Two Faces of Alkaloids

Chemistry for Everyone

Two Faces of Alkaloids Ji ˇ rí Dostál Department of Biochemistry, Masaryk University, Faculty of Medicine, Komenského námestí 2, CZ-662 43 Brno, Czech Republic; [email protected]

The term “alkaloid” was introduced around 1819 by the German pharmacist Wilhelm Meissner (cited in ref 1). The Arabic–Greek compound al-kal-oid means literally alkali like. Indeed, most alkaloids are basic compounds, although there is a small group of nonbasic alkaloids (see below). The traditional definitions of alkaloids (2, 3), emphasizing their bitter taste, basicity, plant origin, and physiological actions, have been gradually modified to become more general and rational. For example, Pelletier created a simple definition of an alkaloid as “a cyclic organic compound containing nitrogen in a negative oxidation state which is of limited distribution among living organisms” (4 ). The presence of at least one nitrogen atom is a general chemical feature of the alkaloids. A nitrogen atom in an organic molecule can be trivalent and electroneutral or tetravalent with a positive charge. Depending on the pH, alkaloids occur in two principal forms: an ionic ammonium salt or a neutral free base. These forms differ substantially in their physicochemical properties, appearance, occurrence, practical uses, and bioavailability. They are interconvertible; that is, the alkalization of the salt yields the free base and the acidification of the free base reconstitutes the salt. This reversible acid–base reaction has become a key principle in the isolation of alkaloids from plant extracts (5, 6 ). Alkaloids occur in plants as polar salts of various organic acids and they can therefore be easily extracted with polar solvents, typically methanol. The free bases of alkaloids are compounds having basic properties: their aqueous or aqueous-alcoholic solutions are alkaline to litmus. The degree of basicity is expressed by the

pKb and depends on the chemical nature of the alkaloid. The free bases are formed by treating the salt with one of various alkalizing agents such as NaOH, Ca(OH)2, Na2CO3, NH3, or lower amines, depending on the pKa of an ammonium salt. Generally, the pH must be adjusted at least one pH unit above the pKa of a protonated form. The free bases of most of the alkaloids are water-insoluble substances, and there are two general methods for preparing them. In Method A, an aqueous solution of the alkaloid salt is made alkaline and the precipitate thus formed is separated, washed with water, and dried. The product is an amorphous material obtained almost quantitatively. Method B involves one additional step. The precipitate is extracted with a nonpolar solvent such as diethyl ether, benzene, or chloroform. The organic layer is separated, concentrated, and allowed to stand until it crystallizes. In this article, the dualism of several well-known alkaloids is discussed in detail. Nicotine, morphine, and cocaine are the examples of typical alkaloids. Sanguinarine, allocryptopine, and magnoflorine are included because they are very common in plants, and although their acid–base behavior is different, they illustrate the richness of structural motifs in natural products. Textbooks of (bio)organic chemistry (e.g., 7–9) usually do not distinguish between these forms explicitly. Undergraduate students who are not majoring in chemistry, especially those in medical schools, are apt to encounter a number of important alkaloids as medicines, drugs, or toxins, and often become confused about this. This article addresses such issues. Therapeutic uses for such compounds are given in Table 1.

