Chiral benzannulated carbocyclic frameworks widely present in pharmaceuticals and natural products. The asymmetric Photoenolization/Diels–Alder (PEDA) reaction provides an efficient route to access such scaffolds. However, the high reactivity of photoenols has long hindered the development of catalytic asymmetric versions. The inherent challenges of the PEDA reaction are threefold: (1) fleeting photoenols; (2) intrinsic racemic background reactions; and (3) competing reactions. Existing strategies to achieve enantioselective PEDA transformations typically require highly electron-deficient olefins and a substoichiometric amount of chiral catalyst. Consequently, the development of mild and efficient catalytic asymmetric PEDA reactions remains highly significant yet extremely challenging.
Given the significance of expanding the chemical space of chiral benzannulated carbocyclic frameworks for drug discovery, Xiao and Cheng devised a chiral Brønsted acid-catalyzed enantioselective PEDA reaction. This strategy enables straightforward access to azaarene-containing chiral carbocyclic adducts bearing multiple stereocenters with good yields and excellent enantioselectivity. Moreover, the method also enables the synthesis of enantioenriched spiro lactones featuring phthalide motifs.
Subsequently, a series of synthetic transformations were carried out to further diversify the resulting chiral benzannulated carbocyclic products. These transformations included oxidation of the pyridine ring, reductive hydrogenation and bromination of the alkynyl group, as well as allylation and esterification of the tertiary alcohol.
To elucidate the reaction mechanism, the authors conducted comprehensive mechanistic investigations into the role of the chiral Brønsted acid catalyst. The results indicate that the chiral Brønsted acid acts as a multifunctional catalyst, simultaneously activating both substrates, stabilizing the photoenol intermediates, and ensuring effective enantiocontrol.