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232
Pharmaceutical Chemistry of Natural Products
Tropolone Alkaloids
Colchicine
NHCOCH
3
O
OMe
MeO
MeO
OMe
1
2
3
4
5
6
7
8
9
10
11
12
Colchicine is an alkaloid obtained from Colchicum autumnale. As the nitrogen in it is not basic in
nature, colchicine is not an alkaloid in the strictest sense. Colchicine is the traditional drug used
for alleviating the infl ammation of acute gouty arthritis.
Colchicine is more specifi c in gout than the nonsteroidal anti-infl ammatory drugs and is
effective in preventing attacks of acute Mediterranean fever, and may have a mild benefi cial effect
in sarcoid arthritis and in hepatic cirrhosis. Acute intoxication after ingestion of large doses of the
alkaloid is characterized by burning throat pain, bloody diarrhoea, shock and haematuria.
Mode of action: Colchicine produces its anti-infl ammatory effects by binding to the intracellular
protein tubulin, thereby preventing its polymerization into microtubules and leading to the
inhibition of leukocyte migration and phagocytosis. It also inhibits the formation of leukotriene
B
4
. Adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis.
Uses: Used to treat the infl ammation of acute gouty arthritis.
Structural elucidation
The structure of colchicine is established as follows:
1. Molecular formula: The molecular formula of colchicine is found to be C
22
H
25
NO
6
.
2. Presence of enol methyl ether group: Hydrolysis of colchicine with dilute acids yields an
acidic (but not carboxyl) substance called colchiceine with a molecular formula of C
21
H
23
NO
6
and methanol, which indicates the presence of enol methyl ether group in the colchicine.
CHON
22 25 6
⫹ CH OH
3
⫹ HO
2
Dilute
acid
CHON
21 23 6
Colchicine Colchiceine Methanol
3. Presence of acetamido group: Trimethyl colchicinic acid, C
19
H
21
NO
5
, having a 1° NH
2
group along with acetic acid molecule is obtained upon more strenuous acidic hydrolysis of
colchicine, which confi rms the presence of an acetamido group.
⫺NHCOCH
3
⫺NH
2
⫹ CH COOH
3
HCl
4. Presence of three methoxy groups: By Zeisel’s test, trimethyl colchicinic acid is found
to possess three –OCH
3
groups.
5. Presence of unreactive carbonyl group: The remaining, i.e. sixth, O does not undergo
acylation and does not react with carbonyl reagents and hence indirectly it is established as
an unreactive carbonyl group.
Alkaloids
233
6. Tricyclic nature of colchicines: Thus, colchicines may now be represented as below:
CH
16 9
= O
4 OMe⫺
⫺NHCOCH
3
Thus, the parent hydrocarbon of colchicine is C
16
H
16
. Catalytic hydrogenation of
colchicine yields hexahydrocolchicine (two double bonds and the ketonic group are
reduced) which still possesses an isolated double bond shown by the fact that it forms
an epoxide; hence the colchicine must possess three double bonds (two are reduced on
catalytic hydrogenation, the third is diffi cult to reduce, as it is completely substituted).
Moreover, colchicine and many of its derivatives may be oxidized to 3,4,5-
trimethoxyphthalic acid indicating the presence of a benzenoid nucleus in colchicine and
also in its derivatives.
Thus, the fully reduced hydrocarbon corresponding to colchicine would have the
composition C
16
H
28
(C
16
H
16
+ 6H for three double bonds and 6H for the benzenoid nucleus)
and thus it must be tricyclic, as its completely saturated hydrocarbon corresponds to the
general formula C
n
H
2n-4
for tricyclic compounds.
The nature of three different rings are established as mentioned below.
7. Nature or size of one of the rings (A): Colchicine is oxidized to 3,4,5-trimethoxyphthalic
acid. The structure of ring A and also position of the three methoxy groups are established
from this degradation product.
MeO
MeO
COOH
COOH
OMe
8. Nature or size of the second ring (B): Colchicine on treatment with KI yields
N-acetyliodocolchinol which on O-methylation followed by reduction yields N-acetylcolchinol
methyl ether. The N-acetylcolchinol methyl ether on heating with P
2
O
5
yields two compounds,
i.e. deaminocolchinol methyl ether and isodeaminocolchinol methyl ether.
The correct structure of N-acylcolchinol methyl ether and the above formed two
nitrogen-free substances are established as follows:
(a) N-Benzoyltrimethylcolchicinic acid on oxidation gives N-benzoylcolchicinic anhydride
which on heating with P
2
O
5
gives an ‘N’-free anhydride. The N-free anhydride does
not resemble naphthalene in chemical behaviour and yields a dihydro derivative on
reduction. The proposed structure is mentioned below and confi rmed by synthesis.
