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432
Pharmaceutical Chemistry of Natural Products
Structural elucidation of flavonols
By taking fl avonol, a typical example of this group, general methods for the structural elucidation
of fl avonols are discussed.
1. Molecular formula: Molecular formula of fl avonol is found to be C
15
H
10
O
3
.
2. Presence of hydroxyl group: Results from usual standard chemical reactions (acetylation,
oxidation method) revealed that fl avonol possesses one hydroxyl group.
C H O (OH)
15 9 2
Flavonol
⫹ CH COCl
3
C H O (OCOCH )
15 9 2 3
⫹
HCl
Monoacetyl derivatives
of flavonol
3. Structure of fl avonol:
(a) Flavonol upon methylation followed by fusion with potassium hydroxide yields phenol
and benzoic acid. Absence of the methoxy group in the products obtained shows that
the methoxy group must be present at C
3
which must have been lost upon fusion with
potassium hydroxide.
CHO
15 10 3
Methylation and
fusion with KOH
OH COOH
Phenol Benzoic acid
Flavonol
⫹
(b) Boiling of fl avonol with an alcoholic potassium hydroxide yields a mixture of
o-hydroxybenzoylmethanol and benzoic acid. The formation of these products indicates
that fl avonol is having a hydroxyl group at C
3
. Hence, fl avonol structure is proposed as
3-hydroxyfl avone.
CH
65
OH
O
O
Flavonol
(c) Based on the above proposed structure of fl avonol, the aforementioned reactions can
be depicted as follows:
Flavonoids
433
Acetyl derivative of flavonol
O
O
CH
65
OCOCH
3
CH COCl
3
(a)
O
O
CH
65
OH
Methylation
(CH ) SO /NaOH
32 4
O
O
CH
65
OCH
3
KOH
Fusion
OH
⫹
Phenol
HOOC
Benzoic acid
(b)
Flavonol
KOH Boil
(c)
OH
OH
OH
CH
65
C
O
OH
OH
COC H
65
H
O
o-Hydroxybenzoyl
methanol
OH
COCH OH
2
Benzoic acid
HOOC
⫹
⫹
HCl
4. Synthesis (Robinson’s): The above proposed structure of fl avonol is confi rmed by
Robinson’s synthesis.
COCH OCH
23
OH
(C H CO) O
65 2
⫹
O
O
OCH
3
CH
56
HI
O
O
OH
CH
56
Flavonol
434
Pharmaceutical Chemistry of Natural Products
QUERCETIN
HO
HO
O
O
1
2
3
4
5
6
7
8
OH
OH
1’
2’
3’
4’
5’
6’
OH
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4 -chromen-4-oneH
Introduction
In the bark of Quercus tinctoria, it exists as the glycoside quercitrin. Quercetin gives bright yellow colour
with UV and UV + ammonia solutions. Upon reaction with acid, quercitrin yields one molecule of
quercetin and one molecule of rhamnose. Quercetin is found to be present in signifi cant amounts
in almost all plant tissues and is a powerful antioxidant, scavenging on free radicals, chelating
metals and preventing oxidation of low-density lipoprotein.
CHO
21 20 11
⫹ HO
2
HCl
CHO
15 10 7
⫹
CH (CHOH) CHO
34
Quercetin
Rhamnose
Structural elucidation of quercetin
1. Molecular formula: Molecular formula of quercetin is found to be C
15
H
10
O
7
.
2. Presence of hydroxyl group: Results from the usual standard chemical reaction
(acetylation) revealed that quercetin possesses fi ve hydroxyl groups.
3. Structure of quercetin:
(a) Upon fusion with potassium hydroxide, quercetin yields phloroglucinol and protocate-
chuic acid.
Quercetin
KOH
Phloroglucinol
Protocatechuic acid
⫹
Fusion
(b) Quercetin, when methylated, yields pentamethyl quercetin, which when boiled with
an alcoholic potassium hydroxide solution yields a mixture of 6-hydroxy-ω,2,4-
trimethoxy acetophenone and veratric acid.
Quercetin
Methylation
Pentamethyl quercetin
Alc. KOH
6-Hydroxy- -2,4-trimethoxy acetophenonew
+ V
eratric acid
Flavonoids
435
(c) To explain the above reactions structure (I) (3,3′,4′,5,7-pentahydroxyfl avone) is
proposed for quercetin.
