Mesembrine alkaloids

The mesembrine alkaloids, e.g. mesembrine (97), bear a strong structural resemblance to the Amaryllidaceae alkaloids of the crinine type, e.g. haemanthamine (91), but careful investigation has shown that the only aspect of biosynthesis 

Full details have been published of part of the research on the biosynthesis of the mesembrine alkaloids of Sceletium strictum (Aizoaceae). Some of the work has appeared in a preliminary communicationand has been reviewed. 

Key intermediates in the biosynthesis of the crinine alkaloids are norbelladiene and 4 -0-methylnorbelladine (90). It became clear, however, as the result of experiments with doubly labelled precursors that neither these compounds nor 3 -0-methyl-, iV-methyl-, or 3 -OiV-dimethyl-norbelladine were directly involved in mesembrine biosynthesis the moderate levels of incorporation observed were found to be the result of prior fragmentation of the precursors. In an ultimate test 

Phenylalanine is incorporated into the aromatic ring of mesembrine (97) with complete loss of its side-chain whilst tyrosine serves as the source of the carbon atoms of the octahydroindole portion of the molecule. A most important result came from the feeding of 2, 6 - H2]phenylalanine [as (101)]. It 

The authors make two final comments. One is that in retrospect perhaps the differences in the biosynthesis of crinine and mesembrine alkaloids are not entirely unexpected in view of the widely different phylogenetic origins of the 

The group of alkaloids exemplified by mesembrine (6.202), shows a structural kinship with Amaryllidaceae alkaloids of the haemanthamine (6.187) type. However, the only aspect of biosynthesis common to these two groups of alkaloids is their origin in phenylalanine and tyrosine results, crucially with doubly labelled precursors, showed that various norbelladine (6.180) derivatives were only incorporated after fragmentation [148]. 

The octahydroindole moiety in these alkaloids derives from tyrosine via tyramine, and iV-methyltyramine [149]. Phenylalanine is the source of the unusual, if not unique, mesembrine Cg unit. As with other metabolites phenylalanine is utilized by way of cinnamic acid and, in this case, mono- and di-hydroxy-derivatives may be involved too. Late-stage aromatic hydroxylation is also possible, for 

The octahydroindole moiety of these alkaloids, e.g. mesembrenol (101), is known to arise from tyrosine whereas the aryl residue has a separate genesis in phenyl-alanine. ° Utilization of phenylalanine in alkaloid biosynthesis usually occurs via cinnamic acid and its derivatives. This has proved true for mesembrine bases too, efficient incorporations of cinnamic acid (95) and its 4 -hydroxy-derivative (96) being observed. A series of conventional feeding, as well as trapping and dilution, experiments established that alkaloid formation may occur via phloretic 

A major pathway to mesembrenol (101) via (95), (96), and (99) with further hydroxylation at a late stage of biosynthesis is supported by the observation that sceletenone (100), which has a singly oxygenated aromatic ring, is an efficient precursor for mesembrenol (101). Details of this work, previously reported in preliminary form, are now available in full.  

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The H NMR spectrum of sceletium alkaloid A4, a tetracyclic system related to the octahydroindole members of the mesembrine alkaloids, is summarized in [152]. The close similarity of the 13C NMR spectra of... 

Mesembrine Alkaloids.—Previous results have indicated that mesembrine (110) and related alkaloids originate from one molecule each of tyrosine and phenylalanine by way of an intermediate which may be formalized as (105).84 The natural occurrence of sceletenone (106) and other alkaloids which, in contrast to, e.g.,... 

The mesembrine alkaloids, a group of alkaloids named after the most important representative, mesembrine, have been studied in detail only recently. The basic skeleton of these alkaloids is formed by mesembrane (I), an A -methyl-3a-(3, 4 -dimethoxyphenyl)-d5-octahydroindole. The mesembrine alkaloids are closely related to the 5,10b-ethanophenan-thridine group of the Amaryllidaceae alkaloids which are derived from crinane (II). 

The mesembrine alkaloids were discovered in a drug preparation that was named Channa or Koegoed by the bushman of Namaqualand 1-3). 

The mesembrine alkaloids can be separated chromatographically by the ascending method on paper (Schleicher and Schuell 2042 b mgl), impregnated with a solution of formamide in acetone (1 4), with the solvent systems A (methyl ethyl ketone heptane = 2 3) and B (methyl ethyl ketone xylene = 1 1), in an atmosphere saturated with ammonia (12). After spraying with Dragendorff reagent an extract from /S. nama-quense showed at least nine alkaloids. The Rf values of the mesembrine alkaloids are given in Table II. 

Chromatography of the mother liquors afforded this crystalline base from ethyl acetate 11). It possesses the molecular formula C20H24N2O2 and contains two methoxyls, probably in a veratryl group, and one N-methyl. It is not affected by catalytic hydrogenation with platinum in acetic acid. The presence of a second nitrogen in the molecule must allocate this alkaloid to a separate structural group in the mesembrine alkaloids. 

Mesembrine Alkaloids.— The way in which tyrosine, labelled in the side-chain, is incorporated into mesembrine alkaloids suggests that it is the source of all the carbon atoms of the octahydroindole moiety (phenylalanine provides the remaining C(, unit). The incorporation of L-[3, 5 - H2, f/- C]tyrosine [as (116)] into mesem-brenol (119) with retention of both labels (incomplete in the case of tritium see below) proves that this is so. Further, similar incorporations were recorded for [3, 5 - H2, l- C]tyramine [as (117)], [3, 5 - H2, l- C]-N-methyltyramine [as (118)], and [3, 5 - H2, N-merfty/- C]-N-methyltyramine thus defining the sequence tyrosine (116) — tyramine (117) A -methyltyramine (118)(119) as a major pathway in the biosynthesis of mesembrine alkaloids. 

Two new syntheses of racemic mesembrine have been described. In the first, outlined in Scheme 1, an improved synthesis of the penultimate 2-pyrroline (8) was achieved annelation of this afforded ( )-mesembrine (9). The second (Scheme 2) incorporates a regioselective borohydride imide reduction. Investigations on the biosynthesis of mesembrine alkaloids have revealed that a stereospecific protonation occurs at C-7 [see formula (9)] as one of the late stages. ... 

Recent indications point to the fact that the mesembrine alkaloids constitute a larger group than previously envisaged and for this reason it has been proposed that the mesembrane skeleton (26 = H) be used as a basis for nomen-... 

The heavy synthetic activity in the mesembrine alkaloid field has been summarised. Details and extensions of one of these efforts have appeared. The key step involved a double cyclisation of (28 X = Y = CN X = CN, Y = C02Me X = COjMe, Y = CN) to give the intermediate (29) which was converted into (30) cis-trans mixture) by unexceptional steps. Alternatively, the same compound (30 c/s-form) can be prepared with less effort from the pyrrolidinone (27). ... 

As the body of knowledge accumulates, it becomes increasingly unlikely that many pathways remain to be discovered. Thus, it is hardly surprising that many of the compounds under investigation this year have been found to arise by modification of already established pathways. However, there is promising evidence that the mesembrine alkaloids are biosynthesized by an unexpected, novel route and the past year has produced its full quota of surprises and puzzling results from both new and established pathways. 

Structural relationships are not always what they seem it has recently been demonstrated that the mesembrine alkaloids, superficially related to those of the Amaryllidaceae, arise by a quite different pathway, albeit from the same amino-acids (see p. 22). 

Amaryllidaceae and Aizoceae families. Second, without use of doubly labelled precursors erroneous conclusions on mesembrine alkaloid biosynthesis would have been reached. 

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