The oxidation of clavine alkaloids.
Creators: name: Choong, Tung-Chung
Publisher: name: University of Utah
Year: 2012
Subjects: Pharmaceuticals
Biosnthesis

description: Earlier studies have demonstrated the peroxidase oxidation of the delta8-ergolines agroclavine and elymoclavine to their respective 10-hydroxy-delta9, and other derivatives.  It was suggested that peroxidase may be involved in the biosynthesis of some of the ergot alkaloids.  The important biosynthetic intermediate chanoclavine-I is a tricyclic analog of agroclavine and elymoclavine and might be expected to undergo similar peroxidase-catalyzed oxidations but the expected products have not observed in nature.  However, the biosynthesis of the recently isolated rugulovasines could conceivably involve at some stage 10-hydrosylation such as occurs in the peroxidase oxidation of agroclavine and elymoclavine.  The main objective of this investigation was to study the effect of peroxidase on chanoclavine derivatives in an attemp to clarify the possible role of this enzyme in the biosynthesis of the ergot alkaloids.  The study later led in some unanticipated directions which resulted in the development of a new synthesis of lysergic acid derivatives and the isolation and synthesis of a new secoergoline alkaloid.  Chanoclavine-I (and isochanoclavine-I) was found to be readily oxidized by horseradish peroxidase.  However, in contrast to agroclavine and elymoclavine, this reaction provided a complex mixture of products which consisted largely of non-ergolines and only small amounts of unstable ergolines which could not be isolated and characterized.  Several observations suggested that oxidation was occurring primarily at C-10 as in the tetracyclic alkaloids and that an unstable 10-hydroxy derivative was formed.  The ease of decomposition of this key intermediate in ergoline biosynthesis suggested, however, that peroxidase may be more important in the biological degradation and lack of accumulation of ergolines than in their biosynthesis.  Chanoclavine-I-aldehyde was rather unexpectedly found to be resistant to the action of peroxidase.  For this reason, attempts were made to synthesize and determine the effects of the enzyme on its tetracyclic analog, delta-8-lysergaldehyde.  All efforts to prepare this compound from elymoclavine resulted in failure as they had earlier for other investigators.  However, these studies did result in the development of a three step synthesis of lysergic acid methyl ester from elymoclavine in an overall yield of approximately 30%.  This is the first successful attempt to convert an ergot clavinet to a lysergic acid derivative in reasonable yield and the results indicate that the method can be used to synthesize a variety of other lysergic acid derivatives.  An unidentified "ergoline acid" had been previously reported as the major alkaloid in the seeds of Ipomoea violacea var. "Pearly Gates."  Several suggested that this may be a chanoclavine acid derivative.  The alkaloid was isolated from the seeds of this plant in about 0.01% yield and was characterized as chanoclavine-I-acid.  The compound was also synthesized from chanoclavine-I-acid.  The compound was also synthesized from chanoclavine-I using a modification of the procedure used for the synthesis of lysergic acid methyl ester.  Chanoclavine-I-acid was also detected in the seed of I. violacea varieties "Heavenly Blue" and   "Flying Saucers" but no in those of Argyreia nervosa which suggests that it may be of value in the chemotaxonomy of the convolvulaceae family.  The alkaloid was also found in small amounts of a strain of Penicillium islandicum along with chanoclavine-I and the previously reported rugulova sines.  Interestingly, chanoclavine-I-aldehyde was also detected in cultures of this proposed intermediate in ergoline biosynthesis has been detected in nature.