Abstract:
Annotinolide C (26) is a lycopodium alkaloid which was isolated from the club moss Lycopodium annotinum, native to China, in 2016. Annotinolide C (26), along with the other natural products within the family, are the first lycopodium alkaloid to show inhibitory activity against amyloid beta aggregate formation (inhibitory ratio at 50 µM, annotinolide C (26): 36.1%); a key pathogenesis in the development of Alzheimer’s disease. Annotinolide C (26) possesses a highly complex caged structure comprised of a 7,8-seco-lycopodane-derived 8,5-lactone bridge and an α-tertiary amine centre (C-13). Additionally, annotinolide C (26) contains an unprecedented spirobutenolide motif rendering it unique in comparison to conventional lycopodium alkaloids. The complex molecular architecture of annotinolide C (26) makes it an attractive target for total synthesis. This thesis will describe the synthesis of core structure 149 and synthetic endeavours towards the elaboration of core 149 to annotinolide C (26). . . The synthetic strategy towards model core 149 hinged on construction of the tricyclic scaffold from an intramolecular furan addition of reactive iminium species 150, which in turn, would be generated in situ from hemiaminal 261. Initially, the synthesis of tricyclic cores 313a/b was achieved by the reduction of lactam 303, followed by the intramolecular cyclisation of resulting hemaiminal 308, giving the cycloadducts with pronounced diastereoselectivity for diastereomer (±)-313a (18:1, (±)-313a: (±)- 313b). was subsequently used to access enone (±)-325 over four steps. Addition of diethyl malonate to enone (±)-325 provided diester (±)-371 and a concurrent Boc deprotection and epimerisation of the C-4aꞌ (blue)stereocentre of diester (±)-371 produced ketoamines 372a/b (dr = 3.5:1), with major diastereomer (±)-372a possessing the relative configuration of annotinolide C (26). The lactone bridge of advanced intermediate 373 was thought to have been assembled through a reduction/lactonisation sequence of ketoamines 372a/b, affording the requisite tetracyclic framework of the natural product. Unfortunately, due to lack of advanced material and time restrictions complete investigations of this pivotal step were prohibited. This approach provides a foundation for the total synthesis of annotinolide C (26), whereby further investigations of this synthetic route may allow for the elaboration of lactone 373 to the natural product.