Table 1. An Illustrative List of Alkaloids Used in Human Medicine Alkaloid

Plant or Fungal Source a

The Usual Form

Atropine

Atropa belladona

Sulfate

Therapeutic Category Cholinergic antagonist, spasmolytic

Cocaine b

Erythroxylon coca

Hydrochloride

Local anesthetic

Codeine b

Papaver somniferum

Phosphate

Antitussive

Colchicine

Colchicum autumnale

Colchicine

Antimitotic, gout suppressant

Emetine

Cephaelis ipecacuanha

Hydrochloride

Antiamebic, emetic

Ephedrine

Ephedra vulgaris

Hydrochloride

Adrenergic agonist, bronchodilator

Ergotamine

Claviceps purpurea

Tartrate

Antimigraine

Morphine b

Papaver somniferum

Hydrochloride, sulfate Analgesic

Papaverine

Papaver somniferum

Hydrochloride

Spasmolytic

Pilocarpine

Pilocarpus jaborandi

Hydrochloride

Cholinergic agonist

Pseudoephedrine

Ephedra vulgaris

Hydrochloride

Adrenergic agonist, vasoconstrictor

Quinidine

Cinchona officinalis

Sulfate

Antiarrhytmic

Quinine

Cinchona officinalis

Sulfate

Antimalarial

Sanguinarine

Sanguinaria canadensis

Chloride

Antiplaque agent

Scopolamine

Scopolia carniolica

Hydrobromide

Cholinergic antagonist, antiemetic

Vincristine

Vinca rosea

Hydrochloride

Antineoplastic

Yohimbine

Corynanthe yohimbe

Hydrochloride

Adrenergic antagonist, aphrodisiac

aOnly

common examples are given. bControlled substance.

JChemEd.chem.wisc.edu • Vol. 77 No. 8 August 2000 • Journal of Chemical Education

993


Nicotine

Table 2. Some Properties of Two Forms of Nicotine

Nicotine (1a) has been known since 1809. It occurs in tobacco leaves (Nicotiana tabacum, Nicotiana rustica) in a protonated form (1b) accompanied by physiological anions such as malate, citrate, or tartrate. Nicotine free base (1a) is an oily liquid (Table 2), which can be isolated by either alkalinesteam distillation or alkaline-chloroform extraction. The isolation of nicotine from cigarettes is a common laboratory experiment in high schools and colleges (10, 11). An aqueous solution of nicotine is alkaline to litmus. Nicotine possesses the methylated pyrrolidine nitrogen (pKb = 6.16) and the less basic pyridine nitrogen (pKb = 10.96). To liberate free nicotine (1a) the pH of a tobacco extract must be adjusted above the pKa of the protonated N-methylpyrrolidinium (8.08, 15 °C). This condition is readily fulfilled by using NaOH, Ca(OH)2, or Ba(OH)2 solutions (10, 11). 1

2

Property

Nicotine (1a) (Free Base)

Nicotine Ditartrate (1b) (X = Y = Tartrate)

Molecular formula

C10H14N2

C10H14N2⭈ 2C4H6O6

Molecular weight

162.23

462.41

Appearance

Colorless oily liquida Colorless crystals

Melting point (°C)

᎑79b

pKb (15 °C)

6.16;c 10.96d

—

Solubility in water

Soluble

Soluble

93–95

Solubility in benzene Soluble

Insoluble

Tobacco smokee

Occurrence

Tobacco

darkens upon exposure to air. bBoiling point 243–248 °C. cPyrrolidine moiety. dPyridine moiety. eThe forms of nicotine depend on the smoke’s acidity. aSlowly

Table 3. Some Properties of Two Forms of Morphine Y− N H + CH3

N CH3

N 1a

X−

N+ H

1b

During smoking, approximately one-third of the nicotine salts present in dry tobacco is pyrolyzed into simpler derivatives. The remaining two-thirds distills into the smoke, which is inhaled. Depending on the acidity of the smoke, nicotine can be predominantly either protonated (most cigarettes) or un-ionized (pipes, cigars). Nicotine passes quickly from the lungs to the blood and reaches nicotine acetylcholine receptors in the brain and other tissues. After binding to the receptor, a conformational change induces the opening of a Na+/K+ channel for microseconds. Sodium ions enter the cell and trigger a cascade of further events, which eventually result in the release of neurotransmitters including dopamine, serotonin, and β-endorphin. Nicotine’s ability to make people feel good seems to be linked to dopamine liberation. The almost instantaneous relationship between a single puff and central nervous system effects allows smokers to modulate the actions of nicotine to a desirable level. This is probably behind the high addictiveness of smoking. Other effects of nicotine can be described as cardiovascular (vasoconstriction, rise in blood pressure), endocrine (cortisol release, risk of osteoporosis), and metabolic (increased metabolic rate, catecholamine release, “silent stress”). They all seriously contribute to smoking-related health dangers and illnesses.

