Of -mesembrine

In an extension to this work, this group applied the protocol to the synthesis of (—)-mesembrine (258). The key ylide formation and cycloaddition sequence was performed in xylenes at 250 °C in a sealed tube, furnishing the desired pyrrolidine lactone 259 as a single isomer in excellent yield, and further chemical elaboration yielded the target compound 258. Again it can be postulated that the stereochemical outcome is due to the bulky benzyloxymethyl group lying in an equatorial environment in the transition state (Scheme 3.88). 

Activated olefins (acrylonitrile, methyl acrylate), and halides such as allyl bromide and ethyl bromoacetate were used as electrophiles. In nonpolar solvents, the enamines (126a) were alkylated with high enantioselectivity, but poor chemical yields. In polar solvents, the chemical yields were acceptable, the optical yields poor 148). A similar reaction sequence has been used successfully for the synthesis of (+)-mesembrine (133)149 >. 

Sceletium Alkaloids.—Another synthesis of ( )-mesembrine has been described,9 and also the first total synthesis of (—)-mesembranone (ll),10 summarized in Scheme 1. 

Sceletium Alkaloids.—A new synthesis of (+)-mesembrine has been reported it uses a chiral y-lactone as a synthon." An alternative synthesis of ( )-sceletium alkaloid A4 has also been described.12... 

The transformation depicted in Scheme 8.114, representing the last step in a clever synthesis of Mesembrine, is noteworthy because the benzenesulfonamide... 

Hydroxymethylaziridines of this type can also be induced to engage in a Lewis acid-mediated rearrangement to the corresponding aminocarbonyl compound. Thus, the bicyclic tosylaziridine 172 provided 173 in near quantitative yield when treated with zinc bromide in methylene chloride. The rearrangement involves a stereospecific 1,2-migration of the aryl group. The latter compound was used as a key intermediate in the synthesis of mesembrine <03OL2319>. 

The production of quaternary centers was also utihzed by Kosugi to develop a synthesis of mesembrine [132]. Lactones bearing fluorinated side-chains are also available by this methodology [133]. The lactonization of a 50 50 mixture of cyclohexylsulfinyl butenolides has been examined. It was expected that a mixture of bis-lactones would be produced in 50 50 ratio. Instead, an 80 20 mixture of dichloro bis-lactones was obtained and, dehalogenation with Ra - Ni gave the lactone shown as the major isomer of a 95 5 mixture [133] (Scheme 19). 

Chiral imidazolines such as 4, obtained by condensation of iminoether hydrochlorides with (15,25)-1,2-diaminocyclohexane, may be metalated and alkylated with high stereoselectivity. This process is highly efficient for the stereoselective synthesis of quaternary benzylic stereogenic centers, and has been applied to a total synthesis of mesembrine (eq 6). (15,25)-1,2-Diaminocyclohexane here again gives higher diastereomeric excesses than 1,2-diphenyl ethylenediamine in this reaction. 

A sequential lithiation-alkylation based on the dianion chemistry was utilized in an efficient synthesis of (—)-mesembrine (Scheme 175 <1998TL8979>. 

This reaction has been developed by Stevens for a refined access to various alkaloid families. Equation 29 shows the short synthesis of mesembrine, where methyl vinyl ketone is annulated to the endocyclic enamine. The precursors for the imines are usually cyclopropyl aldehydes and the corresponding amines or cyclopropyl nitriles combined with suitable organometallics as demonstrated in a simple myosmine synthesis (equation 30). Additional examples will not be discussed here since excellent review articles exist on this topic ... 

The content of alkaloids in the Channa drug ranges from 1.0 to 1.5%. The hydrochlorides of mesembrine and mesembrenine were isolated in yields of 0.7 and 0.2 %, respectively, from the drug. The other alkaloids occur only in very small quantities. Mesembrine, mesembrenine, and chanaine could be isolated by the following method ... 

Upon treatment with hydroxylamine mesembrine gave an oxime, isolated as a crystalline hydrochloride (6). This ketoxime was reduced with lithium aluminum hydride to a primary amine 9). By catalytic hydrogenation mesembrine yields an optically active alcohol, mesem-brinol (6, 7). Condensation with benzaldehyde formed a dibenzylidene derivative of mesembrine (9). 

Crystallization of mesembrine hydrochloride from ethanol unexpectedly produced the hydrochloride of the enol ether IV (10). 

Evidence for the basic skeleton of mesembrine was furnished by the following sequence of reactions (7) ... 

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 ... 

