Pericyclic Umpolung in a Catalytic Asymmetric Diels–Alder Reaction of Tropone with Enol Ethers

One remarkable feature of catalysis in chemical synthesis is its capacity to override substrate-imposed reactivity and selectivity. The inversion of normal reaction patterns, commonly known as Umpolung, can be divided into (1) functional group Umpolung, where electrophilic groups are rendered nucleophilic (or vice versa), and (2) pericyclic Umpolung, in which the regioselectivity of pericyclic reactions is reversed relative to the predictions of frontier molecular orbital (FMO) theory. Although catalytic functional group Umpolung has been extensively investigated, the highly organized, concerted nature of pericyclic reactions makes inverting their conventional regioselectivity particularly challenging. To date, such inversion has been achieved only using engineered substrates or near-stoichiometric amounts of molecular cages. Here, we report an example of a chiral confined acid-catalyzed, asymmetric Umpolung of the Diels-Alder reaction. In our system, tropone reacts with enol ethers to deliver "contra-FMO" products with high yield, stereoselectivity, and regioselectivity. Mechanistic and computational studies indicate that a network of attractive noncovalent interactions, including π-π-interactions, nonclassical hydrogen bonding, and dispersion, governs the inverted regioselectivity. We anticipate that confined acid catalysis will open new avenues for addressing challenges in pericyclic Umpolung and regioselectivity control.