Alkaloids Amaryllidaceae family

The Ley research group [76] developed a flow process for the multistep synthesis of ( )-oxomaritidine, an alkaloid found in the Amaryllidaceae family, known to have antineoplastic activity (Scheme 34) [77, 78]. The route does not involve intermediate purification of the products, which is necessary in the previously reported... 

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. 

The variety of structural types that are encountered in alkaloids belonging to the Amaryllidaceae family can be conveniendy classified, from the point of view of their basic skeleton, along the following lines (see Figure 1) ... 

Intramolecular ene reactions of acylnitroso compounds have been studied extensively32 and used in the synthesis of alkaloids of the Amaryllidaceae family. In these cases the only-stereochemical control observed was in the cyclization to form r/s-fused bicyclo[4.3.0] systems 133,34... 

C-Aromatic lycorine-type alkaloids have been discovered in the plants of the Amaryllidaceae family. Two new 2-oxo-pyrrolophenanthridinium alkaloids, zefbetaine (59) and zeflabetaine (60), together with several known Amaryllidaceae alkaloids, have been isolated from fresh mature seeds of Zephranthes flava by gradient solvent extraction, chromatography, and deri-vatization (108). Their structures were characterized by comprehensive spectroscopic methods, chemical transformations, and synthesis. They are listed in Fig. 9. 

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). 

Although tazettine (59) is one of the most widely distributed alkaloids in the Amaryllidaceae family, it was found to be an extraction artifact of pretazettine (61) (209). The presence of an A/-methyl group (2.4-2.5 ppm) in tazettine type alkaloids inmediately distinguishes them from the haemanthamine type, from which they proceed biosynthetically. Moreover the H NMR spectrum always shows the signal corresponding to the methylenedioxy group. 

Plant species belonging to the Amaryllidaceae family are widely distributed in several countries in the world. They are also cultivated as ornamental plants for their beautiful flowers and for the production of volatile oil. The study of Amaryllidaceae alkaloids began in 1877 with the isolation of lycorine [37, Fig. (9) and Table 2] from Narcissus pseudonarcissus [9], and the interest around this group of naturally occurring compounds has increased in time because of their effective antitumoral and antiviral activities. 

These alkaloids are among the most abundant of the bases derived from the [2]benzopyrano[3,4gf]indole nucleus in the Amaryllidaceae family, and the title of this section is derived from this fact. Lycorenine (LXVI) was one of the first Amaryllidaceae alkaloids to be studied and a summary of the chemical degradations leading to this structure (without stereochemical implications) has been given in Volumes II and VI. Lycorenine and the corresponding lactone, homolycorine (LXVII), not only serve as the reference alkaloids of the group for recent spectroscopic studies but also provides a chemical correlation with the lycorine-type alkaloids. Several important chemical interconversions are given below. 

As the alkaloids of the Amaryllidaceae family species fall mainly into one of these subgroups, they can serve as a classifying tool for including genera and species in this family. Thus, the genus Behria, in spite of having been classified as... 

Plants of the Amaryllidaceae family have been used for thousands of years as herbal remedies. The alkaloids from their extracts have been the object of active chemical investigation for nearly 200 years. Over the past two decades many have been isolated, screened for different biological activities, and synthesized by a number of research groups. An important handicap is the availability of these alkaloids, which are obtained only in minute quantities from natural sources. Since isolation in larger quantities is not praetieal, there is a strong case for the development of syntheses or semisyntheses of these alkaloids and their derivatives as potential prodrugs (35). 

Tazettine (62) is a widely reported alkaloid in the Amaryllidaceae family, particularly in Narcissus (see Tables VIII and IX), although it is known to be an extraction artifact of pretazettine (64) (75). All the alkaloids of the tazettine type that are isolated from Narcissus species show the typical methylenedioxy group between the C-8 and C-9 positions. Obesine (67) is an exceptional tazettine-type alkaloid with a seven-membered ring 76). 

