Pyroglutamic acid and 6 oxopipecolic acid as chiral synthons for compounds of medicinal interest

• Main Author: Ahmed, Omar
• Published: University of Sussex 2003
• Subjects: 547.7; Glutamate antagonists
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288609

Prevention of the neurotoxic effect that excess glutamic acid has on its receptors can lead to the treatment of a number of neurodegenerative diseases and pathological conditions. Developments of new methods for the stereospecific synthesis of novel amino acids will allow identification of compounds which might be effective at these receptors to be prepared. (2S)-Pyroglutamic acid was used as a chiral template for the synthesis of a key aldehyde for use in a novel synthesis of glutamate antagonists. Subsequent ring transformation ('ring-switching') reactions using bisnucleophiles then afforded a number of homochiral pyridazines that, when deprotected and oxidized, would possess the structural requirements of glutamate antagonists. A number of other routes requiring protection of the aldehyde were studied with the aim of synthesising a library of substituted homochiral pyridazines. Ring transformations involving an a, ß-unsaturated lactam with methyl hydrazine were also briefly studied, furnishing chiral pyrazolidin-3-ones with potential for glutamate receptor activity. The second area of research involved investigation of a stereoselective route to 5- alkylated 6-oxopipecolates from a 5-substituted enaminone. Initial attempts to prepare the enaminone tert-butyl ester from tert-butyl (2S)-N-tert-butoxycarbonyl-6- oxopipecolate were unsuccessful, but the enaminone methyl ester was eventually successfully prepared from methyl (2S)-N-tert-butoxycarbonyl-6-oxopipecolate. This enaminone was reacted with a number of Grignard reagents to afford a range of 5- alkylidene derivatives which were all (E)-isomers. Catalytic reduction of these was stereoselective and so an effective route to methyl (2S, 5S)-5-alkyl-6-oxopipecolates has been developed. A route involving alkylation of methyl (2S)-N-tert-butoxycarbonyl-6- oxopipecolate followed by enhancement of stereoselectivity using a hindered proton source was also investigated.