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Fig. 3.15 Schizanthines, unique dimeric tropane alkaloids of the genus Schizanthus

(Spacer linking tropanol monomers: itaconic acid) Schizanthine D: mesaconic acid linked isomer of schizanthine E

Fig. 3.15 Schizanthines, unique dimeric tropane alkaloids of the genus Schizanthus alkaloids could be separated already some 50 years ago from hyoscyamine/sco-polamine by steam distillation since they turned out to be volatile in contrast to the tropoyl esters (Rosenblum 1954).

There are only a few species containing T1-type metabolites without any other tropane type, e.g., Nierembergia linariaefolia and Withania somnifera; in both species only the common 3a-tigloyloxytropane has been detected. Though the occurrence of this metabolite in Solanum betaceum (syn.: Cyphomandra betacea, tree tomato) has been tentatively reported [TLC - comparison with an authentic sample, but ". ... insufficient material prevented complete identification." (Evans et al. 1972d)], it is still equivocal since it has never been confirmed neither by these authors nor by others. A unique alkaloid, 3a-nonyloxytropane has been discovered in the leaves of Duboisia myoporoides besides butropine, valtropine, and 3a-tropoyl congeners (Shukla and Thakur 1992). Acylated 3a,60- and/or 3a,7b-Hydroxytropanes (T2/T3)

Acylated 3a,6b-Dihydroxytropanes (T2). As already mentioned the occurrence of tropane alkaloids covering the literature up to June 1992 is based mainly on the review of Lounasmaa and Tamminen (1993). These authors have used the generally accepted uniform numbering system of the tropane skeleton with the consequence that ". . most disubstituted tropane alkaloids designated as C-3,C-6 disubstituted in the literature become C-3,C-7 disubstituted". This has also been done ". ... where the choice between the C-3,C-6 and C-3,C-7 notation in the literature has been arbitrary." However, if ". . the determination of absolute configuration has a solid basis, and where the structure is correctly presented by the C-3,C-6 notation also in the present numbering system", i.e., in the generally accepted one, "has the original C-3,C-6 notation been retained." With regard to the adjustment of Lounasmaa and Tamminen, only two monoesters of 3a,6P-dihydroxytropane are known. (i) An aliphatic ester, 3 a-isovaleryloxy-66-hydroxy tropane (valeroidine) discovered in Duboisia myopo-roides has been found also in three Cyphanthera spp. and Anthocercis ilicifolia (Australian members of the Nicotinoideae) as well as in Brugmansia sanguinea and B. candida x aurea (members of the S-American Datureae clade, Solanoideae). (ii) The second well supported monoester of the 3,6-dihydroxytropane-type, anisodamine (66-hydroxyhyoscyamine) is described below (T5/T6), because it has to be considered in a special, biosynthetic connection. Therefore anisodamine has not been taken into account as a T2-type metabolite in Table 3.1.

Recent extensive studies by Berkov and his group on GC/MS analyses of Datura stramonium, D. ceratocaula, and D. inoxia (Philipov and Berkov 2002; Berkov et al. 2003; Berkov 2003; Berkov and Zayed 2004) apparently still have ignored the standards of Lounasmaa and Tamminen concerning the problematic of the stereochemistry at C-6 and C-7. Thus, all 6-substituted tropanes mentioned in these four reports are equivocal since the notation is based on GC/MS data only. Doerk-Schmitz et al. (1994) had already shown the necessary distance to their own C3,C6 notations in a comparable study (Hyoscyamus albus) with the following comment: "Whether it is (3^,6K)-6P-hydroxy-3a-acyloxytropane (= 7b, if numbered clockwise proceeding from the 1R bridge carbon of 3a-hydroxytropane) or (3S,6S) (= 6b) cannot be deduced from the GC/MS data, since both compounds are enanti-omers and do not separate on an optically inactive GC-column" (bold face added by the author).

