Phenylalanine-derived Alkaloids

These alkaloids can also be derived from non-aminoacid precursors. The N atom is inserted into the molecule at a relatively late stage, for example, in the case of steroidal or terpenoid skeletons. Certainly, the N atom can also be donated by an amino acid source across a transamination reaction, if there is a suitable aldehyde or ketone. Pseudoalkaloids can be acetate and phenylalanine-derived or terpenoid, as well as steroidal alkaloids. Examples of pseudoalkaloids include such compounds as coniine, capsaicin, ephedrine, solanidine, caffeine, theobromine and pinidine (Figure 6). More examples appear in Table 1. 

L-methionine L-phenylalanine Phenylalanine-derived alkaloids Piperidine alkaloids Quinolizidine alkaloids Indolizidine alkaloids True alkaloids... 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

The 1.2.3.4-tetrahydroisoquinoline skeleton represents the framework found in many isoquinoline alkaloid derivatives and not only from plants. Some derivatives attracted much interest because of their anti-cancer activity [124], which has prompted many groups to invest in their chemical synthesis. The Pictet-Spengler reaction has become an important method in the preparation of this alkaloid type, and has often been described with phenylalanine derivatives and pyruvates as starting materials. Synthesis of appropriate tetrahydroisoquinoline-3 and the corresponding tetrahydroisoquinoline-1-carboxylic acid has been the key target [125]. 

Aromatic and phenolic compounds can mediate UV-protecting activities, which might be favorable for plants living in UV-rich environments, such as high altitudes [1[. Alkaloids (such as isoquinoline, quinoline, and indole alkaloids) that derive from aromatic amino acids, such as phenylalanine, tyrosine, and tryptophan, may have UV-absorbing properties, besides antiherbivoral and antimicrobial activities. 

The majority of alkaloids have been found to be derived from amino acids, such as tyrosine, phenylalanine, anthranilic acid, tryptophan/tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid (Fig. 2.1). However, alkaloids maybe derived from other precursors such as purines in case of caffeine, terpenoids, which become aminated after the main skeleton has been synthesized i.e. aconitine or the steroidal alkaloids, are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock alkaloid, coniine. 

All ephedra plants contain phenylalanine-derived alkaloids, including ephedrine, pseu-doephedrine, methylephedrine, and trace amounts of phenylpropanolamine. Previously marketed herbal supplements typically stated total ephedra alkaloid content, although actual levels of individual alkaloid varied depending on raw material and production runs. 

The chemistry and nomenclature of these compounds are somewhat confusing, and are best understood by reference to the synthetic route used by plants to make ephedrine. All ephedra plants contain phenylalanine-derived alkaloids. Plants use phenylalanine as a precursor, but incorporate only seven of its carbon atoms. Phenylalanine is metabolized to benzoic acid, which is then acetylated and decarboxylated to form pyruvic acid. Transamination, results in the formation of forms (-)-cathinone. 

Bisbenzylisoquinolines received importance based on their presence in the pharmacologicaUy active arrow poisons of South American Indians. A recent review gives the chemistry, biogenesis and syntheses [92]. A comprehensive tabular review of over 400 of these phenylalanine-derived alkaloids was published by Guha [93] and Schiff [93]. 

Apart from their main roles, particularly their use as building blocks for condensation into peptides and proteins, a-amino acids are used by plants, fungi and bacteria as biosynthetic building blocks. Many alkaloids are derived from phenylalanine and tyrosine (e.g. Figure 1.6 and penicillins and cephalosporins are biosynthesized from tripeptides, Chapter 8). 

Ephedrine is the predominant alkaloid of ephedra plants. Other phenylalanine-derived alkaloids found in ephedra plants are (+)-pseudoephedrine, (—)-norephedrine, (-l-)-norpseudoephedrine, (l)-A-methylephedrine and phenylpropanolamines. Ephedrine is a potent central nervous system (CNS) stimulant. Because ephedra is both an a- and p-adrenergic agonist, ingestion of quantities over 50 mg lead to a rise in blood pressure, heart rate and cardiac output. 

Phenylalanine and tyrosine acts as precursor for opium alkaloid biosynthesis. Tryptophan is a significant source of Vinca alkaloids. Alkaloids are derived from anthranilic acid, which is an intermediate in biosynthesis of tryptophan. Some alkaloids are derived from acetate, terpene or shikimic acid. Shikimic acid is a significant metabolite as most of the aromatic constituents are derived from shikimic acid pathway. 