Property

Morphinea (2a) (Free Base)

Molecular formula

C17H19NO3

C17H19NO3⭈ HCl

Molecular weight

285.33

321.79

Appearance

Colorless crystals

Colorless crystals

Melting point (°C)

253–254

285–300

pKb (20 °C)

6.13

—

Solubility in water

Insoluble

Soluble

Solubility in benzene

Slightly soluble

Insoluble

Medically useful

No

Yes

aControlled

substance.

value it follows that morphine should be extracted at pH ~9. Moreover, morphine bears one phenolic hydroxyl with pKa 9.85. Therefore, at pH > 10, formation of the phenolate will prevent morphine from passing into nonpolar solvent. HO

HO

O

O N

HO

Morphine (2a), discovered in 1817, is the principal alkaloid of the opium poppy (Papaver somniferum), a plant species that has been cultivated all over the world for more than 2,000 years (12). Morphine is obtained from opium, the dried latex of the unripe capsules, where it is found largely as the salt of meconic acid. Morphine has also been isolated as a minor alkaloid from the closely related species Papaver setigerum (13) and Papaver decaisnei (14). A saturated aqueous solution of morphine is alkaline to litmus. The pKb constant of morphine (2a) is 6.13 and the pKa of morphinium (2b) is 7.94 (20 °C). From the latter

994

H X− N + CH3

CH3 HO

2a

Morphine

Morphinea Hydrochloride (2b) (X = Cl)

2b

Morphine is used in medicine as a potent analgesic, especially in the treatment of severe chronic pain. Morphine free base (2a), whose formula is frequently presented in chemistry textbooks (e.g. 7–9), is extraordinarily insoluble in water and is consequently therapeutically useless. As much as 5 L of water is required to dissolve 1 g of morphine (15). In contrast, morphine hydrochloride (2b, X = Cl) is highly water soluble (1 g dissolves in 17.5 mL of H2O). Morphine hydrochloride is administered mainly by injection. Recently, enteric-coated tablets containing morphine sulfate (2b, X = 1 ⁄2 SO4) have been introduced. Table 3 shows some properties of morphine free base and its hydrochloride.

Journal of Chemical Education • Vol. 77 No. 8 August 2000 • JChemEd.chem.wisc.edu


Table 4. Some Properties of Two Forms of Cocaine a

Property

Cocaine (3a) (Free Base)

Molecular formula

C1 7 H2 1 NO4

C1 7 H2 1 NO4 ⭈ HCl

Molecular weight

303.35

339.81

Cocaine Hydrochloridea (3b) (X = Cl)

Appearance

White powder

Colorless crystals

Melting point (°C)

95–98

195–202

pKb (15 °C)

5.59

—

Solubility in water

Slightly soluble

Soluble

Solubility in benzene

Soluble

Insoluble

Abused by

Smoking

Snorting, injection

aIllegal

substance.

Table 5. Some Properties of Two Forms of Sanguinarine Property

Sanguinarine (Free Base) (4b)

Sanguinarine Chloride (4a)

Molecular formula

C4 0 H2 8 N2 O9

C2 0 H1 4 NO4 + Cl ᎑

Molecular weight

680.68

332.34 (cation)

Appearance

Colorless crystals

Copper-red crystals

Melting point (°C)

258–260

282–283

pK (25 °C)