3a,6P-Dihydroxytropane itself has been detected in Schizanthus hookeri and S. littoralis in contrast to the corresponding esters. Unfortunately, there is again a confusion in the literature since Schizanthus-specific esters with a 3a,6P notation have been reported originally. This has not been accepted by Lounasmaa and Tamminen in contrast to 3a,6P-dihydroxytropane itself. Thus, these esters were assigned to the 3a,7P notation (Fig. 3.15).

Esters of 3a,7b-Dihydroxytropane (T3). This type is characterized by the same saturated and unsaturated aliphatic acyl moieties like the esters of type T1; the only additional acyl moiety is formed by angelic acid, the trans-isomer of tiglic acid (structures of both acyl residues: Fig. 3.15). In contrast to T1 four principal variations are given, two for mono- and diesters each. These variations include (I) 3a-acyloxy-7P-hydroxytropanes, (II) 3a-hydroxy-7P-acyloxytropanes, (IIIa) 3a, 7P-diacyloxy congeners with identical acyl moieties, e.g., 3a,7P-ditigloyloxytropane, (IIIb) 3a,7P-diacyloxy congeners with different acyl moieties, e.g., 3a-tigloyloxy-7P-propionyloxytropane. Esters of all these types (I-IIIb) containing at least one tigloyl residue show a frequent occurrence.

Though occasionally also present in some other taxa (Anisodus, Atropa, Hyoscyamus, Physochlaina, Mandragora), such T3-type tropanes are frequent in the species of the Symonanthus / Anthocercis clades (Nicotianoideae) and the Datureae clade (Solanoideae). In certain species many individual metabolites of this type have been detected due to the variations mentioned above, in the lead Brugmansia candida x aurea (16 metabolites) and Datura inoxia (15). However, usually the number of such congeners ranges between two and five. In addition, those results with certain Datura spp. reported by the group of Berkov and mentioned already above (T2) should be placed here following Lounasmaa and Tamminen.

On the other hand, it should be appended to the adjustments of these Finnish authors their own saving clause: "The strict application of the system adopted here is certainly in several cases a simplification of the real situation and should be regarded as such." The frequently unsatisfactory situation with regard to this problem has given reason to the author of the present monograph to combine T2- and T3-type alkaloids in one column of Table 3.1.

A unique compound, physochlaine [3a-(4'-methoxyphenylacetoxy)-7P-hydroxytropane; Fig. 3.16] has been discovered in Physochlaina alaica. Another specific situation is given by the genus Schizanthus (Schizanthoideae). Its species also contain the variations (I) and (II), but not (IIIa) and (IIIb). Instead they are characterized by schizanthines, unique 3a,7P-diacyloxytropanes (schizanthines A, F-I, K-M) and their corresponding dimeric congeners, the monomers linked by dibasic unsaturated acids (mesaconic acid, itaconic acid; schizanthines B-E, Y, Z). These dimeric compounds (Fig. 3.15) are listed as type T7-D (see below). Schizanthus pinnatus, reported to contain 11 alkaloids of type T3, has shown a specific profile: Besides the dimeric schizanthine B tropane monomers with 7P-tigloyloxy, 7P-angeloy-loxy or 7P-senecioyloxy substituents and derivatives of these dibasic acids mentioned above as substituents at C-3a (one of the following monoesters: 1-methyl- or 1-ethyl-mesaconyloxy, 1-methyl- or 1-ethyl-itaconyloxy, 3-ethoxycarbonylmethacryloyloxy).

