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Asymmetric Brønsted Acid Catalysed Enamine Aldol Reaction: New Methodology and Synthetic Applications

Objective

The catalytic asymmetric aldol reaction is the most important reaction for the construction of beta-hydroxy carbonyl compounds in enantioenriched fashion. These product compounds are key building blocks and intermediates in the synthesis of biologically im portant polyketide natural products such as the immunosuppressant discodermolide, and the family of potent anticancer compounds known as the spongistatins.To date, many of the asymmetric reactions that lead to the production of such beta-hydroxy carbonyl m otifs use stoichiometric amounts of chirality in the form of ligands or auxiliaries and/or toxic transition metal catalysts to promote the key carbon-carbon bond forming step. Here we propose a conceptually new approach to the beta-hydroxy carbonyl compoun d products by utilising "simple" organic Bronsted acid catalysts (derived from commercial enantiopure diols and amines) to promote the aldol reaction between readily made enamine nucleophiles and readily available aldehydes. Preliminary studies have shown that these catalysts are indeed active and lead to moderate to good levels of enantiofacial control in the reactions. We wish to explore and develop this novel aldol reaction in the hope of securing the most scalable asymmetric route to beta hydroxy carbo nyl compounds to date. This will be possible by employing parallel synthesis methods to identify the optimal catalyst and reagent combinations. The proposed chemistry falls into the class of asymmetric organocatalysis - no toxic transition metals are used and the reactions should be efficient and clean. The reactions will be insensitive to moisture and air thus making them attractive to industry. The developed catalytic reaction will be investigated to probe the reaction scope and then applied to the synthe sis of biologically important and/or naturally occurring compounds. New models explaining the stereochemical outcomes will be proposed using molecular mechanics calculations to support the predictions.

Field of science

  • /natural sciences/chemical sciences/inorganic chemistry/metals
  • /natural sciences/chemical sciences/organic chemistry/aldehydes

Call for proposal

FP6-2002-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Address
The Old Schools, Trinity Lane
Cambridge
United Kingdom