Clavines, synthesis

As mentioned in Section 10.1.2, Padwa and co-workers (40,41) employed the Pummerer reaction to generate and trap isomtinchnones. This group (190,191) has now adapted the intramolecular version of this tactic to the synthesis of several alkaloids of the pyridine, quinolizidine, and clavine classes. In each case, a 2-pyridone serves as the keystone intermediate. For example, Kuethe and Padwa (190) employed this Pummerer reaction of imidosulfoxides that contain tethered iz-bonds in a formal synthesis of the frog alkaloid ( )-pumiliotoxin C. They also used this methodology to synthesize the azafluorenone alkaloid onychine (295) (Scheme 10.42) (191). Generation of the thionium ion 291 under standard... 

To begin with the more classic transformations, the total synthesis of a clavine alkaloid, (+ )-isosetoclavine (24) reported by Kornfeld and Bach (27) deserves mention. Using the same tetracyclic ketone (23) as starting material as in their famous synthesis (28) of lysergic acid (43) (cf. Vol. VIII) 24 was built up stereospecifically in two steps as demonstrated below. 

In his thorough review (385 references), Voigt (55-57) covers the literature up to 1967. The article also comprises microbiological aspects of alkaloid synthesis in saprophytic cultures as well as in vivo studies. Biogenetic interrelationships between different species of clavine alkaloids apart from the main pathway are also discussed there. 

In saprophytic cultures of the Pennisetum ergot fungus, only tryptophan, deuterated in the 5 or 6 position, was used for the synthesis of the clavine alkaloids without loss of the deuterium. Deuterium in the 4 position was lost. These experiments showed that the hypotheses, according to which 5-hydroxytryptophan would be an intermediate stage in the biosyntheses (126, 127), could not be correct (128). 

Dehydrogenation. The final step in a total synthesis of the ergot alkaloid activated manganese dioxide in chloroform at 25°. ... 

A general synthetic route from elymoclavine (56 A ) to a variety of substituted A -ergolenes, by displacement reactions on the related allylic chloride, has been developed. A rather more exciting contribution is the partial synthesis of agro-clavine (63) from chanoclavine-I (61) and isochanoclavine-I (62) (Scheme 9) the... 

Ergot alkaloids are derived from the fungus Claviceps purpurea, which grows on rye and other grains. These alkaloids are extracted from ergot produced parasitically on rye. These compounds may also be produced by partial or total synthesis. There are four different classes of ergot alkaloids clavine... 

In the 1980s Muratake and Natsume (202) in a number of reports presented a new, interesting approach to the synthesis of substituted indole derivatives that focused on their use as intermediates in the preparation of a variety of clavine alkaloids and mycotoxins. The method elaborated by the authors consisted of constructing the specifically substituted benzene portion of the indole nucleus, with 1-methoxycarbonylpyrrole being the starting material. The functionalized 4-alkylindole thus obtained was transformed to a tricyclic indole derivative which appeared to be a common intermediate for the synthesis of several ergot alkaloids, as exemplified by the synthesis of ( )-dihydrosetoclavine (203-205) (Scheme 42). Recently, the application of this method was extended by the authors (206) to the syntheses of a series of marine alkaloids, the hapalindoles. Most of these alkaloids have a tetracyclic framework made up of 3,4-substituted tryptamine and two isoprene units. 

Synthesis of Clavine Alkaloids and Lysergic Acid Derivati Use of Tryptophan as the Starting Material. ... 

Synthesis of Clavine Alkaloids and Lysergic Acid Derivatives... 

The synthesis of dimethylallyltryptophan (132) by a crude extract of Claviceps purpurea from tryptophan and dimethylallyl pyrophosphate recorded earlier has been reported again recently. In addition to (132), the formation of (133) was observed. (The latter compound, with unspecified stereochemistry around the double bond, has also been isolated from a C. purpurea culture ). It was found further that both (132) and (133) could act as precursors for lysergic acid amides in C. paspali cultures. Both (133) and its (Z)-isomer have been found to act as precursors for elymoclavine (137) but not chanoclavine-I (138) or agro-clavine (136), which are considered to be normal intermediates in elymoclavine biosynthesis.It may be concluded, however, from the combined evidence, that elymoclavine, lysergic acid, and related compounds may normally be formed along an alternative pathway via these allylic hydroxy-compounds. 

