Die Synthese der Alkaloide der Ergotoxin‐Gruppe. 70. Mitteilung über Mutterkornalkaloide [1]

Abstract

The syntheses of the alkaloids of the ergotoxine-group z.e. ergocristine, aand bergokryptine, and ergocornine, are described. Using starting material with known stereochemistry these syntheses allowed to determine the absolute configurations also a t C-2' and C-12' in the peptide part, which could not be derived from analytical data. All crgot alkaloids of the peptide type possess t h c same stereochemical structure.Die Peptid-Mutterkornalkaloide Ergocristin, aund p-Ergokryptin und Ergocornin werden unter der Bezeichnung Ergotoxin-Gruppe zusammengefasst, weil ein isomorph kristallisierendes Gemisch dieser Alkaloide fruher fur ein einheitliches Alkaloid gehalten und als ((Ergotoxin)) bezeiclinet worden war [2] 131. Diese Alkaloide bilden auch in cheniiscli-struktureller Hinsiclit eine Gruppe, indeni sie in ihrem Peptidteil den gleichen a-Hydroxy-a-amino-saure-Baustein, namlich das a-Hydroxy-L-valin, enthalten und sich dadurch von den Alkaloiden der Ergotamin-Gruppe, denen das a-Hydroxy-L-alanin gemeinsain ist, und vom Ergostin, das als Bindeglied zwischen Lysergsaure-Rest und Peptidteil a-Hydroxy-L-a-aminobuttersaure aufweist, unterscheiden. (Vgl. allgemeine Formel A).

Dihydroergotoxine: Separation and Determination of Four Components by High-Performance Liquid Chromatography

“…The Arya I1 variety from western Iran has a particularly high content of thebaine (5). The Arya I1 variety from western Iran has a particularly high content of thebaine (5).…”

“…; stationary phase, C, 10 prn; mobile phase, acetonitrile-lO-* M ammonium carbonate in water (0.82:l v/v);jlow, 7 mllmin; pressure, 5000 psi; detection, 280 nm and 0.4 absorbance unit; and injection, 50 p l of oral solution = 50 pg of dihydroergotoxine mesylate.Chromatographic conditions for different stationary phases were: Phase C,5 pm in a 15-cm column, 3 mm i.d., water-acetonitrile-triethylamine ( 3 2 8 1 v/v/v) with a 1.0-ml/min flow, corresponding to a linear velocity of 0.3 cm/sec and a pressure of 4000 psi; Phase B, water-acetonitrile-triethylamine (75:40:1 v/v/v) with a 0.8-ml/min flow, corresponding to a linear velocity of 0.3 cm/sec and a pressure of 2000 psi; and Phase D, water-acetonitrile-triethylamine (22.811.4:l v/v/v) with a 2.0-ml/min flow, corresponding to a linear velocity of 0.4 cm/sec and a pressure of 5000 psi. The conditions were: column, 30 cm X 4.6 mm id.…”

Synthetic Route to Ergot Alkaloids

“…Above, we described the synthesis of the ()-lysergic acid (32a) component of a-ergocryptine (1). The synthesis of the peptide part has already been described [32] by a research group from Sandoz Pharmaceutical Co. Our task was to improve the efficiency, especially the efficiency of the reaction sequence concerning configuration, and to make a scale-up procedure possible.…”

“…The malonic acid derivative ()-37 was transformed to the acid chloride and allowed to react with lactam 39, the product was deprotected by hydrogenolysis, and the resulting cyclolester was hydrolyzed to the socalled cyclolcarboxylic acid. After several steps, 40 was obtained [32]. Several methods were tried for the coupling of ()-lysergic acid (32a) with the peptide part 40.…”

“…By reacting the suspension of the aminocyclol hydrochloride (40) in CH 2 Cl 2 with lysergic acid chloride hydrochloride [34] at À 128 in the presence of pyridine, a-ergocryptine (1) was isolated in 41% yield (as its phosphate salt) [35]. In the coupling procedure, due to a partial epimerization of the lysergic acid part at C(8), a-ergocryptinine (41) [32] was also formed and isolated (31%) after chromatographic workup. Since a thermodynamic equilibrium exists between the two stereoisomers in favor of 1 (1/41 3 : 1) in boiling MeOH or in other solvents [36], in principle there is a possibility to transform 44 into 1 on a preparative scale.…”