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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
452
Pharmaceutical Chemistry of Natural Products
Colour vision
Cones are responsible for bright and colour vision. Visual cycle comparable to rods is also present
in cones. Presence of colour-sensitive pigments such as porphyropsin (red), iodopsin (green) and
cyanopsin (blue) are responsible for colour vision. One or more of these pigments are bleached
when bright light strikes the retina, depending on the colour of the light. The pigments dissociates
to all-trans retinal and opsin, as in case of rhodopsin. The above reaction passes on a nerve impulse
to brain which results in the perception of different colour by the brain.
Deficiency
Vitamin A defi ciency is rare in the Western world, but in developing countries it is one of the most
widespread, yet preventable, causes of blindness. The earliest symptom of vitamin A defi ciency is
impaired dark adaptation, or night blindness or nyctalopia.
Severe defi ciency causes a condition called xerophthalmia, characterized by dryness in the
conjunctiva and cornea and keratinization of epithelial cells. White triangular plaques known as
biot’s spots are seen in certain areas of conjunctiva. If xerophthalmia persists for a long time, corneal
ulceration and degeneration are observed. The above symptoms lead to destruction of cornea, a
condition known as Keratomalacia, causing total blindness. The appearance of skin lesions (follicular
hyperkeratosis) is also an early indicator of inadequate vitamin A status.
Growth retardation is a common sign in children. Because vitamin A is required for the normal
functioning of the immune system, even children who are only mildly defi cient in vitamin A have
a higher incidence of respiratory disease and diarrhoea, as well as a higher rate of mortality from
infectious diseases than children who consume suffi cient vitamin A.
Some diseases may themselves induce vitamin A defi ciency, most notably liver and
gastrointestinal diseases, which interfere with the absorption and utilization of vitamin A.
The reproductive system is adversely affected during vitamin A defi ciency. Degradation of
germinal epithelium leads to sterility in males. Vitamin A defi ciency during pregnancy leads to
malformations in fetal development. Termination of pregnancy due to fetal death is observed.
The skin becomes rough and dry. Keratinization of epithelial cells of GIT, urinary tract and
respiratory tract is noticed. This leads to increased bacterial infection. Vitamin A defi ciency is
associated with formation of urinary stones. The plasma level of retinol-binding protein is decreased
in vitamin A defi ciency.
Hypervitaminosis of Vitamin A
Excess consumption of vitamin A leads to toxicity. Dermatitis, enlargement of liver, skeletal
decalcifi cation, tenderness of long bones, loss of weight, irritability, loss of hair, joint pains, etc.,
are the common symptoms of hypervitaminosis A. In case of pregnant woman, it is associated
with the risk of congenital malformation in the developing fetus.
Vitamins
453
Recommended Dietary Allowance (RDA)
The RDA of vitamin A is around 1000 retinol equivalents (3500 IU) for men and 800 retinol
equivalents (2500 IU) for women. One IU equals 0.3 µg of retinol. The requirement increases in
growing children, pregnant woman and lactating mothers.
Structural elucidation of vitamin A (retinol or axerophthol)
Karrer and Heilborn established the molecular structure of vitamin A on the basis of following
synthetic and chemical evidences:
1. Molecular formula: Analytical data reveals that the molecular formula of vitamin A is
C
20
H
30
O.
2. Presence of primary alcoholic group: Formation of ester with p-nitro benzoic acid
shows that the nature of the oxygen is alcoholic. In addition, oxidation of vitamin A yields
an aldehyde indicating that the hydroxyl group is primary alcoholic in nature.
3. Presence of fi ve double bonds: Vitamin A on catalytic reduction absorbs fi ve molecules
of hydrogen forming perhydroretinol (C
20
H
40
O) in the presence of platinum
or aluminium
or amalgam, which reveals the presence of fi ve double bonds in vitamin A.
