Probing the mechanism of diastereoselectivity of pseudoephedrine amide enolate alkylations

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Awarding institution
  • University of Strathclyde
Date of award
  • 2011
Thesis identifier
  • T13504
Qualification Level
Qualification Name
Department, School or Faculty
  • Pseudoephedrine was first used by Myers as a practical auxiliary for the asymmetric alkylation of amide enolates. The pseudoephedrine amide enolate intermediate is proposed by Myers et al. to adopt a staggered conformation that is supposed to be responsible for the high diastereoselectivity outcome. This reactive conformation involves a lithium alkoxide that is thought to create a steric screening which forces the attack onto one face. However, Procter and his group carried out several experiments on the alkylation using immobilized pseudoephedrine that may contradict the Myers' proposed mechanism. DFT calculations suggested that a π-cation interaction between the aromatic ring and the lithium cation may account for the diastereoselectivity of the alkylation. Modification of this interaction by either adding electron donating or withdrawing groups onto the aromatic ring was expected to respectively lead to higher or lower diastereoselectivity. Based on this last hypothesis, investigation of the mechanism of action of the pseudoephedrine chiral auxiliary by synthesising selected analogues of pseudoephedrine was the basis for this project. A route to synthesise analogues of pseudoephedrine involved the reduction/alkylation of protected L-alanine derivatives. This reaction necessitated much investigation to obtain analogues of pseudoephedrine amino alcohol bearing electron donating group in the aromatic ring. Five analogues of this type has been successfully synthesised with high diastereoselectivity.
Resource Type
Date Created
  • 2011
Former identifier
  • 995977