Tropane ring

The natural products 112-115 contain a y-pyrano group attached to the 3,4 position of the tropane ring. 

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. 

Robins, R. J., Parr, A. J. and Walton, N. J. 1991. Studies on the biosynthesis of tropane alkaloids in Datura stramonium L. transformed root cultures. 2. on the relative contributions of L-arginine and L-ornithine to the formation of the tropane ring. Planta, 183 196-201. 

The magnetic non-equivalence of the 13C nuclei of the tropane ring in protonated scopolamine [260] and in protonated atropine [261] indicates the tropic acid group to be near C(6) and C(7) in [260] but to be in a position affecting all the carbon nuclei on one side of the tropane ring in [261], (170) The absorption of the equatorial and axial A-methyl 13C nuclei in [261] and [260] respectively may be compared to the corresponding absorptions in methylatropine [262],... 

TA belong to a class of small molecules characterized by a derivatized tropane ring skeleton (8-methyl-8-azabicyclo[3.2.1]octane). Hydroxylated tropane (tropine) is esterified with diverse organic acids often representing structural analogues of, e.g. tropic, benzoic or mandelic acid (Fig. 1). Manifold variations are found either in natural sources or as (semi-) synthetic active pharmaceutical ingredients (API) with individual optimized properties. 

The 80 MHz H n.m.r spectrum of 7V-(cylcopropylmethyl)scopolaminium bromide in D20 has been analysed and the conclusions have been compared with those from X-ray crystal-structure studies.19 They were consistent with the equatorial position of the cyclopropylmethyl group, as shown in (17). All protons in symmetrical positions (1 and 5, 6 and 7, 2 and 4) of the tropane ring were found to be magnetically non-equivalent, as in scopolamine hydrobromide and in atropine. This was attributed to the different shielding effects that arise from the aromatic substituent which is attached to the asymmetric centre of the tropic acid moiety. The carboxyl group of the tropate residue was found to be opposite to H-3. 

The first committed step in TA and nicotine biosynthesis is catalyzed by putrescine JV-methyltransferase (PMT) (Fig.7.4).82 A PMT cDNA isolated from tobacco showed extensive homology to spermidine synthase from mammalian and bacterial sources.83 A-Methylputrescine is oxidatively deaminated to 4-aminobutanal, which undergoes spontaneous cyclization to form the reactive A-methyl-A1-pyrrolinium cation. Although the enzymes involved are unknown, the A-methyl-A1-pyrrolinium cation is thought to condense either with acetoacetic acid to yield hygrine as a precursor to the tropane ring, or with nicotinic acid to form nicotine. 

In fact, the enantiospecific syntheses of the two potent anti-Alzheimer s agents like (+)-ferruginine (Aggarwal et al. 2004), a tropane ring system, and two enantiospecific syntheses of the anatoxin-a, were submitted essentially simultaneously at the beginning of 2004 (Mori et al. 2004 Brermeman and... 

Duran-Patron R, O Hagan D, Hamilton JTG, Wong CW. Biosynthetic studies on the tropane ring system of the tropane alakloids from Datura stramonium. Phytochemistry 2000 53 777-784. 

Alkaloids that contain pyrrolidine and pyrrolizidine ring systems are derived from the nonprotein amino acid, L-ornithine. Cocaine (Nl) and (—)-hyoscyamine, the two important pyrrolidine alkaloids that contain a tropane ring system, have been found to occur in coca (Erythroxylon coca, Erythroxylaceae) leaves and the whole plant of the deadly nightshade (Atropa belladonna, Solanaceae). The hepatotoxic alkaloid senecionine (N2) contains a bicyclic pyrrolizidine skeleton derived from two molecules of L-ornithine. 

A substitution in the tropane ring, e.g., the introduction of oxygen functions onto C-6 (and C-7), as with the 6-methoxytropinone XXIX, considerably changes the relative abundance of the species. Instead of a-cleavage (C-l/C-2), the bond between the two hetero atoms will be... 

Both alkaloids have (+) and (-) forms but only the (-) hyoscyamine and (-) scopolamine are active. The biosynthetic pathway of tropane alkaloids, Fig. (1) is not totally understood, especially at the enzymatic level. Edward Leete has pioneered the biosynthetic studies of tropane alkaloid since 1950"s using whole plants and isotope labels [85-86]. The tropane alkaloid hyoscyamine is bioconverted by the enzyme H6H (hyoscyamine 6p-hydroxylase, EC 1.14.11.11) to scopolamine via 6p-hydroxyhyoscyamine. Hyoscyamine is the ester of tropine and (S)-tropic acid. The (S)-tropic acid moiety derives from the amino acid L-phenylalanine, while the bicyclic tropane ring derives from L-omithine primarily or L-arginine via tropinone. Tropinone is stereospecifically reduced to form either, tropine which is incorporated into hyoscyamine, or on the other hand into pseudotropine which proceeds to calystegines, a group of nortropane derivates that were first found in the Convolvulaceae family [87]. 

However, as demonstrated by Hardegger and Ott (272), some tropane ring systems can assume a conformation in which the piperidine ring is a boat. Therefore, the possibility of ring inversion in (226) and (227) cannot be precluded, and as with the piperidine and thiane rings, conformational integrity is questionable. 

The Ester Linkage at C(3). In cocaine, the 3a epimer "allococaine" (38)has considerably reduced activity compared to that of cocaine itself (177). This structural change, however, causes the tropane ring to favor the... 

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... 

In a different series, the effect of replacing the piperidine by a tropane ring was explored [54], This new class of 4-diarylaminotropanes exhibited high affinity for 8 receptors with Kis in the nanomolar range. Affinity was measured by inhibition of [3H]-DPDPE and [3H]-DAMGO to 8 opioid and p opioid receptors from rat brain membranes, respectively. The endo isomers were in general more potent and selective than their nonbridged 4-diarylaminopiperidine counterparts and also more selective that the exo isomers. The SAR of the endo isomers parallels other series [41, 45, 51, 52],... 

The subsequent reactions leading from 7V-methylpyrrolinium to tropinone remain doubtful since no enzymes have yet been demonstrated. For a long time, it was believed that the formation of the tropane ring from the jV-methyl-A -pyrrolinium cation occurred by condensation with an acetoacetyl unit, with the release of CO2, to form hygrine. This was... 

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