Highly enantioselective synthesis of fused bicyclic dihydropyranones via low-loading N-heterocyclic carbene organocatalysis

Highly diastereo and enantioselective [ 4+2] cycloadditions have been achieved between pyrrolidone-derived cyclic enones and alpha-haloaldehydes under mild conditions. Relying on extremely reactive in-situ generated chiral N-heterocyclic carbenes, this stereoselective annulation proceeds efficiently even on the gram scale with the catalyst loading as low as 0.025 mol% ( 250 ppm). A variety of cis-substituted bicyclic dihydropyranones can be produced in up to 96% yield with up to >99% ee. In addition, simple, inexpensive linear aldehydes such as n-propanal can be used directly in asymmetric cycloadditions via oxidative N-heterocyclic carbene organocatalysis with low catalyst loading. This method may provide an economical and practical approach for the asymmetric synthesis of medicinally relevant molecules.