Tyrosine Amaryllidaceae alkaloids

The Amaryllidaceae alkaloids (e.g., lycorine) are derived from the phenol oxidative coupling of a C6C2NC6C1 unit. One unit (C6C2N) is derived from tyrosine, whereas the other (CsCi) is projected to be... 

Previous studies45 have demonstrated that tyrosine and phenylalanine follow separate pathways in providing the hydroaromatic C6—C2—N unit and the aromatic C6 unit of mesembrine. In this respect mesembrine follows the pattern, already established for the biosynthesis of the structurally related Amaryllidaceae alkaloids derived from O-methylnorbelladine, e.g. haemanthamine (70). The present investigation46 followed this lead and started with a reasonable working hypothesis (Scheme 12) in which the biosynthesis proceeds via O-methylnor-belladine (68) and intermediates of the crinine type such as (75). However, feeding... 

Although amino-acids have been administered to plants on occasions legion in number, rarely has attention been paid to the question of whether there is any selectivity for the D- or L-amino-acid in alkaloid biosynthesis. An exception appears in work on the Amaryllidaceae alkaloids where it was shown that d- and L-tyrosine were equally well utilized in lycorine biosynthesis. The question has now been answered in Nicotiana glauca for the biosynthesis of anabasine (118) and pipecolic acid (113) from lysine. Pipecolic acid was found to be derived preferentially from the D-isomer ( 48 times better), in accord with a similar preference in intact rats and corn seedlings, whereas L-lysine was the more effective precursor ( 30 times) for anabasine. 

Although phenylalanine and tyrosine are closely related in chemical structure and in mammalian metabolism, these amino acids form separate sections of the Amaryllidaceae alkaloids. Phenylalanine contains no oxygen in the aromatic ring yet it serves as a primary precursor of the C-6—C-1 fragment in alkaloids which may contain as many as three oxygenated substituents in ring A. Tjrosine is a universal precursor of ring C and the two-carbon side chain (Ce—C2). Phenylalanine is not... 

In analogy with the biosynthesis of the Amaryllidaceae alkaloids (see Chapter 10) in which phenylalanine and tyrosine account for different... 

Some Amaryllidaceae plants possess a group of alkaloids containing a Cg— C2-N-C1-C6 unit. In this unit, the C6-C2-N moiety is derived from tyrosine or tyramine, and the C -Ci part is derived from phenylalanine through cinnamic acid, p-coumaric acid, and protocatechualdehyde [1]. Tyramine (C6-C2-N unit) and protocatechualdehyde (C -Ci unit) are then combined and methylated to form O-methylnorbelladine, which is a common biosynthetic precursor of various Amaryllidaceae alkaloids. Through para,ortho -, ortho,para - and para,paw-phenol coupling of norbel-ladine, the lycorine, galanthamine, and crinine type alkaloids are formed, respectively [2]. 

The biosynthesis of several types of alkaloids involves both phenylalanine and tyrosine. These alkaloids occur in the closely related families Amaryllidaceae and Liliaceae and in the Cephalotaxaceae and Mesembryanthemaceae. The last two families are not closely related to each other, nor to the first two families. 

The approximately 100 alkaloids of this series occur in the family Amaryllidaceae. This family is considered closely related to the Liliaceae and some taxonomists (e.g., Cron-quist, 1981) have merged the two into one large family. The alkaloids of the Amaryllidaceae are similar to colchicine and other related alkaloids of the Liliaceae in that both phenylalanine and tyrosine are involved in their synthesis. All Amaryllidaceae alkaloids, however, are derived from a single intermediate, norbelladine (4). The three major structural types are found at times in individuals of the same species. 

Amaryllidaceae alkaloids are derived from both tyrosine and phenylalanine. The adduct of these two amino acids, norbelladine (5), is an intermediate in the three major types of Amaryllidaceae alkaloids (Fig. 33.3). This adduct arises by prior conversion of phenylalanine to 3,4-dihydroxybenz-... 

Although the stmctures of Amaryllidaceae alkaloids are greatly diverse, they are considered to be biogenetically related and have a common precursor alkaloid norbelladine 2, which originally derived from the natural amino acids L-phenylalanine (Phe) and L-tyrosine (Tyr). Conventionally, according to molecule skeletons of the alkaloids, the large number of Amaryllidaceae alkaloids was classified mainly into nine different types, as represented by lycorine 1,... 

The same year, Canesi s group reported an asymmetric s5mthesis of the levoro-tatory enantiomer of the Amaryllidaceae alkaloid fortucine [105]. The L-tyrosine-derived phenol 163 was treated with DIB in HFIP to induce an oxo-spirocyclization into the para-quinolic lactone 164, which was treated with methanolic KOH to mediate both the opening of the lactone unit and an aza-Michael addition of the amide onto the cyclohexa-2,5-dienone moiety in high yield and stereoselectivity. The resulting aza-bicyclic intermediate 165 was then converted in 11 steps into (-)-fortucine (Fig. 41). This first asymmetric synthesis of fortucine led to the correction of the absolute configuration of the natural (+)-fortucine [105]. 

The group of alkaloids exemplified by mesembrine (6.202), shows a structural kinship with Amaryllidaceae alkaloids of the haemanthamine (6.187) type. However, the only aspect of biosynthesis common to these two groups of alkaloids is their origin in phenylalanine and tyrosine results, crucially with doubly labelled precursors, showed that various norbelladine (6.180) derivatives were only incorporated after fragmentation [148]. 

