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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
242
Pharmaceutical Chemistry of Natural Products
CH
510
N
Na C H⫺
52
OH
N N
(3H⫹
2
)
CH
510
N
H
(b) Now because the nitrogen atom of pyridine moiety is present as =N–, the nitrogen
atom of the side chain must possess the methyl group (point 2). Hence, the side chain
having N-methyl group may be mentioned as C
4
H
7
NCH
3
.
(c) The addition product nicotine–zinc chloride is obtained when nicotine is treated with
zinc chloride. Upon heating with lime, the zinc chloride product yields pyridine, pyrrole
and methylamine.
CHN
10 14 2
.ZnCl .2HCl.H O
22
N
⫹
N
H
⫹
C .NH
32
H
Lime
Nicotine zinc chloride
This step clearly reveals that the side chain is a pyrrole derivative. As already pointed
out the side chain is having one N–CH
3
group, and hence, it is N-methyl pyrrolidine.
The point of attachment of the side chain: The C-3 of the position of the pyridine nucleus
may be attached either to C-2 or C-3 of N-methyl pyrrolidine. Hence, the side chain of
nicotine may be depicted as below:
HC
CH
2
HC
2
CH
2
N
CH
3
CH N
510
or
CH
2
HC
2
CH
2
N
CH
3
CH
(i) Nicotine hydriodide gives nicotine isomethiodide upon treatment with CH
3
I, which
on oxidation with potassium ferricyanide followed by dichromate oxidation gives
N-methylproline (hygrinic acid).
CHN
10 14 2
(i) HI
(ii) CH I
3
CHN
10 14 2
CH I
3
K Fe(CN)
36
CHN
10 13 2
OCH
3
CrO
3
N
CH
3
HOOC
N-Methyl proline
This indicates that C-2 position of pyrrolidine unit is attached to position 3 of the
pyridine nucleus.
Alkaloids
243
(ii) Reaction of nicotine with Br
2
/HBr yields dibromo nicotinic acid, which upon
heating with barium hydroxide at 100°C, affords nicotinic acid, malonic acid and
methylamine.
CH
47
NCH
3
Br
2
/HBr
N
CH
47
NCH .2Br
3
N
Ba(OH)
2
COOH
N
⫹
COOH ⫺ CH COOH CH NH
232
⫺⫹
The formation of malonic acid is possible if the nicotine has the following structure, which
explains that the linkage carbon is oxidized to –COOH and the other ‘3C’ is oxidized to
malonic acid.
N
CCCC⫺⫺⫺
CH
3
N
This confi rms that the C-2 position of pyrrolidine is attached to C-3 of pyridine nucleus.
5. On the basis of aforementioned observations, nicotine structure can be represented as
follows, which explains all the reactions of nicotine.
N
CH
CH
2
HC
2
CH
2
N
CH
3
(i) HI
(ii) CH
3
I
N
⫹
CH
CH
2
HC
2
CH
2
N
CH
3
CH I
3
⫺
KFe
36
(CN)
CH
CH
2
HC
2
CH
2
N
CH
3
N
CH
3
O
Nicotone
N
CH
3
HOOC
Hygrinic acid
Nicotine
Nicotine isomethiodide
CrO
3
244
Pharmaceutical Chemistry of Natural Products
6. Synthesis: Finally the structure of nicotine is confi rmed by the synthesis.
COOC H
25
⫹
N
CH
3
CH
25
ONa
N
CH
3
CO
O
HCl
N
N
CO.CH.CH .CH .NHCH
322
COOH
-Keto acid
⫺CO
2
N
CO
CH
2
HC
2
CH
2
HN
CH
3
CH
25
OH NaOH⫺
N
CHOH
CH
2
HC
2
CH
2
HN
CH
3
HI
200°C
N
CHI
CH
2
HC
2
CH
2
HN
CH
3
NaOH
N
N
CH
3
( ) Nicotine⫾
Ethylnicotinate
N-Methyl pyrrolidine
Zn dust
N
O
130°C
PROBABLE QUESTIONS
1. What are alkaloids? Write the isolation of alkaloids from natural sources and classify them with two examples for each.
2. Describe in detail the general methods used for determining the structure of alkaloids.
3. Write a note on various degradation methods used in structural determination of alkaloids.
4. How is the presence of the following found?
a. Two reactive methylene groups in tropinonone
b. Five- and seven-membered rings in tropine
5. Describe the method used for the estimation of methoxyl groups in alkaloids.
6. Describe the method used for the estimation of C-methyl, N-methyl and O-methyl groups in alkaloids.
7. What is Hofmann’s exhaustive methylation? Explain with chemical reaction how it is useful in elucidating the structure of
tropine.
