Tryptophan ergot alkaloids

Rebek, J., Jr., Tai, D.R, Shue, Y.K. (1984) Synthesis of Ergot Alkaloids from Tryptophan. Journal of the American Chemical Society, 106, 1813-1819. 

The a for ergot alkaloids is L-tryptophan and the j8 is four-steps alkaloid reaction chain. The

lysergic acid (Figure 71). Ergotamine and ergometrine are the best-known members of this group. 

Ergot Alkaloids.—4-(yy-Dimethylallyl)tryptophan (122) is the first intermediate beyond tryptophan in ergot alkaloid biosynthesis. Chanoclavine-I (127) is the first tricyclic base (cf. Vol. 10, p. 26, and ref. 2). Recently, (124 labels as shown) has been found to be a very efficient and intact precursor for elymoclavine (128).45 The high level of incorporation indicates that (123) is a probable intermediate situated between (122) and (127). The decarboxylation product (125) was not utilized for biosynthesis, so, although decarboxylation of (123) is required for the conversion of (123) into (127), either it is intimately associated with ring-closure or an imine that is related to (126) is involved. 

Since the last review on ergot alkaloids, important new alkaloids from different sources, mostly from new ergot strains, have been discovered. Their proposed structure could in some cases be confirmed by synthesis. Some of them seem to be intermediates in the biogenetic pathway from tryptophan to the peptide alkaloids. Others are considered as end products of secondary plant metabolism. In any case we find many interesting structures among these recently discovered substances. 

Ergot Alkaloids.—The enzyme which catalyses the first step in ergot alkaloid biosynthesis, namely the conversion of tryptophan into dimethylallyltryptophan (126),110 has been isolated from a Claviceps species and characterized.111 The biosynthesis of clavicipitic acid (127) may be a major alternative to the synthesis of other ergot metabolites, and further results in a study112 of an enzyme from C. purpurea which catalyses the formation of clavicipitic acid (127) from (126) have been published.113... 

In P. semperviva it has been demonstrated that tryptophan is a precursor of psilocybin (93a). It was simultaneously suggested that a similar oxidation of tryptophan or a tryptophan metabolite at the 4-position constitutes an important intermediate stage in the biosynthesis of the ergot alkaloids from tryptophan. 

In all hypotheses relating to the biogenesis of the ergoline-lysergic acid moiety of ergot alkaloids, it was assumed that tryptophan constituted a main structural element. This assumption was later shown by experiment to be correct. 

The biosynthesis of the ergot alkaloids involves condensation of dimethyl-allyl pyrophosphate (derived from mevalonic acid) with tryptophan. Closure of the C- and D-rings of the alkaloid involves specific hydroxylations by cytochrome P450-dependent oxidases and rearrangements. Further modifications involve N-methylation in the presence of S-adenosyl methionine and/or condensation with amino acids and peptides. Coupling of lysergyl CoA with certain peptides forms the peptide alkaloids which are the most bioactive of the ergot alkaloids. 

The formation of ergot alkaloids from L-tryptophan is well-known (Herbert, 1989 Groeger and Floss, 1998 Markert et al., 2008). L-Tryptophan condenses with dimethylallylpyrophosphate (DMAPP) to give y,y-dimethylallyltryptophan (DMAT), which is modified via chanoclavine 1 to give agroclavine and finally elymoclavine (Fig. 2.14). Lysergic acid maybe formed from this last alkaloid. 

Shibuya, M., Chou, H.-M., Fountoulakis, M., Hassam, S., Kim, S.-U., Kobayashi, K., Otsuka, H., Rogalska, E., Cassady, J.M. and Floss, H.G. (1990) Stereochemistry of the isoprenylation of tryptophan catalysed by 4-( Y, Y-dimethylallyl)tryptophan synthase from Claviceps, the first pathway-specific enzyme in ergot alkaloid biosynthesis. /. Am. Chem. Soc., 112, 297-304. 

The biosynthetic pathway to the ergoline nucleus proceeds through 4-dimethylallyl tryptophan (4-DMAT), chanoclavine-I, agroclavine, and lysergic acid. Two cis, trans isomerizations occur one before chanocla-vine-I and the other before agroclavine, as shown by experiments with [2- C]-mevalonic acid and [Z-CH3]-4-DMAT (Fig. 36). The peptide unit is derived from a combination of three amino acids, one of which is always proline. Several genera in the plant family Convolvulaceae Rivea, Ipomoea, etc.) also produce ergot alkaloids. 

The amino acid tryptophan is a precursor of several fungal metabolites that affect the central nervous system. We have already met it as a constituent of the ergot alkaloids. Roquefortine (9.25) is a metabolite of Penicillium roqueforti and P. camemberti, which are found on some cheeses. Roquefortine is one of a series of mycotoxins that affect the central nervous system and induce tremors. The more complex penitrems are tremorogenic neurotoxins that are produced by the P. crustosum series. They are biosynthesized from a tryptophan and a triterpene unit. 

Ergot Alkaloids.—The tryptophan and tryptamine derivatives (30) and (31) respectively, labelled in each case with 14C at the carbinol carbon, have been shown20 to be precursors of the alkaloids agroclavine (32) and elymoclavine (33). These results throw further light on the sequence of intermediates leading from tryptophan to the ergoline system. 

Wang J. dmaW encoding tryptophan dimethylallyltransferase in ergot alkaloid biosynthesis from Clavicipitaceous fungi. PhD dissertation, University of Kentucky, Lexington, KY, 2000. 

The early steps in the ergot alkaloid biosynthetic pathway are outlined in Fig. 1. The first determinant and rate-limiting step is the prenylation of tryptophan to 4-(y,y-dimethylallyl)tryptophan (DMAT), catalyzed by dimethy-lallyl-diphosphate L-tryptophan dimethylallyltransferase (DMAT synthase EC 2.5.1.34) (Heinstein et al., 1971 Gebler and Poulter, 1992). The prenyl group for the DMAT synthase reaction is provided in the form of dimethylallyl diphosphate (DMAPP), which is derived from mevalonic acid. After the formation of DMAT, the free amino group of this intermediate is N-methylated with a methyl group donated by S-adenosylmethionine (AdoMet). The N-methylated DMAT is then converted into chanoclavine I by closure of the... 

Figure 1 Key intermediate and enzymes from the first committed step in ergot alkaloid biosynthesis through the synthesis of lysergic acid. Simple amides of lysergic acid and ergopeptines are covered in Figs 2 and 3, respectively. Abbreviations DMAPP = dimethylallyl pyrophosphate DMAT = dimethylallyl tryptophan AdoMet = S-adenosyl-methionine.

Secondary metabolism leading to the ergot alkaloids begins with tryptophan. It has been found that the naphthylalanines... 

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