Amaryllidaceae alkaloid

Amaryllidaceae Alkaloids.— Narciclasine (92) has been found to incorporate 0-methylnorbelladine (101) and oxocrinine (93), and thus arises by a pathway similar to that of haemanthamine (105). In the late stages to narciclasine the two-carbon bridge is lost from the oxocrinine skeleton, and preliminary experiments to determine the nature of the late intermediates have been reported.  

Whereas ( )-[3- H]epicrinine (94) and (+)-[ ,3,4b- H3]epinormaritidine (96) gave no significant incorporation into narciclasine and haemanthamine in daffodils, ( )-[3- H]crinine (95), ( )-[l,3,4b- H3]normaritidine (97), and ( )-[l,4b- H2]noroxomaritidine (98) were efficiently utilized. Degradation showed 

Although racemic crinine was well incorporated into narciclasine it was likely that only one enantiomer was involved in the biosynthesis, either crinine or vitta-tine (99). Accordingly, whereas narciclasine (92) and haemanthidine (106) were both labelled by [2,4- H2]vittatine in Pancratium maritimum, [2,4- H2]crinine was not incorporated into narciclasine in daffodils. The relative activities for positions 2 and 4 of narciclasine (92) after the vittatine feed were 2 1, confirming the finding that half the expected activity at C-4 is lost, presumably on hydroxy-lation. These results, when considered together with those from an X-ray study, allowed assignment of the stereostructure (92) to narciclasine (with revised relative stereochemistry). 

0-Methyl[l- C l - H]norbelladine (101) was incorporated into haeman-thamine (105), haemanthidine (106), pluviine (102), and lycorenine (104). The results show that no tritium is lost into (102) and (105) but that subsequent hydroxylation, as might be expected, leads to loss of half the tritium in the formation of (104) and (106), respectively. The reaction is therefore stereospecific. 

Detailed evidence has been published following the preliminary report implicating tyrosine as the progenitor of the C(,-C2 unit of mesembrine (107) in Sceletium strictum on the one hand, and phenylalanine as the source of the unusual, if not unique, Q unit on the other. The results showed that (a) methionine served as the specific precursor of the N- and 0-methyl groups (b) whereas dl-[2 - C]- and DL-[3 - C]-phenylalanine gave inactive alkaloid, DL-[ar-U- C]phenylalanine specifically labelled the aromatic ring of mesembrine and (c) dl-[3 - C]- and DL-[2 - C]-tyrosine were incorporated. Degradation of the mesembrine after administration of the former tyrosine precursor 

Amaryllidaceae Alkaloids.—Detail has been added to the fairly thoroughly delineated pathways to the Amaryllidaceae alkaloids.75 76 11-Hydroxyvittatine (94), previously shown to be a precursor for narciclasine (96),76 has been proposed as an intermediate in the biosynthesis of haemanthamine (92) and montanine (95) following the observed specific incorporation of vittatine (93) into the two 

Results of experiments with labelled (—)-crinine (98), and less conclusively with oxovittatine (99), indicate that the two naturally occurring enantiomeric series represented by (98) and (99) are not interconvertible.77 

The observation79 in an earlier more extensive study that norpluviine (100) is a precursor for lycorenine (102) has been confirmed.80 Incorporations were also recorded with both norpluviine (100) and pluviine (101) for other alkaloids of related structure to norpluviine, including galanthine (103). Although radio-active narciclasine (96) was also isolated in the experiment with norpluviine, its known derivation76,81 by way of a different pathway through vittatine (93) indicates that this is not significant. 

Conflict exists in deciding on the stereochemical course of the hydroxylation at C-2 of, e.g., norpluviine (100), which leads to lycorine (104). One set of results indicates that hydroxylation occurs with normal retention of configuration82 whereas the other set, obtained in a different plant, indicates that the reaction occurs with unusual inversion of configuration.83 The conversion of [2/8-3H, 9-OMe - 14C]pluviine [as (101)] into galanthine (103), in King Alfred daffodils, with retention of 79% of the tritium label confirms that the hydroxylation of C-2 may occur with inversion of configuration.80 

Mesembrine Alkaloids.—Previous results have indicated that mesembrine (110) and related alkaloids originate from one molecule each of tyrosine and phenylalanine by way of an intermediate which may be formalized as (105).84 The natural occurrence of sceletenone (106) and other alkaloids which, in contrast to, e.g., 

Diverse though the structures of these alkaloids seem they may be classified into three main groups represented by 6.185), 6.187) and 6.190). The quite brilliant recognition that the three groups of 

