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

Jeffrey Yam Wing Mak (2011). Total synthesis of (−)-neovibsanin G and (−)-14-epi-neovibsanin G and synthetic studies towards other related caged neovibsanins PhD Thesis, School of Chemistry & Molecular Biosciences, The University of Queensland.

       
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Author Jeffrey Yam Wing Mak
Thesis Title Total synthesis of (−)-neovibsanin G and (−)-14-epi-neovibsanin G and synthetic studies towards other related caged neovibsanins
School, Centre or Institute School of Chemistry & Molecular Biosciences
Institution The University of Queensland
Publication date 2011-11
Thesis type PhD Thesis
Supervisor Craig Williams
Total pages 265
Total colour pages 19
Total black and white pages 246
Language eng
Subjects 030503 Organic Chemical Synthesis
Abstract/Summary 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).
Keyword neovibsanin
enantioselective
asymmetric
total synthesis
natural product
Diterpene
bicyclo[3.3.1]nonane
Additional Notes Colour pages: 30, 37, 43, 49, 62, 66, 86, 93, 96, 97, 116, 177, 183, 186, 193, 198, 237, 240, 244

 
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