The Amaryllidaceae alkaloids are restricted to the monocot family that coined their name. They are derived from one molecule of tyrosine and protocatechuic aldehyde, which originates from phenylalanine. The central intermediate of their biosynthetic pathway is norbelladine. Nearly 500 structures of Amaryllidaceae alkaloids are known, and some of them possess significant pharmacological activities (Jin, 2007) (Fig. 10). For example, the isocarbostyrils pancratistatin from the spider lily Hymenocallis littoralis) and narciclasine from Narcissus species show promising antineoplastic properties (Dumont et al., 2007 McLachlan et al, 2005). Lycorine that occurs, e.g., in Clivia, Crinum and Galanthus... 

Lastly, norbelladine (top of Scheme 1.7) is issued from the reductive amination of 3,4-dihydroxybenzaldehyde (derived from phenylalanine) with tyramine (derived from tyrosine) and constitutes a biosynthetic node leading to Amaryllidaceae alkaloids such as galantamine, crinine, or lycorine depending on the topology of phenolic couplings. In all these biosynthetic routes, radical phenolic couplings are key reactions for C—C and C—O bond formations and rearrangements [30, 31]. 

The manifold possibilities for the elaboration of structurally intriguing natural products via the aforementioned oxidative aryl-aryl coupling reactions emphasize the importance of phenolic coupling reactions in the biosynthesis of tyrosine-derived alkaloids. This important reaction not only plays a significant role in the biosynthesis of benzyltetrahydroisoquinoline alkaloids but also for the construction of phenethylisoquinoline alkaloids and Amaryllidaceae constituents, discussed in the following sections. 

The biosynthesis of 4 -D-methylnorbelladine (65), the common biosynthetic intermediate for aU Amaryllidaceae alkaloids, is straightforward, and the route is outlined in Scheme 12.11. Tyrosine is converted to tyramine (3) and the amine is then reacted with phenylalanine-derived dihydrox-ylated aldehyde 63. The short biosynthetic sequence is then concluded after methylation of one of the phenolic hydroxyl moieties in 64. 

Amaryllidaceae species have been identified as rich source of structurally intriguing tyrosine-derived secondary metabolites. The great structural diversity of Amaryllidaceae alkaloids is rationalized by the different possibilities to connect the aromatic portions of 4 -0-methylnorbelladine as outlined in the biosynthetic section of this chapter. 

Research over a period of seven years has provided an immense amount of information on the chemical nature of the precursors utilized by the Amaryllidaceae for alkaloid formation and the chemical processes involved. However, many fundamental questions concerning the role of the alkaloids in plant metabolism remain unanswered. Enzymes for the various transformations have not been purified or characterized. Alkaloid catabolism is a relatively unexplored research area. One paper has appeared which relates the quantitative estimation of various amino acids, both free and combined in the plant protein, with the period of plant development of the Narcissus Golden Sceptre. Phenylalanine and tyrosine are most prevalent during the periods of active growth, i.e., leaf and flower formation (175). Maximum alkaloid content was observed to occur during the dormant period. 

Actually there are no good definitions of alkaloids (Bate-Smith and Swain, 1966) since each one is either too narrow or too broad. Even in the restricted Winterstein and Trier definition, at least five alkaloid families exist that can be derived from different amino acids consequently, there is a need to establish the proper biosynthetic pathways to permit the application of the alkaloid character to chemotaxonomy, It has been mentioned above that canadine (berberidine) may be found in plants of six partially unrelated botanical families. This fact is not surprising when considered in relation to the biochemical investigations of canadine biosynthesis. Many reactions are necessary to convert tyrosine into canadine consequently, one might even wonder why the distribution of this alkaloid is so limited. In contrast, other plants (and even some that produce canadine) can produce many alkaloids that are derived from tyrosine but have a marked difference in structure. Tyrosine serves as the key precursor of alkaloids of the isoquinoline type, but other types of alkaloids, such as colchicine and the Amaryllidaceae and the Erythrina alkaloids, may be synthesized from this amino acid. The nucleus of an alkaloid molecule can arise from different precursors thus the indole nucleus in Erythrina alkaloids arises from tyrosine, while in brucine it comes from tryptophan (Figure 1.5). The alkaloids cinchonamine and cinchonine differ in that cinchonamine has an indole nucleus, while cinchonine (like quinine) has a quinoline nucleus however, they exist in a precursor-product relationship (that is, the quinoline type is derived from the indole type in a one-step reaction). 

A widespread alkaloid family is made up of phenylalanine-tyrosine derivatives. These amino acids are precursors of a variety of compounds alkaloids, flower pigments, phenylpropane acids, lignins, etc. In most cases, deamination is the first reaction, but sometimes decarboxylation, O-methylation, or A-methylation occurs. The resultant protoalkaloids can be transformed into an impressive number of alkaloids. In closely related orders, e.g., Ranales, Berberidales, Aristolochiales, and Rhoeadales, the commonly synthesized compound is norlaudanosoline, and it acts as a precursor for all alkaloids in these plants. In some orders such as Aristolochiales, the alkaloids can be converted into compounds that do not give an alkaloid-positive reaction. Another group of plants with tyrosine- and phenylalanine-derived alkaloids are the Amaryllidaceae and related taxa. 

The starting materials for- the biosynthesis of the approximately one hundred known alkaloids of the family Amaryllidaceae are the amino acids phenylalanine and tyrosine (Fig. 126). Tyrosine is decarboxylated to... 

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