The Tropane Alkaloids

In 1958 Romeike reported a successful cross between Datura ferox and Datura stramonium, D, ferox is a small, virus-susceptible plant that produces only minute amounts of alkaloids, but its alkaloid is the valuable drug hyoscine. The other parent, a vigorous and non-virus-susceptible plant containing at least ten times as much alkaloid, produces hyoscy-amine, which could not readily be converted to hyoscine chemically. The difference is in the oxidation level, hyoscine being the epoxide of hyoscy-amine. There are at least three reactions necessary to perform the oxidation. The Fi plants inherited the high alkaloid level of Datura stramonium and the oxidation ability of Datura ferox. The yield of alkaloids per plant 

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The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

Aziridinocyclopropanes 163 derived from 2-phenylsulfonyl-l,3-dienes undergo BF3-induced rearrangement to bicyclic amines 165, which feature the skeleton of the tropane alkaloids. The reaction proceeds via cyclopropyl carbinyl cation 164, an intermediate also invoked in the analogous epoxide rearrangements. Trapping by fluoride ion is a competing pathway <96TL3371>. 

The tropane alkaloids have been reviewed on five earlier occasions in this series (1-5). Since the last review in 1977 the number of known structures has grown markedly, to a present count of 139. In this chapter, the literature is covered up to the end of 1986. 

The tropane alkaloids are a well-recognized group of structurally related natural products. Long before elucidation of the structures, the mydriatic and anesthetic action of several compounds was exploited (6). The very extensive literature covering the pharmacological properties of the tropane alkaloids will be considered only briefly in this chapter. Readers with a deeper interest in the subject are referred to other publications (7-14) and to the references given in Section VII. 

The tropane alkaloids contain as a common structural element the azabicyclo [3.2.1] octane system, and the systematic name of tropane is 8-methyl-8-azabicyclo [3.2.1] octane (Fig. 1). Contradictory results concerning the C-6 and/or C-7 substitution of several C-3,C-6- and C-3,C-7-disubstituted and C-3,C-6,C-7-trisubstituted tropane alkaloids have been presented in the literature. In many cases both optical antipodes of these tropane alkaloids are known, either separately or as a racemic mixture. 

The tropane alkaloids occur mainly in the plant family Solanaceae but are also found in the families Convolvufaceae, Erythroxylaceae, Proteaceae, and Rhizophoraceae. In addition, the presence of tropane alkaloids has occasionally been indicated in the families Euphorbiaceae and Cruciferae (cf. Tables II and III). For a detailed account of the distribution of tropane alkaloids among species, interested readers should consult Refs. (15-23) and references therein. 

Noyori and co-workers have developed a new and useful general synthesis of the tropane alkaloids (89-91). The Fe2(CO)9-aided reaction of tetra-bromoacetone and Af-carbomethoxypyrrole (165) (3 3 1 ratio) in benzene at... 

Since most of the fundamental chemical transformations of the tropane alkaloids were discovered during the pioneering elucidation of the structures, the most important reactions have been described in earlier chapters in this treatise (7-5). Two developments will be discussed here the recent progress in the demethylation of tropane derivatives and the use of tropinone enamines as synthetic intermediates. 

Only H NMR, 13C NMR, and mass spectrometry, the three most important spectroscopic methods for the tropane alkaloids, will be treated here. 

The relationship between cuscohygrine and the tropane alkaloids, their cooccurrence, and their important pharmacological properties justify the numerous citations of cuscohygrine in the literature. The presence of cuscohygrine has been noted in the following families, genera, and species ... 

The pivotal role of hygrine in the biosynthesis of cuscohygrine and of the tropane alkaloids has justified numerous investigations. The following scheme represents the now generally admitted pattern of formation of these bases. Ornithine (119) is first converted to putrescine or V-methylputrescine (120)... 

S. Wada, T. Yoshimitsu, N. Koga, H. Yamada, K. Oguri, H. Yoshimura, Metabohsm in vivo of the Tropane Alkaloid, Scopolamine, in Several Mammaban Species , Xenobiotica 1991, 21, 1289-1300. 

The cholinergic hallucinogens all have common chemical constituents that are responsible for their pharmacological effects (Robbers et al. 1996). These are the tropane alkaloids hyoscyamine, scopolamine (or hyoscine), and atropine (figure 9.16). It is scopolamine, and not atropine or hyoscyamine, which primarily produces the central and hallucinogenic effects because it is the only one that passes the blood-brain barrier sufficiently. However, all three have peripheral effects. Datura stramonium contains 0.1-0.65% tropane alkaloids, which is principally... 

The tropane alkaloids (—)-hyoscyamine and (—)-hyoscine are found in the toxic plants deadly nightshade (Atropa belladonna) and thornapple (Datura stramonium) and are widely used in medicine. Hyoscyamine, usually in the form of its racemate atropine, is used to dilate the pupil of the eye, and hyoscine is employed to control motion sickness. Both alkaloids are esters of (—)-tropic acid. 

The Mannich reaction was used for the first synthesis of tropine, the parent alcohol of the tropane alkaloids. One of the natural tropane alkaloids used medicinally is hyoscyamine, sometimes in its racemic form atropine. Hyoscyamine is an anticholinergic, competing with acetylcholine for the muscarinic site of the parasympathetic nervous system, and thus prevendng the passage of nerve impulses. 

Nicotine affects the nervous system, interacting with the nicotinic acetylcholine receptors, and the tight binding is partially accounted for by the structural similarity between acetylcholine and nicotine. Curare-like antagonists also block nicotinic acetylcholine receptors (see Box 6.7). There are other acetylcholine receptors, termed muscarinic, that are triggered by the alkaloid muscarine. The tropane alkaloid hyoscyamine (see Box 10.9) binds to muscarinic acetylcholine receptors. 

The tropane alkaloids, especially hyoscine (scopolamine) (18), have been used to treat PD since they increase DA activity by antagonizing cholinergic activity at the muscarinic receptors in the striatum. The naturally occurring alkaloids, foimd in various genera of the Solanaceae, are not... 

Synaptic dopamine transporters are inhibited by various psychotropic alkaloids including the tropane alkaloid cocaine [189, 190], the indole alkaloid ibogaine [191] and by amphetamine (methylphenethylamine) and related compounds [192, 193]. 

Synaptic serotonin (5-hydroxytryptamine) transporters are inhibited by amphetamines, the tropane alkaloids cocaine and ecgonine [194] and by the indole alkaloid ibogaine (12-methoxyibogamine) and its demethylation product ibogamine [191, 195]. Hyperforin is a major antidepressant constituent of St. John s Wort (Hypericum perforatum) and inhibits serotonin uptake by elevating cytosolic Na+ [196]. The additional... 

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