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

There are two possible conformations of mesembrine (XXa and XXb). The most probable is XXa, since it has only one axial substituent on the cyclohexane ring 10). 

The remaining problem of the structure of mesembrine, the absolute configuration, was solved by an application of the octant rule (10). The enantiomer XXa should exhibit a negative Cotton effect and mesembrine, dissolved in dioxane did show such a negative effect. 

Some preliminary results regarding the biosynthesis of mesembrine were obtained by Jeffs by feeding Sceletium plants with radioactive precursors (I6 ). It was possible to show that the Ce—C2—X unit of mesembrine is derived from tyrosine and that the six carbons of the aromatic ring are derived from phenylalanine. 

Mesembrenine (XXVIII) was isolated from the mesembrine mother liquors as its hydrochloride (6). It contains, in addition to the functional groups of mesembrine, a carbon-carbon double bond. 

Mesembrinol is a dihydromesembrine and was obtained by the catalytic hydrogenation of mesembrine (6). Catalytic hydrogenation of mesembrenine or mesembreninol afforded (+ )-mesembrinol (6). Reduction of mesembrine with sodium borohydride, however, produced a mixture of almost equal quantities of mesembrinol and epimesembrinol, differing only in the configuration of the hydroxyl 11). The crystalline base, mesembrinol, could be separated from the oily base, epimesembrinol, by crystallization or column chromatography. 

Attempts to elucidate the structure of mesembrinol by degradation— before the structure of mesembrine had been established—proved to be unsuccessful 11) ... 

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. ... 

The mood elevating properties of Sceletium tortuosum have been attributed to mesembrine [9], an alkaloid with potent selective serototun (5-HT) re-uptake inhibition activity 86). Other sceletium alkaloids as they are now referred to are mesembrenone, mesembrenol and tortuosamine. The use of mesembrine-type alkaloids was patented 92). Selective serotoiun (5-HT) re-uptake inhibitors (SSRls), like mesembrine, have become important treatments in the therapeutic management of depression 93). Several southern African medicinal plants, in particular Amaryllidaceae, have shown in vitro affinity for serotoiun re-uptake transporters 94,95). Several active alkaloids have been identified from Boophone and Crinum species 95, 96). 

Two efficient processes for the synthesis of rivastigmine, one of the potent drugs for the treatment of Alzheimer s disease, have been developed for industrial applications with Ir-(5)-28a-catalyzed asymmetric hydrogenation as the key step [70]. Additionally, the Ir-28a-catalyzed asymmetric hydrogenation of ketones was also used as a key step in the synthesis of natural products of (-)-mesembrine [71] and (-)-centrolobine [72]. 

Few isolations of mesembrine-type alkaloids have been reported. Two examples are the isolation of amisine (379) (from Hymenocallis arenicola) (183) and of mesembrenol (380) (from Crinum oliganthum) (184) from the Amaryllidaceae family. A third example is the isolation of mesembrenone (381), belonging to the mesembrine group, from the aerial parts of Narcissus palladulus (77) growing in Iberia. The structure was elucidated by spectroscopic and chemical methods (Fig. 22). 

The synthesis of mesembrine-type alkaloids belonging to the Sceletium alkaloid family has been carried out extensively in order to seek a... 

A formal synthesis of ( )-mesembrine (387) has been performed by means of an intramolecular conjugate addition 146). Namely, condensation... 

It was most convenient to isolate the products after acidic conversion to cyclohexenones. Structures of the products were assigned by chemical correlation and circular dichroism and the enantiomeric purities were based on optical rotations. The selectivities obtained, although impressive for the era, are moderate at best, despite significant attempts to optimize the substrates and reaction conditions. Use of substituted cyclohexanones (29) and other aldehydes (30) lead to optically active products but the extent of enantiomeric induction in these products was not determined. This technology was used for the partial asymmetric synthesis of (+ )-mesembrine (12.1) (29) and (+ )-podocarpic acid (12.2) (31). 

Previous studies45 have demonstrated that tyrosine and phenylalanine follow separate pathways in providing the hydroaromatic C6—C2—N unit and the aromatic C6 unit of mesembrine. In this respect mesembrine follows the pattern, already established for the biosynthesis of the structurally related Amaryllidaceae alkaloids derived from O-methylnorbelladine, e.g. haemanthamine (70). The present investigation46 followed this lead and started with a reasonable working hypothesis (Scheme 12) in which the biosynthesis proceeds via O-methylnor-belladine (68) and intermediates of the crinine type such as (75). However, feeding... 

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