It is well established that profiles of alkaloids vary with time, location, and developmental stage. In many instances, the site of biosynthesis is restricted to a single organ, but accumulation of the corresponding products can be detected in several other plant tissues. Long-distance transport must take place in these instances. There are only a few data on the ontogenic variations and distribution of alkaloids in species of the Amaryllidaceae family, and some results have been obtained in Narcissus species, such as N. assoanus (with only lycorine-type alkaloids) or N. confusus (with alkaloids of the homolycorine, hemanthamine, tazettine, and galanthamine types) 84,87). 

Although tazettine (62) is one of the most widely reported alkaloids in the Amaryllidaceae family, it was found to be an extraction artifact from pretazettine (64) (75). 

Haemanthamine and haemanthidine A P dissipation, cell cycle arrest with increased pl6 expression and Chkl Ser345 phosphoiylation Human leukemic Juikat cells Alkaloids isolated from plants of Amaryllidaceae family. Haemanthidine is more active that haemanthamine as apoptotic inductor. [134]... 

The most important alkaloid containing families are the Amaryllidaceae, Apocynaceae, Asteraceae (Eupatorieae, Se-necioneae), Boraginaceae, Euphorbiaceae, Fabaceae, Laur-aceae, Liliaceae, Loganiaceae, Menispermaceae, Papavera-ceae, Ranunculaceae, Rubiaceae, Rutaceae, and Solanaceae (Cordell, 1978 Dalton, 1991). 

The synthesis of 1-arylcyclopropylimines has been improved (34), and their conversion to A - or A -pyrrolines for further elaboration wiA methyl vinyl ketone and methyl vinyl ketone analogs has been brilliantly employed by Stevens and his co-workers for eflScient syntheses of not only Sceletium alkaloids and the structurally related alkaloids of the Amaryllidaceae family, but alkaloids of diverse structure representing other alkaloid families (46). 

Plants of the Amaryllidaceae family, including ca. 75 genera and about 1,100 species, are among the top 20 in the most widely considered medicinal plant families. A number of pharmacologically active compounds, such as phenols, alkaloids, lectins, peptides, etc., have been identified and characterized from this family. As primary constituents, up to 500 structurally diverse Amaryllidaceae... 

Alkaloids of this type belong to another new subgroup isolated from the Amaryllidaceae family plants and own a 7-arylindole or 7-aryl-2,3-dihydroindole skeleton (Table 17.10). It is interesting that alkaloids of this type 171-174 recently isolated from the genus Narcissus cultivar show a rare axial chirality [45]. 

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... 

Chapter 3 by S. Prabhakar and M.R. Tavares summarizes recent advances in the synthesis of Amaryllidaceae alkaloids, an important class of naturally-occurring bases and neutral compounds. The increased activity in the synthesis of these alkaloids over the last decade is undoubtedly due to the fact that certain members of this family possess interesting and useful biological properties. Many elegant syntheses, chiral and otherwise, of structures incorporating many asymmetric centres are reviewed. 

The discovery of lycorine-1-O-p-D-glucoside (4) and the related alkaloid pseudolycorine-1 -0- (i-D-glucoside (10) in Pancratium biflorum represented the first report of the natural occurrence of glucosyloxy alkaloids in the family Amaryllidaceae (73). The structures of 4 and 10 were deduced from H NMR and mass spectroscopy coupled with the observation that hydrolysis of the glycosides with emulsin afforded lycorine (1) and pseudolycorine (9), respectively, together with D-glucose. 

Although the alkaloids of the mesembrane type are structurally similar to certain alkaloids of the family Amaryllidaceae, they are generally found in the plants of the family Aizoaceae, but there have been several exceptions to this generalization. For example, amisine (580) has been isolated from Hymenocallis arenicola Northrop (57), and mesembrenol (581) has been isolated from Crinum oliganthum (41). The isolation of 580 and 581 represented the first instances in... 

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