Date of Award

December 2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

James M. Cook

Committee Members

Alan Schwabacher, Mahmum Hossain, Andy Pacheco, MarK Dietz

Abstract

Part I. The first enantiospecific, stereospecific total synthesis of ervincidine 89 has been accomplished from commercially available D-(+)-tryptophan 37 which has served both as the chiral auxiliary and the starting material. Moreover, this is the first synthesis which unequivocally sets the stereochemistry of the hydroxyl group at C-6 in sterospecific fashion, as well as the C-16 hydroxy methyl group. The stereospecific conversion of D-(+)-tryptophan 37 into the key template (−)-Na-H, Nb-benzyl tetracyclic ketone 49 via the asymmetric Pictet-Spengler reaction (600 gram scale) and Dieckmann cyclization on multi-hundred gram scale was reduced to only two reaction vessels. The optically active tetracyclic ketone 49 was converted into the core pentacyclic framework 56 using the intramolecular palladium-mediated enolate cross coupling reaction which was developed here in Milwaukee to afford the core pentacylic framework 56. This robust reaction could be scaled up to multigram scale in this series. Important to success here were the sequence of chemical reactions which included a Wittig reaction, a regioselective hydroboration and protection/deprotection steps in order to provide regiospecific oxidation at C-6. The IBX mediated oxidation and the Luche reduction using CeCl3. 7H20 in the presence of NaBH4 afforded the first enantiospecific, stereospecific total synthesis of ervincidine 89. The indole alkaloid ervincidine 89 could be prepared from D-(+)-tryptophan 37 in 13 reaction vessels in 19.2% overall yield. Another important experiment was the epimerization of the C-6 alcohol with 0.2N HCl which indicated that care must be employed in isolation of these alkaloids which contain a benzylic hydroxyl group. This research process developed here also provides a general entry to the C-6 hydroxy substituted indole alkaloids of either alpha or beta stereochemistry. Two other diasteromers were made to rule them out as potential structures. This research corrects the errors in Glasby's book and Lousnamma's review and clarifies the work of Yunusov et al. as well as providing the correct absolute configuration of the C-6 hydroxyl function in ervincidine 89.

Part.II..GABAA/BzR chloride ion channels comprise the major inhibitory neurotransmitter system in the CNS. This central role carries with it a direct influence on many diseases of the CNS. Inverse agonists acting at α5 subunits containing GABAA receptors are thought to act as cognitive enhancers while eliminating unwanted side effects associated with non-selective compounds. From the recent work of Rowlett, Cook et.al. it was demonstrated that novel alpha5 selective inverse agonist PWZ-029 was evaluated as a cognitive enhancer in rhesus monkeys in the CANTAB paradigm. This ligand had the ability to reverse cholinergic deficits in performance induced by the antimuscarinic scopolamine under mixed trial conditions. In the ORD task, PWZ-029 showed only a modest trend for enhancement of performance, but when task difficulty was increased by testing with difficult trials only, PWZ-029 robustly increased performance. This enhancement was reversed by administration of the alpha 5 GABA (A) subtype selective antagonist XLi-093 and this antagonism in turn was reversed by increasing the dose of PWZ-029. In addition, PWZ-029 enhanced performance in the DNMS task using the 10 minute delay with distracters. This ligand also exhibited anxiolytic activity in some primates and was an orally active anticonvulsant in rats. These findings are consistent with a key role for alpha5 GABAA receptors in the treatment of age-associated memory impairment and Alzheimer's disease.

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