All ephedra plants contain phenylalanine-derived alkaloids. These include (-)-ephedrine, (+)-pseudoephedrine, (-)-norephedrine, (+)-norpseudo-ephedrine (also called cathine because it is a major alkaloid of Catha edulis or khat, a plant used as a stimulant in North Africa), (-)-A-methylephedrine and (+)-A-methylpseudoephedrine, (+)-pseudoephedrine, and (+/-)-norephedrine (phenylpropanolamine). Significant enantioselective differences with regard to both pharmacokinetic and pharmacodynamic effects of these agents are possible. All of these alkaloids have important effects on the cardiovascular and respiratory systems, but not to the same degree. 

Phenylalanine is one of the 10 essential amino acids that must be obtained from outside the body, as distinguished from the 11 nonessential amino acids that occur naturally within the body, including tyrosine. Exclusive of the nonessential amino add hydroxyproline, both sets comprise 20 common amino adds that are found in aU proteins, and they conform with, or are derived from, the common genetic code. It may be further noted that a large array of alkaloids are derived from phenylalanine and tyrosine, according to Cordell s Introduction to Alkaloids, as presented by Hoffman (1999, p. 145). 

By means of labeled tracers and chemical degradations it was shown that the aromatic ring in the Sceletium alkaloids is derived from the aromatic ring of phenylalanine but not of tyrosine and that the per-hydroindole moiety is derived from tyrosine and not from phenylalanine. The S-methyl group of L-methionine provides the 0- and A-methyl groups 170). 

Alkaloids are a class of about 3000 nitrogenous compounds made in plants. They include substances, such as morphine (a narcotic) and colchicine (microtubule assembly inhibitor). Many of these substances have potent physiological effects in animals, but their function in plant metabolism is not well understood. Many alkaloids are derived from the aromatic amino acids tyrosine and phenylalanine. 

Biosynthesis The concomitant occurrence of C. a. and homoerythrina alkaloids indicates a common biosynthesis. Both types of alkaloids are derived from 1-phenethylisoquinoline with (see phenethyltetrahydroi-soquinoline alkaloids) ring A originating from tyrosine and ring B from phenylalanine. The acid components, e. g., harringtonic, isoharringtonic, and deoxyharring-tonic acids are derived from leucine. 

Two total syntheses of pyrrolidine alkaloids have been reported. (—)-Codonopsinine (85), an imino-pentitol which exhibits antibiotic and hypotensive activity, has been synthesized in seven steps in 16% overall yield from dihydropyrrole 84. The enantioselective synthesis of the potent antifungal agent (-l-)-preussin (87) has also been achieved from L-phenylalanine derivative 86. The pyrrolidine skeleton was established by hydrogenolysis of an intermediate oxazoline and subsequent diastereoselective reductive cyclization of the resultant aminoketone using Pearlman s catalyst. ... 

Ephedrine, isolated from Ephedra sp. (Ephedraceae), possesses a Cg—C2-N skeleton. Therefore, it was initially considered that this alkaloid would be derived from phenylalanine. However, it was established that part of the carbon framework of this alkaloid was derived from a C6-C1 unit, and that the nitrogen atom was not provided by retaining the C-N bond of an amino acid. 

There are no reports on the biosynthesis of this type of alkaloid. It is possible that the origin of these alkaloids is phenylalanine, as for other isoquinoline-type alkaloids. However, because this type of alkaloid possesses a methyl moiety attached to the carbon alpha to the nitrogen atom, like ephedrine and related alkaloids, it is also possible that these alkaloids are derived from a C6-Ci unit, such as benzoic acid or benzaldehyde, as in the case of ephedrine and related alkaloids. That is why these alkaloids are included in this chapter. Elucidation of the biosynthetic pathway for these alkaloids is awaited. 

Most alkaloids are derived biosynthetically from ornithine, lysine, nicotinic acid, anthranilic acid, phenylalanine, tyrosine, and tryptophan (Fig. 27.1) (Leete, 1983). In some groups, however, the source of the nitrogen is not from an amino acid. 

In terms of biosynthesis, these alkaloids are derived from tyrosine, phenylalanine, and ornithine (Fig. 30.16). Phenylalanine appears to be converted to cinnamic acid before incorporation. Phenacylpyrrolidines (such as 46) are defined as key intermediates. Doubly-labeled compounds of this type were incorporated intact into tylophorinine (47). Oxidative coupling steps yield tylophorine (45) and tylophorinine (47) (Bick and Sinchai, 1981 Herbert, 1985 Specialist Periodic Reports, Alkaloids, 1978, 1979). 

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-... 

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