8. Explain Zeisel’s method of estimation of methoxy group.
9. Describe a method used for the fi ssion of C–N linkages in alkaloids with suitable example.
10. Write the various chemical tests used for the detection of alkaloids.
11. Describe the various methods of degradation used in determination of structure of alkaloids with suitable example.
Alkaloids
245
12. Write a brief note on the graded oxidation of papaverine and describe its importance in the determination of the structure
of papaverine.
13. Describe the synthetic and degradative methods used to determine the structure of quinine.
14. Describe the structural elucidation of morphine.
15. Write the mode of action of the following:
a. Morphine
b. Quinine
c. Reserpine
16. Describe the degradative and synthetic methods in establishing the structure of papaverine.
17. Describe the essential steps in the structural elucidation of colchicine.
18. Discuss the importance of colchicines in plant genetic studies.
19. Describe the pharmacological properties and constitution of reserpine.
20. Describe the analytical and degradative evidences in support of the structure of morphine.
21. How will you demonstrate the following?
a. Presence of quinoline ring in quinine
b. Presence of isoquinoline nucleus in papaverine
22. Explain the structural elucidation of atropine.
23. Write notes on the following:
a. Hofmann exhaustive methylation
b. Emde degradation
c. Von Braun’s degradation
24. How will you prove the following in morphine?
a. Presence of phenanthrene
b. Point of attachment of –CH
2
–CH
2
–N–CH
3
chain
25. How will you perform the following conversion?
a. Morphine to phenanthrene
b. Veratrole to papaverine
c. Tropine to pimelic acid
d. Nicotinic acid to (–) nicotine
e. 3,4-Dimethoxybenzyl chloride to papaverine
f. Tropine to 2-ethyl pyridine
g. Nicotine to hygrinic acid
26. Write the importance of exhaustive methylation in the study of structure of alkaloids. Support your answer with suitable
examples.
27. How will you determine the structure of tropine and tropic acid?
28. Mention different heterocyclic system present in alkaloids with a suitable example.
29. How will you prove that nicotine contains a pyrrolidine nucleus?
30. Outline the synthesis of tropinone.
246
Pharmaceutical Chemistry of Natural Products
SUGGESTED READINGS
Atta-ur-Rahman and Choudhary MI (1990). The Alkaloids, Chemistry and Pharmacology (ed Brossi, A), Vol 38. Academic, San
Diego, pp. 225–323.
Atta-ur-Rahman and Choudhary, MI (1998). The Alkaloids, Chemistry and Pharmacology (ed Cordell, GA), Vol 50. Academic,
San Diego, pp. 61–108.
Atta-ur-Rahman and Choudhary MI (1999). Diterpenoid and steroidal alkaloids. Nat Prod Rep 16: 619–635. (Earlier reviews:
1997, 14: 191–203; 1995, 12: 361–379).
Bentley, KW (1957). The Alkaloids, Part I. Interscience Publishers, New York.
Bentley, KW (1965). The Alkaloids, Part II. Interscience Publishers, New York.
Bentley, KW (2000). β-Phenylethylamines and the isoquinoline alkaloids. Nat Prod Rep 17: 247–268. (Earlier reviews: 1999,
16: 367–388; 1998, 15: 341–362).
Bernfeld, P (ed) (1967). Biogenesis of Natural Compounds, 2nd Ed. Pergamon, Oxford.
Bosch, J, Bonjoch, J and Amat, M (1996). The Alkaloids, Chemistry and Pharmacology (ed Cordell, GA), Vol 48. Academic,
San Diego, pp. 75–189.
Boye, O and Brossi, A (1992). The Alkaloids, Chemistry and Pharmacology (eds Brossi, A and Cordell, GA), Vol 41. Academic,
San Diego, pp. 125–176.
Brossi, A, Pei X-F and Greig, NH (1996). Phenserine, a novel anticholinesterase related to physostigmine: total synthesis and
biological properties. Aust J Chem 49: 171–181.
Brownstein, MJ (1993). A brief history of opiates, opioid peptides, and opiate receptors. Proc Natl Acad Sci USA 90: 5391–
5393.
Budzikiewicz, H, Djerassi, C and Williams, DH (1964). Structure Elucidation of Natural Products by Mass Spectrometry, Vol
1. Holden-Day, Inc., San Francisco.
Budzikiewicz, H, Djerassi, C and Williams, DH (1964). Structure Elucidation of Natural Products by Mass Spectrometry, Vol
2. Holden-Day, Inc., San Francisco.
Cervoni, P, Crandall, DL and Chan, PS (1993). Kirk–Othmer Encyclopedia of Chemical Technology, Vol 5, 4th Ed. Wiley, New
York, pp. 207–238.
Chiara, GD and North, RA (1992). Neurobiology of opiate abuse. Trends Pharmacol Sci 13: 185–193.
Crombie, L, Crombie, WML and Whiting, DA (1990). The Alkaloids, Chemistry and Pharmacology (ed Brossi, A), Vol 39.