Physochlaine [ 3 a -(4'-methoxyphenylacetoxy)-7G-hydroxytropane] Physochlaina alaica

Physochlaine [ 3 a -(4'-methoxyphenylacetoxy)-7G-hydroxytropane] Physochlaina alaica

3a-Methylmesaconyloxy-7G-cinnamoyloxytropane Schizanthus litoralis
Fig. 3.16 Unique tropane alkaloids detected in certain solanaceous species

Thus, instead of an esterification with a second hydroxytropane monomer (like in the dominating dimeric schizanthines of, e.g., Schizanthus grahamii) the second carboxyl group of the dibasic acids, the one geminal to the methyl group of mesaconic acid and the one geminal to the methylene group of itaconic acid, respectively, is esterified by methanol or ethanol. In the case of a 3-ethoxycarbonylmethacryloyloxy substituent this esterification with ethanol has happened at the opposite second carboxyl group of mesaconic acid, i.e., the one with the vicinal hydrogen. A unique metabolite, 3a-methylmesaconyloxy-7P-cinnamoyloxytropane (reported as 6P-cinnamoyloxytro-pane-3a-methylmesaconate) (Fig. 3.16), was discovered in the leaves of Schizanthus litoralis (Muñoz et al. 1996). Acylated 3a,6b,7b-Trihydroxytropanes (T4)

The principal adjustments of Lounasmaa and Tamminen have to be taken into account here, too. The theoretical number of possibilities for structural variations is enhanced compared with T3-type compounds due to the presence of three hydroxyls at the tropane skeleton. Nevertheless, the real number of T4-type compounds is very limited. Two alkaloids turned out to be the most frequent ones: (i) 3a-tigloyloxy-6p,7p-dihydroxytropane, named meteloidine because it has been discovered in Datura meteloides DC (valid synonym: D. inoxia Mill.; Pyman and Reynolds 1908), and (ii) 3a,7P-ditigloyloxy-6P-hydroxytropane, discovered in Datura stramonium (Evans and Wellendorf 1958). Both alkaloids are typical constituents of the taxa from the Symonanthus / Anthocercis clades (Nicotianoideae) and the Datureae clade (Solanoideae). Meteloidine turned out to be the major alkaloid of Anthocercis genistoides (Griffin and Lin 2000). Two rare T4-diesters with diverging acyl residues are 3a-tigloyloxy-6p-hydroxy-7p-isovaleryloxytropane, confined to Brugmansia sanguinea, B. candida, and Datura ferox (Vitale et al. 1995), and its 7-propionyl congener, identified in D. stramonium (Berkov et al. 2003). Two further T4-monoester, 3a-(2'-hydroxy-3'-phenylpropionyloxy)-6p,7P-dihydroxytropane (6p,7p-dihydroxylittorine) and 3a,7p-dihydroxy-6p-tigloyloxytropane have been discovered in B. candida and B. suaveolens, respectively. No further congeners have been found in the Solanaceae. This implicates that no 3a,6p,7p-triacyloxytropanes seem to be present. However, such a triacylated metabolite has been found in the family Erythroxylaceae (El-Imam et al. 1987). Finally, it should be pointed out that even mono- and diacylated T4-type compounds are rather rare in the family Solanaceae since they are confined to the few clades mentioned above. Esters of 3a-Hydroxytropane/-«ortropane and 60,70-Epoxy-3a-hydroxytropane (Scopine/Vorscopine) with Solanaceae-specific Phenylpropanoid Acids (T5-T7-B)

Common Esters (T5, T6) (Figs. 3.13 and 3.14). The occurrence and distribution of hyoscyamine/atropine and scopolamine (hyoscine) are documented in an extraordinarily extensive manner in the literature due to their great significance in pharmacology and toxicology. First of all it must be considered that these alkaloids as well as their closely related congeners, i.e., esters with (i) tropic acid including

6P-hydroxy derivatives (anisodamine = 6P-hydroxyhyoscyamine), nor derivatives (norhyoscyamine/noratropine, norscopolamine) and N-oxides (T7-B), (ii) (-)-anisodinic acid (2'-hydroxytropic acid) (anisodine; T7-A), (iii) phenyllactic acid (littorine), and (iv) 4-hydroxyphenyllactic acid (4'-hydroxylittorine) are confined to the Solanaceae. One report on the occurrence of scopolamine in Heisteria olivae Steyerm., Olacaceae (Cairo Valera et al. 1977) is very questionable; it is only based on an insufficient chromatographic detection and improbable that only one single tropane alkaloid without any congener is present in a species.

