White, Nicola Jane; (2005) Studies towards a biomimetic synthesis of agelastatin A. Doctoral thesis , UCL (University College London).

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Abstract

Agelastatin A is a tetracyclic alkaloid isolated from the marine sponge Agelas dendromorpha. It exhibits cytotoxicity towards KB and lymphocytic leukaemia cells, arthropod toxicity and insecticidal activity and selectively inhibition of glycogen synthase kinase-3. Agelastatin A is one of a structurally related group of pyrrole- imidazole alkaloids derived from the "linear" skeleton of oroidin and it is postulated that it is biologically derived from oroidin via the generation of an N-acyliminium ion, which undergoes two cyclisations, via a second N-acyliminium ion, followed by hydration to afford the natural product. This thesis describes the work undertaken towards the biomimetic synthesis of Agelastatin A and efforts towards the synthesis of an oroidin-like precursor from which the N-acyliminium ion could be generated. Disconnection of the precursor gave a 3-pyrroline A-ring, which was prepared using a Birch reduction, but efforts to synthesise the D-ring imidazolone fragment were hampered by low solubility, necessitating the use of protecting groups. Selective introduction of the Z-alkene was made difficult by conjugation to the imidazolone and efforts to maintain the Z-alkene geometry failed. Parikh-Doering oxidation of a propargylic alcohol intermediate afforded a novel thioaldehyde that underwent an acid-catalysed cyclisation via an N-acyliminium ion analogous to the second N-acyliminium ion in the proposed biomimetic synthesis. The thioaldehyde forced the required alkene conformation and was therefore applied in the synthetic route to the imidazolone fragment. The introduction of a leaving group was ultimately unsuccessful, but a precursor for generation of the ion by oxidation was prepared by reductive amination of the corresponding aldehyde. The precursor was treated with trityl tetrafluoroborate but the expected oxidation did not occur, instead an acid-catalysed cyclisation was observed. This cyclisation again proceeded via an N-acyliminium ion analogous to that predicted to be generated in the biomimetic synthesis, to afford a novel bicycle. Therefore although the double cyclisation required for the biomimetic synthesis was not mimicked, the two novel cyclisations provide good evidence that both cyclisations are plausible.

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