Examination of 6.180) indicates an assembly from a Cg-Ci and a Cg-Cg unit (thickened bonds) which can be traced through into the alkaloids 6.185), 6.187) and 6.190). It was established for representative alkaloids by the results of feeding radioactive compounds, that the C6-C2 unit arises from tyrosine (a common source for such units) via tyramine and that the Cg-Cj unit arises from phenylalanine (a common source of Cg-C, and Cg-Cs units) by way of cinnamic acid, its 3,4-dihydroxy-derivative, and protocatechualdehyde 6.184) [125-128]. It is interesting to note that, as is often the case in plant alkaloid biosynthesis, hydroxylation of phenylalanine to give tyrosine 

Further experimental results established norbelladine 6.180) and some of its methylated derivatives (clearly not others) as key biosynthetic intermediates in the biosynthesis of, e.g., lycorine 6.185), haemanthamine 6.187) and galanthamine 6.190) [125-128, 132, 133]. As elsewhere (see Section 6.3) hydroxy-groups ortho and/or para to sites of new bond formation between aromatic rings are essential for biosynthesis to proceed, a telling set of examples in support of the phenol-oxidative coupling hypothesis. Of further interest is the reported isolation of an enzyme, from a plant of the Amaryl-lidaceae, which, when incubated with norbelladine and 5-adenosylmethionine (source of methyl groups), yielded almost entirely the 0-methylnorbelladine, 6.181), that is involved in alkaloid biosynthesis [134]. 

The hydroxylation of 6.182) to give lycorine 6.185) would be expected to proceed with retention of configuration, the orthodox result (see Section 1.2.3). It has been found, however, that although this is true for biosynthesis in one plant, the opposite is true in another plant [137, 138]. 

The third group of alkaloids which arise from norbelladine 6.180) this time by para-para phenol oxidative coupling, is exemplified by haemanthamine 6.187)., and biosynthesis is proved to be by way of compounds of type 6.186). Haemanthamine 6.187) shows an extra hydroxy-group at C-11, which has been shown to arise by hydroxylation with normal retention of configuration [139, 140]. 

The final biosynthetic section of this chapter is devoted to the field of Amaryllidaceae alkaloids, which are common secondary metabolites in plants of the daffodil and narcissus 

Despite their structural differences, all Amaryllidaceae alkaloids are Wosynthetically derived frcwa 4 -D-melhylnort)elladine (65), and the variety arises from different oxidative coupling reactions of this key intermediate. 

Several members of the Amaryllidaceae family of alkaloids display pronounced biological activities, and some Amaryllidaceae plants have played an important role in traditional herbal medicine for the treatment of various ailments. The most prominent examples of Amaryllidaceae alkaloids of biological relevance are narciclasine (55) and its congeners (pancratistatin and 7-deoxypancratistatin) and galantamine (62) (also commonly spelled galanthamine). These natural products also find application in modem medicine, and in this respect, pancratistatin is used in clinical 

Despite the great importance of some members of the Amaryllidaceae family of alkaloids, only limited information on the subsequent steps of their biosynthesis is available to date. However, in analogy to other classes of secondary metabolites presented within this chapter, the diversity of 4 -0-methylnorbelladine (65)-derived natural products can easily be explained by means of different oxidative phenolic 

SCHEME 12.12 Biosynthesis of Amaryllidaceae alkaloids via different aryl-aryl coupling reactions of 4 -0-methylnorbelladine (65). 

An investigation of the alkaloid content of Crinum augustum resulted in the isolation of lycorine (8), buphanisine (1 R1 = R2 = H, R3 = Me), and crinamine (2) and the identification of six new alkaloids.1 Augustine, one of the latter group, was shown by a thorough study of its H n.m.r., 13C n.m.r., and mass spectra to be an epoxide with relative structure (3).2 Four of the new alkaloids were separated into two pairs of compounds and were shown by n.m.r. and mass spectroscopy to be 

6-a- and 6-/ -hydroxybuphanisine (1 R1 = H, R2 = OH, R3 = Me) and (1 R1 = OH, R2 = H, R3 = Me), respectively, and 6-a- and 6-/Miydroxycrinine (1 R1 = R3 = H, R2 = OH) and (1 R1 = OH, R2 = R3 = H), respectively. Within each pair, epimerization at C-6 to an equilibrium mixture of stereoisomers occurred readily and the constituents could not be separated by chromatographic methods. The constitution of the remaining new alkaloid was not established it has a molecular formula of C17H,9N04, contains an TV-methyl group but no olefinic protons, and may represent a new type of carbon skeleton in the Amaryllidaceae alkaloids. 