Bemardi L, Gandini E, Temperilli A (1974) Ergoline Derivatives. XIV. Synthesis of Clavine Alkaloids. Tetrahedron 30 3447... 

Fig. 9. Inhibition of alkaloid synthesis by elymo-clavine in protoplasts of Clavlceps strain SD 58.

Biosynthesis. In Claviceps purpurea, and presumably also in higher plants, E.a. are biosynthesized from tryptophan and isopentenylpyrophosphate (see Terpenes). Synthesis proceeds via 4-dimethylallyl-tiyptophan, which is converted into the alkaloid chanoclavine (by hydroxylation, methylation, decarboxylation and formation of a new C-C bond). All the other clavine alkaloids and the lysergic acid derivatives are derived from chanoclavine. The peptide moieties of the ergotamine and ergotoxin alkaloids are formed by a multienzyme complex (Fig. 2). E.a. are prepared from the sclerotia of rye, previously inoculated with Claviceps and they are also produced by culture of the fungus on artificial growth media. 

Cavender, EL. and Anderson, J.A. (1970) The cell-free synthesis of clavine alkaloids. Biochem. Biophys. Acta, 208, 345-348. 

The synthesis of clavine derivatives substituted in the C-14 position was described by Benes and Beran (1989). A mixture of 1-ferf-butyl-, -0-d -tert-butyl-, 2, 13-di-tert-butyl- and 2, 14-di-fert-butyl-elymoclavine resulted from the reaction of elymoclavine with tert-butylalcohol and trifluoroacetic anhydride. Sauer et al. (1990) prepared 13, 14-dibromo derivatives by bromination of 2-methyl-ergolines by different bromination reagents (bromine, pyridinehydrotribromide, pyrrolidone-hydrotribromide) in trifluoroacetic acid. When only one equivalent of bromine was used, 13-bromo derivative was preferentially formed. 

Bernard , L., Gandini, E. and Temperilli, A. (1974) Ergoline derivatives-XIV. Synthesis of clavine alkaloids. Tetrahedron, 30, 3447-3450. 

Sajdl, R, Kozova, J. and Reha k, Z. (1978) Synthesis of clavin alkaloids and basic metabolism of a submerged culture of Claviceps purpurea 129. Abstract Book, 14tb Ann. Meet. Czecboslov. Soc. Microbiol., Prague, October 17—19, 1978, 30. 

Another system which Floss et al. (1974) describe regulates alkaloid precursor synthesis, which had been studied to some extent in the ergot fungus Claviceps purpurea. The clavine ergot alkaloids are derived from tryptophan, mevalonic acid, and the methyl group of methionine (Weygand and Floss, 1963) in the biosynthetic pathway shown in Figure 6.35. Ross et al. (1974) and Arcamone et al. (1962) have studied the effect of various... 

Synthesis of (-)-aurantioclavine, (-)-lobeline, and (-)-sedamine Several alkaloids contain chiral benzyl alcohol residues and they can be prepared via oxidative kinetic resolution of the corresponding racemic mixtures. Examples of the application of Pd(II)-(—(-sparteine catalyst to this class of natural products were provided by Stoltz et al. " that proposed alternative synthesis for (—(-aurantio-clavine 133, which is an ergot alkaloid that contains a tricyclic ring system and a single stereocenter. The... 

With slant cultures of an Elymus-type Claviceps strain, Ohashi and Abe (1970) obtained cell-free conversion of agroclavine and elymoclavine to peptide alkaloids. There have been no reports so far of cell-free peptide alkaloid synthesis with shake cultures. Groger s laboratory (Maier et al., 1972) studied the activation reactions that could be involved in peptide alkaloid biosynthesis. They observed cell-free synthesis of lysergyl-CoA and activation of valine, serine, leucine, and proline. Activation was found in nonproducing, clavine alkaloid-producing, and peptide alkaloid-producing strains. The connection between these activities and peptide alkaloid synthesis is therefore uncertain. 

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