The total syntheses of ring -A substituted ergolines
Abstract
Three types of ergolines, having a substituent in ring A were designed and their total syntheses were attempted. N-substituted 12-methoxyergolines were synthesized as potential serotonergic agents to test the hypothesis of bioisosterism between the C8 carbonyl oxygen of LSD and an ortho oxygen or a 5-oxygen atom in hallucinogenic phenethylamines and tryptamines, respectively. To investigate the enhanced dopaminergic effect of 13-hydroxylation of ergolines, 2-hydroxybenzergolines and 13-hydroxyergoline were designed. A variety of approaches were examined to effect the construction of these targets. A classical approach involving the construction of 4-keto-7-methoxybenz[ cd ]indole as a synthon was unsuccessful. Several different attempts to prepare this tricyclic ketone all failed, apparently due to the decreased reactivity of the indole-4-position that results from the presence of the methoxy group at the 6-position of indole in the necessary precursors to the tricyclic ketone. Alternative synthetic approaches involved Suzuki cross-coupling of 6-methoxyindole-4-boronic acid with either a 4-substituted isoquinoline or 3-substituted pyridine precursor. Although the coupling reactions proceeded well, intramolecular ring closure reactions to construct ring C generally failed. Of particular note, however, is potential for a Hammick reaction to effect this transformation, and promising preliminary results in this thesis work suggesting that future efforts employing this approach may be fruitful. An additional promising route involved the Minisci reaction, which in this work was successfully employed to produce a 13-methoxy-4-oxoergoline.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology|Biomedical research|Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.