Alkaloids from Anthranilic Acid

No data is available on the biosynthesis of 2-alkylquinoline/4(l//)-one alkaloids from anthranilic acid in plant. However, the structures of many alkaloids isolated, especially from the Rutaceae (Tables 24.18,24.23, and 24.24), have provided much indirect evidence for the route proposed at Scheme 24.13. 

S.2.2.3 Alkaloids from Anthranilic Acid 5.2.23.1 Quinoline and Furoquinoline Alkaloids... 

The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362-366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway... 

The monomeric acridone alkaloids are derived from anthranilic acid and acetate via a polyketide. First studies, in which [ C]-acetate was utilized by cell cultures of Ruta graveolens, indicated that the C-ring of the acridone nucleus was acetate derived. Further research revealed that anthranilic acid is specifically incorporated into the A-ring of rutacridone (Baumert et al, 1982). 

Of all the alkaloid-producing families, one of the most prolific is the Rutaceae (Waterman, 1975). The alkaloids obtained included 1-benzyltetrahydroisoquinoline, simple tryptophan derivatives, imidazoles and, most commonly, quinoline alkaloids originating from anthranilic acid. The Rutaceae was the only family in which the direct use of anthranilic acid in alkaloid production occurs to any extent. 

Treatment of the sulfinamide anhydride, prepared from anthranilic acid and thionyl chloride, with carboxamides and thiocarboxamides 1 affords quinazolin-4(3//)-ones 2. Thiocarbox-amides, being much more easily dissolved than carboxamides in nonprotic solvents such as benzene, are more suitable as starting materials. This approach has been used by Kametani et al. in the synthesis of the quinazoline alkaloids glomerine, homoglomerine, chrysoginc, and glycosminine. " ... 

Highly significant results have been obtained by Monkovic and Spenser 160) from a study of the biosynthesis of dictamnine using tracer methods. Mature plants of Dictamnus albus incorporate carboxyl- C-labeled anthranilic acid to give radioactive dictamnine, specifically labeled at C-4, strongly supporting the derivation of the alkaloid directly from anthranilic acid failure to incorporate radioactivity from tryptophan-jS- C shows that the 4-hydroxyquinoline unit is not derived... 

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. 

Quinoline and Acridone Alkaloids.—Earlier studies have shown that the quinoline nucleus of skimmianine (38) and dictamnine (37) is derived from anthranilic acid and acetate. Whilst incorporation of mevalonate into dictamnine in Dictamnus albus and into the furanoquinoline alkaloids of Skirnmia japonica could not be demonstrated, positive results have been obtained in Fagara coco. [4- " C]Mevalonic acid, [5- " C]mevalonic acid, and [l- " C]dimethylallyl alcohol were satisfactorily incorporated into skimmianine (38) and the activity was confined essentially to C-2, C-3, and C-3 respectively. 

Quinoline alkaloids are biogenetically derived from anthranilic acid and occur mainly in Rutaceous plants (14). These alkaloids were encountered in Sri Lankan plants of the families Annonaceae and Moraceae, in addition to the Rutaceae. 

The isolation of alkaloids bearing the 8-hydroxyquinoline moiety prompted postulation (17) of a biosynthetic pathway to 1 from the amino acid tryptophan, for which chemical analogies are known (22) (Scheme 2). It should be noted, however, that, in general, quinolines are biosynthesized from anthranilic acid (14). Biosynthesis of broussonetine (4) would involve condensation of two molecules of 1 with a molecule of acetyl-CoA followed by cyclization, as depicted in Scheme 3. 

Quinazoline Alkaloids.— The biosynthesis of vasicine (=peganine) (163) has been investigated in Adhatoda vasica (Acanthaceae) and Peganum harmala (Zygo-phyllaceae). In both plants the anthranoyl portion is known to derive from anthranilic acid [the reported incorporation of tryptophan (0.017 %) suggested as via anthranilic acid seems of questionable significance]. The remaining atoms of vasicine, however, appear to arise by different pathways in the two plants. 