—

8.05

Solubility in water

Insoluble

Soluble

Solubility in chloroform

Soluble

Insoluble

Cocaine, one of the most widespread stimulant drugs, is a very dangerous, illegal, and highly addictive substance (18). Cocaine hydrochloride (3b, X = Cl) is its water-soluble ammonium salt. It is abused by snorting because it is absorbed through the nasal mucosa or, less frequently, injected intravenously (19). The so-called “crack” cocaine became available in the early 1980s. Chemically, crack is the free base of cocaine (3a) (20). Crack cocaine, a low-melting substance rather volatile above 90 ºC, is abused by smoking (Table 4). In contrast, cocaine hydrochloride decomposes in the burning process. Sanguinarine In 1827, the alkaloid sanguinarine (4a) was discovered as the main red constituent of the North American herb Sanguinaria canadensis (21). When cut, S. canadensis exudes an intensely red latex containing salts of sanguinarine (4a) and the related benzo[c]phenanthridine alkaloids (22). For this reason the plant is known colloquially as “bloodroot”. In Europe, the only related species producing sanguinarine is greater celandine (Chelidonium majus). Owing to its antimicrobial, antiplaque, and antiinflammatory properties, sanguinarine is used as a component in numerous toothpastes, dental gels, and oral rinses (23). O O N +

O O

CH3

O

X−

O 4a N

CH3

O O

Cocaine Cocaine (3a) is the main alkaloid of the South American coca shrub (Erythroxylon coca) (16 ). It has been known since 1860. The popular beverage Coca-Cola, invented in 1886 by John Pemberton (17), originally contained extracts from coca leaves in addition to the essence of cola nuts (Cola acuminata). In 1904, American authorities outlawed the coca ingredient. Today, the only reminder of cocaine in Coca-Cola is the first part of the compound name. An aqueous solution of cocaine is alkaline to litmus. The pKb of cocaine (3a) is 5.59 and the pKa of the conjugate acid (3b) is 8.65 (15 °C). CH3

N

COOCH3 O

C O

3a

H CH3

N+

X−

COOCH3 O 3b

C O

O

O O

CH3

N

O O 4b

Sanguinarine is an iminium cation with the nitrogen atom as part of an aromatic ring. The molecular weight of the sanguinarine free base is more than twice that of the cation (Table 5). The acid–base process here is more complex than for the previous alkaloids (24 ). The hydroxide ion adds to the electron-deficient carbon of the C=N+ bond, yielding an unstable hydroxy adduct, which immediately undergoes a condensation reaction to give bis(dihydrosanguinarinyl) ether (4b). The equilibrium between the quaternary cation and a tertiary free base is described by a pK = 8.05 which is analogous to pKa for Brønsted acids (25, 26 ). It means that at pH ~ 10 the conversion of sanguinarine to its free base is complete. Because of the breakdown of its conjugation, the free base is colorless. The process is essentially reversible; treating the base 4b with an acid gives the quaternary salt 4a. This brings out another interesting feature: sanguinarine acts as an acid–base indicator. In acidic solution it is red; in an alkaline environment, colorless.


995


This property can be easily demonstrated using an overhead projector and an oral rinse containing sanguinarine. I used Santoin (CZ), but the demonstration should work similarly with other sanguinarine dental rinses such as Viadent, Dentosan S, or Perioguard. A Petri dish (60 mm o.d.) is placed on the projector stage. A small amount (5–10 mL) of a rinse is poured in and its typical coloring is projected on a screen. Then 6 M NaOH is added dropwise (stir gently) until the color disappears. The addition of 6 M HCl reconstitutes the quaternary salt of sanguinarine and the original color reemerges. Other components in oral rinse formulas (ethanol, glycerol, menthol, thymol, zinc chloride, sodium saccharine, etc.) do not disturb the reaction. The color change is striking, and at the same time, the experiment may stimulate students’ interest in oral hygiene.

Table 6. Some Properties of Two Forms of Allocr yptopine

Property

Allocryptopine (5a) (Free Base)

Allocryptopine Hydrochloride (5b) (X = Cl)

Molecular formula

C2 1 H2 3 NO5

C2 1 H2 3 NO5 ⭈ HCl

Molecular weight

369.40

405.86

Appearance

Colorless crystals

Colorless crystals

Melting point (°C)

160–161a 171–172b

210–212

pKb (25 °C)

4.89

—

Solubility in water

Insoluble

Soluble

Solubility in chloroform Soluble

Insoluble

Feature IR band (cm᎑1 )c 1646 (C=O)

3377 (OH)

α-allocryptopine. β-allocryptopine (crystal modification). cKBr pellets. aFor bFor