HO
OH
O
O
OH
OH
OH
Structure of Quercetin (I)
(d) Based on the structure (I) for quercetin, all the above reactions are explained as
follows:
O
HO
OH
O
OH
OH
OH
KOH fusion
OHHO
OH
COOH
OH
⫹
Phloroglucinol
(I)
O
O
Veratric acid
HO
OH
⫹
HOOC
Protocatechuic acid
(CH)SO
32 4
Methylation
HCO
3
OCH
3
OCH
3
OCH
3
OCH
3
Ethanolic KOH
6-Hydroxy- ,2,4-trimethoxy
acetophenone
OCH
3
HCO
3
COCH OCH
23
OCH
3
OCH
3
4. Synthesis (Robinson’s): The above proposed structure of quercetin is confi rmed by
Robinson’s synthesis.
436
Pharmaceutical Chemistry of Natural Products
OH
HO
OH
COO
O
O
HO
HI
Quercetin
HO
O
OH
O
HO
OH
OH
HO
COCH OCH
23
-Methoxyphlorocetophenone
O
O
O
⫹
OCH
3
OCH
3
OCH
3
OCH
3
Veratric anhydride
Potassium veratrate
OCH
3
OCH
3
KOOC
HCO
3
HCO
3
OCH
3
OCH
3
OCH
3
O
O
COO
HCO
3
HCO
3
KOH/EtOH
OCH
3
OCH
3
OCH
3
Addition of hydroxyl group in the eighth position to quercetin gives gossypetin which is
yellow coloured in primrose and cotton plants.
Flavonoids
437
ISOFLAVONES (ISOMERIC FORM OF FLAVONES)
Introduction
These are hydroxylated derivatives of isofl avones, formed by partial alkylation of 3-phenyl
chromone. They form a quite distinct subclass of fl avonoid class and exist as either in the free state
or as glycosides. Isofl avones are more susceptible than fl avones to alkali hydrolysis. Isofl avonoids
can be divided into three classes depending on the physical properties. The simple isofl avones
mimic the shape and polarity of the steroid hormone oestradiol and exhibits suffi cient oestrogenic
activity which affects the reproduction of grazing animals. Therefore, they are termed as phyto-
oestrogens. Isofl avonoids in the human diet (e.g. from soya) serve as dietary oestrogen supplements,
which helps in the reduction of menopausal symptoms, in a similar way to hormone replacement
therapy. They also provide some protection against oestrogen-dependent cancer such as breast
cancer.
1
2
3
4
5
6
7
8
O
O
1’
2’ 3’
4’
5’6’
3-Phenyl-4 -chromen-4-oneH
Some of the examples of isofl avonoids obtained from soya (genistein and daidzein) and red
clover (biochanin A and formononetin) glycosides and their aglycosides are shown below.
O
OH O
HO
Genistein
O
O
HO
Daidzein
OH
OH
O
O
HO
OH
OH
HO
Genistin (genistein glucoside)
OH
O
O
HO
OH
OH
HO
Daidzin (daidzein glucoside)
O
O
OH
O
O
OH
438
Pharmaceutical Chemistry of Natural Products
O
O
Biochanin A
OCH
3
O
O
HO
OH
OH
HO
Ononin (biochanin A glucoside)
O
O
HO
OH
OH
OCH
3
O
O
Formononetin
OCH
3
O
O
HO
OH
OH
HO
Sissotrin (formononetin glucoside)
O
O
HO
OCH
3
Structural elucidation of isoflavones
1. Molecular formula: Molecular formula of isofl avonol is determined fi rst.
2. Presence of hydroxyl group and methoxyl group: Using the usual standard chemical
reactions (acetylation, oxidation method, Zerewitinoff’s reaction and Zeisel’s reaction), the
number of hydroxyl groups and methoxyl groups present in isofl avones are estimated.
3. Structure of isofl avonol:
(a) Upon fusion with potassium hydroxide, isofl avone molecule is cleaved into two
fragments, namely, (i) phenolic compound and (ii) phenyl acetic acid or its derivative.
(b) Upon hydrolysis with ethanolic potassium hydroxide, isofl avone yields one molecule
of formic acid and a hydroxylated benzyl-o-hydroxyphenyl ketone.
(c) The hydroxylated benzyl-o-hydroxyphenyl ketone upon further degradation with
strong alkali yields hydroxylated phenyl acetic acid and polyhydric phenol.
(d) The above reactions may be depicted with the typical example of daidzein.
HO OH
OH
⫹
KOH fusion
O
OH
HO
O
Daidzein
Alc. KOH
m-Hydroxy phenol p-Hydroxy phenyl
acetic acid
HOOCH C
2
Flavonoids
439
CO
HO
OH
OH
HCOOH
HO
OH
⫹
CH
2
p-Hydroxybenzyl-2,4-hydroxyphenyl ketone
Strong alkali
m-Hydroxy phenol p-Hydroxy phenyl acetic acid
HOOCH C
2
OH
⫹
(e) Oxidation of isofl avones with alkaline hydrogen peroxide can also be employed
for degrading isofl avones. It is useful in knowing the substituents in the 3-phenyl
nucleus.