Chakraborty et al. (26) synthesized 1 by cyclization of the < -acyl-aminobenzamide 13 with diphosphorus pentoxide. Kametani et al. have developed a one-step synthesis of quinazolinone derivatives by condensation of sul-phinamide anhydrides generated from anthranilic acids and thionyl chloride with amides (27,28), imines (29,30), or thioamides (31). This reaction was applied to the synthesis of 1 (28,31,32), glycosminine (6) (28,31), glomerin (2) (27,31), homoglomerin (27), glycerine (3) (27), chrysogine (7) (27), and other quinazoline alkaloids (Scheme 1). 

Kametani and co-workers have applied their preparation of quinazolines from sulphinamide anhydrides cf. Vol. 8, p. 83) to the synthesis of the alkaloids glycorine (33 R = Me, R = H), glomerine (33 R = R = Me), and homo-glomerine (33 R = Me, R = Et). The reaction of the sulphinamide anhydride derived from anthranilic acid with O-benzyl-lactic acid amide furnished the quinazolinone [34 R = CH(OBz)Me], which was converted into the alkaloid crysogine [34 R = CH(OH)Me] by acid hydrolysis. 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid, and 1-deoxyxylulose 5-phosphate (Figure 2.1). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate, and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthranilic acid as aromatized CoA ester, anthraniloyl-CoA). Shikimic acid is a product of the glycol5dic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyr-uvate and erythrose 4-phosphate (Figure 2.1). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline, and acridine. 

Pig. 6) into the culture solution. Both alkaloids are synthesized from anthranilic acid and L-phenylalanine (3 cf. Pig. 1 of Luckner, this volume),... 

This approach though also has some complications, particularly when the alkaloid has more than one nitrogen and more than one biosynthetic amino acid precursor unit. For example, evodiamine and rutaecarpine, from the fruits of Euodia mtaecarpa (Rutaceae), can be classified as alkaloids derived from tryptophan. In addition, one of the nitrogen atoms of each alkaloid is derived from an anthranihc acid unit. Therefore, these alkaloids can be classified as alkaloids derived fiom tryptophan and as alkaloids derived from anthranilic acid. In this volume, these alkaloids are discussed in Chapter 2.19 as alkaloids derived from tryptophan. 

On the other hand, chorismic acid, which is derived from shikimic acid, is also a precursor of phenylalanine and tyrosine, which are essential amino acids [1]. Among the alkaloids, there is a group derived specifically from anthranilic acid, and this chapter presents some of these alkaloids. 

In the biosynthetic pathway of the alkaloids derived from anthranilic acid, the carbon atom corresponding to the carboxyl carbonyl group is included in the resulting alkaloids, except for those alkaloids with the phen-azine skeleton. The main groups of alkaloids derived from anthranilic acid are classified as quinoline, acridone, and quinazoline alkaloids. These alkaloids are typically isolated from rutaceous plants, except for febrifugine and related alkaloids, which possess the quinazoline skeleton these are isolated from plants of the Saxifragaceae family. 

In the biosynthesis of rutacridone, it is proposed that 1,3-dihydroxyacri-done is first formed from anthranilic acid and three C2 units, then the N-10 nitrogen is methylated to form 1,3-dihydroxy-N-methylacridone. Next, a C5 unit, IPP or DMAPP, is attached to 1,3-dihydroxy-N-methylacridone to fc>rm glycocitrine II, which is probably oxidized to produce an as-yet-uniden-tified epoxide. The epoxide is cyclized and dehydrated to give rutacridone [4]. Though rutacridone is a small molecule, as in the case of the quinoline alkaloids, three main biosynthetic precursors are involved in the biosynthesis of this alkaloid. Namely, the shikimic acid, the polyketide, and probably the iso-prenoid pathways all provide precursors for the biosynthesis of rutacridone. 

An additional group of alkaloids that arises from anthranilic acid, the harman alkaloids, is discussed in Chapter 35. Avenalumins, 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), and related compounds are treated in Chapter 7. 

Both the H- and C-NMR (nuclear magnetic resonance) spectra and techniques for the isolation and characterization of several groups of alkaloids derived from anthranilic acid have been reviewed (Crabb, 1982 Gray, 1993). The results of feeding studies leading to several alkaloids derived from anthranilic acid have been tabulated (Leete, 1983). 

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