Academic, San Diego, pp. 139–164.
Curzon, G (1990). How reserpine and chlorpromazine act: the impact of key discoveries on the history of psychopharmacology.
Trends Pharmacol Sci 11: 61–63.
Evans, WC (1990). Datura, a commercial source of hyoscine. Pharm J 244: 651–653.
Evers, N and Caldwell, D (1959). The Chemistry of Drugs, 3rd Ed. Ernest Benn Ltd., London, 201.
Geissman, TA and Crout, DHG (1969). Organic Chemistry of Secondary Plant Metabolism. Freeman, Cooper and Co, San
Francisco.
Gilman, H (1943). Organic Chemistry: An Advanced Treatise, Vol 1. Wiley, New York.
Gilman, H (1943). Organic Chemistry: An Advanced Treatise, Vol 2. Wiley, New York.
Ginsburg, D (1962). The Opium Alkaloids. Interscience Publishers, New York.
Glenn, AL (1954). The structure of ergot alkaloids. Quart Rev 8: 192.
Groger, D and Floss, H (1998). The Alkaloids, Chemistry and Pharmacology (ed Cordell, GA), Vol 50. Academic, San Diego,
pp. 171–218.
Henry, TA (1913). The Plant Alkaloids, 1st Ed. London, Churchill.
Henry, TA (1949). The Plant Alkaloids, 4th Ed. London, Churchill.
Herbert, RB, Venter, H and Pos, S (2000). Do mammals make their own morphine? Nat Prod Rep 17: 317–322.
Alkaloids
247
Ihara, M and Fukumoto, K (1996). Recent progress in the chemistry of non-monoterpenoid indole alkaloids. Nat Prod Rep 13:
241–261. (Earlier review: 1995, 12: 277–301).
Kalix, P (1991). The pharmacology of psychoactive alkaloids from Ephedra and Catha. J Ethnopharmacol 32: 201–208.
Klayman, DL (1992). Kirk–Othmer Encyclopedia of Chemical Technology, Vol 3, 4th Ed. Wiley, New York, pp. 489–526.
Kutchan, TM (1998). The Alkaloids, Chemistry and Pharmacology (ed Cordell, GA), Vol 50. Academic, San Diego, pp. 257–
316.
Lounasmaa, M and Tamminen, T (1993). The Alkaloids, Chemistry and Pharmacology (ed Cordell, GA), Vol 44. Academic,
San Diego, pp. 1–114.
Maat, L and Beyerman, HC (1983). The Alkaloids, Chemistry and Pharmacology (ed Brossi, A), Vol 22. Academic, San Diego,
pp. 282–331.
Michael, JP (2000). Quinoline, quinazoline and acridone alkaloids. Nat Prod Rep 17: 603–620. (Earlier reviews: 1999, 16:
697–709; 1998, 15: 595–606).
Molyneux, RJ, Nash, RJ and Asano, N (1996). Alkaloids, Chemical and Biological Perspectives (ed Pelletier, SW), Vol 11.
Elsevier, Amsterdam, pp. 303–343.
Noble, RL (1990). The discovery of the Vinca alkaloids—chemotherapeutic agents against cancer. Biochem Cell Biol 68:
1344–1351.
Pelletier, SW (ed) (1970). Chemistry of the Alkaloids. Van Nostrand Reinhold Co, New York.
Sangster, AW (1960). Determination of alkaloids structure. J Chem Educ 37: 454.
Sangster, AW and Stuart, KL (1965). Ultraviolet spectra of alkaloids. Chem Rev 65: 69.
Schmidhammer, H (1998). Opioid receptor antagonists. Prog Med Chem 35: 83–132.
Schneider, MJ (1996). Alkaloids, Chemical and Biological Perspectives (ed Pelletier, SW), Vol 10. Elsevier, Amsterdam, pp.
155–299.
Stockigt, J (1995). The Alkaloids, Chemistry and Pharmacology (ed Cordell, GA), Vol 47. Academic, San Diego, pp. 115–172.
Swan, GA (1967). An Introduction to the Alkaloids. Blackwell Scientifi c Publications, Oxford.
Szantay, C, Dornyei, G and Blasko, G (1994). The Alkaloids, Chemistry and Pharmacology (ed Cordell, GA), Vol 45. Academic,
San Diego, pp. 127–232.
Takano, S and Ogasawara, K (1989). The Alkaloids, Chemistry and Pharmacology (ed Brossi, A), Vol 36. Academic, San Diego,
pp. 225–251.
Wills, S (1993). Drugs and substance misuse: Plants. Pharm J 251: 227–229.
STEROIDS
Steroids are a unique class of chemical compounds found widely in the animal and plant kingdom.
