Alkaloids separation scheme

A variety of different approaches lead to successful natural product separation schemes. Representative (as well as some unusual) HPLC separation methods for selected natural product groups (isoprenoids, phenolics, and alkaloids) are reviewed in Section 9.02.5. 

In their route to (- )-3, Hua and his coworkers demonstrated Ae usefiilness of chiral a-sulfinyl ketimine anions as intermediates in alkaloid synthesis (Scheme 4) (43). Treatment of the anion of 28 with (S)-( - )-menthyl p-toluenesulfinate afforded a 1 1 mixture of the separable diastereomers 29 and 30, while use of (/ )-( + )-menthyl p-toluenesulfinate afforded the enantiomers ent-29 and ent-30. Conjugate addition of the anion of 30 to methyl 2-(rerr-butoxycarbonylamino)acrylate was followed by spontaneous cyclization to give the unsaturated indolizidines 31 and 32 in a ratio of 2 3. Similar treatment of the anion of ent-29 yielded 33 and 34 in the ratio 1 2. Both sets of indolizidine diastereomers were readily separated by chromatography. The synthetic routes converged when reduction of either 32 or 33 with Raney nickel gave the same 5-oxoindolizidine 35, fiom which ( - )-slaihimine... 

The first scheme for the separation of the six chief alkaloids of opium, VIZ., morphine, codeine, thebaine, papaverine, narcotine and narceine, is probably that of Plugge. Much later Kljatschkina investigated for each of these six bases the properties by means of which isolation and estimation could probably be effected and, on the basis of the results, devised a plan for such analyses. More recently Anneler has published a detailed account of a scheme with the same objective. l Attention had already been given to complex, systematic analyses of this kind, in connection with examination of the mixtures of opium alkaloids, which have long been in use in medicine in these at first only morphine and other alkaloids were determined, but in the more recent schemes provision is made for the estimation of each alkaloid. ... 

Alkaloids of Remijia Purdieana. The bark of Bemijia Purdieana, a tree related to that yielding cuprea bark, contains a little cinchonine and a series of other alkaloids, for which Hesse gives a scheme of separation with descriptions. 

Jin and Weinreb reported the enantioselective total synthesis of 5,11-methano-morphanthridine Amaryllidaceae alkaloids via ethynylation of a chiral aldehyde followed by allenylsilane cyclization (Scheme 4.6) [10]. Addition of ethynylmagnesium bromide to 27 produced a 2 1 mixture of (S)- and (R)-propargyl alcohols 28. Both of these isomers were separately converted into the desired same acetate 28 by acetylation or Mitsunobu inversion reaction. After the reaction of 28 with a silyl cuprate, the resulting allene 29 was then converted into (-)-coccinine 31 via an allenylsilane cyclization. 

An efficient route to both cis- and frans-deethylebumamonines is a further example of the efficacy of the epimerization reaction [36]. These unnatural compounds are close derivatives of the well-known, pharmacologically important indole alkaloid, ebumamonine. For the synthesis of m-deethylebumamonine (3), Scheme (12), trans-ester 6 was epimerized in refluxing TFA to give a readily separable mixture of starting material and cis-ester 7 (ratio 22 78). 

Thiols may be enantioselectiveiy added in a conjugate fashion to a,p-unsaturated carbonyl compounds in the presence of chiral hydroxyamine catalysts e.g. chinchona alkaloids).242,244 249 252-261-269 In some cases ee of up to >80% were achieved e.g. Scheme 77).242-261-262 This methodology was utilized for the kinetic resolution of compound rat-86 Scheme 34) in a multigram scale.94 Related enantioselective 1,4-additions of thioacetates270-271 and selenophenols272 to enones are also known. Epoxidations, based on the asymmetric nucleophilic addition of peroxide anions to enones, are discussed separately.273... 

Several syntheses of 1-hydroxymethylpyrrolizidines have been reported. Borch and Ho1 have utilized a reductive cyclization method for their synthesis of ( )-isoretronecanol (6) and ( )-trachelanthamidine (7). The cycloheptenone ester (1), prepared by a novel route (Scheme 1), was reductively aminated to give a mixture of the diastereoisomeric amino-esters (2) and (3) in 48% yield. These esters could not be separated. Oxidative cleavage of the double bond of the esters, followed by reductive cyclization, gave a 35% yield of the pyrrolizidine esters (4) and (5). Separation of these compounds was achieved by preparative t.l.c., and a final reduction step afforded the racemic alkaloids (6) and (7). The second reductive amination process was stereoselective, because reduction of the unseparated ester mixture (4) and (5) gave a 1 2 ratio (g.l.c.) of the 1-hydroxymethylpyrrolizidines. 

The synthesis of the glucosidic alkaloid buchananine has been reported (Scheme 5). The penultimate product (21), though crystalline, was shown by n.m.r. spectroscopy to be a mixture of a- and / -anomers, confirmed chemically by the last step, which led to a separable mixture of two tetra-acetates. This same mixture of acetates resulted when 1,2,3,4-tetra-O-acetyl-D-glucopyranose was esterified with nicotinyl chloride. It is concluded that buchananine is itself a mixture of a- and / -anomers (21), as a consequence of its ability to catalyse its own mutarotation.31... 

As a final test of the synthetic strategy in the indolizidine alkaloid field, Weinreb turned to the fungal neurotoxin slaflamine (132) (82JA7065). Methylol acetate 125 was prepared in several steps from amide 124. When methylol acetate 125 was heated in refluxing o-dichlorobenzene, a separable 1 1.8 mixture of epimeric Diels-Alder adducts 127 and 128 (82%) was obtained via the N-acylimine intermediate 126. Catalytic hydrogenation of adduct 127, followed by basic hydrolysis, produced acid lactam 129. Curtius rearrangement of this compound led to carbamate lactam 131 (70JA7615) and to racemic slaflamine (132) (Scheme 18). 

Scheme 75). The D/E ring system of these alkaloids has been constructed by the intramolecular [4 + 2]-cycloaddition of an oxadiene with an ot,P-unsaturated amide. Thermolysis of the diene 580 at 190°C in xylene produced a 4.5 1 mixture of the cis and trans- cycloadducts 581 and 582, respectively. They could be separated to provide cis-lactam (73%). Subsequent hydride reduction of 581 with aluminum hydride produced the tertiary amine 583. Acylation of 583 with trichloroacetyl chloride followed by a haloform cleavage gave the ester 584. Finally, hydrogenolysis of the iV-benzyl group provided the known bicyclic amine 585, which was previously converted to a mixture of 586 and 587. 

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