Second, it has to be pointed out that the co-occurrence with scopolamine (hyoscine) is a consistent trait in hyoscyamine-containing species. Furthermore, this fact involves that anisodamine (6P-hydroxyhyoscyamine) must also be synthesized in all these species because it is an intermediate representing the direct precursor in the biosynthesis of scopolamine (Fig. 3.14). Nevertheless, due to a certain accumulation this intermediate could be identified in many species, e.g., in the genera Anthocercis, Cyphanthera, Duboisia, Datura, Hyoscyamus, Physochlaina. The trivial name of this alkaloid has been given due to its occurrence in Anisodus acutangulus.

This biogenetic argument is also true in favour of hyoscyamine in one single case in which only scopolamine (but not hyoscyamine) has been detected (Symonanthus aromaticus). No occurrence of scopolamine has been reported to date for only two hyoscyamine-containing species (Anthocercis fasciculata, Physochlaina dubia). It may be assumed that these exceptions have been caused by very low concentrations of scopolamine in the corresponding sample. There are two arguments for this assumption. (i) All further Anthocercis spp. checked (10 taxa) as well as all further Physochlaina spp. checked (five taxa) have turned out to be sco-polamine-positive. (ii) The sequence hyoscyamine ^ anisodamine ^ scopolamine is catalyzed just by one enzyme in two steps, hyoscyamine 6-hydroxylase (see Sect. 3.4.4), and at least anisodamine has been found in P. dubia.

T5/T6-type alkaloids are absent in the Schizanthoideae. They have been detected in the Cestroideae (only Latua pubiflora), in all clades of the Nicotianoideae except the Nicotianeae clade, and in the Solanoideae-clades Hyoscyameae, Mandragoreae, Solandreae (only Solandrinae subclade), Datureae. With the exception of the Cestroideae these alkaloids represent a consistent trait in all these taxa, i.e., they are their chemotaxonomic markers. Due to the fact that these alkaloids are potent poisons the discovery and distribution of the hyo-scyamine/scopolamine-containing plant species has been facilitated. Therefore it is improbable that species of the Schwenckioideae, Goetzeoideae, and Solanoideae-clades Nolaneae as well as Solandreae (only Juanulloinae subclade) might contain such alkaloids in considerable amounts though these subfamilies represent chemical "terra incognita". Taxa which are phytochemically well-studied ought to be unequivocally T5/T6-negative; otherwise it would have been published (negative results are almost never reported). These taxa are Petunioideae, Nicotianeae clade (Nicotianoideae), Cestroideae (except Latua pubiflora), and the Solanoideae-clades Jaboroseae, Lycieae, Nicandreae, Solaneae, Capsiceae, Physaleae. There are a few questionable reports: (i) Though the occurrence of hyoscyamine in Solanum betaceum (syn.: Cyphomandra betacea, tree tomato) has been tentatively reported due to TLC-comparison with an authentic sample (Evans et al. 1972d) it is still equivocal since it has never been confirmed neither by these authors nor by others. It would be "the first reported example of a plant which produces both atropine-like alkaloids and edible fruits" (Evans et al. 1972d). (ii) The occurrence of hyoscyamine and scopolamine, reported for Lycium barbarum (Harsh 1989) could not be confirmed by other, more careful authors, e.g., Christen and Kapetanidis (1987). (iii) A tentative report on the occurrence of hyoscyamine on Salpichroa origanifolia, Physaleae clade/Salpichroinae subclade (Evans et al. 1972a) has never been confirmed. However, finally it has to be pointed out that hyoscyamine and scopolamine have been detected unequivocally in 75 species belonging to 19 genera (additional subspecies/varieties and hybrids not included). This is a very remarkable contribution to the reasons why the Solanaceae is called a poisonous family.

