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Asymmetric copper-catalyzed alkylations and autocatalysis

PhD ceremony:Ms T. (Tilde) Pellegrini
When:March 08, 2019
Supervisors:prof. dr. S. (Syuzanna) Harutyunyan, prof. dr. W.R. (Wesley) Browne
Where:Academy building RUG
Faculty:Science and Engineering
Asymmetric copper-catalyzed alkylations and autocatalysis

Natural chiral compounds, like sugars and amino acids, are biologically synthesized as a single enantiomer. For this reason, chiral biologically active compounds, like drugs, have different activities depending on their configuration. Organic synthesis provides different methods for the synthesis of chiral molecules, and among those, asymmetric catalysis is very valuable because it allows the use of expensive chiral auxiliary in substoichiometric amount.

In the first part of this thesis, chiral compounds bearing two heteroaryl moieties are prepared by addition of Grignard reagents to 1,2-disubstituted heteroaryl alkenes mediated by a chiral copper catalyst. The use of a Lewis acid in this reaction allows for the activation of the heteroaryl alkene towards this reaction. Pyridines are recurrent moieties in medicinal compounds, but at the same time, their reactivity is tricky. For this reason, special attention is given to pyridyl alkenes.

In the second part of this thesis, those asymmetric reactions are studied where the product can orchestrate its own synthesis. This kind of mechanism, called autoinduction and autocatalysis, constitutes a possible explanation for the presence of natural molecules as only one enantiomer. Autoinduction was observed in the copper-catalyzed addition of Grignard reagents to ketones and aldehydes, where the product, once formed, interacts with the catalyst to make it more efficient, thus, more enantioselective. Finally, the design of an enantioselective autocatalytic reaction inspired by the Corey-Bakshi-Shibata reduction of carbonyl compounds is described.