MeO
OMe
MeO
CO
O
C
O
234
Pharmaceutical Chemistry of Natural Products
(b) The two isomers, deaminocolchinol methyl ether and isodeaminocolchinol methyl
ether, give the same dihydro derivative on reduction, indicating that they differ only in
the position of the double bond.
(c) These two isomers are oxidized with OsO
4
to two isomeric diols and then to two dial-
dehydes with Pb(OAc)
4
. The two isomeric dialdehydes are converted into crystalline
monoaldehydes; 2,3,4,7-tetramethoxy-10-phenanthraldehyde (from deaminocolchi-
nol methyl ether) and 2,3,4,7-tetramethoxy-9-phenanthraldehyde (from isodeamino-
colchinol methyl ether) on treatment with alkali. These reactions suggest that the ring
B of colchicine is seven membered.
MeO
OMe
MeO
OMe
CHO
MeO
OMe
MeO
OMe
CHO
2,3,4,7-Tetramethoxy-10-phenanthraldehyde 2,3,4,7-Tetramethoxy-9-phenanthraldehyde
(d) The seven-membered nature of the ring B is confi rmed by the oxidation of deami-
noiodocolchinol methyl ether to an iodo acid which on reduction gives the following
iodine-free acid.
MeO
OMe
CH
2
COOH
MeO
OMe
COOH
Thus the above reactions may be explained by the following structure of the
isomeric deaminocolchinol methyl ether.
MeO
OMe
CH
2
CHO
MeO
OMe
CHO
MeO
OMe
MeO
OMe
MeO
OMe
MeO
OMe
CHO
OsO
4
MeO
OMe
MeO
OMe
OH
OH
Pb(OAc)
4
Alkali
Diaminocolchinol methyl ether
2,3,4,7-Tetramethoxy-10-phenanthraldehyde
Alkaloids
235
MeO
OMe
CHO
MeO
OMe
MeO
OMe
MeO
OMe
(i) OsO
4
(ii) Pb(OAc)
4
(iii) Alkali
Isodeaminocolchinol methyl ether 2,3,4,7-Tetramethoxy-9-phenanthraldehyde
Windaus reaction, i.e. formation of 9-methylphenanthrene from deaminocolchinol
methyl ether by demethylation followed by zinc dust distillation may also be well
explained by the fact that the same compound is formed by zinc dust distillation of
3,4,5,6-dibenzocycloheptatriene (a compound having seven-membered B ring).
(i) Demethylation
(ii) Zn
MeO
OMe
MeO
OMe
CH
3
Zn
3,4,5,6-Dibenzocycloheptatriene Deminocolchinol methyl ether
Finally, the presence of seven-membered nature of ring B in colchicine has been
confi rmed by the syntheses of its derivative, i.e. N-acetylcolchinol methyl ether.
MeO
OMe
CH
3
MeO
OMe
OsO
4
MeO
OMe
CH
3
MeO
OMe
OH
OH
MeO
OMe
CH
3
MeO
OMe
CHO
OC
Pb(OAc)
4
Alkali
MeO
OMe
O
MeO
OMe
Deaminocolchinol methyl ether
(i) Reduction of double bond
(ii) NH OH (oxime formation)
(iii) 4H (reduction of oxime)
2
236
Pharmaceutical Chemistry of Natural Products
MeO
OMe
MeO
OMe
NH
2
( ) form acetylated⫺
MeO
OMe
MeO
OMe
NHCOCH
3
( ) Colchinol methyl ether⫾ ( ) N-Acetylcolchinol methyl ether⫺
9. Nature of the third ring (C): Dewar in 1945 proposed that in colchicine, ring C has a
seven-membered tropolone-like structure. The nature of the C ring is seven membered,
which is supported by the following evidences:
(a) Colchicine on hydrogenation gives hexahydrocolchicine having an ethylenic double
bond proved by the formation of epoxide; and thus three double bonds and a ketonic
group in the same ring indicate that it is seven membered and not six membered.
(b) Hexahydrocolchicine on oxidation with Pb(OAc)
4
or HIO
4
affords a cyclic
monoaldehyde through an acyclic dialdehyde, which shows that the ring C must be
seven membered.
(c) Colchicine does not exhibit any ketonic property and resembles tropolones and
γ-pyrones. However, when two of the double bonds are reduced, the compound
tetrahydrocolchicine exhibits ketonic properties, such as reaction with hydroxylamine
hydrochloride and 2,4-dinitrophenylhydrazine.
(d) Formation of N-acetyliodocolchinol from colchicine upon reaction with cold alkaline
hypoiodite may be explained by the fact that the tropolone ring C undergoes benzilic
acid rearrangement as mentioned below.