The structure of clivacetine (4 R = COCH2COMe), a new alkaloid isolated from Clivia miniata, was established by spectroscopic studies and by its conversion into O-acetylclivatine [4 R = COCH2CH(OAc)Me. 3 

A new synthesis of tetrahydrometinoxocrinine (14), a degradation product of crinine, has been reported 6 an important stage is cyclization of the isocyanate (15) to the lactam (16) with polyphosphoric acid. 

Kobayashi, H. Ishikawa, E. Sasakawa, M. Kihara. T. Shingu, and A. Kato, Chem. Pharm. Bull.. 1980. 28. 1827. 

The bulbs of Hippeastrum ananuca have been shown to contain lycorine, homolycorine, and the rare alkaloid maritidine (1). Lycorine has also been isolated for the first time from the rhizomes of Curculigo orchioides and from the leaves of Ungernia tadshicorum maritidine is a constituent of Zephyranthes robusta and of Z. sulphurea and an X-ray crystallographic study of the alkaloid has been carried out. Two new alkaloids, hippeastidine (2) and 17-epi-homolycorine (3), were obtained from Hippeastrum ananuca and their structures were established by X-ray analysis. 

Crinium ornatum and C. natans were previously reported to be devoid of alkaloids, but a re-investigation has shown that the bulbs contain small amounts. 

The search for new sources of galanthamine continues, and Galanthus nivalis, G. woronowi, Eucharis subedentata Leucojum aestivum, and Vallota speciosa have been investigated this year. 

A full account of Irie s synthesis of the alkaloids clivonine and clividine has appeared (cf. Vol. 5, p. 174) and the conversion of the intermediate anhydrides (5), (6), and (7) into a-, jS-, and 5-lycoranes, respectively, is described. The 

Tanaka, H. Irie, S. Baba, S. Uyeo, A. Kuno, and Y. Ishiguro, J. Chem. Soc., Perkin Trans. 1,1979, 535. 

L-Tryptophan is an aromatic amino acid containing an indole ring system, having its origins in 

The fact that more than 50% of the tritium is retained suggests that O-methyl-norbelladine is incorporated into narciclasine via path a rather than path b and this conclusion was confirmed by degradation to show that the tritium in narciclasine resides at both C(2) and C(4) as would be expected. 

Further evidence for the operation of path a to narciclasine was obtained by feeding [3H]oxocrinine (69). The precursor was labelled specifically with tritium as indicated and was incorporated into narciclasine to label the corresponding positions C(2) and C(4). 

The research on mesembrine (76) has been much less straightforward but after several setbacks it has now reached a particularly interesting stage. The story of this problem so far shows how frustrating biosynthetic work can be when a persuasive structural relationship gives a false lead to the biosynthesis. 

The first group47 synthesized the late precursor O-methylnorbelladine (82) stereospecifically labelled with tritium on the marked carbon. The (R)- and (S)-isomers were fed separately to daffodil plants in admixture with a 14C standard the former isomer (82 HR = T) largely lost its tritiumj in the biosynthesis, whereas with the latter (82 Hs = T) the tritium was largely retained. Since the stereochemistry of the hydroxy-group of haemanthamine is known, this result shows that hydroxylation has occurred with retention of configuration. 

However, before mechanistic conclusions can be drawn from this experiment it is essential to determine whether the neighbouring methylene, C(l) of O-methylnorbelladine (82), is involved in the hydroxylation process. This possibility was ruled out by showing that no tritium was lost with respect to an internal standard on incorporation of 0-methyl-[l,l-3H2]norbelladine (82). Thus, the hydroxylation reaction corresponds to a direct insertion of an oxygen species into a C—H bond. 

The belladine, lycorine, lycorenine, crinidine, galanthamine and tazettine alkaloid groups belong to this class. 

The Dragendorff reagent (Nos. 96 and 98) is used for detection. Laiho and Falbs [117 b] have used sihca gel and chloroform-ethyl acetate-methanol (20 + 20 + 60) for preparative separation of the components in a study of the quasi-racemic alkaloid narcissamine. 

The procedure permits also a ready separation of alkaloids which show only slight structural differences amongst themselves, as, e. g., the following epimers, isomers and dihydro-compounds  

Sandberg [199] employs TLC in phytochemical investigations of the alkaloid composition in the individual organs of Pancratium maritimum L. He uses a two-dimensional procedure on silica gel G, with the solvents ethanol-methanol-diethylamine (65 +10 + 6) (first dimension) and chloroform-methanol-diethylamine (92 + 3 + 5) (second dimension) the hi /-values of lycorine were 34 and 22, respectively. Altogether 52 bases could be detected in this way and a few new alkaloids were separated and crystallised. 

