Total synthesis of (−)-neovibsanin G and (−)-14-epi-neovibsanin G and synthetic studies towards other related caged neovibsanins

Vibsanins are rare diterpenoid natural products derived from the Viburnum species, which can be divided into three subtypes based on their carbon skeleton: eleven membered ring compounds, seven-membered ring compounds, and the rearranged type, also known as the neovibsanins. The neovibsanins can be further divided into three subclasses; the bicyclic, ketal, and caged neovibsanins. The natural products (±)-2-O- methylneovibsanin H and (±)-neovibsanin B represent respective targets from the bicyclic and ketal subclasses that have succumbed to total synthesis via biomimetic routes. As the synthesis of the caged neovibsanins had not previously been explored, the synthesis of this subclass was needed in order to further substantiate the biosynthesis proposed by Fukuyama. Furthermore, successful synthesis of the caged neovibsanins would contribute towards the development of a general synthesis of the neovibsanins. In the light of this, the first synthesis of two natural products belonging to the caged subclass, (−)- neovibsanin G and (−)-14-epi-neovibsanin G, was completed (Chapter 2). Key to this endeavour was a late stage ethyl aluminium dichloride mediated skeletal rich cascade leading to the bicyclo[3.3.1]nonane core in one step. This established the absolute configuration of neovibsanin G and 14-epi-neovibsanin G as 11S. The success of this biogenetically inspired synthesis lends overwhelming support for Fukuyama’s proposed biosynthesis of the neovibsanins. It was postulated that both 15-O-methylneovibsanin F and 14-epi-15-O-methylneovibsanin F were artefacts of isolation formed during the process of isolating neovibsanin G and 14-epi-neovibsanin G, which involved a prolonged methanolic extraction. Based on this hypothesis, efforts were made to divert the aforementioned successful synthetic route towards the synthesis of these oxygenated caged neovibsanins (Chapter 3). The results of this campaign, however, suggested that the artefact hypothesis was incorrect. Only the core of 14- epi-15-O-methylneovibsanin F could be accessed, while the 15-O-methylneovibsanin F core eluded synthesis. Chapter 4 details a separate synthetic campaign towards 15-O-methylneovibsanin F, utilising a early stage bicyclo[3.3.1]nonane cyclisation approach. Although this led to the synthesis of an advanced bicyclic intermediate, the construction of the final ring system could not be completed. Despite these setbacks, this study nonetheless established unprecedented synthetic access to the caged neovibsanins. Moreover, the findings of this study may lead to the synthesis of spirovibsanin A, a complex and structurally related natural product which has thus far eluded synthesis (Chapter 5)