Enantioselective access to tricyclic tetrahydropyran derivatives by a remote hydrogen bonding mediated intramolecular IEDHDA reaction

Although the hetero-Diels-Alder reaction is a staple of organic chemistry, catalytic asymmetric versions of the inverse-electron demand variant often require specially engineered substrates for the reaction to work. Here the authors cyclize non-activated alkenes with alpha,beta-unsaturated ketones or aldehydes to form chiral fused heterocycles using a chiral phosphoric acid catalyst. Inverse-electron-demand-hetero-Diels-Alder reactions of alkenes with alpha,beta-unsaturated keto compounds allow rapid access to the tetrahydropyran ring found in numerous natural products and bioactive molecules. Despite its synthetic interest, catalytic asymmetric versions of this process remain underdeveloped, especially regarding the use of non-activated alkenes reacting with alpha,beta-unsaturated ketone or aldehyde, for which no report can be found in the literature. Herein, we describe the catalytic inverse-electron-demand-hetero-Diels-Alder reactions between neutral alkenes and an alpha,beta-unsaturated ketones or aldehydes to produce a variety of trans-fused [5,6,8] tricyclic structures containing a central, chiral tetrahydropyran ring. This complex transformation, which is achieved using a chiral phosphoric acid, allows for the formation of four stereogenic centers in a single step with high regio-, diastereo- and enantioselectivity (up to 99% ee). Such level of stereocontrol could be achieved by a key remote double hydrogen atom bonding interaction between the linear substrate and the catalyst.