The Ireland-Claisen rearrangement of 3-alkoxypropenol amino esters as an entry to sphingolipid amino acid natural products

  • Nathan Fairhurst

Student thesis: Doctoral ThesisPhD


The Ireland-Claisen rearrangement is a powerful synthetic tool which allows predictable diasterocontrol and chirality transfer in the synthesis of γ,δ-unsaturated carboxylic acids. Previous work within the Carbery group has developed a novel protocol for the synthesis of β-alkoxy- and aryloxy-α-amino acids.Chapter 2 covers the initial volume of work on developing this methodology further to allow the synthesis of sterically congested α-quaternary carbon centres in β-alkyoxy- and aryloxy-α-amino acids. Individual substrate optimisation allowed improvement of both the yields and diastereoselectivity of this rearrangement, along with the isolation of a key degradation product. A series of heteroproline-based rearrangements laid the groundwork for remote chirality transfer within this Ireland-Claisen rearrangement.The principle of self-regeneration of stereocentres is applied in an Ireland-Claisen context in Chapter 3. Showing exceptional levels of remote stereocontrol the rearrangement is shown to be general, offering almost exclusively diastereoselectivities of >99:1. Allylic enol ether amino esters saw yields of 47 – 83% and provided functional handles allowing for further synthetic manipulations. Carbon substituted allyl amino esters allowed facile access into β-hydroxy-α-amino acid derivatives of proteinogenic amino acids leucine and isoleucine (amongst others) with excellent selectivity.The synthesis of both enantiomers of mycestericin G in Chapter 4 highlights the synthetic utility of this methodology, in addition to allowing a revision of absolute configuration of this natural product. The synthesis of a mycestericin G analogue, derived from threonine, is also presented.Finally, Chapter 5 exploits these rearrangement products as chiral diene ligands in rhodium-catalysed conjugate addition reactions. Both ligand and reaction condition optimisation led to a range of aryl boronic acids used in the 1,4-addition to 2-cyclohexenone with yields of 24 – 100% and enantioselectivities of 74 – 93% observed.
Date of Award29 Nov 2012
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorDavid Carbery (Supervisor)

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