Clavine alkaloids

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... 

A specific relationship between exogenous tryptophan and alkaloid level was found in P. roqueforti (Kozlovsky et ai, 1982 Reshetilova and Kozlovsky, 1985). This strain produces two types of alkaloids, clavines (festuclavine, isofumigaclavine A and isofumigaclavine B) (Figure 2) and diketopiperazines (roquefortine and 3,12-dihydroroquefortine) (Figure4) (Kozlovsky etal., 1979) that have both a common precursors—tryptophan and mevalonic acid. Exogenous tryptophan has different effect on these alkaloid types. Biosynthesis of diketopiperazines was enhanced by the precursor addition, whereas the production of clavines did not depend on the precursor and sometimes it was even inhibited by its addition (Reshetilova and Kozlovsky, 1985). 

For example, ergot alkaloids produce without exception blue chromatogram zones, while clavine alkaloids primarily produce green colors [4], Urea derivatives and primary aromatic amines yield yellow chromatogram zones [28,33,34,36,37] and PR toxin and PR imine emit intense blue fluorescence on excitation with long-wavelength UV light (X = 365 nm) [44],... 

Citrinine la 69,147,148 Citronellal la 158,159 CitroneUol la 68-70,327 Citronellyl acetate la 68 Claisen-Tischenko reaction 15 54 Clathrate complex 15 303 Clavin alkaloids 15 243 Clavine alkaloids 15 246,252 Cleanup la 119 Clemastin 15 354 Clenbuterol 15 106,107,354 Clobutinol 15 354 Cloforex 15 194,296 Clomethiazole lb 354 Clomipramine 15 352,354,355 Clonacillin lb 301 Clonidine 15 354 Clopamide 15 354 Clorexolon 15321 Clotrimazol 15 98,99,401,402 Cloxacillin 1584,188 Clozapin 15 354 Cnicin 15 290... 

Die Clavin-Alkaloide kommen besonders in Sklerotien verschiedener Claviceps-S cvts vor, die auf femostlichcn und afrikanischen Grasem parasitieren. Saprophytische Kulturen dieser Pilze bilden ebenfalls diese einfachen Ergolin-Dcrivatc. In Spuren sind sie auch in Sklerotien und saprophytischen Kulturen von Claviceps purpurea nachgewiesen worden. 

Da es auch gelungen ist, die spater zu besprechenden Clavine sterisch mit der Lysergsaurc zu verknupfen, ist auch die absolute Konfiguration der Clavin-Alkaloide gesichert. 

Tatsachlich konnte diese Arbeitsgruppe zeigen, daB Mevalonsaure in Clavin-Alkaloide 38) inkorporiert wird. Das ist der erstc experimentcUe Beweis uberhaupt, daB Mevalonsaure nicht nur eine Vorstufe fur typi-... 

Spilsbury, J. F., and S. Wilkinson The Isolation of Festuclavine and Two New Clavine Alkaloids from Aspergillus Fumigatus Fres. J. chem. Soc. [London] 1961, 2085. 

L. C. Vinmg, and R. A. Heacock Clavine and Lysergic acid Alkaloids in Varieties of Morning Glory. Ph3rtochemistry 2, 65 (1963). 

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... 

In an approach to the clavine alkaloids [170] based on intramolecular nitrone-alkene cycloaddition, the condensed tetracyclic system is probably favored by steric factors. Equilibration at higher temperature leads to predominantly a bridged oxabicyclo-[3.2.1]nonae derivative in which a portion of the molecule contains polarity alternation sequence (OCOC=0, N-C-C-C=0). 

The unusual structure of cycloclavine as the first known pentacyclic clavine alkaloid was derived from physical data (mass spectrum M+ 238 NMR signals of the cyclopropyl methylene group = 0.46 and 1.60) and some chemical transformations (hydrogenation, reductive ring opening, and quaternization). The remaining details of its constitution were finally determined by an X-ray analysis of the metho-bromide. Thus it was shown that the chirality of 11 is 5B, 8R, 10R. 

The first new alkaloid (C16H20N2O mp 276-278° [a]D —51° in pyridine) was identical with the hydrogenation product (15) of seto-clavine. The other two unknown alkaloids were called paspaclavine (16 C18H 22N20 mp 204-206° [a]D +88° in pyridine) and paliclavine... 

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. 

It had already been stated earlier that clavine alkaloids are formed from L-tryptophan and mevalonic acid, the methyl group in position 6 originating from methionine (53, 54). There was also evidence that 4-dimethylallyltryptophan (3) is an early intermediate in the biosynthetic pathway (58). 

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. 

Hydroxylation of clavine alkaloids in vitro can be brought about by horseradish peroxidase using hydrogen peroxide as the oxidant, and numerous other tissues (70). This leads only to 8-hydroxylation, e.g., no elymoclavine (54) can be detected from 53. On the other hand, this hydroxylation step also occurs in ergot as a minor metabolic pathway, but it will not be considered here in detail. The reader is referred to the review articles of Voigt (55-57) and of Ramstad (70). 

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