Norhyoscyamine/noratropine as well as norscopolamine (norhyoscine) were found in many species - though in low concentrations - in co-occurrence with the corresponding N-methyl congener. Interestingly, norscopolamine was shown to be a principal alkaloid of the corollas of Brugmansia suaveolens (Evans and Lampard 1972). Almost a century ago it was reported that norhyoscyamine ("solandrine") represented the major alkaloid of Solandra longiflora leaves (Petrie 1917a).

All hyoscyamine-containing species are able to synthesize littorine, since it is the direct biogenetic precursor of hyoscyamine. However, this does not mean that this intermediate is detectable in all these species. Its name was based on the occurrence in Anthocercis littorea (Cannon et al. 1969) though it had already been discovered shortly before in Brugmansia sanguinea sub nom. Datura sanguinea (Evans and Major 1968). Furthermore, it was detected in other species of Anthocercis and Brugmansia as well as in the genera Duboisia, Datura, and Hyoscyamus.

The unusual specific co-occurrence of nicotinoids and tropanes in Duboisia spp. has been already discussed in Sect. 3.3.2.

Rare Derivatives of Hyoscyamine and Littorine Not Included in Table 3.1. The principal adjustments of Lounasmaa and Tamminen (see T2/T3) have to be taken into account here again. 7P-Hydroxyhyoscyamine was identified - beside its 6P congener and scopolamine - in the leaves of a Duboisia myoporoides x D. leichhardtii hybrid, in the roots and root cultures of Atropa belladonna and Hyoscyamus albus, as well as in root cultures of Datura inoxia, Brugmansia candida x aurea, and H. niger (Ishimura and Shimomura 1989; Doerk-Schmitz et al. 1994).

The alkaloids traditionally named 6P-hydroxyhyoscyamine and 7P-hydroxyhy-oscyamine represent two natural diastereoisomers, namely (+)-(3R,6R,2'S)- and (-)-(3S,6S,2'S)-6P-hydroxyhyoscyamine, respectively (Muñoz et al. 2006). This is again a consequence of the C-3 (pseudo)stereocenter of 3-hydroxytropane.

7P-Acyloxyhyoscyamines (acyl residues: isovaleryl-, 2-methylbutyryl-, tigloyl-) could be identified by GC/MS analysis in the roots and hairy root cultures of Datura inoxia (Witte et al. 1987; Ionkova et al. 1994). An ester of anisodamine, 6P-hydroxyhyoscyamine diacetate, turned to be a constituent of Physochlaina dubia (Mirzamatov et al. 1972). For 6P,7P-dihydroxylittorine see above (T4).

Another, 6,7-disubstituted derivative of hyoscyamine with the proposed structure 7P-hydroxy-6P-propenyloxy-3a-tropoyloxytropane was reported as a minor constituent of the seeds of Datura ferox (Vitale et al. 1995); however, due to the fact that the structure was determined only by GC/MS data the stereochemistry of this compound was not elucidated unequivocally; this also implicates that it is not in accordance with the adjustment of Lounasmaa and Tamminen (1993). Thus, it might be alternatively the 6P-hydroxy-7P-acyloxy isomer. By the way, the structural formula given by the authors is in accordance with this alternative if the usual numbering for tropanes would have been chosen by them.

Rare Derivatives of Scopolamine (Hyoscine) Not Included in Table 3.1. Another 3-acyloxyscopine derivative, 3-phenylacetoxy-6P,7P-epoxytropane was identified in the seeds of Datura ferox (Vitale et al. 1995). It may be assumed that this metabolite is 3a-substituted since only 3a-acyloxy congeners were found in this species and natural 3P-substituted scopines are unknown in general; however, the stereochemistry at C-3 has not yet been determined.

