Tropane, structure

Despite the presence of polar moieties including, e.g. tertiary amine, ester-, hydroxyl- and epoxy-groups, non-protonated uncharged TTA are quite lipophilic. Lipophilicity is mainly caused by the heterocyclic tropane structure and aromatic (substituted) phenyl rings (Fig. 1). 

Requirement for the Intact Tropane Ring System. We have seen earlier that there is no absolute requirement for the basic nitrogen in the tropane structure, and that even a polar oxygen isostere replacement is not needed for cocaine congeners to possess potent... 

Although cocaine occurs naturally in plant material, a number of related, naturally occurring alkaloids based upon the tropane structure may be isolated from the plant material and subsequently converted into cocaine. These include ecgonine, ecgonine methyl ester and benzoyl ecgonine There are two principle routes by which extraction can be achieved prior to cocaine synthesis. 

These are complex molecules containing pyrrolidine and piperidine ring structures, derived from the precursors ornithine and phenylalanine. Isoleucine and acetate also play a role in the biosynthesis of tropane structures. Alkaloids used in medicine are restricted largely... 

Heckrodt TJ, Mulzer J (2005) Marine Natural Products from Pseudopterogorgia Elisabe-thae Structures, Biosynthesis, Pharmacology and Total Synthesis. 244 1-41 Heinmaa I, see Samoson A (2005) 246 15-31 Helm L,see Toth E (2002) 221 61-101 Helmboldt H, see Hiersemann M (2005) 243 73-136 Hemscheidt T (2000) Tropane and Related Alkaloids. 209 175-206... 

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. 

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. 

The H-NMR technique has proved to be a valuable tool for structural determinations of tropane alkaloids and their synthetic analogs, and H-NMR data are now available for most of the basic tropane alkaloid structures (42,59,142-146). Recent high-frequency H-NMR data of some basic tropane alkaloids are summarized in Table IV. 

These data, together with extensive evidence for divergent structure activity relationships between the two tropane-based classes of dopamine uptake inhibitors (the... 

Tropane derivative tesofensine, also known as NS2330 (28), is reported to be a triple reuptake inhibitor. Its efficacy as a monotherapy in early Parkinson s disease was evaluated in a clinical trial however, it did not provide significantly greater benefits than placebo [90]. NS2330 is also reported to be in clinical trials for obesity [68]. NS2359 (GSK 372475, structure not disclosed), also a triple reuptake inhibitor, is reportedly in clinical development for depression and ADHD, as well as addictive disorders [68]. 

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 bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

Tropane alkaloids have a tropane (C4N skeleton -f) nucleus. Structurally, these alkaloids synthesize as postcursors of pyrrolines (Figure 57). a, /3,

tropane alkaloids (e.g., atropine, hyoscyamine, cocaine, tropinone, tropine, littorine and cuscohy-grine) have a strong biological activity, especially as neurotransmitters. 

Numerous UCNMR investigations on alkaloids have been reported in the literature [598, 599]. In Table 5.13 the 13C chemical shifts and structures of representative alkaloids of different types are collected Pyrrolidine, piperidine and pyridine [600-602], tropane [600, 603-605], izidine [606-612], indole [600, 603, 613-633], isoquinoline [599, 630, 634-647], quinolinic [648-656], imidazole [657], yuzurimine alkaloids [658], alkaloids with exocyclic nitrogen [659, 660], diterpenoid [661-663], steroid [664-666] and peptide alkaloids [667-671], The complete signal assignment for the alkaloids given in Table 5.13 was achieved using the correlations between 13C NMR spectral parameters and structural properties and the 13C chemical shift values of model compounds described in Chapters 3 and 4 of this monograph. 

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