: 485–490.
Simonsen, JL and Barton, DHR (1952). The Terpenes, Vol III, 2nd Ed. Cambridge University Press.
Simonsen, JL and Owen, LN (1947). The Terpenes, Vol I, 2nd Ed. Cambridge University Press.
Simonsen, JL and Owen, LN (1949). The Terpenes, Vol II, 2nd Ed. Cambridge University Press.
Simonsen, JL and Ross, WCJ (1957). The Terpenes, Vol IV, 2nd Ed. Cambridge University Press.
Simonsen, JL and Ross, WCJ (1957). The Terpenes, Vol V, 2nd Ed. Cambridge University Press.
Stewart, AW and Graham, H (1948). Recent Advances in Organic Chemistry, Vol III, Longmans Green and Co., London.
Templeton, W (1969). An Introduction to the Chemistry of the Terpenoids and Steroids. Butterworths, London.
Wise, ML and Croteau, R (1999). Comprehensive Natural Products Chemistry, Vol 2. Elsevier, Amsterdam, pp. 97–153.
INTRODUCTION
Flavonoids are a group of organic compounds which include fl avones, isofl avones, fl avonols,
etc. They are yellow pigments, also called anthoxanthins, occurring in plants either in free state
or as glycosides or associated with tannins. Large amount of fl avonoids occur as water-soluble
glycosides. Flavones are yellow solids, pure fl avones are colourless (Latin: fl avus means yellow),
soluble in water, ethanol, dilute acids and alkalis, and precipitated by lead salt. Flavones give either
a dull green or a red brown colour with ferric chloride. Signifi cant quantities of fl avonoids are
consumed every day in our vegetable diet, providing protective effects to the body which includes
antioxidant protection of DNA and low-density lipoprotein, inhibition of platelet aggregation,
modulation of infl ammation, oestrogenic effects and modulation of adhesion receptor expression
which diminishes the toxic biological effects on man. Flavonoids have astringent organoleptic
character, but the lower molecular weight fl avonols have bitterness. The taste has tactile sensation
and is not apparent through recognition by taste receptors.
Flavonoids are obtained from red wine (quercetin, kaempferol and anthocyanidins) and tea
leaves (catechins and catechin gallate esters). They are found to be useful antioxidants. Their
polyphenolic nature enables them to scavenge on injurious free radicals such as superoxide and
hydroxyl radicals. Some of the fl avonoids act as antioxidants and provide defence against certain
forms of cancer and cardiovascular diseases. The fl avonol glycoside, rutin, and the fl avanone
glycoside, hesperidin, are included in dietary supplements as vitamin P for treating capillary bleeding.
Chemically, they are partially alkylated hydroxy fl avones (2-phenyl-4- chromone). Hydroxy groups
may be present in 3,4,5 positions and the methyl groups are present in positions 3,5.
O
1
2
3
4
5
6
7
8
1’
2’
3’
4’
5’
O
O
O
Chromone
Flavone
Flavonoids
8
CHAPTER
428
Pharmaceutical Chemistry of Natural Products
Flavones may exist as C-glycosyl derivatives as well as O-glycosides (e.g. vitexin and isovitexin).
When hydrolysed with mineral acids, fl avones give aglycone and one or more molecules of sugars.
The sugars are generally glucose and rhamnose.
O
O
HO
G
OH
OH
Vitexin
O
O
HO
OH
OH
G
Isovitexin
Some of the examples of common fl avones are fl avone, chrysin (5,7-dihydroxyfl avone) and
luteolin (3′,4′,5,7-tetrahydroxyfl avone).
Flavone
1
2
3
4
5
6
7
8
O
O
1’
2’
3’
4’
5’
6’
HO
OH O
O
1
2
3
4
5
6
7
8
1’
2’
3’
4’
5’
6’
Chrysin
HO
OH
O
O
OH
OH
1
2
3
4
5
6
7
8
1’
2’
3’
4’
5’
6’
Luteolin
A group of compounds called fl avonolignans possesses the combination of fl avonoid and lignin
structure. Flavonolignans are formed by the oxidative coupling processes between a fl avonoid and
a phenylpropanoid usually coniferyl alcohol.
ISOLATION OF FLAVONES
Earlier, thin-layer chromatography (TLC) and paper electrophoresis were the major separation
techniques for phenolics. TLC is still the workhorse of fl avonoid analysis. For the polyphenolic
compounds in plant extracts and fractionation work, TLC is used as a simple, rapid and versatile
method. Recently, majority of researchers used qualitative and quantitative applications of high-
performance liquid chromatography (HPLC) for analysis. By coupling HPLC to ultraviolet (UV),
mass or nuclear magnetic resonance detectors, fl avonoids can be separated, quantifi ed and
identifi ed. The capillary electrophoresis has been getting importance in modern days.
