CATALYTIC ASYMMETRIC HETERO-DIELS-ALDER REACTIONS OF KETONES - CHEMZYMATIC REACTIONS

A general catalytic hetero-Diels-Alder reaction for ketones has been d eveloped, and for the first time a general reaction protocol is disclo sed where the selectivity and activity of a chiral Lewis acid are appr oaching the ones displayed by enzymes. A variety of combinations of di fferent C-2-symmetric ligands and Lewis acids have been tested as cata lysts for the hetero-Diels-Alder reaction between ethyl pyruvate and a n activated diene, and it has been found that the readily accessible c opper(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 aci d catalyst observed (down to 0.05 mol %). The catalytic hetero-Diels-A lder reaction of ketones has been developed to be a general reaction w hich proceeds well with very high turnover numbers, isolated yield, an d regio-, diastereo-, and enantioselectivity for various cl-diketones and a-keto esters. The potential and scope of the reaction are demonst rated by the reaction of various ketones, and it is shown that cl-dike tones, such as 2,3-pentanedione and 3-phenyl-2,3-propanedione, react p rimarily at the methyl ketone fragment, giving 97.8% and 96.4% ee, res pectively, in the presence of only 0.05 mol % of the catalyst. Further more, both aliphatic and aromatic a-keto esters react smoothly, giving very high ee of the hetero-Diels-Alder product. On the basis of the s ynthesis of a hetero-Diels-Alder product with known absolute stereoche mistry, a model for the approach of the diene to the copper(II) bisoxa zoline-alpha-diketone intermediate is proposed and the mechanism for t he reaction discussed.