Towards a spintrap for superoxide

• Main Author: Gibson, N.
• Published: University of Aberdeen 1991
• Subjects: 547.59
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.592486

Several approaches to the synthesis of 1-pyrroline 1-oxides bearing an ester or alkyl halide substituent at 3-C were investigated. These compounds were sought as potentially useful spintraps for the superoxide radical anion. 5,5-Dimethyl-l-pyrroline 1-oxide (DMPO), 3,5,5-trimethyl-l-pyiroline 1-oxide (MesPPO), 2,5,5-trimethyl-l-pyrroline 1-oxide (TMPO), 4-phenyl-5,5-dimethyl-l-pyrroline 1-oxide, 2-phenyl-5,5-dimethyl-l-pyrroline 1-oxide and 2,3,5,5-Tetramethyl-3-Hydroxy-l-pyrToline 1-oxide were prepared by standard procedures. 3-Phenyl-5,5-Dimethyl-l-pyrroline 1-oxide (DMPPO) was isomerised to 3-Phenyl-3-Hydroxy-5f5-Dimethyl-1-pyrroline upon treatment with aqueous acid. This process was investigated by 1H nmr spectroscopy. DMPPO was rapidly destroyed by aqueous base and was isomerised to 3-phenyl-5,5-dimethyl-2-pyrrolidinone upon treatment with non-aqueous base. The alkylation and acylation of the enamines of 4-methyl-4-nitropentanal and 2,4-dimethyl-4-nitropentanal was slow in the absence of a Lewis acid catalyst. However the corresponding 2-dimethoxymethylaldehydes were obtained from the enamines upon treatment with stannic chloride and trimethylorthoformate and were selectively reduced to the corresponding 2-dimethoxymethyl-4-hydroxylaminopentan-l-ols. The acid-catalysed de-protection of these formyl acetals did not result in the formation of the expected 3-hydroxymethyl-1-pyrroline 1-oxides. DMPO and DMPPO reacted as an oxygen nucleophile when treated with ethyl chloroformate and acid halides in the presence of either sodium hydride or lithium diisopropylamide and gave 3-acyloxy-l-pyrrolines as products. No 3-keto-l-pyrroline 1-oxides, formed from reaction at 3-C, were isolated although some evidence of their formation in small yield was obtained from esr spectroscopy. No benzylation was observed when either DMPO or DMPPO was treated with benzyl bromide and LDA. Benzoyla-tion of MesPPO gave 3-benzoyloxy-5f5-dimethyl-l-pyrroline. Benzoylation of 4-phenyl-5,5-dimethyl-1-pyrroline 1-oxide gave 2-benzoyloxy-4-phenyl-5,5-dimethyl-pyrrolidine. Benzoylation of 2,3,5,5-Tetramethyl-3-Hydroxy-l-pyrroluie 1-oxide resulted in the dimeric tricyclic acyloxyamine 5,6,8,8^',5 -heptamethyl-3'-hydroxy-6, 1 '-dibenzoyloxy-2-oxa-1 -azabicyclo[3.1.0]octane-3 -spiro-2' -py rrolidine. The peroxyacid oxidation of 3-acyloxy-l-pyrrolines bearing one substituent at 3-C gave the corresponding oxaziridines in good yield and in enantiomeric excesses between 62 and 100%. Increasing the size of a co substituent at 3-C resulted in a corresponding decrease in the selectivity of the oxidation. The oxaziridines were unexpectedly resistant to rearrangement in ethanolic hydrogen chloride. 2,2-Dimethyl-4-benzoyloxy-6-oxa-l-azabicyclo[3.1.0]hexane isomerised to 3-benzoyloxy-5,5-dimethyl-2-pyrrolidinone when heated at reflux in xylene.