OH
COOH
OH
O
OH
By degradation reactions, the above two structures could not be differentiated, and
therefore X-ray crystallographic studies were carried out which revealed that structure
I is more probably correct.
NHCOCH
3
O
OMe
MeO
MeO
OMe
MeO
MeO
OMe
O
OMe
NHCOCH
3
III
Alkaloids
237
10. Synthesis of colchicine: The structure I for colchicine was confi rmed by its synthesis.
MeO
MeO
OMe
(i) CH = CH CN
2
⫺
(ii) BrZnCH COOC H
225
(iii) NaOH
O
MeO
MeO
OMe
CH COOH
2
OH
CH
2
CH
2
COOH
(i) DCC
(ii) NCH
22
MeO
MeO
OMe
CH COCH
23
O
OH
Na NH⫺
3
MeO
MeO
OMe
OH
OH
O
(i) Cu(OAc)
(ii)
2
TsOH
MeO
MeO
OMe
O
O
NBS
MeO
MeO
OMe
OH
O
(i)
(ii)
CH N
NBS
22
MeO
MeO
OMe
O
OCH
3
Br
(i) NaN
3
(ii) –PdH
2
(iii) HCl ( H O)⫺
2
NH
2
O
OH
OMe
MeO
MeO
Trimethyl colchicinic acid
Colchicine
(i) N-Acetylation
(ii) O-Methylation
238
Pharmaceutical Chemistry of Natural Products
Pyridine/Piperidine Alkaloids
Piperine
O
O
HC
2
CH CH CH CH CO
N
1234
5
1’
2’
3’
4’
5’
6’
7’
The alkaloid piperine is so named because it occurs in the kernel of the ripe white pepper and in
the unripe black pepper or Piper nigrum. Piperine is found in black pepper to an extent of about
5–9% and is responsible for the sharp taste of the pepper.
Structural elucidation
The structure of piperine is established as follows:
1. Molecular formula: The molecular formula of piperine is found to be C
17
H
19
NO
3
.
2. Presence of an amide-type bond: Piperine yields a well-known base piperidine and an
acid called piperic acid upon alkaline hydrolysis.
NaOH
CHO
17 19 3 2
NH
Piperine
⫹
HO
2
CH
511
N
⫹
CHO
12 10 4
Piperidine Piperic acid
The products of hydrolysis reveal that the piperidine and piperic acid moieties are
linked by an amide-type bond in piperine molecule. This is confi rmed by the formation
of piperine, when piperic acid chloride was heated with piperidine in benzene. Because
the constitution of piperidine (hexahydropyridine) is well known, the next step is the
elucidation of the structure of piperic acid.
3. Structure of piperic acid (C
12
H
10
O
4
)
(a) Presence of two olefi nic double bond: It is found to possess two olefi nic double bond (C=C)
by catalytic reduction and bromination test.
(b) Presence of –COOH group: Results of the usual standard tests reveal that it possesses one
–COOH.
(c) Oxidation: Upon oxidation with KMnO
4
, piperic acid fi rst gives piperonal and fi nally
piperonylic acid along with tartaric acid and oxalic acid.
(d) Piperonylic acid upon heating with HCl at 200°C under pressure yields protocatechuic
acid (3,4-dihydroxybenzoic acid) and HCHO.
HO
COOH
HO
Protocatechuic acid
(O)
CHO
12 10 4
CHO
863
(O)
CHO
864
HCl
200°C
Piperic acid Piperonal Piperonylic acid
⫹
HCHO
Alkaloids
239
As piperonylic acid has no free –OH group, the origin of two –OH groups in
protocatechuic acid and formation of HCHO as a by-product can only be explained by
assuming that piperonylic acid has methylenedioxy group, i.e. it is 3,4-methylenedioxy
benzoic acid and it is proved by the synthesis.
O
O
COOH
HC
2
HO
COOH
HO
NaOH
Heat
Protocatechuic acid Piperonylic acid
⫹
CH I
22
Therefore, piperonal must be the corresponding aldehyde.
O
O
CHO
HC
2
[O]
O
O
COOH
HC
2
Piperonal
(CHO
863
)
Piperonylic acid
(CHO
864
)
(e) From the above observations, it is obvious that piperic acid has a benzene nucleus having
methylenedioxy group and only one side chain having acidic group (since only one –CHO
or one carboxyl group is developed during oxidation). Now the difference in the molecular
formulae of piperic acid (C
12
H
10
O
4
) and piperonal (C
8
H
6
O
3
) indicates that the side chain is
C
4
H
4
and its unsaturation properties suggest two double bonds [see point 3(a)].
