Ergot alkaloids precursors

The Schmidt reaction with the dienone 11/102 (Scheme 11/15) yields the 1,4-thiazepine, 11/103. Treatment of its dihydroderivate, II/104, gives exclusively the enlargement product 11/105, in which the methylene group migrated [82]. A similar reaction can be observed if the synthetic ergot alkaloid precursors of type 11/106 are treated with in situ generated hydrazoic acid. Again no trace of the isomeric lactam can be observed [83]. 

Carbon-carbon double bonds directly attached to indole rings have been shown to participate in cyclization reactions. The vinyl ether (395), on treatment with A -methylhydroxylamine, undergoes a 1,3-dipolar cycloaddition to the adduct (396) (Equation (110)) <85JA2569>. The intramolecular addition of a nitroalkane anion to an allylsulfinate gives a similar ergot alkaloid precursor (Equation (111)) <86TL3169>. 

Kozikowski AP, Ishida H, Chen YY (1980) New Synthesis and Some Selected Reactions of the Potential Ergot Alkaloid Precursor Indole-4-carboxaldehyde. J Org Chem 45 335... 

Agurell, S. and Lindgren, J.-E. (1968) Natural occurence of 4-dimethylallyl-tryptophan— an ergot alkaloid precursor. Terahedron Lett., 5127-5128. 

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. 

Protoplasts of C. purpurea have been prepared which are able to synthesize the peptidic ergot alkaloids ergotamine (69) and ergocryptine de novo.63 Various radioactive amino-acids were incorporated into the alkaloids, and D-lysergic acid (70) stimulated their utilization. It was the only precursor to stimulate the synthesis of alkaloids, and the proposal was made that the concentration of (70) in the cells is a rate-limiting factor in alkaloid synthesis. 

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. 

Synthesis of the eco-analogues 173 of ergot alkaloids was achieved employing an intramolecular Heck-reaction on the precursor 174, followed by full deprotection of the intermediate 17S. The same ring system was also created by a ring-closing metathesis approach <03OL3519>. 

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. 

Dimethylallyltryptophan (139) has been identified as the first intermediate after tryptophan in ergot alkaloid biosynthesis.In experiments with a Claviceps species, clavicipitic acid (140) was identified as a major product formed from (139).(The enzyme catalysing this transformation was identified in both the supernatant and microsonal fractions oxygen is necessary for the reaction but cytochrome P-450 does not appear to be involved.) But radioactive clavicipitic acid was found to be a much less efficient precursor than (139) for elymoclavine and thus is in all probability not an intermediate in ergot alkaloid biosynthesis. 

Chanoclavine-I (119), festuclavine (130), dihydroelymoclavine (131), and di-hydrolysergic acid (132) were found to be present in S. sorghi The dihydrobases (130), (131), and (132) were shown to be similarly efficient precursors of (129), which suggested the biosynthetic sequence (130)— (131)— (132)- (129). This is in contrast to normal ergot alkaloid biosynthesis where successive oxidation of the C-8 methyl group occurs on A -substrates. 

Autacoids are endogenous molecules with powerful pharmacologic effects but poorly defined physiologic roles. Histamine and serotonin (5-hydroxytryptamine 5-HT) are two of the most important autacoids. Both are synthesized in the body from amino acid precursors and then eliminated by amine oxidation the pathways of synthesis and metabolism are very similar to those used for catecholamine synthesis and metabolism. The ergot alkaloids are a heterogeneous group of drugs that interact with serotonin receptors, dopamine receptors, and alpha receptors. They are included in this chapter because of their effects on serotonin receptors and on smooth muscle. 

Intramolecular alkylation can be accomplished by generating an appropriate electrophilic site. Because of the availability of 3-substituted precursors, most examples involve cyclization at the 2-position, designated herein as [3-2]. However, [2-3] and [1-2] cyclizations are also common. The ergot alkaloids, as well as other natural products, have been obtained by [3-4] cyclization. 

Directed biosynthesis is a possible method for the synthesis of new ergot alkaloid molecules and for probing the biosynthetic pathway by feeding Claviceps spp. with natural and unnatural amino acids and synthetic precursors. 

FIGURE 1.8 L-tryptophan, with its aromatic side chain, is a precursor of indole, terpenoid indole, quinoline, pyrroloindole, and ergot alkaloids. 

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