The synthesis of 8-substituted indolizidines from enaminone precursors

Abstract

Indolizidine alkaloids are found in several natural sources such as higher plants, fungi and bacteria as well as vertebrates and invertebrates from both marine and terrestrial sources. This dissertation describes investigations aimed at preparing indolizidines bearing carbon or heteroatomic substituents at C-8 as model systems for various classes of alkaloids. In addition, we intend to synthesise tricyclic benzo-fused indolizidine derivatives and attempt to introduce similar substituents into these compounds. Key intermediates in our approach are enaminones, which can show both electrophilic and nucleophilic behaviour. A convenient way to prepare them is to proceed via thiolactams, which allows for the Eschenmoser sulfide contraction with a- halocarbonyl compounds to make the enaminone intermediates. The simple bicyclic enaminone 2,3,5,6-tetrahydroindolizidin-7(1H)-one (54) was prepared in five steps and 22% overall yield. This was achieved by thionating pyrrolidin-2-one to pyrrolidin- 2-thione with phosphorus pentasulfide, followed by N-alkylation with acrylate esters, then Eschenmoser sulfide contraction with ethyl bromoacetate to give enaminones (vinylogous urethanes) in which the double bond was exocyclic to the pyrrolidine ring. The products were then cyclised to give ethyl 7-oxo-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate (55), which was hydrolysed and decarboxylated to give compound 54. Several addition and substitution reactions were then attempted on this compound, including acylation at C-8 with acryloyl chloride, alkylation with 1,4-dibromobutane, as well as oxygenation attempts with sodium percarbonate and meta-chloroperbenzoic acid, and amination with a diazonium salt. To extend our methodology to tricyclic benzo-fused analogues, ethyl 5-oxo-1,2,3,5- tetrahydropyrrolo[1,2-a]quinoline-4-carboxylate (49) and 4-ethyl 9-methyl 5-oxo-1,2,3,5- tetrahydropyrrolo[1,2-a]quinoline-4,9-dicarboxylate (101) were synthesised from methyl anthranilate. Synthesis of these compounds proved to be slightly more difficult, resulting in interesting side-products such as methyl 2-(methylamino)benzoate (91), methyl 2-{4-[2- (methoxycarbonyl)phenylamino]butanamido}benzoate (92) and 3a-methyl-3,3a-dihydro-1Hbenzo[ d]pyrrolo[2,1-b][1,3]oxazin-5(2H)-one (98)