4. Synthesis: The proposed structure by the chemical and analytical methods is fi nally
confi rmed by synthesis.
Benzyl- -hydroxy phenyl
ketone
o
O
CH
2
CH
65
OH
⫹
HCOOC H
25
Ethyl formate
Na
O
OH
HC
O
⫺
C
CH
65
H/ HO
⫹
⫺
2
O
O
Isoflavone
The structural elucidation of amygdalin and arbutin is discussed in Chapter 3—Glycosides.
PROBABLE QUESTIONS
1. What are fl avonoids? Write their biological importance and briefl y outline the chemistry of fl avones.
2. Write in detail about the chemistry of quercetin.
3. What are isofl avones? Write their biological importance and briefl y outline the chemistry of isofl avones.
4. Outline the structural elucidation of fl avonol.
5. Describe the occurrence, isolation and chemistry of quercetin. Also outline its synthesis.
6. Write short notes on isolation and purifi cation of fl avones.
440
Pharmaceutical Chemistry of Natural Products
SUGGESTED READINGS
Barnes, S (1998). Phytoestrogens and breast cancer. Ballieres Clin Endocrinol Metab 12: 559–579.
Bentley (1960). The Natural Pigments. Interscience, New York, p. 306.
Das, A, Wang, JH and Lien, EJ (1994). Carcinogenicity, mutagenicity and cancer preventing activities of fl avonoids: a structure–
system–activity relationship (SSAR) analysis. Prog Drug Res 42: 133–166.
Dean, FM (1963). Naturally Occurring Oxygen Ring Compounds. Butterworths, London, p. 281.
Dixon, RA (1999). Comprehensive Natural Products Chemistry, Vol 1. Elsevier, Amsterdam, pp. 773–823.
Donnelly, DMX and Boland, GM (1998). Isofl avonoids and related compounds. Nat Prod Rep 15: 241–260 (Earlier review:
1995, 12: 321–338).
Gilman, H (1943). Organic Chemistry II. John Wiley, New York, p. 1172.
Harborne, JB and Williams, CA (2000). Advances in fl avonoid research since 1992. Phytochemistry 55: 481–504.
Heller, W and Forkmann, G (1994). The Flavonoids: Advances in Research Since 1986, Harborne, JB (Ed.). Chapman & Hall,
London, p. 499.
Mitchell, JH, Gardner, PT, Mcphail, DB et al. (1998). Antioxidant effi cacy of phytoestrogens in chemical and biological model
systems. Arch Biochem Biophys 360: 142–148.
Stohs, SJ (1995). The role of free radicals in toxicity and disease. J Basic Clin Physiol Pharmacol 6: 205.
Weisburger, JH (1991). Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants and carotenoids.
Am J Clin Nutr 53: 226S.
Wiseman, H (1999). The bioavailability of non-nutrient plant factors: dietary fl avonoids and phyto-oestrogens. Proc Nutr Soc
58: 139–146.
INTRODUCTION
Vitamins may be defi ned as organic compounds required in the diet in small amounts (in addition
to carbohydrates, proteins, fats, minerals and water) to perform specifi c biological functions for
normal maintenance of optimum growth and health of organism, as they cannot be synthesized
by the body except vitamin D. Because of their slow degradation, vitamins are required in small
amounts. The bacterium Escherichia coli can synthesize all the vitamins; hence, it does not require
any vitamin.
Vitamins are a class of organic compounds categorized as essential nutrients for life and
maintenance of normal health. These are required in small quantity for the body, thus falling in
the category of micronutrients, because body uses them without breaking down, as happens to
other micronutrients.
Vitamins are essential food factors required for the proper utilization of the proximate principles
of food like carbohydrates, lipids and proteins. These act as cofactor in many enzyme systems
and are therefore cardinal for various body functions such as energy production, haemopoiesis,
reproduction, neurological functions, hydroxylation and synthesis of fats, amino acids, nucleic
acids and nucleoprotein. Any aberrations in these critical mechanisms cause profound changes in
the nervous system and integrity of skin, mucous membrane, synthesis and repair of connective
tissue and drug metabolism. Therefore, vitamins serve the needs of growth, differentiation and
maintenance of normal cellular function.
History
In the beginning of twentieth century, it was clearly understood that diets containing purifi ed
carbohydrates, proteins, fats and minerals were not adequate to maintain the growth and health
of experimental rats, but could be obtained through natural foods (such as milk). Hopkins coined
the term accessory factors to the unknown and essential nutrients present in the natural foods.
In 1912 Kazimierz Funk, a Polish biochemist, isolated an active principle (an amine) from rice
polishing and later in yeast, which could cure beriberi in pigeons. This compound was later known
Vitamins
9
CHAPTER