CHO
20 30
5H
2
Vitamin A
Pt/Al/Hg
Reduction
CHO
20 40
Perhydro retinol
The formula of perhydroretinol (C
20
H
40
O) indicates that the formula of parent hydrocarbon
will be C
20
H
40
which corresponds to the general formula C
n
H
2n
for compounds having one
ring. Furthermore vitamin A forms an adduct with maleic anhydride which shows the
presence of conjugated double bond. This is further confi rmed by the UV spectrum.
4. Presence of -ionone nucleus: Vitamin A on ozonolysis yields one molecule of geronic
acid. Since the same acid is also obtained by the ozonolysis of known compound β-carotene
and β-ionone, there must be one β-ionone nucleus present in vitamin A.
CHO
20 30
HC
3
CH
3
COOH
C
O
CH
3
CH
3
HC
3
Geronic acid
Geronic acid
C
O
CH
3
Ozonolysis
O
3
Ozonolysis
O
3
CH
3
H
3
C
CH
3
CH CH C O
CH
3
-Ionone
Vitamin A
COOH
454
Pharmaceutical Chemistry of Natural Products
5. Presence of —C
CH
3
groups: Oxidation of vitamin A with alkaline potassium permanganate
at high temperature yields two molecules of acetic acid per mole of vitamin A. This reveals
the presence of two —C
CH
3
groups in the side chain. Further, with hot chromic acid (Kuhn–
Roth method of oxidation), it gives three molecules of acetic acid. This indicates the presence
of three C-methyl group in the form of moiety
—
—
C—C
—
—
CH
3
. As a comparable group could
be accounted for β-ionone ring system also, the side chain is considered to have two such
moieties.
CHO
20 30
Vitamin A
Alk. KMnO
4
High temp.
2CH COOH
3
CHO
20 30
Vitamin A
Hot chromic acid
Kuhn–Roth oxidation
3CH COOH
3
6. Position of C-methyl groups: The position of C-methyl group in the side chain was
suggested by the fact that most of the carotenoids and many other naturally occurring
compounds consist of isoprenoid units.
C
H
C
H
C CH
2
Isoprene
CH
3
The above facts suggested the structure of vitamin A is half of the β-carotene structure.
7. Number of isoprene units:
(a) Alkaline oxidation of vitamin A with potassium permanganate at high temperature
yields two moles of acetic acid, which indicates the presence of two isoprene units.
α,α-Dimethyl glutaric acid, α,α-dimethyl succinic acid and α,α-dimethyl malonic acid
are the other products formed.
(b) When vitamin A was treated with ethanolic hydrogen chloride, it yielded an anhydro
form which on selenium dehydrogenation yielded 1,6-dimethyl naphthalene.
Formation of this product is explained only if there are two isoprene units in vitamin
A.
CHO
20 30
Vitamin A
Ethanolic HCl
Vitamin A
(anhydro form)
Dehydrogenation
Se
1,6-Dimethyl naphthalene
8. Structure: On the basis of above facts, the structure (I) may be assigned to vitamin A.
CH CH CCH
CH
3
CH CH C CH
CH OH
2
CH
3
Vitamin A (I)
Vitamins
455
Based on the above proposed structure, the foregoing reactions can be explained as
follows.
Structure (I) of vitamin A
KMnO /O
43
HC
3
CH
3
CH
3
CH CH C O
CH
3
-Ionone
C
O
CH
3
COOH
Geronic acid
COOH
COOH
, -Dimethyl glutaric acid, -Dimethyl succinic acid
COOH
HOOC
,- Dimethyl malonic acid
COOH
COOH
Structure (I) of vitamin A
C H OH / HCl
25
HC
C
HH
CCCH OH
2
CH
3
Dehydrogenation Se
1,6-Dimethyl naphthalene
CH
3
CH
3
9. Confi rmation of structure: Structure of vitamin A was further confi rmed by the synthesis
of perhydroretinol A
1
from β-ionone (Karrer, 1933) that was found to be identical with the
product obtained by the reduction of vitamin A.
