Chanoclavine I acid

The seeds of Ipomoea violacea, variety Pearly gates , were earlier reported to contain an ergoline acid of unknown constitution, which proves to be chano-clavine-I acid (56), since reduction (LiAlH4) gives rise to chanoclavine-I (57) conversely, oxidation of chanoclavine-I by means of manganese dioxide gives the related aldehyde, which, on further oxidation by manganese dioxide in methanol in the presence of cyanide ion, affords chanoclavine-I acid methyl ester directly. " ... 

Chanoclavine-I acid, a unique metabolite of Ipomoea tricolor Cav. (Choong and Shough 1977)... 

Choong TC, Shough HR (1977) The isolation and synthesis of chanoclavine-I acid. Tetrahedron Lett 3137-3138... 

The flrst total synthesis of chanoclavine I acid (47), a major alkaloid in the seeds of Ipomea violacea (48), was completed by Somei et d. who employed the key intermediate 51 for the formation of chanoclavine I (36), and also for the synthesis of chanoclavine 1 acid (69). Compound 51 was oxidized with pyridinium chlorochromate in dichloromethane to give the aldehyde 53, which was further oxidized to the carboxylic acid 64 by employing sodium hypochlorite in the presence of 2-methyl-2-butene (49), as shown in Scheme 11. 

Methylation of 64 with ethereal diazomethane afforded the methyl ester 65, which was then reduced with amalgamated zinc and hydrochloric acid to give the amine 66. Methylation of the primary amine with dimethyl sulfate in the presence of potassium carbonate afforded a mixture of the monomethylamine 67 and the (hmethylamine 68, which were separated. Alkaline hydrolysis of 67 in methanol and subsequent column chromatognq>hy on Ambo lite IRA-120 completed the total synthesis of ( )-chanoclavine I acid (69). 

In a related approach, Murakami synthesized clavicipitic acid and costaclavine [79], and later extended this chemistry to a synthesis of chanoclavine-I featuring the intramolecular Heck vinylation 240 to 241 [266], The corresponding enone failed to cyclize under these conditions. Noteworthy is that radical cyclizations, which often compete successfully with Heck reactions, were poor in this system. 

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. 

Ergot Alkaloids.—The hemiterpenoid unit of the ergot alkaloids is interesting in that, as expected, only one carbon atom is labelled by [2- C]mevalonic acid [marked by in formulae (14)—(17)] but the stereochemistry of this atom changes. Extensive studies by Floss etalf indicate that chanoclavine I (14) is converted into elymoclavine (17) via the aldehyde (15) and possibly via agroclavine (16) (however, see ref. 36a). This process involves two isomerisations about the isolated double bond. In dimethyl allyl pyrophosphate (5) the trans-methyl is labelled by... 

C]mevalonic acid. This stereochemistry is presumably retained in the C-4 alkylated tryptophane derivative (see also claviceptic acid ) which precedes chanoclavine I (14). When the stereochemistry is reversed to give (14) the 9-H, labelled by [2- C,3/ ,4/ - H]mevalonic acid, is retained. However, in the second reversal (15)—>(16) there is a significant loss of this hydrogen atom. Elemo-clavine is one of the few terpenoids for which it has been proved that only the (3/ )-enantiomer of mevalonic acid is metabolised (see footnote p. 224). 

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... 

Ergot Alkaloids.—Three new clavine alkaloids have been isolated from the saprophytic cultures of a strain of Claviceps paspali Stevens et Hall which produces as main metabolite 6-methyl-A -ergolen-8-carboxylic acid (37), together with chanoclavine-I, isochanoclavine-I, penniclavine, and elymoclavine. The new bases... 

Stereoselective allylic rearrangement. Irradiation of either chanoclavine-I (1) or isochanoclavine-1 (2) (ergot alkaloids) in the presence of sulfuric acid... 

Additional support was obtained by studying the incorporation of a 1 1 mixture of [2- C]- and [4- H2]-mevalonic acid into chanoclavine-I and elymoclavine. Mass spectral analysis showed that none of the chanoclavine-I molecules contained deuterium and C. On the other hand the elymoclavine and penniclavine were made up of molecules containing both C and deuterium. 

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. 

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. 

Incomplete substrate specificity or stereoselectivity of enzyme reactions appears to be responsible for several spur products, examples of which are shown in Scheme 10. Although different chanoclavine isomers are produced 10), the stereochemistry of the tetracyclic clavines and 1 implies that chanoclavine I (Id), but not chanoclavine II (30), is an intermediate. Also, 22 can isomerize spontaneously to 1 or isolysergic acid (31). Typically, both C(8) diastereomers of ergopeptines are obtained in preparations, and those with an isolysergic acid moiety - which are... 

Agroclavine is converted into elymoclavine (5) and ultimately into lysergic acid (1). An enzyme preparation that catalyzes the aerobic conversion of agroclavine to elymoclavine (in addition to several other types of activity) has been studied. Feeding experiments with mevalonate-3-D3 established that both methylene hydrogens at C-17 of chanoclavine I (7), but only one (at C-7) of elymoclavine (5) comes from C-3 of mevalonate. The hydrogen that remains was shown to be the pro-lS hydrogen. 

Infected individuals of several grass species are more resistant to a number of insect herbivores (Clay, 1988). Further, seeds of infected species are more resistant to herbivore attack (Cheplick and Clay, 1988). Lysergic acid amide (10), isolysergic acid amide, 8-hydroxylysergic acid (15), ergonovine, chanoclavine I (7), and A(-formylloline all were isolated from Stipa robusta infected with an Acremonium endophyte (Petroski et al., 1992 Powell and Petroski, 1992). 

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