Photodecarboxylative additions to phthalimides and their application in the synthesis of AKS-186 and its analogues
Hatoum, Fadi (2008) Photodecarboxylative additions to phthalimides and their application in the synthesis of AKS-186 and its analogues. PhD thesis, Dublin City University.
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Photochemical methods have been widely neglected by industry for the search of novel pharmaceutical lead compounds. The photodecarboxylative addition of various carboxylates to phthalimides has been developed in our group as a powerful access to hydroxyl- and methylene-isoindolinones. Likewise, the intramolecular version yields the corresponding cyclisation products.
In this thesis the intermolecular version, i.e. the photodecarboxylative addition of carboxylates to phthalimides, has been further investigated. Various heteroatom-substituted carboxylates have been studied in order to establish a mechanistic understanding of the photoinduced electron transfer processes involved. N-methylphthalimide was used as a model substrate and was irradiated at λ = 300 nm in aqueous acetone and in the presence of excess amounts of potassium carboxylates, the latter generated from the corresponding carboxylic acid and potassium carbonate. The evolution of carbon dioxide was tested using barium hydroxide solutions and was deemed positive when barium carbonate precipitation was formed. Among the carboxylates used were alkyl-, benzyl- and heteroatom-substituted carboxylates. Alkylated amino acid derived carboxylates solely underwent photoreduction whereas N-acylated amino acid readily furnished the desired addition products. To investigate the possibility of deactivation by certain electron-donors, various phthalimides with potential electron-donor substituents in the N-side chain have been studied. In these cases potassium propionate served as model carboxylate.
In an extension of the decarboxylative addition, alkyl benzoylformates were irradiated in the presence of sulphur-containing carboxylates and the corresponding addition products were obtained in moderate to good yields. Due to their less favourable electrochemical properties, these compounds do not undergo photoinduced electron transfer reactions with alkyl-, benzyl- or oxygen-containing carboxylates, respectively.
The optimised irradiation conditions were applied to the synthesis of AKS-186 and its derivatives. AKS-186 has demonstrated promising cardiovascular drug activities and became readily accessible from N-(4-acetoxybenzyl)phthalimide using the developed photochemical method as key-step. Depending on the nature of the chosen carboxylate the addition products were obtained in poor to good yield of 10-76%. Subsequent dehydration/deprotection gave the desired target compounds in good to excellent yield of 70-96%.
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