Enantioselective synthesis of dihydropyrans. Catalysis of hetero Diels-Alder reactions by bis(oxazoline) copper(II) complexes

C-2-symmetric bis(oxazoline)-Cu(II) complexes 1 and 2 catalyze the inverse electron demand hetero Diels-Alder reaction of alpha,beta-unsaturated carbo nyl compounds (heterodiene) with electron-rich olefins (heterodienophile) i n high diastereo- and enantioselectivity, alpha,beta-Unsaturated acyl phosp honates and beta,gamma-unsaturated a-keto esters and amides are effective h eterodienes, while enol ethers and sulfides function as heterodienophiles. A range of substitution patterns is possible on the heterodiene: terminal a lkyl, aryl, alkoxy, and thioether substituents are all tolerated. The enant ioselective synthesis of dihydropyrans by this method has been shown to be straightforward: cycloadditions may be conducted with as little as 0.2 mol % of the chiral catalyst and are readily run on multigram scale. The reacti ons exhibit a favorable temperature-enantioselectivity profile, with select ivities exceeding 90% even at room temperature. A simple reaction protocol that employs a solid air-stable catalyst, convenient reaction temperatures, and low catalyst loadings is described. The utility of the derived cycload ducts in the preparation of chiral building blocks is demonstrated. Models for asymmetric induction are discussed considering product stereochemistry, X-ray crystallographic data for the solid catalysts, and mechanistic studi es.