Synthesis 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 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). 

The synthesis of (-)-mesembrine (12) has also been achieved from D-mannitol, which could be readily converted to (5 )-(-)-benzyl 2,3-epoxypropyl ether (1) " (Scheme 1). ... 

The Stork-Dolfini synthesis of the amino ketone 458 requires some 11 steps clearly, this is an area for improvement. One method used has been that of methyl vinyl ketone annelation (237). This procedure had been used previously in a synthesis of mesembrine (238) involving 2- -rolines. Stevens hoped to extend this technique to endocyclic enamines to give compounds in the octahydroquinolone series. 3-Ethylpiperid-2-one (549) was prepared from the y-lactone 550 according to standard procedures (239). N-Benzylation followed by reduction with diisobutyl-aluminum hydride (DIBAL) gave enamine 473. Addition of the enamine to methyl vinyl ketone (551) gave an almost quantitative yield of a hydroquinoline 552, which could be readily debenzylated to the known amino ketone 458. As with the Stork method of synthesis, this route to the Aspidosperma nucleus is efficient for the parent compounds but appears to lack the potential for diversification required to synthesize the more complex alkaloids such as vindoline (101) or even tabersonine (28). 

Sceletium Alkaloids.—Full details of an earlier briefly reported synthesis of ( )-mesembrine (3) have been published and a new synthesis has been described. The latter is outlined in Scheme 1 A new Sceletium alkaloid has been isolated from S. namaquense. It has been formulated as (4) on spectral evidence, the assignment of structure being confirmed by direct spectral comparison between the natural base and racemic (4), synthesized earlier. Channaine, another alkaloid of this family, from S. tortuosum, has structure (5) on the basis of an X-ray diffraction analysis of its hexahydrate. It may be an artefact arising from the condensation of a pair of iV-desmethylmesembrenone molecules (6) during isolation. ... 

Rigby s studies on the synthesis of alkenylisocyanates fostered the preparation of a suitable substituted aryl enamide, which on photocyclization yielded the polysubstituted pentacyclic system. Key to the success of this process is the hydrogen bond between the phenolic OH and the carbonyl group, which restricts the rotation around the aryl-amide bond and directs the cyclization. Further functionalization allowed the total synthesis of pancratistatin (272) and narciclasine (68) (275) (Scheme 11). The [4-1-1] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates was the key process in a recent synthesis of (+)-mesembrine (92) 274). 

Utilization of the endocyclic enamine 62 for the synthesis of mesembrine and mesembrenone Avas reported almost simultaneously from three different... 

Scheme 16. Utilization of the enamine 62 and 63 for the synthesis of mesembrine, mesem-brenone, and sceletenone.

Synthesis of Mesembrine and Joubertiamine Alkaloids via Routes Involving Geminal Aklylation at a Carbonyl Center... 

Metalloenamines are more nucleophilic than enamines and thus provide greater flexibiUty in choice of alkylating agents. This flexibility proved advantageous in that a properly functionalized nitrogen-containing side chain could be introduced directly ultimately, it led to a facile synthesis of ( )-mesembrine in 40% overall yield from veratraldehyde. 

Ketene-Alkene Cycloadditions and Aza-Ring Expansion of Cyclobutanones in the Synthesis of Mesembrine and Joubertiamine-Type Alkaloids... 

Scheme 22. Alternate synthesis of ( )-mesembrine via alkylation of a metalloenamine.

A recent synthesis of (+)-mesembrine reported by Wijnberg and Speckamp (54) utilizes an interesting solvolytically induct intramolecalar cyclization of an acetylene with an a-acylimmonium ion for the construction of the octahydroindole ring system. 

Extension of this approach to the synthesis of (+)-mesembrine is presented in Scheme 27. In its fundamental approach it is similar in concept to that developed later by Martin s group, in that an intermediate aldehyde 105,... 

Scheme 27. Enantioselectiue synthesis of (+)-mesembrine. Legend (7) is polyphosphoric acid (2) TsOH (J) N H (4) HCO Ac then LiAIH (5) HCOiAc then McjCCJ,...

The photocycloaddition-retro-Mannich-Mannich methodology is featured in a concise synthesis of mesembrine. Irradiation of vinylogous amide 114 effects photocycloaddition-re/ro-Maimich sequence to give product 116 via the cyclobutane intermediate 115. Methylation with trimethyloxonium tetrafluoroborate followed by treatment with DMAP produces mesembrine in 84% yield. Other applications include construction of the bicyclic core of peduncularine and synthetic approaches to hetisine alkaloids and 8-substituted 6-azabicyclo[3.2.1]octan-3-ones. ... 

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