Development of Aza-Heck cascades and the total synthesis of pileamartine A

  • Ben T Jones

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Aza-Heck reactions are a powerful tool for the synthesis of nitrogen heterocycles. Typically, these reactions terminate with β-hydride elimination to generate alkene products. However, incorporation of a substituent to block β-hydride elimination allows for further reaction in a cascade fashion. The research presented in this thesis details studies towards the development of aza-Heck cascades to form functionalised pyrrolidines. Chapter 1 introduces and summarises palladium-catalysed cyclisations which generate nitrogen heterocycles, with a particular emphasis on cascade processes. In Chapter 2, studies towards the development of intermolecular 1,2-aminoarylation cascades are described. This work aimed to build upon previous studies from within the Bower group by variation of the oxygen-based leaving group; however, unfortunately, no improvements were made.

Three classes of aza-Heck cascade have been developed to a practical level. Chapter 3 summarises the work on 1,2-aminocarboxylations to generate β-amino acids, using an atmosphere of CO to install the carbonyl unit. A range of pyrrolidines were obtained in good yield, bearing sterically demanding tetrasubstituted centres α to nitrogen. Polysubstituted examples were formed in variable yields and poor diastereoselectivity, and unfortunately, studies towards asymmetric cyclisations were unsuccessful.

In Chapter 4, the construction of complex polyheterocycles using C(sp²)–H functionalisation is described. The intramolecular 1,2-aminoarylation cascade provided a range of ring-fused and spirocyclic nitrogen heterocycles in good yield. Bulky 1,1-disubstituted alkenes were highly efficient, and heterocyclic aryl nucleophiles were tolerated to access diverse ring systems. The observed diastereoselectivity for these processes provided good evidence for reversible alkene aza-palladation. Additionally, in Chapter 5, C(sp²)–H functionalisation cascades were successfully applied to the total synthesis of pileamartine A. The nine-step synthesis features a diastereoselective aza-Heck cascade to construct the core of the natural product, in addition to a concise and stereoselective route to the catalysis precursor. A discrepancy between the data for synthetic and natural material prompted a revision of the absolute stereochemistry of natural pileamartine A.

Finally, Chapter 6 details the discovery of C(sp³)–H functionalisation cascades to generate aminocyclopropanes. The position of C–H palladation was controlled by substrate design to form either spirocyclic or ring-fused aminocyclopropanes. Initial substrate scope found that sterically demanding and conjugated alkene substituents were tolerated, and early investigations towards asymmetric cascades using a novel chiral trioxaphosphaadamantane ligand were promising. Furthermore, the concept for the in situ generation of donor-acceptor cyclopropanes was established, which may have interesting applications in future work.
Date of Award21 Jun 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorM C Galan (Supervisor) & John Bower (Supervisor)

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