Synthesis of Tyrosine-Derived Alkaloids

The following section is devoted to the discussion of selected chemical syntheses of tyrosine-derived alkaloids. The great variety of these biologically and structurally fascinating natural products complicates or even renders any attempt to comprehensively cover this field and to present a complete overview of synthetic achievements impossible. The section is organized in a similar fashion as the section on biosynthetic routes to tyrosine-derived secondary metabolites. Syntheses of the most prominent members of each class of alkaloids are described in detail. 

During the discussion of the biosynthetic pathways toward tyrosine-derived metabolites, the importance of aryl-aryl couplings and oxidative phenolic coupling reactions becomes obvious, and the most important methods for the aryl-aryl bond formation are outlined in the previous section. Because of the predominant importance of coupling reactions in the biosynthesis and synthesis of tyrosine-derived metabolites, the subsequent section covers biomimetic synthetic achievements with interesting or unusual protocols for the coupling of the ring motifs. 

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Clearly, this section is not intended to completely cover the huge field of aryl-aryl coupling methods but should provide a representative overview of different reactions. Additionally, oxidative protocols are discussed in the third section of this chapter dealing with the synthesis of tyrosine-derived alkaloids. 

As pointed out earlier, of all approaches published so far, BanweU s route is the closest to the proposed biosynthetic pathway and also highlights the importance and relevance of oxidative coupUng reactions in the preparation of tyrosine-derived alkaloids. Such oxidative coupling reactions have also been used in other approaches. Quite early, Scott [166] employed an oxidative coupling of 270 in his synthesis of desacetamidocolchiceine. Equation 12.47-1, Scheme 12.47 (colchiceine varies from colchicine in the methoxy substituent on the tropolone ring, colchiceine bears a hydroxyl... 

Because of their pronounced biological activities, tyrosine-derived alkaloids also belong to the first natural products, which have been isolated from plant sources, and these early scientific achievements substantially helped to advance the newly emerging scientific disciplines. The ongoing interest in the isolation, biological evaluation, and synthesis of tyrosine-derived secondary metabolites is a clear indication for their great importance. 

In an analogous fashion, total synthesis of cytotoxic marine alkaloid, gym-nastatin A (24), which was isolated from the sponge Halicondria japonica, was accomplished via the spirolactol (143) derived from the tyrosinal derivative (142) with PIFA [101] (Scheme 15). 

The main focus of this chapter rests on the discussion of biosynthetic rontes and biomimetic synthesis. Detailed information on (he enzymatic mechanisms is omitted. Also, the huge amount of research resnlts and scientific contributions available on tyrosine-derived alkaloids does not allow an in-depth coverage of the field. References to book chapters, review articles, and research papers are inclnded for further literature study. 

The biosynthesis of benzyltetrahydroisoquinoline alkaloids has been thoroughly studied—mainly because of the medicinal and commercial importance of opium alkaloids— and commences with the preparation of (5)-reticuline (19). Reticuline then presents a point of divergence and as starting point for the biosynthesis of the previously named tyrosine-derived alkaloids with different skeletal structures [14-16]. The route to (5)-reticuline is outlined in Scheme 12.3. Both reaction partners for the condensation reaction and formation of (S)-norcoclaurine (16) are derived from tyrosine. The aromatic portions in (S)-reticuline (19) possess an ortho-dihydroxylation pattern as present in dopamine (4). However, only the northern portion in 19 is derived from dopamine, and the second hydroxyl functionality in the southern part is introduced after the formation of the tetrahydroisoquinoline ring system. The synthesis of the southern portion in... 

Aryl-aryl coupling reactions play an utmost important role in the biosynthesis and the chemical synthesis of many tyrosine-derived alkaloids. Furthermore, the biaryl substructure is a common motif in natural products and unnatural derivatives of great scientific or industrial importance. Many compounds such as antibiotics, anticancer drugs, agrochemicals. 

Aromatic compounds arise in several ways. The major mute utilized by autotrophic organisms for synthesis of the aromatic amino acids, quinones, and tocopherols is the shikimate pathway. As outlined here, it starts with the glycolysis intermediate phosphoenolpyruvate (PEP) and erythrose 4-phosphate, a metabolite from the pentose phosphate pathway. Phenylalanine, tyrosine, and tryptophan are not only used for protein synthesis but are converted into a broad range of hormones, chromophores, alkaloids, and structural materials. In plants phenylalanine is deaminated to cinnamate which yields hundreds of secondary products. In another pathway ribose 5-phosphate is converted to pyrimidine and purine nucleotides and also to flavins, folates, molybdopterin, and many other pterin derivatives. 

Application of the above procedure to the known N-protected phenol 342, derived from L-tyrosine and veratraldehyde, resulted in smooth oxidative cyclisation to the dienone 343 in 66% yield. Since the latter had been previously converted [90] via (+)-epimaritidine (344) into (+)-maritidine (345) [91] in six steps with an overall yield of 1.26%, the preparation of 343 constituted a formal synthesis of the alkaloid. 

Since a-amino-acids serve as starting materials for the synthesis of protein and the elaboration of many plant alkaloids, there must be a sharing of any amino-acid which is required for both of these activities. The extent to which this happens has been the subject of a new study in one particular plant, Lophophora williamsii, which produces isoquinoline and j8-phenethylamine alkaloids. These bases are derived from the a-amino-acid tyrosine and the results from feeding L-[f/- C]tyrosine indicate that this amino-acid is incorporated into the alkaloids approximately three times more efficiently than into protein. Only the L-isomer was examined and one wonders what the results with D-tyrosine would be in the light of the known preference for particular optical isomers of lysine in pipecolic acid and piperidine alkaloid biosynthesis. 

The multibranched shikimic acid pathway provides the intermediates for the synthesis of the three amino acids phenylalanine, tyrosine and tryptophan in microorganisms and plants. In plants, these three amino acids are precursors for a variety of secondary metabolites such as alkaloids, coumarins, flavonoids, lignin precursors, indole derivatives and numerous phenolic compounds (Fig. 1). The role of the aromatic amino acids in protein synthesis is well known as is the role of indoleacetic acid in plant development however, the function of the various secondary products is much less clear. Various physiological roles have been proposed including pest resistance, chromagens in flowers and fruits, and precursors for the structural component, lignin. 

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]. 

In this review, we discuss the isolation, structure, physicochemical and spectral data of all bromotyrosine derivatives isolated from marine organisms. The biosynthesis, total synthesis, and bioactivity of the bromotyrosine derivatives are also reviewed. Neither tyrosine derivatives without halogenation, nor indole alkaloids (with or without halogenation), are included in this review. Proteins or peptides containing bromotyrosine units are not included in this review since they are considered as primary metabolites. Cyclopeptides containing halogenated tyrosine units are, however, discussed in this review. 

In addition to acetyl-CoA, shikimic acid, mevalonic acid, and deoxyxylulose phosphate, other building blocks based on amino acids are frequently employed in natural product synthesis. Peptides, proteins, alkaloids, and many antibiotics are derived from amino acids, and the origins of the most important amino acid components of these are briefly indicated in Figure 2.1. Intermediates from the glycolytic pathway and the Krebs cycle are used in constructing many of them, but the aromatic amino acids phenylalanine, tyrosine,... 

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