These are characterized by the presence of a 1,2-cyclopentanoperhydrophenanthrene nucleus in
their structure. The steroids include a wide variety of naturally occurring synthetic substances,
such as sterols (including vitamin D), bile acids, adrenal cortical and sex hormones, various
contraceptive drugs, cardiac-active lactones (cardiac glycosides), sapogenins and certain alkaloids
and antibiotics.
26
1
2
3
5
4
7
10
9
11
12
17
13
16
1514
8
6
A
B
C
D
Steroid template
Phenanthrene
CH
3
CH
3
Steroid backbone
1
2
3
5
6
7
4
10
8
9
14
13
12
11
18
19
CH
3
CH
3
21
20
22
23
24
25
27
17
16
15
HH
H
Cholestane template
Steroids and Hormones
6
CHAPTER
250
Pharmaceutical Chemistry of Natural Products
The term cholesterol was derived from the Greek words bile (which means ‘chole’) and solid
(which means ‘sterols’). The modern era of steroid research began with steroid chemistry in the
1900s. Dr AO Windaus worked for over 20 years and received the Nobel Prize in 1928 for his
research on the ‘constitution of sterols’.
Drs Heinrich and Wieland engaged in natural products chemistry, including bile acids, and
were awarded the Nobel Prize in 1928.
A total of six Nobel Prizes were awarded to scientists working in the area of steroids, among
the six, four prizes were in the steroid chemistry category. The pioneer work of Adolf Windaus and
Heinrich Wieland in the structural elucidation of a number of important steroids led to the many
signifi cant discoveries in the world of steroids.
The two interesting discoveries mentioned (points ‘1’ and ‘2’ below) in the late 1940s and
early 1950s had a dramatic effect not only on steroid research but also on the pharmacological
applications of steroids. This led to an extensive research on medicinal chemistry, pharmacology
and clinical studies of steroid agonists and antagonists.
1. The clinical report on the anti-infl ammatory effect of cortisone in patients with rheumatoid
arthritis.
2. The use of oestrogen and progestin preparations for contraception.
Steroids when dehydrogenated with selenium at 360°C yield Diels’ hydrocarbon. On the basis
of this reaction, a steroid may be defi ned as any compound which yields Diels’ hydrocarbon when
distilled with selenium. However, if the steroids are distilled with selenium at 420°C, they mainly
yield chrysene and a small amount of picene.
Diels’ hydrocarbon
CH
3
Chrysene
Picene
Steroids and Hormones
251
The overall class of steroids is found almost entirely as solids and the melting points for
steroids range from approximately 100 to 250°C. Generally steroids are insoluble in water, but
they are reasonably soluble in organic solvents such as ethanol, acetone, chloroform and dioxane.
Oestrogens with a phenolic hydroxyl group on the aromatic A ring are soluble in dilute sodium
hydroxide.
Nomenclature of Steroids
1. Steroids consist of four fused rings (A, B, C and D). Chemically these hydrocarbons are
cyclopentanoperhydrophenanthrenes. They contain a fi ve-membered cyclopentane (D)
ring and three rings of phenanthrene, i.e. perhydrophenanthrene (rings A, B and C) is the
completely saturated derivative of phenanthrene.
Cholestane template
1
2
3
5
6
7
4
10
8
9
14
12
11
18
19
CH
3
CH
3
21
20
22
23
24
25
27
17
16
15
H
H
H
26
Steroid template
1
2
3
4
A
5
7
10
9
11
12 17
13
16
15
14
8
6
B
C
D
13
2. Earlier, the various steroids were generally designated by their common or trivial names,
such as cholesterol, progesterone, testosterone and oestradiol. However, these names were
discarded due to developments in chemistry and systematic names as per the International
Union of Pure and Applied Chemistry (IUPAC) nomenclature were favoured.
3. The steroid scaffold contains 17 carbon atoms, and the numbering of the carbon atoms begins
with the carbons of the phenanthrene, followed by numbering the remaining carbons of the
cyclopentane ring. Additional carbon atoms on steroids including angular methyl groups
attached to C-10 and C-13 and alkyl substituents on C-17 are numbered.
4. The systematic names for steroids are based upon the stem name (Figure 6.1) which in turn
is based on the hydrocarbon system. Cholestane is the term used for steroids with 27 carbon
atoms, pregnanes are steroids with 21 carbon atoms, androstanes have 19 carbon atoms, estranes
have 18 carbon atoms and gonanes have 17 carbon atoms.
5. If any unsaturation (double bond) is present in the steroid, the ‘ane’ ending of the stem name
is replaced by ‘ene’ if it contains one double bond, ‘diene’ if it contains two double bonds,
‘triene’ if it contains three double bonds.
6. The symbol Δ is often used to designate a C=C bond in a steroid. If C=C is in between carbons
4 and 5, the compound is referred to as a Δ
4
steroid,
and if the C=C bond is between positions
5 and 10, the compound is designated as Δ
5(10)
steroid.