Rare Congeners of Type T7-A and T7-B Integrated in Table 3.1: Anisodine (T7-A). (-)-Anisodine (daturamine) is the rarely occurring 2'-hydroxy congener of scopolamine [acyl residue: (-)-anisodinic acid (2'-hydroxytropic acid)] (Xie et al. 1983). It was detected only in the Solanoideae; even in this large subfamily it is confined to two Anisodus spp. (the alkaloid is named after this genus), Przewalskia tangutica (Hyoscyameae clade), and two Brugmansia spp. (Datureae clade).

N-Oxides of T5- and T6-type Alkaloids (T7-B). Two isomeric N-oxides of hyoscyamine (isomer 1 with equatorial N+-O-; isomer 2 with axial N+-O-) were isolated from five famous species of the Solanoideae which have been widely used as medicinal plants: Atropa belladonna, Hyoscyamus niger, Scopolia carniolica (Hyoscyameae clade), Mandragora officinarum (Mandragoreae clade), and Datura stramonium (Datureae clade) (Philippson and Handa 1975b). In addition, isomer 1 of the N-oxides of scopolamine (hyoscine) was identified in the same species with the exception of M. officinarum. It may be assumed that these compounds are also present in other species in minor concentrations; they might have been overlooked in other studies on tropane alkaloids of the classical tertiary amine type due to the fact that the identification of N-oxides needs different methods. It may be added that also anisodamine N-oxide was identified in one species (Physochlaina alaica). Esters of 3a-Hydroxytropane with Solanaceae-unspecific Phenylpropanoid Acids (T7-C)

3a-Cinnamoyloxytropane and 3a-phenylacetoxytropane, two alkaloids already known from the Erythroxylaceae, were detected for the first time in the Solanaceae family in Latua pubiflora (Muñoz and Casale 2003) and Atropa belladonna

(Hartmann et al. 1986), respectively. To date, 3a-phenylacetoxytropane was found again only in transformed root cultures of a Brugmansia candida x aurea hybrid (Robins et al. 1990) as well as of Hyoscyamus x gyorffyi (Ionkova et al. 1994), whereas the occurrence of 3a-cinnamoyloxytropane is confined to L. pubiflora. A stereochemically not determined 3-phenylacetoxy-6,7-epoxytropane, found in the seeds of Datura ferox, has been mentioned already above (Vitale et al. 1995). "Dimeric" and "Trimeric" Alkaloids Based on 3a-Hydroxytropanes (T7-D)

Apoatropine is an artefact spontaneously formed from genuine hyoscyamine or its racemate atropine by dehydration forming an atropic acid (2-phenylprop-2-enoic acid) residue (see also Sect. 3.4.1). Two molecules of apoatropine may be dimerized spontaneously yielding two isomeric derivatives, called a- and P-belladonnine, respectively. This reaction is favoured by acid or basic conditions as well as by increased temperatures. Though small amounts of such artefacts may be present in the living plant they are caused mainly by the procedures used for drying and/or extraction of the plant material. These dimerizations are due to the reactivity of the double bond in the atropic acid residue of apoatropine. The latter as well as bella-donnine were found, e.g., in dried roots of Mandragora spp. but could not be detected in fresh roots (Jackson and Berry 1973). Thus, the belladonnines like their monomer, apoatropine, though often considered still today to be minor alkaloids of hyoscyamine-containing medicinal plants are no natural metabolites. This is also true for the analogous scopadonnines spontaneously formed from genuine scopo-lamine via aposcopolamine (apohyoscine). Consequently, such artefacts are not integrated in Table 3.1.

