The Alkaloid

Although far less numerous than the terpenoid/isoprenoid or polyketide NPs, the alkaloids (with an estimated 20,000 different structures) have a special place in NP research because a few are of great value to humans—for example, morphine, theobromine, caffeine, vincristine, quinine, codeine, cocaine, nicotine and strychnine. These often complex chemicals are found in about 20% of vascular plants and a smaller number of fungi, marine invertebrates and a few bacteria.  

Ranunculaceae (herbaceous) Berberidaceae Menispermaceae Nympheraceae (herbaceous) Aristrochiales Aristrochiaceae Papaverales 

Very often the definition of alkaloids is associated with their strong biological activities. Here again, however, we know a great many examples of alkaloids that do not show any recognizable physiological activities. 

On the basis of the above considerations, we define the alkaloids here as a group of low-molecular weight nitrogeneous compounds that are apparently different from simple amines, amides, small peptides, and other nitrogeneous metabolites directly related to primary metabolism. 

The plant parts in which the alkaloids are synthesized is an interesting subject. Very often alkaloids are abundant in the roots, stem bark, leaves, and seeds. Generally the alkaloid content is low in the woody parts of the plants. There is a large difference in alkaloid structures depending on the part of the plant where they are found. The important plant families that include alkaloid-producing woody plants are shown in Table 5.2.1 (5.2.2.6.7). The role of alkaloids in the living plants remains unclear, but this is not a problem specific to alkaloids. Alkaloids should probably be treated as members of a wide variety of secondary products such as phenolics, terpenoids, various kinds of glycosides, and others. 

The above criteria will be adopted in this chapter to classify alkaloids. It is important to note that these classifications are concerned only with the main skeletal part or the part of interest in the molecules. Almost all alkaloids have some sort of additional building blocks, C-1 units of various origins being the smallest members. 

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In the commercial extraction of alkaloids from the drugs in which they exist, the powdered drug, or an alcoholic extract of it, is treated with an alkali such as ammonia or lime to liberate the alkaloid and the alkaloid is then extracted by means of an organic solvent. The crude material thus obtained is purified and finally crystallized either as the base itself or as its water-soluble salts. 

Colourless liquid with a characteristic ammo-niacal smell m.p. 9 C, b.p. 106°C. Miscible with water. It is present in pepper as the alkaloid piperine from which it can be obtained by healing with alkali. It can also be prepared by the reduction of pyridine, either electrolytically or by other means. Piperidine is a strong base, behaving like the aliphatic amines. 

CgHjoO,. A compound of largely historical interest for its role in establishing the structure of many natural products. Methylation of vanillin gives veratraldehyde which may be oxidized to veratric acid. Veratric acid was identified as a degradation product of the alkaloid papaverine. 

The alkaloid dubamine contains a single bond between the two heteroarene units. This lond was formed in 79% yield by the generally valuable palladium-catalyzed eoupling of an ryltrimethylstannane with an aryl triflate (see section 1.6). The requisite stannane was pre-ared from l,3-benzodioxol-5-yl triflate and hexamethyldistannane with the same palladium atalyst, the triflate ester was obtained from 2(1 f/)-quinolinone and trifluoromethanesulfonic jihydride (A.M. Echavarren, 1987). An earlier attempt to perform this aryl coupling by dassical means gave a yield of only 1 %. 

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

Another o-aminobenzyl anion equivalent is generated by treatment of A-trimethylsilyl-o-toluidinc with 2.2 eq. of n-butyllithium. Acylation of this intermediate with esters gives indoles[2]. This route, for example, was used to prepare 6.2D, a precursor of the alkaloid cinchonamine. 

The disease takes two different forms depending apparently on whether ergotoxia, the alkaloid ia ergot, attacks predomiaantiy the aervous or the circulatory system. The former coaditioa is characterized by severe coavulsive seizures the latter produces an iatense burning and itching of the skin called St. Anthony s Fire. 

