Synthetic studies directed toward azaspirocyclic alkaloids using spironitrone intermediates

Foley, Michael (2024) Synthetic studies directed toward azaspirocyclic alkaloids using spironitrone intermediates. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

HTX 1 is a 6,6-azaspirocyclic alkaloid found to naturally accumulate in the skin of certain frog species and has shown to exhibit activity as a non-competitive inhibitor of neuromuscular and central neuronal nicotinic acetylcholine receptors. A structurally similar, 6,5-azaspirocyclic system, is seen in the marine anti-inflammatory alkaloids pinnaic acid 2 and halichlorine 3. Despite both halichlorine and pinnaic acid having different mechanisms of action, both exhibit anti-inflammatory properties of interest to the academic community. It is due to these properties of interest and the scarcity of this natural product analogue’s availability from their natural sources that have led to synthetic studies being undertaken. This study aimed to develop a common synthetic route to the core structures of all three natural products. The use of this approach towards a formal/total synthesis of all three and libraries of analogues was also investigated. The strategy centred on the use of a 6,5 or 6,6-spitonitrones 105 and 232 respectively. It was planned to access these nitrones by oxidative ring opening of the corresponding isoxazolidines 22 and 23. While the preparation of multigram quantities of nitrone 105 was achieved a similar oxidation of isoxazolidine 23 was unsuccessful. Nevertheless, isoxazolidine 23 was used to access 6,6-azaspirocycles such as 222 and 223. A similar library of 6,5-azaspirocycles was also accessed from the corresponding isoxazolidine 22. Nitrone 105 was used to access the core structures of both pinnaic acid 2 and halichlorine 3 via preparation of the allylated spirocycle 161 accessed via Grignard addition to nitrone 105. Furthermore, addition of a range of Grignard reagents to this nitrone was used to prepare a small library of pinnaic acid analogues. The core structure of pinnaic acid 2 was prepared from allyl-derivative 170 via oxidative cleavage and subsequent Wittig homologation. The quinolizidine core structure 181 of halichlorine was accessed via intramolecular RCM from diene 180 - also prepared from key allylated spirocycle 170. This thesis also investigated the further functionalisation of spirocyclic core 195 towards a formal synthesis of pinnaic acid. While homologation at C11 was achieved the formation of a rigid tricycle 192, to allow stereoselective introduction of the C12 methyl group of pinnaic acid was unsuccessful.