However, the basal genus Schizanthus which is not able to synthesize hyoscyamine and scopolamine, respectively, is characterized by the genuine, enzymatically catalyzed production of unique dimeric tropanols esterified with the dicarboxylic acids mesaconic acid or itaconic acid as spacers linking the two monomers (Fig. 3.15). One monomer may be 3a-hydroxytropane, the second 3a-hydroxy-7P-angeloyloxytropane, linked by a mesaconic acid moiety (schizanthine C; San-Martin et al. 1987). Another typical example is represented by schizanthine Z involving 3a,7P-dihydroxytro-pane and 3a-hydroxy-7P-tigloyloxytropane as monomers and itaconic acid as the linking spacer (Muñoz and Cortez 1998). As already discussed above, it should be taken into account that the application of the uniform numbering system of tropanes requires that in many cases compounds designated as C-3, C-6 disubstituted in the literature have to be designated as C-3, C-7 disubstituted. This is again true for the schizanthines (Lounasmaa and Tamminen 1993). The first dimeric congener, discovered in the epigeal vegetative parts of Schizanthus pinnatus, was schizanthine B (Ripperger 1979), followed by C-E (S. grahamii; San-Martin et al. 1987), X (S. grahamii, Muñoz et al. 1991), a C-isomer (S. littoralis, Muñoz et al. 1996), and finally Y and Z (S. porrigens; Muñoz and Cortes 1998). Unfortunately, the term

"schizanthines" does not include such spacer linked dimeric tropanes only, but also 3,7-disubstituted monomeric tropanes [schizanthines F-I, K-M; see above (T3)].

An unusual "trimeric" tropane alkaloid was isolated from S. grahamii (Hartmann et al. 1990). This congener of the schizanthines, named grahamine (Fig. 3.16), is characterized by three acylated 3a,7P-dihydroxytropane moieties thus forming altogether six ester groups with two mesaconic acid moieties (= four ester groups: at C-3a, C-7'P, C-3'a, C-3''a), one cinnamoyl residue (at C-7''P), and one angeloyl residue (at C-7P). Moreover, a cyclobutane ring is formed apparently caused by intramolecular [2+2] cycloaddition from (i) the mesaconic diester partial structure between the first and the second tropane skeleton and (ii) the cinnamic ester partial structure of the third one. Such cycloadditions between two unsaturated moieties are caused photochemically by the UV light of the sun inside the living plant as already shown for the intermolecular dimerization products of cinnamoylcocaine (truxillines), the cinnamic acid analogue of cocaine (Roth 2005).

Unfortunately, the authors caused a confusion in the literature because they named this compound "grahamine" ignoring the fact that a pyrrolizidine alkaloid from Crotalaria grahamiana Wight & Arn. (Fabaceae) had already been named grahamine two decades before (Atal et al. 1969). It is evident that it is not useful to create trivial names for natural compounds using only the epithet of the producing organism. Therefore, e.g., "schizangramine" would be more suitable for the trimeric alkaloid from Schizanthus grahamii.

The genus Schizanthus comprises 12 species, primarily from Chile, with one exception, S. grahamii, whose dispersal area reaches Argentina. Cladistic relationships in this genus, based primarily on morphology and chemical characters (tropane alkaloids), have been presented. According to the results of this study the chemical evolution within the genus runs, in parallel from the pyrrolidine to the tropane series, with subsequent unique dimerization or even trimerization (Peña and Muñóz 2002). It would be interesting to compare the results of this study with phylogenetic trees obtained by DNA-based cladistic analyses (see also Sect. 3.7). 30-Acyloxytropanes (T8)

In contrast to the 3a congeners the total number of alkaloids of this structural type identified as solanaceous metabolites is very low. It is confined to 3P-acetoxytropane, 3P-tigloyloxytropane (tigloidine; Fig. 3.13), 3P-(2-methylbutyryloxy)tropane, and 3P-phenylacetoxytropane (Fig. 3.13). However, tigloidine is a characteristic and rather frequent metabolite in the tropane-synthesizing taxa of the family. This is not very surprising since tiglic acid has turned out to be a frequent acyl supplier also for an esterification of 3a-hydroxytropane (see T1), for mono- and diesters of 3a,7P-hydroxytropane (T3) as well as for mono- and diesters of 3a,6P,7P-trihydroxytropane (T4). Tigloidine was discovered as a minor alkaloid (0.1%) in the leaves of Duboisia myoporoides by Barger et al. (1937) and later on also identified in other genera of the Nicotianoideae [Symonanthus (1 species), Anthocercis (4), Cyphanthera (1)] as well as in five genera of the Solanoideae [Hyoscyamus (1),