The class of indole alkaloids includes most of the compounds in this chapter. There are some medically important indole alkaloids. They can be subdivided into a number of groups, on the basis of the ring skeleton. 

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Scheme 9.33 Synthetic strategy toward carba-sugars, Amaryllidaceae alkaloids, and undecenolides.

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

Amaryllidaceae, alkaloids in, 2 75 Amator, gold-based dental alloy, 8 307t Amator 2, gold-based dental alloy,... 

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. 

The allenylsilane ene reaction is also well suited for the synthesis of cyclohexane rings. Jin and Weinreb have described the process of Eq. 13.55 in a synthesis of 5,11-methanomorphanthridine, an Amaryllidaceae alkaloid [64], Conversion of aldehyde 163 to imine 164 with piperonylamine took place in situ. Heating the solution of imine at reflux in mesitylene for 2 h led to cyclization through the conformer shown. The yield of 165 from aldehyde 163 was 66%. 

Kita et al. found that phenolic oxidative coupling in case of 272 provides seven-membered N heterocyclic compounds 274 and 275 by bond shift of the initially formed spiro intermediate 273 under suitable conditions. Besides 274 and 275, piperidino-spiroquinone 276 is also formed in this oxidation (Scheme 68). Of particular interest is the recently developed synthesis of amaryllidaceae alkaloids such as (+)-maritidine (Scheme 69) (96JOC5857). 

Galantamine and other amaryllidaceae alkaloids (refer to Structures 8)... 

Lopez S, Bastida J, Viladomat F, Acetylcholinesterase inhibitory activity of some Amaryllidaceae alkaloids and Narcissus extracts. Life Sciences 71 2521-2529, 2002. 

Weniger B, Italiano L, Beck JP et al (1995) Cytotoxic activity of Amaryllidaceae alkaloids. Planta Med 61(l) 77-79... 

Iminium ion-vinylsilane cyclizations closely related to the one described here have been used to prepare indolizidine alkaloids of the pumiliotoxin A and elaeokanine families, indole alkaloids, amaryllidaceae alkaloids, and the antibiotic (+)-streptazolin. The ability of the silicon substituent to control the position, and in some cases stereochemistry, of the unsaturation in the product heterocycle was a key feature of each of these syntheses. 

Prabhakar and colleagues used ethyl propiolate (38, R = H, R = Et) to synthesize the Amaryllidaceae alkaloid Pratosine (43) (equation 13). On heating 42 in DMSO in the presence of water, a cascade of reactions is initiated, namely a [3,3]-sigmatropic rearrangement, ester hydrolysis, decarboxylation and cyclization, to afford Pratosine (43) in one step, albeit in modest yield. 

L-proline L-serine L-threonine L-tryptophan Tryptophan-derived alkaloids Phenylethylamino alkaloids Phenylisoquinoline alkaloids Amaryllidaceae alkaloids True alkaloids... 

L-vatine Non-protein aminoacids PhenethyUsoquinoUne alkaloids Amaryllidaceae alkaloids Protoalkaloids Phenylethylamino alkaloids... 

Jim6nez, A., Santos, A., Alonso, G. and Vazquez, D. 1976. Inhibitors of protein synthesis in eukaryotic cells. Comparative effects of some Amaryllidaceae alkaloids. Biochimica et Biophysica Acta, 425 342-348. 

Elgorashi, E. E., Stafford, G. I. and Van Staden, J. 2004. Acetylcholinesterase enzyme inhibitory effects of Amaryllidaceae alkaloids. Planta Medica, 70 258-260. 

Abd El Hafiz, M. A., Ramadan, M. A., Jung, M. L., Beck, J. P. and Anton, R. 1991. Cytotoxic activity of Amaryllidaceae alkaloids from Crinum augustum and Crinum bulbispermum. Planta Medica, 57 437-439. 

An impressive enantiopure synthesis of Amaryllidaceae alkaloids has been achieved through the formation of sugar-derived homochiral alkenyl nitrone 265 (Fig. 1.7).[280] While this reagent required lengthy preparation, it underwent an intramolecular dipolar cycloaddition to establish the required stereochemistry of the polycyclic pyrrolidine skeleton of (—)-haemanthidine (266), which was converted to (+)-pretazettine and (+)-tazettine by established procedures (281). 

Baxendale, I.R., Ley, S.V. and Piutti, C., Total Synthesis of the Amaryllidaceae Alkaloid (+)-plicamine and its unnatural enantiomer by using solid-supported reagents and scavengers in a multistep sequence of reactions, Angew. Chem., Int. Ed. Engl., 2002, 41, 2194. 

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