Inverse-electron-demand-hetero-Diels-Alder reactions of alkenes with α,β-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 α,β-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 α,β-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.

The Elansolid A1/A2 is metabolite from the gliding bacterium Chitinophaga sanctii and shows antibiotic activity against Gram-positive bacteria. Up to now, the total synthesis of this natural product has not been reported yet due to its structure complexity, which arises from the trans-tetrahydroindane unit and (Z)-(E)-(Z) triene motif as well as a 19-member macrolactone. In this study, two new O-functionalized substrates were synthesized to undergo the biomimetic intramolecular Diels-Alder reactions (IMDA) catalyzed by a chiral phosphoric acid to build the key trans-tetrahydroindane core of Elansolid A1/A2 via a vinylic p-quinone methide intermediate. This result shows that an improved dr (1.8∶1) of IMDA reaction and shorter synthetic steps could be achieved.