Until separation techniques such as chromatography (28,29) and counter-current extraction had advanced sufficientiy to be of widespread use, the principal alkaloids were isolated from plant extracts and the minor constituents were either discarded or remained uninvestigated. With the advent of, first, column, then preparative thin layer, and now high pressure Hquid chromatography, even very low concentrations of materials of physiological significance can be obtained in commercial quantities. The alkaloid leurocristine (vincristine, 22, R = CHO), one of the more than 90 alkaloids found in Catharanthus roseus G. Don, from which it is isolated and then used in chemotherapy, occurs in concentrations of about 2 mg/100 kg of plant material. 

Early investigators grouped alkaloids according to the plant families in which they are found, the stmctural types based on their carbon framework, or their principal heterocycHc nuclei. However, as it became clear that the alkaloids, as secondary metaboUtes (30—32), were derived from compounds of primary metabohsm (eg, amino acids or carbohydrates), biogenetic hypotheses evolved to link the more elaborate skeletons of alkaloids with their simpler proposed pregenitors (33). These hypotheses continue to serve as valuable organizational tools (7,34,35). 

The pomegranate alkaloids, pelletierine (46) and pseudopelletierine (48) as well as minor accompanying bases, have a long history as salts of tannic acid as an anthelmintic mixture for intestinal pinworms (see Antiparasitic AGENTS, ANTHELMINTICS). The alkaloids themselves (as the taimates) are obtained from pomegranate tree (Punkagranatum L.) root bark and are among the few bases named after an individual (P. J. Pelletier) rather than a plant. 

Both of the alkaloids anhalamine (62) from l ophophora williamsii and lophocerine (63) from l ophocereus schotti were isolated (after the properties of purified mescaline had been noted) in the search for materials of similar behavior. Interestingly, lophocerine, isolated as its methyl ether, after dia2omethane treatment of the alkaU-soluble fraction of total plant extract, is racemic. It is not known if the alkaloid in the plant is also racemic or if the isolation procedure causes racemization. 

R = UH3), and morphine (2, R = H), a different derivative of 77 (R = H), ie, (+)-/V-norprotosinomenine (86), serves as the pregenitor of erythraline (87), one of the bases found ia E thnna cristagalli (60). The alkaloids fouad ia all plant parts of E thnna have been iatensively studied because many of them produce smooth muscle paralysis, much like tubocurariae (9). 

Destmction of the aluminum complex with ammonia then permits hydrocarbon extraction of the alkaloid. The alkaloid is subsequently both isolated and used as its tartrate salt. This nonnarcotic dmg, for which tolerance may develop, is frequently used orally with caffeine (16) for treatment of migraine it acts to constrict cerebral blood vessels, thus reducing blood flow to the brain. 

Ergonovine (100, R = NHCH(CH3)CH2 0H) was found to yield lysergic acid (100, R = OH) and (+)-2-aminopropanol on alkaline hydrolysis during the early analysis of its stmcture (66) and these two components can be recombined to regenerate the alkaloid. Salts of ergonovine with, for example, malic acid are apparently the dmgs of choice in the control and treatment of postpartum hemorrhage. 

Tabersonine (108), clearly a reduced and simplified version of the second-half of the alkaloids 22, was originally isolated inoxsi Pimsonia tabemaemontane V. and is considered to be a simplified parent of a rather more elaborate subgroup of indole alkaloids. 

In addition to the alkaloids such as cyclobuxiae-D (129) and solanidine (130) where the stmctural similarities to steroids are clear (although it must be remembered that detailed evidence actually linkiag the compounds is lacking) there are the less obvious (but nonetheless also clearly related) Veratrum alkaloids. These compounds, of which protoverattine A [143-57-7] (131), obtained from the rhizome of Veratrum album L. (LiUaceae), is a... 

Two other commonly found sources of caffeine (16) are kola Cold) from the seeds of, for example. Cola nitida (Vent.) Schott and Engl., which contains 1—4% of the alkaloid, but Httie theophylline or theobromine, and cocoa (from the seeds of Theobroma cacao L.), which generally contains about 3% theobromine and significantiy less caffeine. 

J. S. Glasby, Encyclopedia of the Alkaloids, Vols. 1 and 2, Plenum Press, New York, 1975. 

D. R. Dalton, The Alkaloids—A Biogenetic Approach, Marcel Dekket, New York, 1979. 

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