A general catalytic hetero-Diels-Alder reaction for ketones has been developed, and for the first time a general reaction protocol is disclosed where the selectivity and activity of a chiral Lewis acid are approaching the ones displayed by enzymes. A variety of combinations of different C-2-symmetric ligands and Lewis acids have been tested as catalysts for the hetero-Diels-Alder reaction between ethyl pyruvate and an activated diene, and it has been found that the readily accessible copper(II) bisoxazolines are very effective catalysts for the reaction, leading to products with very high enantiomeric enrichment (up to 99.8% enantiomeric excess) using the lowest loading of a chiral Lewis acid catalyst observed (down to 0.05 mol %). The catalytic hetero-Diels-Alder reaction of ketones has been developed to be a general reaction which proceeds well with very high turnover numbers, isolated yield, and regio-, diastereo-, and enantioselectivity for various cl-diketones and a-keto esters. The potential and scope of the reaction are demonstrated by the reaction of various ketones, and it is shown that cl-diketones, such as 2,3-pentanedione and 3-phenyl-2,3-propanedione, react primarily at the methyl ketone fragment, giving 97.8% and 96.4% ee, respectively, in the presence of only 0.05 mol % of the catalyst. Furthermore, both aliphatic and aromatic a-keto esters react smoothly, giving very high ee of the hetero-Diels-Alder product. On the basis of the synthesis of a hetero-Diels-Alder product with known absolute stereochemistry, a model for the approach of the diene to the copper(II) bisoxazoline-alpha-diketone intermediate is proposed and the mechanism for the reaction discussed.