Mesembrane

Although the alkaloids of the mesembrane type are structurally similar to certain alkaloids of the family Amaryllidaceae, they are generally found in the plants of the family Aizoaceae, but there have been several exceptions to this generalization. For example, amisine (580) has been isolated from Hymenocallis arenicola Northrop (57), and mesembrenol (581) has been isolated from Crinum oliganthum (41). The isolation of 580 and 581 represented the first instances in... 

Sceletium Alkaloids.—(-)-Mesembrane has been isolated from S. namaquense L. Bolus X-ray diffraction analysis of its hydrochloride monohydrate revealed its relative and absolute configuration (10). (-)-Mesembrine has the absolute configuration (11), in accord with (10), and it is now firmly established that alkaloids of this family belong to a single antipodal series.13... 

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). 

In support of the structure which was derived from the results of the degradation, mesembrane (I), the basic skeleton of mesembrine was synthesized (S). The synthesis was performed in analogy with the synthesis of ( + )-crinane (II) by Wildman (13) as follows ... 

Besides ( + )-mesembrane the isomeric ( + )-isomesembrane (XV R = CH3) with trans fusion of the octahydroindole system was obtained, when the methiodide, derived from the hexahydroindole XII, was catalytically hydrogenated. Reduction of the hexahydroindole XII with complex hydrides yielded almost equal quantities of ( )-normesem-brane and ( + )-norisomesembrane (XV R = H) (12). 

The synthesis of mesembrane, the parent skeleton of mesembrine, did not solve the position of the keto group for which there remained two... 

When mesembrenine was catalytically hydrogenated over palladium on charcoal ( + )-mesembrine was isolated from which ( + )-mesembrane could be produced by Wolff-Kishner reduction (8) consequently only structure XXVIII is possible for mesembrenine. 

H y drochlorido Bromo-d-camphor sulfonate + )-Mesembrane Hydrochloride Des-N-methylmosembrane Hydrochloride Des dcs mosembrane Aminoinesembrane Dihydrochloride Dimethiodide Mesembrene VII Hydrochloride... 

A detailed account concerning the isolation and characterization of the pyrido-mesembran alkaloids A4(7) and iV-formyltortuosamine (8) and the mesembran bases (9 R = H, R = OMe), (10), and (9 R = R = H) from Sceletium namaquense and S. strictum has appeared. Their structures were established by detailed H and... 

Mori et al. have shown that asymmetric alkylation with an allylic tosyl amide followed by a zirconium-promoted cyclization provides an efficient route to mesembrine and mesembrane alkaloids [107]. The best ee was obtained with BINAPO as the ligand. Scheme 28. The product was obtained in 86% ee and following recrystallization the sulfonamide was obtained in 99% ee. 

Apart from the accepted structural types of this class, this report will be concerned with the mesembrane group (26), miniatine (24), and cherylline (25) because of their obvious biogenetic relationship. 

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-... 

Synthetic work on the mesembrane group will no doubt be further stimulated by reports on their central nervous system activity and somewhat surprising biosynthesis. An interesting asymmetric synthesis of unnatural (+ )-mesembrine (38) has been announced (Scheme 4). The key intermediate (35), prepared in nine steps from 1,2-dimethoxybenzene, was treated with L-proline pyrrolidide (36) under conditions typical for the preparation of enamines. The product was not isolated but subjected to reaction with methyl vinyl ketone followed by acid treatment to give the cyclohexenone (37) in 38 % overall yield. The last step in the synthesis [(37) — (38)] was based on previous synthetic work on mesembrine alkaloids. The synthetic (+ )-mesembrine (38) was shown to exhibit a positive Cotton effect and thus an antipodal relationship to natural (— )-mesembrine. The mesembrine analogues (40 = H or OMe, = H, Me, or CHjPh) have... 

