Synthesis of Medium Ring Heterocycles by Directed C-C Bond Activation

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

In Chapter 1, a summary of transition-metal catalysed C–C bond cleavage of small ring systems that are pertinent to this thesis is presented. In Chapters 2 and 3, a modular Rh(I)-catalysed entry to various 7- and 8-membered N-heterocycles is outlined. Under an atmosphere of CO, aminocyclopropanes equipped with pendant nucleophiles undergo directed C–C bond activation to provide versatile rhodacyclopentanone intermediates. Subsequent intramolecular nucleophilic addition of an aryl or N-based nucleophile to the rhodacyclopentanone intermediate is followed by C–C or C–N bond formation to provide a range of sp3-rich N-heterocycles. These studies demonstrate how the combination of cyclopropane strain release and the templating effect of catalytically generated metallacycles can be utilised to achieve challenging medium-sized ring closures.
Chapter 4 details a conceptual blueprint that enables direct and atom economical access to a selection of complex polyheterocycles. These processes capitalise upon the amphiphilic reactivity of rhodacyclopentanones for the construction of two new ring systems, the first of which is enabled by the intrinsic electrophilicity of rhodacyclopentanones, and the second by their latent nucleophilicity. Importantly, this reactivity mode is only unveiled by carbonylative C–C bond activation of a stable aminocyclopropane precursor. By using this approach, a diverse array of polycyclisations are achieved, including systems that involve powerful dearomatisations and medium ring formations.
In Chapter 5, studies are directed towards the total synthesis of (rac)-conolidine and related indole alkaloids. The newly developed 7-step synthetic route to (rac)-conolidine features a Rh(I) catalysed carbonylative ring expansion of a cyclopropylamide to establish the 8-membered C ring and a Ni(0) catalysed enolate coupling to construct the azabicyclo[4.2.2]decane core.
Date of Award26 Nov 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorJohn Bower (Supervisor)

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