Towards the synthesis of the hasubanan alkaloids and studies towards a homologative cross coupling of aldehydes

  • Lauren G O'Neil

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


The research described in this thesis details significant progress towards the synthesis of the hasubanan alkaloids. The proposed synthesis hinges on a key aza-Heck-Heck cascade to construct the hallmark aza[4.4.3]propellane core. In Chapter 1, a summary of aza-Heck processes that are pertinent to this thesis are discussed, and previously reported syntheses of hasubanan alkaloids are presented.
Chapter 2 describes investigations towards the preparation of a model aza-propellane system. Cheap and commercially available starting materials were used to assess the feasibility of the proposed transformations; ultimately, a six-step synthetic route to several N-acyloxycarbamate and N-sulfonyloxycarbamate substrates from β-tetralone was developed. Following a broad screen of reaction conditions, the proposed aza-Heck-Heck cascade was successfully implemented for the formation of a model aza-propellane intermediate.
In Chapter 3, several synthetic approaches to β-tetralones were surveyed. These studies underpinned Chapter 4, where the six-step synthetic route detailed in Chapter 2 was applied to the “real system”. Studies confirmed that the use of an O-TBDPS protecting group was essential to obtaining high yields and selectivity in most synthetic steps. Further optimisation of the aza-Heck-Heck cascade provided the key aza-propellane structure in excellent yield. Investigations towards the post cascade transformations were conducted with an initial focus on the synthesis of (rac)-8-demethoxyrunanine. Suitable conditions for three of the four steps were identified, with the order of transformations also established.
In Chapter 5, studies towards an asymmetric synthesis were undertaken. Investigations were directed towards the development of an asymmetric allylic alkylation process to set the challenging quaternary centre of the targets. At the current stage, only modest levels of enantioselectivity have been achieved.
Finally, in Chapter 6, a collaborative effort towards a homologative cross-coupling of aldehydes is detailed. The inspiration for this project arose from the observed formation of an α-keto phosphonate side product in a homologative conversion of aldehydes to carboxylic acids. It was proposed that α-keto phosphonates would be suitable electrophiles for use in a subsequent acyl Suzuki cross-coupling. Preliminary screening of catalyst systems found that electron-rich PEPPSI-IPr catalyst successfully promoted cross-coupling, but this process was irreproducible. Alternative electrophiles were assessed, but cross-coupling was not achieved. Finally, studies towards a Heck cross-coupling of enamides were conducted.
Date of Award25 Jan 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorJohn F Bower (Supervisor) & Chris L Willis (Supervisor)

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