In the asymmetric total synthesis of (—)-mesembrane, Mori carried out asymmetric N-allylation of N-tosylallylamine with the 2-substituted cyclohexenyl-3-carbonate 107 using (5)-BINAPO (XV-4). The allylamine attacked one of the allylic termini of the symmetric intermediate 108 to provide 109 with 86% ee. Recrystallization from MeOH gave 109 with 99% ee [41], A similar method was applied to the total synthesis of (—)-tubifoline [42],... 

Almost all of the lycorine-type alkaloids isolated from Narcissus present a trans-rmion between B/C rings, making them especially vulnerable to oxidative processes. It is interesting to observe that four of these alkaloids, namely vasconine (22), tortuosine (23), ungeremine (24), and roserine (25) possess an unusual quaternary nitrogen (67 71). The species N. pallidulus (section Ganymedes), unusual because it contains mesembrane-type alkaloids, is even more exceptional due to the presence of roserine. 

C. Botteghi, L. Lardicci and R. Menicagli, Optically active Heteroaromatic Compounds VI 3-substituted Furans and Thiophenes from a(,B-unsaturated Aldehydes, J. Org. Chem. 38 (1973) 2361-1365 C.P. Forbes, W.J. Schoeman, H.F. Strauss,E.M.M. Venter and A. Wiechers, Applications of substituted Aryl Acetaldehydes in the Total Synthesis of seco-Mesembrane Alkaloids Part I. The Total Synthesis of 1-0-Methyljoubertiamine, J. Chem.Soc. Perkin I 1980, 906-910. 

The synthesis (14) of ( )-mesembrane, which is presented in Scheme 3, followed closely a route which had been used for a previous synthesis of ( )-crinane, and the assignment of the cis-ring fusion to ( )-mesembrane obtained by this route rests on previous results obtained for catalytic hydrogenations of hexahydroindoles (18). 

A subsequent X-ray structure determination (21) of 6-epimesembranol methiodide (16) which had been obtained from (—)-mesembrine confirmed the assignment of the absolute configuration. A more recent (22) X-ray structure determination of (—)-mesembrane hydrochloride has provided further substantiation that the absolute configuration proposed on the basis of the CD work which assumed normal Octant behavior is correct. This result is of some interest, as it is in apparent violation of the rules suggested by Hudec 2J), who has proposed that axial jS-aminoketones should exhibit anti-Octant behavior. 

A further point of interest concerns the reaction of the iminium salts 118 and 120 with borohydride (65). The reduction of 118 or 120 with sodium borohydride gave an identical product mixture in which the major components were 6-0-methylmesembranol (121) and 6 -0-methyl-7a-epimesem-branol (122) in 78% and 16% yields, respectively (see Scheme 32). Two minor components representing less than 6% of the total products were identified as mesembrane and its C-7a epimer 123. While the structures of the compounds with a trans ring fusion rested on spectral evidence, the identity of 6-0-methylmesembranol was established by its synthesis from mesembranol by selective O-methylation of the sodium salt with methyl-p-toluenesulfonate, while that of c -mesembrane was identified by comparison with an authentic sample. 

Asymmetric substitution sodium salt Synthesis of mesembrane and mesembrine Synthesis of amaryllidaceae alkaloids Remote asymmetric induction... 

Further examples of allyl substrates that proceed via a symmetrical intermediate include the allyl carbonate 161, which reacts with allyl sulfonamide 163 to give the product 164. Elaboration of compound 164 afforded the natural product mesembrane 165. Related strategies have been used in the synthesis of a range of other natural products. ... 

D.i.a. Synthesis of Natural Products by Allylation of the Cyclohexenyl Moiety. Many alkaloids have a di-3a-aryloctahydroindole skeleton like mesembrane, mesembrine, or crinane-type alkaloids (Scheme 44). They have been of interest as synthetic targets due to the wide range of biological activities they exhibit. 

Total syntheses of (-)-mesembrane and (-)-mesembrinef ° were based on zirconium-promoted diene, diyne, and enyne cyclizations. This procedure was very useful... 

The mesembrane alkaloid (-)-mesembranone has been synthesized using a neat application of the amide acetal Claisen rearrangement (Scheme 82)/ ... 

---