Studies towards the total synthesis of phyllaemblic acid

Barker, Isobel Claire ORCID: 0009-0004-2769-4716 (2023). Studies towards the total synthesis of phyllaemblic acid. University of Birmingham. Ph.D.

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Abstract

Phyllaemblic acid is a highly oxygenated natural product isolated from the Phyllanthus emblica plant. Key structural features include a 6,5-spirocyclic acetal cis-fused to a functionalised cyclohexane ring. A total synthesis of phyllaemblic acid has yet to be reported.
The Grainger group approach to phyllaemblic acid takes advantage of a highly stereoselective α,α’-annelation of 1,3-dioxan-5-ones with methyl α-(bromomethyl)acrylate to form meso acetal bridged cyclohexanones. However, the ketone functionality in these bicycles showed limited reactivity towards nucleophilic addition. In Chapter 1, synthetic approaches to related natural products are reviewed, along with relevant literature on the π-facial selectivity in nucleophilic additions to carbonyl compounds.

Chapter 2.1 summarises attempts at preparing a less hindered methylene bridged acetal (R=R’=H) in an attempt to improve the reactivity of the ketone. This bicyclic acetal was prepared by AZADOL / TCCA oxidation of glycerol formal followed by α,α’-annelation. Subsequent base-mediated epimerisation gave the ester stereochemistry required for phyllaemblic acid.

The reactivity of the methylene bridged bicyclic ketone is then examined in Chapter 2.2. Two main methods of introducing the right-hand side fragment on a simplified model system were investigated: Horner-Wadworth-Emmons olefination and acetylide addition.
While both routes resulted in successful C–C bond formation, only the alkyne addition route resulted in the desired stereoselectivity. Synthesis of the right-hand side fragment and future applications to the total synthesis of phyllaemblic acid are also described.

In Chapter 2.3 a Norrish-Yang cyclisation was investigated as an alternative method of C–C bond formation at the carbonyl carbon, but the desired transformation was not successful.
Finally, Chapter 2.4 discusses an approach towards the perhydrobenzothiophene ring system of breynolide, a structurally related natural product via an intramolecular Dieckmann cyclisation.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):