From point 3(c), we know that piperic acid upon oxidation also gives some tartaric and
oxalic acids in addition to piperonal; hence piperic acid must have the following structure
to explain all the observations:
O
O
HC
2
CH CH CH CH.COOH
[O]
O
O
CHO
HC
2
⫹
HOOC HC CH
COOH
OH OH
Piperic acid Piperonal Tartaric acid
O
O
COOH
HC
2
[O]
COOH
COOH
2
Oxalic acidPiperonylic acid
(CHO
864
)
Hence, piperine is the condensation product of piperidine and piperic acid.
240
Pharmaceutical Chemistry of Natural Products
4. Synthesis: The above structure for piperine is proved by its synthesis from catechol.
⫹
CHCl
3
CH
2
I
2
NaOH
Reimer–Tiemann
reaction
HO
HO
HO
HO
CHO
NaOH
O
O
CHO
HC
2
Catechol
Piperonal
(CHO
863
)
CH CHO/NaOH
3
(Claisen condensation)
O
O
CH = CH CHO⫺
HC
2
Ac
2
O
AcONa
(Perkin reaction)
O
O
HC
2
CH CH CH CH COOH
Piperic acid Piperonyl acrolein
(i) PCl
(ii) Condensation with piperidine
5
O
O
HC
2
CH CH CH CH CO
Piperine
N
Pyridine–Pyrrolidine Alkaloids
Nicotine
N
N
CH
3
3-(1’-Methylpyrrolidin-2’-yl)pyridine
1’
2’
3’
4’
5’
1
2
3
4
5
6
Nicotine is obtained from Nicotiana tobacum. It is one of the most toxic alkaloids known, the fatal
dose for man being about 40 mg. Low concentration of alkaloid nicotine stimulates autonomic
ganglia and skeletal neuromuscular junction but not autonomic effector cells. The ganglion and
skeletal muscle receptor were therefore labelled nicotinic. Other tobacco alkaloids are nicotimine
(anabasine), nornicotine, nicotyrine, etc. Nicotyrine is responsible for the aroma of tobacco
smoke.
Alkaloids
241
Mode of action: Nicotine acts on the nicotinic acetylcholine receptors, specifi cally the ganglion-
type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla
and elsewhere, while the latter is present in the CNS. In small concentrations, nicotine increases
the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters
through direct mechanisms. The initial response therefore often resembles simultaneous discharge
of both the parasympathetic and the sympathetic nervous systems.
Properties and uses: Hypertension is produced by parenteral injection of nicotine; sympathetic
tachycardia may alternate with a vagally mediated bradycardia. In the gastrointestinal and urinary
tracts, the effects are largely parasympathomimetic: nausea, vomiting, diarrhoea and voiding of
urine are commonly observed. Prolonged exposure may result in depolarizing blockade of the
ganglia. In spite of the smaller ratio of nicotinic to muscarinic receptors in the brain, nicotine and
lobeline have important effects on the brainstem and cortex. The mild alerting action of nicotine
absorbed from inhaled tobacco smoke is the best known of these effects. In larger concentrations,
nicotine induces tremor, emesis and stimulation of the respiratory centre. At higher levels, nicotine
causes convulsions, which may terminate in fatal coma. The lethal effects on the CNS and the fact
that nicotine is readily absorbed form the basis for the use of nicotine as an insecticide.
Structural elucidation
The structure of nicotine is established as follows:
1. Molecular formula: The molecular formula of nicotine is found to be C
10
H
14
N
2
.
2. Presence of two 3° N: Results from the usual standard tests reveal that both the nitrogen
atoms are found to be present as 3° N; it also forms two isomeric monomethiodides under
suitable conditions, with one of the 3° N atoms found to be N–CH
3
group by Herzig–Meyer
method.
3. Presence of substituted pyridine: Upon oxidation, nicotine gives nicotinic acid (pyridine-
3-carboxylic acid).
COOH
N
CHN
10 14 2
(O)
Nicotine
Nicotinic acid
From the above reaction it is indicated that:
(a) Nicotine is 3-substituted pyridine.
(b) After subtracting the molecular formula of a substituted pyridine (C
5
H
4
N) from the
molecular formula of nicotine (C
10
H
14
N
2
), the side chain at position 3 is with the molecular
formula of C
5
H
10
N. Hence, the structure of nicotine may be depicted as follows:
CH
510
N
N
4. Position and nature of the side chain:
(a) The side chain is found to be saturated (nicotine absorbs only 3 moles of hydrogen to
form hexahydro derivative, suggesting that the pyridine nucleus of the nicotine is the
one undergoing saturation and not the side chain).