Allocryptopine Allocryptopine (5a) is a protopine alkaloid, ubiquitous in plants of the Papaveraceae and Fumariaceae families (27, 28). It has been known since 1890. The structural formula 5a with a nonphysiological 10-membered heterocycle depicts its free base. X-ray analysis of the base shows that the distance between the nitrogen atom and the carbonyl carbon opposite is 2.44 Å. This is substantially less than the sum of the van der Waals radii of these atoms (3.15 Å) (29). This indicates a strong electrostatic interaction, which probably stabilizes the conformation of this unusual heterocycle. The action of acid triggers a transannular nucleophilic addition of the tertiary nitrogen to the carbonyl carbon. The resulting allocryptopine salt (5b) is a tetracyclic system with a hydroxyl group and an ammonium nitrogen (30, 31) (Table 6). It is, in fact, the natural skeleton of the protoberberines, another interesting group of isoquinoline alkaloids (32, 33). Allocryptopine free base is readily extractable into ether after alkalization with sodium carbonate at pH 10–11 (34 ). O N +

O

CH3 X −

HO OCH3 O

5b N

O

OCH3

CH3

O OCH3

Table 7. Some Properties of Two Forms of Magnoflorine Property

Magnoflorine Iodide (6a) (X = I)

Magnoflorine "Free Base" (6b)

Molecular formula

C2 0 H2 4 NO4 + I ᎑

C2 0 H2 2 NO4 ᎑

Molecular weight

342.40 (cation)

340.40

Appearance

Colorless crystals

Not known

Melting point (°C)

264–266

Not known

Solubility in water

Soluble

Soluble

Solubility in chloroform

Poorly soluble

Insoluble

charged phenolate-ammonium species is water soluble and cannot pass into nonpolar solvents as do most other alkaloids (Table 7). Standard isolation procedures fail in the case of magnoflorine. Difficulty with the “free base” of magnoflorine was apparently the reason why this alkaloid was discovered only in 1954, considerably later than the other alkaloids discussed here (38, 39). Magnoflorine used to be obtained by precipitation with styphnate, Mayer, or Reineckate reagent (6, 35), but the method is rather tedious and provides a low yield. The more efficient method of extracting magnoflorine iodide (6a, X = I) into chloroform at pH 6–7 has been introduced (36, 37 ). With this more effective extraction and purification scheme now at hand new and useful properties and uses may emerge for this widely distributed alkaloid. CH3O

CH3O CH3

5a OCH3

N X− + CH3

HO

CH3 N + CH3

−O −O

HO

Magnoflorine CH3O

Magnoflorine (6a) is a strongly polar quaternary aporphine alkaloid widely distributed in plants of the Papaveraceae, Magnoliaceae, Berberidaceae, Ranunculaceae, and several other families (35–37 ). It possesses a dimethylammonium group and two phenolic hydroxyl groups. In acidic or neutral solutions, it exists in the form of the salt 6a, which is also present in plant tissues. When a solution of the salt is made strongly alkaline (pH > 11) magnoflorine takes the form of a phenolate anion, 6b. This

996

CH3O 6a

6b

Conclusions 1. Depending on the pH value, alkaloids can occur in two forms denoted as ammonium/iminium salts and free bases. The properties of these two forms differ substantially. The transformation of one form into another is a reversible acid–base reaction.