Flavonoids
429
Quantitatively, the separation is performed as follows:
The plant material containing fl avones or fl avonols is digested with boiling water and the
extract is diluted with water and treated with lead acetate to precipitate tannin impurities. The
mixture is fi ltered to remove the precipitate and diluted with water, acidifi ed with HCl and boiled
for some hours. As a result, precipitation of sugar-free fl avones or fl avonols occurs. The precipitate
of the pigment is extracted with alcohol and it may then be purifi ed by carrying out fractional
crystallization of its acetates or by crystallization from some organic solvents (e.g. benzene, carbon
disulphide and alcohol).
Separation and Purification of Flavones
Various methods for the separation and purifi cation of fl avones are as follows:
1. Paper chromatography: This is a simple and convenient method for separating and purifying
fl avones on the mg scale. A concentrated volume of the plant material (ethanol or methanol)
extract is applied on Whatman No. 3 fi lter paper. Then initial separation of the fl avones present
in the concentrate is performed and the individual bands after elution and concentration are
further fractionated and fi nally purifi ed.
2. TLC: The multilayers of microcrystalline cellulose are employed using the solvent systems
as in paper chromatography. It is a more sensitive method than paper chromatography for
separation of fl avones.
3. Column chromatography: This method is generally used for large-scale separation of fl avones
and fl avonol glycosides. The adsorbents used are polyamide and cellulose (Celite and
Sephadex).
4. Gas–liquid chromatography: The derivatized (trimethylsilyl ether) fl avones are isolated and
analysed by this method.
Structural elucidation of flavones
By taking fl avone (occurs as dust in fl owers and leaves), a typical example of this group, general
methods for the structural elucidation of fl avones are discussed.
Flavone
1
2
3
4
5
6
7
8
O
O
1’
2’
3’
4’
5’
6’
1. Molecular formula: Molecular formula of fl avone is found to be C
15
H
10
O
2
.
2. Absence of hydroxyl group: Results from usual standard chemical reactions (acetylation,
oxidation method) revealed that fl avone does not possess any hydroxyl group.
430
Pharmaceutical Chemistry of Natural Products
3. Structure of fl avone:
(a) Upon fusion with potassium hydroxide, fl avone yields phenol and benzoic acid.
OH COOH
Benzoic acidPhenol
KOH
Fusion
Flavone (I)
CHO
15 10 2
⫹
(b) Upon boiling with alcoholic potassium hydroxide, fl avone yields a mixture of four
compounds, salicylic acid (A), acetophenone (B), o-hydroxy acetophenone (C) and
benzoic acid (D).
OH
C
O
OH
O
OH
HOOC
O
⫹⫹ ⫹
CH
3
CH
3
CHO
15 10 2
Flavone (I)
Salicylic acid (A) Acetophenone (B) o-Hydroxy acetophenone (C)
Benzoic acid (D)
(c) By assuming the structure (I) for fl avones, formation of the above products can be
explained.
O
O
CH
65
(I)
(d) Due to the opening of the pyrone ring of fl avones (I), α-hydroxydibenzoylmethane
(IA) is formed which then undergoes cleavage in two different ways to yield two pairs
of products, i.e. (A) and (B), and (C) and (D).
CH
65
O
O
KOH
Boil
(I)
CH
65
OH
C
OH
O
(I)
OH
CO
CH
2
COC H
65
(1)
(2)
(IA)
Flavonoids
431
Scission
at (1)
Scission
at (2)
C H COOH
65
⫹
COCH
3
OH
C H COCH
65 3
⫹
COOH
OH
(A)
(B) (C) (D)
4. Synthesis (Robinson’s): The above proposed structure of fl avone is confi rmed by
Robinson’s synthesis.
o-Hydroxy acetophenone
(C H CO)
65 2
O
⫹
OH
COCH
3
Benzoic anhydride
C H COONa
65
180°C
OCOC H
65
COCH
3
OH
CH
65
O
O
⫺HO
2
CH
65
O
O
Flavone
FLAVONOL
Introduction
Flavonols are hydroxy fl avones, i.e. the C-3 of fl avones is substituted by hydroxyl group. Flavonols
formed in plants by lignifi cation in leaves and wood and with UV absorption of fl owers. They have
signifi cant applications physiologically, pharmaceutically and pharmacologically.
(1, R OH Flavonol)
( H Flavone)
⫽
R⫽
1
2
3
4
5
6
7
8
O
O
1’
2’
3’
4’
5’
6’
R