Solandra (4), Brugmansia (3), Datura (5), Physalis (1)]. Surprisingly, 3P-acetoxytropane was identified only in a few species of the Solanoideae (H. albus, H. pusillus, B. candida x aurea, D. wrightii, P. peruviana). Finally, 3P-(2-methylbutyryloxy)tropane seems to be confined to D. inoxia (Witte et al. 1987).

3P-Tigloyloxy-6-hydroxytropane (Berkov et al. 2005) as well as 3P-tigloyloxy-6-propionyloxy-7-hydroxytropane could be characterized by GC/MS analysis as minor constituents of D. stramonium (Doncheva et al. 2004). As already explained repeatedly the substitution at C-6 and C-7, respectively, cannot be elucidated by GC/MS data. Thus, this assignment is questionable again in both cases. In the latter report the occurrence of the very first tropic acid ester with a 3b-configurated hydroxytropane derivative, "3P-tropoyloxy-6-hydroxytropane" has also been published. However, this result requires unequivocal stereochemical confirmation, because it is based on GC/MS analysis which would be only proving with a reference compound which was not available. Furthermore, not even a retention index is given in the report. Such a finding would represent a remarkable scientific discovery, if one takes into account that the Solanaceae in general, especially the genus Datura, and finally also this species itself represent taxa which were already well-studied phytochemically.

Rare Unacylated Hydroxytropanes/-nortropanes not Included in Table 3.1.

3a,6P-Dihydroxytropane was detected in Schizanthus hookeri and S. littoralis only, its 3a,7P-isomer in Anthocercis viscosa, Brugmansia arborea, Datura inoxia, and Physochlaina alaica. 3a,7P-Dihydroxynortropane was identified as a constituent of Duboisia leichhardtii (Fig. 3.17); it was absent in Cestrum nocturnum and Solanum dulcamara. However, its 2a,7P-isomer, a metabolite of several convolvu-laceous species (Fig. 3.17), could not be found in any of the three latter solanaceous species (Asano et al. 2001). A strange alkaloid named physoperuvine was discovered in the roots of Physalis peruviana, cape gooseberry/ground cherry (Ray et al. 1976). The free base turned out to be present as an equilibrium mixture of the 1P-hydroxytropane form (aminoketal; Fig. 3.17) and the corresponding monocyclic aminoketone form (4-N-methylaminocycloheptanone; Ray et al. 1982). This compound-immanent behaviour induced the term "secotropane" for this type of alkaloids. In addition, an (+)-N,N-dimethylphysoperuvinium salt could be isolated from the same species (Sahai and Ray 1980). The second N-methyl group of this derivative stabilizes the tropane skeleton.

In this connection it is necessary to mention already here that a novel group of natural tropane derivatives named calystegines (Sect. 3.5) was discovered a decade later. They are polyhydroxynortropanes characterized by the common presence of a 1P-hydroxy substituent, thus sharing the aminoketal partial structure with physoperuvine.

Finally, the discovery of methylpseudoecgonine (2a-carbomethoxytropan-3P-ol) in Datura stramonium should be mentioned; it represents an isomer of methylecgonine (26-carbomethoxytropan-3P-ol), the precursor of cocaine in Erythroxylum spp. (Erythroxylaceae). No further occurrence of methylpseudoecgonine in the Solanaceae family was reported to date; however, it was detected in three convol-vulaceous species.

Physoperuvine Physalis peruviana

Physoperuvine Physalis peruviana

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