Synthesis of chiral nitrogen heterocycles using hydroformylation – cyclisation reactions

  • Nina Jeffrey

Student thesis: Doctoral Thesis (PhD)

Abstract

This thesis concerns the investigation of hydroformylation-cyclisation reactions for the synthesis of chiral, saturated nitrogen heterocycles. The first chapter is a literature review that details the work that has previously been carried out in this area, much of which is focussed on linear regioselective hydroformylation reactions and hence these do not include any introduction of enantioselectivity from the hydroformylation reaction. A few examples use dual catalysts in order to refine the enantiomeric excess after the hydroformylation step, but the examples that introduce enantioselectivity in the hydroformylation step are recent ones and are primarily from the Zhang group and the Clarke group. These are discussed in the most detail.

The second chapter is a discussion of the experimental work on the use of hydroformylation-cyclisation reactions with a Rh/ BOBPHOS catalyst for the synthesis of piperidines. Here it is established that the use of BOBPHOS is necessary for obtaining high branched regioselectivity as well as high enantioselectivity with these unbiased substrates. It is also clearly presented that the use of a sulfonamide protecting group on the nitrogen is key to balancing the nucleophilicity of the nitrogen lone pair with the stability of the hemi-aminal intermediate, which can then be reduced in a one-pot procedure to the piperidine. Expansion of this methodology to substituted piperidines is also discussed.

The third chapter focusses on the formation of 3-methylpyrrolidine through hydroformylation-cyclisation to form the tosyl-protected derivative, followed by a one-pot reduction and subsequent isolation from the crude reaction mixture. Deprotection of such a small, volatile amine as well as measurement of the enantiomeric excess proved challenging and that is also discussed here. Preliminary steps for extending the reactivity of this methodology for the synthesis of an ant venom component, Leptothoracine, through a second HAM reaction of a 1,1-disubstituted alkene are also presented.

The fourth chapter summarises the main outcomes of these results and contextualises the advances that have been made, whilst the final chapter contains the experimental procedures and compound data. Two appendixes are also included: the first describing palladium-catalysed carbonylation reactions for the synthesis of pyrrolidinones and piperidinones; the second appendix contains data for selected key compounds whose synthesis has been discussed within this thesis.
Date of Award29 Nov 2022
Original languageEnglish
Awarding Institution
  • University of St Andrews
SupervisorMatt Clarke (Supervisor)

Keywords

  • Hydroformylation
  • Nitrogen heterocycles

Access Status

  • Full text embargoed until
  • 4 November 2024

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