New Rhodacyclopentanone-Based Methodologies and Studies Towards the Total Synthesis of Otonecine-Type Pyrrolizidine Alkaloids

  • Steven Stanton

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Processes for the synthesis of seven-membered N-heterocycles, involving intramolecular nucleophilic addition to rhodacyclopentanones have been developed. Initially, a (6+1) carbonylative cyclisation of cyclopropylureas, discovered by Dr. McCreanor at Bristol, was optimised and its scope examined. Mechanistic studies were carried out to explain unexpected aspects of this reaction. Subsequently, investigations were directed towards the discovery of other processes involving nucleophilic addition to rhodacyclopentanones, which resulted in the identification of a (6+1) carbonylative cyclisation of cyclopropylmethylamides to form azepanes.
Later, studies were directed towards the asymmetric total synthesis of (R)-otonecine and related pyrrolizidine alkaloids. This built upon the (7+1) carbonylative cycloaddition of cyclopropylacrylamides to form azocanes, developed at Bristol. Further optimisation of the (7+1) reaction conditions identified several beneficial amide and carboxylic acid additives, and an improved reaction set-up, which allowed the cycloaddition of a challenging silylmethylcyclopropane-based substrate. Investigations into the four proposed post-cycloaddition transformations identified suitable conditions for three of these. A Rubottom oxidation and Tamao-Fleming oxidation installed the C7- and C9-alcohols of otonecine. The C2 to C1 alkene isomerisation was achieved under kinetic conditions using newly developed conditions for the hydrobromination of enelactams. The penultimate lactam reduction step failed under various chemoselective conditions.
In parallel studies, a short, asymmetric and diastereodivergent synthesis of the C10 dicarboxylic necic acids was designed. Unoptimised conditions for the asymmetric crotylation of a pyruvate ester formed the C12,C13-vicinal stereocentres of the necic acid targets. Finally, model studies into a sp2-sp3 Negishi cross-coupling suggest that this transformation might be applicable to the proposed synthesis. Realisation of the asymmetric total synthesis of (R)-otonecine and the C10 dicarboxylic necic acids pave the way for the first total synthesis of other otonecine-type pyrrolizidine alkaloids.
Date of Award6 Dec 2019
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorJohn Bower (Supervisor)

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