Mesembrine, synthesis

Scheme 18.SO Vinyl sulfoxide fails as Claisen rearrangement substrate in joubertinamine and mesembrine synthesis.—...

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

An effident total synthesis of the Scektium alkaloid (—)-mesembrine 112 has been accomplished in seven steps and 19% overall yield from the functionally substituted... 

Scheme 11.29. Total synthesis of the Sceletium alkaloid (—)-mesembrine 112 [75],...

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 >. 

Compounds in which two donor atoms are linked by a three-carbon chain undergo C-C bond cleavage readily. Well-known reactions are the retro-aldolization, retro Claisen, retro-Michael, and retro-Mannich reactions. Significant application of such processes to synthesis of complex natural products include approaches to caryophyllene [80], nootkatone [81], trihydroxydecipiadiene [82], hybridalactone [83], and mesembrine [84],... 

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 application of this cycloaddition-retro-Mannich-Mannich sequence to a synthesis of the alkaloid mesembrine is outlined in Scheme 2545. Irradiation of 104 led to the formation of ketoimine 105 in 74% yield. Reaction of 105 with trimethyloxonium tetrafluoroborate then gave iminium ion 106, which on refluxing with 4-dimethylamino-pyridine (DMAP) yielded mesembrine in 84% yield. 

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>. 

Conjugate addition to an a,/i-enone is also the key step of another synthesis of racemic mesembrine (or mesembranone)1. 

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. 

Denmark and Marcin showed that 2,2-disubstituted 1-nitroalkenes undergo facile MAD-promoted [4 -r 2] cycloaddition with n-butyl vinyl ether in toluene at 0 °C to give cyclic nitronates as anomeric mixtures in good yield [173]. This method is a promising route to the stereoselective synthesis of disubstituted pyrrolidines and can thus be applied to the synthesis of the biologically active pyrrolidine alkaloid, mesembrine (Sch. 134). 

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 ... 

In 1981, Keck and Webb applied this methodology to the synthesis of ( )-crinane (312) (81JA3I73), ( )-mesembrine (320) (82JOC1302), and di-hydromaritidine (324) (82JOC1302) having the perhydroindole skeletons of Amarylidaceae alkaloids. The hydroxamic acid 307 was oxidized by tetra-... 

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... 

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. ... 

Aryllead triacetates react with a mixture of isomeric vinylogous keto esters re-giospecifically at C-1. In the synthesis of alkaloids such as ( )-mesembrine [39] and ( )-lycoramine [38], the central quaternary carbon center was installed by this electrophilic arylation reaction (Scheme 13.11). 

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]. 

This reaction was used in a short high-yielding synthesis of the alkaloids ( )lycoramine,15 156 ( )Q methyljoubertiamine and ( )mesembrine. All these syntheses involved in the key step the selective high-yielding arylation of alkyl 4-oxocyclohex-2,3-ene carboxylates (72) with organolead reagents. 

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

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