Thesis

Probing the mechanism of the asymmetric alkylation of pseudoephedrine amides

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Awarding institution
  • University of Strathclyde
Date of award
  • 2013
Thesis identifier
  • T13679
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Abstract
  • One of the most significant issues in organic chemistry today is to create enantiomerically pure compounds. Racemic products, containing both enantiomers in equal quantities, can result is tragic consequences as in the notorious example of the thalidomide drug. A widely used method to synthesize enantiomerically pure compounds is to utilise a chiral auxiliary. A.G. Myers developed a synthetic route using pseudoephedrine, which is an efficient auxiliary to produce enantiomeric enriched ketones, aldehydes and carboxylic acids. Myers and his co-workers proposed a mechanism for this asymmetric alkylation which assumes that a dianion is formed with the alcohol and the enolate that prevents the formation of the undesired diastereomer. Results by D.J. Procter and his co-workers using immobilized pseudoephedrine amides on a Merrifield resin as chiral auxiliaries, when analysed, throw into question Myers' mechanistic model. Procter and his co-workers observed that the polymer-supported systems gave similar diastereomeric excess as the solution-state pseudoephedrine amides. Dr. Gibson from the University of Strathclyde suggested that the mechanism proposed by Myers might be wrong because of Procter's results. Some DFT calculations were carried out which suggested that an alternative π-Li+ transition state might predominate rather than an alkoxide acting as a steric screen. There are two possible routes to try find out which is the correct mechanism: improve the π-Li+ interaction by using more electron-rich aromatic rings or avoid any possible chelation of the lithium with the oxygen of the alkoxide and see how it affects the diastereomeric outcome. This research project focuses on the second route. Therefore, some silyl-protected pseudoephedrine amides were synthesized because they are supposed to prevent lithium chelation. Two silyl ether systems have been investigated: tert-butyldimethylsilyl and triisopropylsilyl. The alkylation has been carried out on the silylated derivatives in two different ways (using benzyl bromide or methyl iodide) and the resulting diastereomeric excess were oberved: · For the TBDMS derivative: 42 % for the benzylation and 17 % for the methylation · For the TIPS derivative: 34 % for the benzylation and 18 % for the methylation These results led us to think that the π-Li+ transition state is the correct one, but more experiments need to be carried out to confirm this result.
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DOI
Date Created
  • 2013
Former identifier
  • 1027081

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