Synthesis of ergoline ethers
Creators: name: Thompson, Brian Lee
Publisher: name: University of Utah
Year: 2012
Subjects: Chemical Synthesis
Ethers

description: The photoaddition of water to the ergot clavinet alkaloid, lysergene, has been reported by Shough and Taylor.  The product of this reaction, 10-hydroxyagroclabine, was found to rearrange in aqueous acid to give the 8-hydroxy derivative setoclavine.  A second photoaddition of water than gave the 8,10-dihydroxy derivative, lumisetoclavine.  It was suggested that this same series of reactions could be run in alcohols to give the analogous 10-alkoxy, 8-alkoxy, and 8,10-dialkoxy ergoline ethers.  Ergolene ethers of this type and clavinet alkaloids, in general, are of current interest due to the recently described prolactin inhibition of certain clavinet alkaloids and the patent alpha-adrenergic blockage of the ergoline ether, nicergoline.  The main objective of this study, then, was to attempt the synthesis or ergolene ethers by various methods including the photoaddition of alcohols to lysergene.  It was also anticipated that certain of these ergolene ethers could be useful as intermediates in a new synthesis of lysergic acid amides starting from the clavinet alkalid elymoclavine.  The photoaddition of methanol to lysergene was accomplished to give 10 alpha-methoxyagroclavine.  This photoaddition reaction was not successful in higher alcohols, however.  The 10 alpha-methoxyagroclavine was, therefore, used to obtain the 8-methoxy, 8-ethoxy, 8-n-proposy, 8-isopropoxy and 8-n-butoxy derivatives by acid catalyzed equilibration in the appropriate alcohol.  An attemp to synthesize the 8,10-dialkoxy derivatives by a second photoaddition of alcohols was, again, unsuccessful.  The failure of this second photoreaction seems to indicate that the photoaddition of alcohols across the 9,10 double bond of ergot alkaloids to form the limi-derivatives in not as general a reaction as had previously been supposed.  Two nonphotochemical methods were also investigated in an attempt to synthesize ergoline ethers.  The solvomercuration-demercuration procedure of Brown was attempted with lysergene, lysergine, agroclavine, elymoclavine and lysergol.  This procedure was unsuccessful in our hands, however, as the starting materials were recovered unchanged.  The oxidation of agroclavine with manganese dioxide in methanol was also attempted.  The expected 10-methoxyagroclavine appeared to be the product along with some lysergene.  The yield was poor, however, and the product could not be isolated.  When this reaction was run in t-butanol, lysergene was isolated in about 20 percent yield.  Earlier, in this lab, we synthesized the 10 alpha-methoxy-delta8,0-lysergaldehyde from elymoclavine.  In the present study this aldehyde was reduce with sodium borohydride to form a 10 alpha-methoxyelymoclavine which was then rearranged in acidic methanol to give the 8-methoxy-6-methyl-delta9,10-8-hydroxymethylergoline.  Also, in this lab, Choong was able to synthesize the lysergic acid methyl ester by a cyanide catalyzed, manganese dioxide oxidation of the 10 alpha-methoxy-delta-8,9-lysergaldehyde.  A modification of this procedure was used in this study to synthesize a series of lysergic and isolysergic acid amides.  The cyanide catalyzed, manganese dioxide oxidation was run  in the presence of the appropriate amine to give 10 alpha-methoxy-delta8,9,-lysergic acid amide, 10 alph-methoxy-delta8,9-lysergic acid piperidine amide, and 10 alpha-methoxy-delta8,9-lysergic acid L-2-amino-1-propanol amide.  The 10-methoxy group was then reduced with zinc and acetic to give isomeric lysergic acid amides.  This represented the first synthesis of lysergic acid from the clavinet alkaloid elymoclavine.