2. The structural differences between these two forms vary from simple proton transfer (nicotine, morphine, cocaine) to fundamental skeleton alterations (sanguinarine, allocryptopine). In most alkaloids, the two forms represent a conjugate pair; that is, they differ in one covalently bonded proton on the nitrogen. 3. Almost all medically important alkaloids are applied exclusively in the forms of their salts of various organic or inorganic acids (Table 1). The alkaloid colchicine (7), used in the treatment of gout, is an exception (see below). The salt–base pair provides a good and interesting example of a conjugate acid–base pair in general chemistry courses. Students can be given the formula of an alkaloid base and asked to write the formula and the name of a salt. 4. Both forms of alkaloids should be carefully distinguished for students and their opposing properties emphasized. Different intermolecular forces in two alkaloid forms are one aspect of general chemistry that can be demonstrated. Weak London dispersion forces and dipole–dipole forces are usually the only interactions in alkaloid free bases. Much stronger electrostatic attractions in alkaloid salts result in their having higher melting points than their corresponding free base. Typical examples are nicotine (Table 2, ∆mp = 174 °C) and cocaine (Table 4, ∆mp = 107 °C). Other nice examples are (᎑)-ephedrine free base (mp 36 °C) vs (᎑)-ephedrine hydrochloride (mp 220 °C, ∆mp = 184 °C) and papaverine free base (mp 147 °C) vs papaverine hydrochloride (mp 225 °C, ∆mp = 78 °C). In morphine, sanguinarine, and allocryptopine, this feature is less pronounced. 5. Another useful concept is the application of the “like dissolves like” (similia similibus solvuntur) rule, which states that a solvent will dissolve a solute if the two have similar properties. As nonpolar species, alkaloid free bases are readily soluble in nonpolar solvents (morphine is an exception). The salts of alkaloids are ionic compounds, which dissolve well in polar solvents. It is understood that only polar alkaloid salts are distributed in a polar aqueous environment of blood plasma and other body fluids and therefore only these forms are used in medicine. 6. In some cases, the free base of an alkaloid is hard to obtain (magnoflorine). Under specific conditions, some alkaloids may decompose upon alkalization; for example, the hydrolysis of an ester bond in some pyrrolizidine or aconitum alkaloids or the more complex conversions in some other alkaloids (berberine). 7. The free bases of alkaloids may be considered as a kind of artifact because they do not occur in more or less acidic plant tissues. 8. The group of nonbasic alkaloids is limited. In view of the title of this article they could be portrayed as “one-face” alkaloids. Chemically, these belong to the amides—for example, colchicine (7) from meadow-saffron (Colchicum autumnale), piperine (8) and related alkaloids of black pepper (Piper nigrum) (40), and capsaicin (9) from red pepper (Capsicum annuum) (41); the lactams—oxosanguinarine (10); the substituted aromatic amines—dihydrosanguinarine (11); the zwitterionic species—narceine (12); and some other groups. They are virtually nonbasic and occur as such in plants. Unlike the basic alkaloids, they can be extracted from acidic or neutral solutions with nonpolar solvents.

CH3O NHCOCH3 CH3O CH3O O 7

OCH3

O O

N

O

8

O CH3O

N H

9

HO

O O N CH3

O O

O 10 O O N CH3

O O

11

CH3 +N

CH3

H O COO −

O CH3O

O 12

OCH3

OCH3

Acknowledgment I thank Professor Ji rˇí Slavík of Masaryk University Brno for valuable comments and suggestions. Literature Cited 1. 2. 3. 4.

Friedrich, Ch.; Domarus, C. Pharmazie 1998, 53, 67–73. Thorburn, A. D. J. Chem. Educ. 1925, 2, 886–899. Hosztafi, S. Pharmazie 1997, 52, 546–550. Pelletier, S. W. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1983; Vol. 1, pp 1–31. 5. Sangster, A. W. J. Chem. Educ. 1960, 37, 454–459.


