Tropane derivative

The basic principle of the synthesis involving 143 has been applied for the preparation of many tropane derivatives [e.g., 6-hydroxytropinone (144) and ( + )-cocaine (98)] (69-71). During recent years, especially in China, considerable attention has been paid to practical applications and modifications of this long known method (70-77), illustrated here by the scheme leading to anisodamine (63) (Scheme 4). 

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. 

A series of DAT selective 3-phenyltropanes have been reported to have potential for treatment of cocaine abuse [33,36,37]. RTI-336,15 (reuptake IC50 — 4.1 nM) was the most potent among these tropane derivatives in locomotor activity and drug discrimination it was less stimulatory than cocaine, and had the slowest onset and longest duration of action. It also reduced self-administration of cocaine in rats and rhesus monkeys. Interestingly, in rhesus monkeys trained to self-administer cocaine, when coadministrated with either citalopram or sertraline, 15 produced significantly more robust reductions in cocaine self-administration compared with 15 alone [38]. 

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]. 

Koh, J. S. Ellman, J. A. Palladium-Mediated Three-Component Coupling Strategy for the Solid-Phase Synthesis of Tropane Derivatives, J. Org. Chem. 1996, 61,4494-4495. 

Tropane derivatives were found not only to decrease the effect of opiate analgesics but also to prevent the development of the analgesic action of opiates.68... 

Tropane derivatives, (III) and (IV), previously prepared by the authors (3) have demonstrated high affinity for cocaine receptors in the brain, particularly dopamine and serotonin transporter sites. 

Nonamine tropane derivatives, (III), prepared by co-author Madras (3) were selective as serotonin transporters and used in the treatment of neuropsychiatric disorders. Other nonamine tropane derivatives, (IV), prepared by the author (4) having a high DAT-to-SERT selectivity were used in treating cocaine addiction. 

Tropane derivatives, (V), prepared by Kozikowski (5) were highly selective as dopamine transporters as well as for selectively inhibiting serotonin reuptake and/or norepinephrine and used in the treatment of psychiatric and neurodegenerative disorders. 

The on-line coupling of CE with electrospray ionization mass spectrometry (CE-ESI-MS) allows high separation efficiency together with high sensitivity and selectivity as well as molecular structural information. A CE-UV-ESI-MS method was developed for the analysis of hoscyamine, scopolamine, and other tropane derivatives [131]. The differentiation of hyoscyamine from littorine, commonly encountered in plant material, was demonstrated using in-source collision-induced dissociation. The developed method was applied to the analysis of these alkaloids in Belladonna leaf extract and in Datura Candida x D. awreahairy root extract. Recently, CE coupled with electrochemiluminescence detection has been used for the determination of atropine and scopolamine in Flos daturae [132]. 

Goldmann, A, Milat, M L, Ducrot, P H, Lallemand, J Y, Maille, M, Lepingle, A, Charpin, I, Tepfer, D, Tropane derivatives from Calystegia sepium. Phytochemistry, 29, 2125-2127, 1990. 

Labelled tropanes, particularly ring radiolabelled cocaines, have been described. A technical synthesis of some tropane derivatives from agricultural waste via 2,5-dimethoxyfuran, followed by hydrogenation to 2,5-dimethoxytetrahydro-furan, has been elaborated. 

Formation of piperidones by cyclization from two moles of aldehyde and one mole each of aceto-nedicarboxylic ester and of ammonia or a primary amine. Used widely in synthesis of tropane derivatives. 

Several examples have appeared in the literature in which this linker has been employed in combinatorial chemistry strategies. Thus, it has been used in a Pd-mediated three-component coupling strategy for the solid-phase synthesis of tropane derivatives [46], in the solid-phase synthesis of aspartic acid protease inhibitors [47], in the attachment of cholic acid as a template for a combinatorial approach [48] and, more recently, in the solid-phase synthesis of pyrrolidines via 2-aza allyl anion cycloadditions with alkenes [49]. 

An interesting new route to tropane derivatives, particularly to anhydroecgonine, has been outlined (122). Methylamine reacts with cycloheptatrienecarboxylic acid giving rise to ( )-anhydroecgonine, that is, trop-2-enecarboxylic acid. This reaction may be looked upon as a reversal of the elimination reaction that takes place with tropinone methiodide and its hydroxy and bromo derivatives (121). 

The Wittig reaction has been used to construct the side-chain in a synthesis of (-)-sirenin (208), a water mold sperm-attacking hormone.ii The intermediate (206) was generated, without competing formation of the structural isomer (207), by reaction of the ylide (205) with (204) under salt-free conditions in DME. Standard Wittig methods have been used to construct the side-chain in an enantioselective synthesis of (+)-(7 , 9Z)-methyl trisporate (209) and its (9E)-isomer.l 12 The reaction of triphenyl-(vinylimino)phosphorane derivatives (210) with tropones provides a convenient synthesis of 1-aza-azulenes (211) and (212) in either one or two steps (Scheme 28).H The mechanism of the one-step reaction was investigated using deuterium-labelled tropane derivatives. 

A new route to tropane derivatives involving reaction of aao a -tetrabromoacetone with N-methoxycarbonylpyrrole and di-ironenneacarbonyl was described in Volume 5. 6,7-Dehydronortropinone derivatives (13) can also be obtained in good yields from aa -dibromoketones and pyrroles (or N-methylpyrroles) with copper and sodium iodide. ... 

Families Genera containing tropane derivatives Nb of species containing tropane alkaloids Approx, nb. of alkaloids described... 

Recently, the development of " Tc-labcled tropane derivatives used as dopamine transporter imaging agents has been reported. The dopamine transporter is a protein complex located prcsynaptically at dopaminergic nerve terminals [247]. It is depleted in Parkinson s disease, and the extent of depletion correlates with the loss of dopamine [248], Among a series of tropane derivatives [249,250] labeled with " Tc, two compounds deserve more attention. 

An impressively efficient new route to the synthesis of tropane derivatives has been reported during the year. - This involves as key stage the promotion of C—C bond formation by means of transition-metal carbonyls. The known cycloaddition of oxyallyl derivatives of type (10) with 1,3-dienes or furan to give products of structure (11a) or (11b) has not previously been applied to tropane synthesis owing to the fact that iV-methylpyrrole gives preferentially products, e.g. (12), arising by electrophilic substitution. This difficulty has now been overcome... 

In an introduction to the n.m.r. spectroscopy of alkaloids, Wenkert et have discussed and interpreted the spectra of a number of tropane derivatives and simple alkaloids. 

A number of alkaloids occur in small amounts associated with Z-hyos-cyamine, Z-scopolamine and Z-cocaine which find no place in the previoiis narrative and, although some of them are not tropane derivatives, they will be briefly mentioned in alphabetical order. 

Discuss "tropane derivatives as potent surface anaesthetie agents. Give examples and synthesis of any one compound selected by you. 

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