456
Pharmaceutical Chemistry of Natural Products
Ethyl bromo acetate
CH C C O
CH
3
-Ionone
Zn
CH BrCOOC H
225
Reformatsky
reaction
CH CH C CHCOOC H
25
CH
3
H /Pt
2
CH
2
CH
2
CH CH CH OH
2
2
CH
3
Na/C H OH
25
Bouveault reduction
CH
2
CH
2
CH CH COOC H
225
CH
3
HBr
CH
2
CH
2
CH CH CH Br
22
CH
3
NaBr
Monosodioethyl malonate
NaCH
COOC H
25
COOC H
25
CH
2
CH
2
CH CH CH CH
22
CH
3
COOC H
25
COOC H
25
2C H OH
25
(i) Hydrolysis
(ii) CO
2
CH
2
CH
2
CH CH CH
22
CH COCH
23
CH
3
BrCH COOC H /Zn
225
Reformatsky
reaction
CH
2
CH
2
CH CH CH
22
CH COCl
2
CH
3
SOCl
2
HCl
SO
2
CH I/Zn
3
CH
2
CH
2
CH CH CH CH
222
COOH
CH
3
CH
2
CH
2
CH CH CH CH
222 2 25
CCH COOC H
CH
3
OH
HO
2
HBr
CH
2
CH
2
CH CH CH CH
222 2 25
CHCH COOC H
CH
3
CH
3
CH COOH/Zn
3
CH
2
CH
2
CH CH CH CH
222 2 25
CCH COOC H
CH
3
CH
3
Br
Na/C H OH
25
Bouveault reduction
CH
2
CH
2
CH CH CH CH
222 22
CHCH CH OH
CH
3
CH
3
Perhydro retinol (Perhydro vitamin A) (II)
CH
3
Perhydro retinol is obtained when vitamin A undergoes reduction.
Vitamins
457
CH CH CCH
CH
3
CH CH C CH
CH OH
2
CH
3
10 [H]
Al–Hg
Vitamin A
CH
2
CH
2
CH CH CH
22
CH CHCH CH OH
222
CH
3
CH
3
Perhydro retinol (Perhydro vitamin A) (II)
10. Synthesis: Lastly, the structure of vitamin A is confi rmed by its synthesis. There are various
methods of synthesis available for vitamin A of which some are given below.
(a) Isler’s synthesis: In this method, two different compounds, i.e. aldehyde and alcohol,
are synthesized separately. Then, condensation of the above two yields vitamin A.
Synthesis of compound (III)
CH CH C O
CH
3
-Ionone
CH Cl COOC H
225
Ethyl chloroacetate
C H ONa
25
in liquid NH
3
CH
3
CH CH C CHCOOC H
25
CH
3
O
Hydrolysis
(III)
CH
2
C CHO
CH
3
Heat with Cu powder
under reduced pressure
CO
2
CH CH CH
CO COOH
CH
3
Isomerization
CH CH CH
CHO
CH
3
CH
458
Pharmaceutical Chemistry of Natural Products
Synthesis of compound (IV)
HC
2
HOH C
2
C
C
H
H
C O
CH
CH
3
CH
3
Methyl vinyl ketone
(i) Acetylene
(ii) Na–liq. NH
3
(iii) H O
2
HC
2
HC CCH
HSO
Allylic rearrangement
24
CC
C H MgBr
25
BrMgOH C
2
C
H
CMgBr
CH
3
CC
(IV)
CH
3
C
OH
Condensation of compounds (III) and (IV)
CH
2
CH C CHO
CH
3
(III)
BrMgC
CC CH CH OMgBr
2
CH
3
CH
2
CH C CH C
CH
3
CC CH CH OH
2
CH
3
OH
CH
2
CH C CH CH
CH
3
CH C CH CH OH
2
CH
3
OH
(III)
CH
2
CH C CH CH
CH
3
CH C CH CH OCOCH
23
CH
3
OH
(CH CO) O( CH OH
32 2
CH OAc)
2
H –Pd
BaSO (Poison for catalyst)
2
4
Trace of I
in benzene solution
(Allylic rearrangement)
2
(IV)
Vitamins
459
CH CH C CH CH
CH
3
CH C CH CH OCOCH
23
CH
3
All-trans
OH
Hydrolysis
CH CH C CH CH
CH
3
CH C CH CH OH
2
CH
3
Vitamin A
(III)
CH
2
CH C CH CH
CH
3
CH C CH CH OAc
2
CH
3
OH
HO
2
–CH COOH
3
(b) Van Dorp and Tishler’s synthesis: Van Dorp synthesized vitamin A acid from β-ionone
and methyl-γ-bromocrotonate through various intermediates. Finally in 1949, Tishler
reduced retinoic acid in presence of LiAlH
4
which resulted in vitamin A.