997

Chemistry for Everyone 6. Maldoni, B. J. Chem. Educ. 1991, 68, 700–703. 7. Taylor, G. A. Organic Chemistry for Students of Biology and Medicine, 3rd ed.; Longman Scientific & Technical: New York, 1991; pp 332–337. 8. Hart, H.; Hart, D. J.; Craine, L. E. Organic Chemistry. A Short Course; Houghton-Mifflin: Boston, 1995; pp 400–402. 9. Streitwieser, A. Jr.; Heathcock, C. H. Introduction to Organic Chemistry, 3rd ed.; Macmillan: New York, 1985; pp 1136–1139. 10. Navari, R. M. J. Chem. Educ. 1974, 51, 748–750. 11. Hiller, J. M.; Mohan, M. S.; Brand, M. J. J. Chem. Educ. 1979, 56, 207–208. 12. Remberg, B.; Krenn, L.; Kopp, B.; Buchbauer, G.; Nikiforov, A. Pharmazie 1994, 49, 766–768. 13. Slavík, J.; Slavíková, L. Collect. Czech. Chem. Commun. 1996, 61, 1047–1052. 14. Slavík, J. Collect. Czech. Chem. Commun. 1980, 45, 2706–2709. 15. The Merck Index, 12th ed.; Budavari, S., Ed.; Merck & Co.: Whitehouse Station: New Jersey, 1996; p 1074. 16. Johnson, E. L. Phytochemistry 1996, 42, 35–38. 17. King, M. M. Pharm. Hist. 1987, 29, 85–89. 18. White, P. T. National Geographic Magazine 1989, 175 (No. 1), 3–47. 19. Warner, E. A. Ann. Intern. Med. 1993, 119, 226–235. 20. Hoyt, W. J. Chem. Educ. 1995, 72, 322. 21. Dana, J. F. NY Med. Phys. J. 1827, 6, 218–224. 22. Krane, B. D.; Fagbule, M. O.; Shamma, M.; Gözler, B. J. Nat. Prod. 1984, 47, 1–43. 23. Symposium Report, Sanguinaria Research; J. Can. Dent. Assoc. 1990, 56 (7), Supplement. 24. Dostál, J.; Bochoˇráková, H.; Táborská, E.; Slavík, J.; Potáˇcek, M.; Budˇe sˇínsk´y, M.; de Hoffmann, E. J. Nat. Prod. 1996, 59,

998

599–602. ˇ 25. Kováˇr, J.; Simek, K.; Koˇzouˇsková, E.; Klukanová, H.; Slavík, J. Collect. Czech. Chem. Commun. 1985, 50, 1312–1328. 26. Kováˇr, J.; Stejskal, J.; Paulová, H.; Slavík, J. Collect. Czech. Chem. Commun. 1986, 51, 2626–2634. 27. Guinaudeau, H.; Shamma, M. J. Nat. Prod. 1982, 45, 237–246. 28. Onda, M.; Takahashi, H. In The Alkaloids; Brossi, A., Ed.; Academic: New York, 1988; Vol. 34, pp 181–209. 29. Marek, J.; Dostál, J.; Slavík, J. Collect. Czech. Chem. Commun. 1998, 63, 416–424. 30. Hussain, S. F.; Gözler, B.; Fajardo, V.; Freyer, A. J.; Shamma, M. J. Nat. Prod. 1983, 46, 251–255. 31. Iwasa, K.; Sugiura, M.; Takao, N. J. Org. Chem. 1982, 47, 4275–4280. 32. Shamma, M. The Isoquinoline Alkaloids: Chemistry and Pharmacology; Academic: New York, 1972; pp 344–358. 33. Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic: Amsterdam, 1998; pp 293–304. 34. Slavík, J.; Slavíková, L.; Dolejˇs, L. Collect. Czech. Chem. Commun. 1984, 49, 1318–1324. 35. Guinaudeau, H.; Leboeuf, M.; Cavé, A. J. Nat. Prod. (Lloydia) 1975, 38, 275–338. 36. Slavík, J.; Bochoˇráková, J.; Slavíková, L. Collect. Czech. Chem. Commun. 1987, 52, 804–812. 37. Slavík, J.; Slavíková, L. Collect. Czech. Chem. Commun. 1995, 60, 1034–1041. 38. Nakano, T. Pharm. Bull. (Tokyo) 1954, 2, 326–328. 39. Nakano, T. Pharm. Bull. (Tokyo) 1954, 2, 329–334. 40. Epstein, W. W.; Netz, D. F.; Seidel, J. L. J. Chem. Educ. 1993, 70, 598–599. 41. Kimbrough, D. R. J. Chem. Educ. 1997, 74, 861–862.


Two Faces of Alkaloids

Recommend Documents