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The catalytic, asymmetric [2+2] cycloaddition reaction between a carbonyl compound and ketenes is an atom economical reaction for the production of chiral b-lactones, which are valuable chiral synthons.  Several catalytic systems have been reported to promote the asymmetric cycloaddition reaction between aldehydes and ketenes (the asymmetric Wynberg reaction).  Previously, we have employed the asymmetric Wynberg reaction as a proof-of-principle reaction in the discovery of a new family of tethered Lewis acid-Lewis base (LA-LB) bifunctional catalysts.  However, ketones are currently not suitable substrates for the intermolecular Wynberg reaction.

            In the first period of this project, we investigated the possibility of expanding the current substrates scope of the Wynberg reaction from aldehydes to ketones, which are more challenging substrates that would require a more active bifunctional catalyst.  Because we have recently demonstrated that increasing the Lewis acidity of the tethered LA-LB bifunctional catalyst greatly enhanced its overall catalytic activity, we focused our efforts on fine-tunneling the electronic properties of the LA for the desired Lewis acidity.  We have successfully designed and synthesized additional salen ligands containing electron-withdrawing groups in multi-gram quantities.  Coordination of these new ligands to Lewis acidic metals led to a more electron deficient LA of the LA-LB bifunctional catalysts.  The ensuing catalytic activity studies of these new catalysts suggested that a fine balance between the steric and electronic properties of the LA moiety is important for the overall catalytic activity of the tethered LA-LB bifunctional catalyst.  In addition, we have gained further mechanistic insights into the LA-LB catalyzed asymmetric Wynberg reaction, when ketene is generated in situ from acetyl chloride and a base at low temperature.