CH CH C O
CH
3
CH Br CH
2
CH COOCH
3
CH CH C
CH
3
OH
(i) Oxalic acid ( H O)
(ii) KOH
2
Methyl-2-bromo crotonate
Zn
Reformatsky
reaction
CH
2
CH CHCOOCH
3
CH CH C CH CH
CH
3
CHCOOH
(i) SOCl
2
(ii) CH Li
3
-Ionone
460
Pharmaceutical Chemistry of Natural Products
(i) Oxalic acid ( H O)
(ii) KOH
2
CH CH CH CH C CH COOH
CH
3
Retinoic acid (Vitamin A acid)
LiAlH
4
CH CH C CH CH
CH
3
CH C
CH COOC H
25
2
OH
CH
3
CH C
CH Br COOC H /Zn
Reformatsky reaction
225
CH CH C CH CH
CH
3
OCH C
CH
3
CH
3
CH CH CH CH C CH CH OH
2
Vitamin A (retinol)
CH C
CH
3
CH
3
(c) Attenburrow synthesis: In this method vitamin A was synthesized from 2,2,6-trimethyl
cyclohexanone.
O
2,2,6-Trimethyl cyclohexanone
OH
HC CH
Na/NH
3
CCH
(i) C H MgBr
25
(ii) CH COCH
3
CH CH
CCH
CH
2
CH
3
3-Methylocta-1,3,5-trien-7-one
C CC
OH
C
H
CH
3
CH CH CCH
CH OH
2
Acid
Allylic rearrangement
C CC
OH
CH
CH
3
OH
CCH
CH
3
CH
2
(i) LiAlH
4
(ii) (CH CO) O
32
CH CH
CH
3
Vitamins
461
OH
HC CH C C
CH
3
H
CH CH CCH
CH
3
CH OCOCH
23
(i) Dehydration by -CHCHSOH
(ii) OH
p
364 3
CH CHCH CH C
CH
3
CH C
CH
3
CH CH OH
2
Vitamin A (Retinol)
(d) Pommer’s fi rst synthesis: Pommer synthesized vitamin A from β-ionone using Wittig
reaction.
CH CH
CH
3
CH C CH CH Br
2
CH
CH
3
CH C CH CH OH
2
CH C CH
CH P Ph Br
23
C H ONa
25
CH
3
CH
CH
3
CH C CH
CH
3
CH PPh
3
(i) CHO C CHCOOC H
(Wittig reaction)
25
(ii) Hydrolysis
CH CH C CH CH CH C CH COOH
Retinoic acid (Vitamin A acid)
LiAlH
4
CH
3
CH
3
CH CH C CH CH CH C CH CH OH
2
Vitamin A (retinol)
CH
3
CH
CH
3
CH C O
-Ionone
CH CH
(i) Na NH
3
CH
CH
3
CHCC CH
OH
H /Pd
2
Quinoline
CH
CH
3
CHCCH CH
2
OH
(i) Ph P HBr
(ii) C H OH
(Allylic rearrangement)
3
25
(ii)
CH
3
HBr