Catalytic Enantioselective\nSynthesis of 1,4-(Hetero)\nDicarbonyl Compounds through α‑Carbonyl Umpolung

The enantioselective synthesis of 1,4-dicarbonyl compounds\ncontinues\nto pose a significant challenge in organic synthesis, and a catalytic\nprocess which generates two adjacent stereogenic centers with full\nstereochemical control is lacking until now. The 1,4-relationship\nof the functional groups requires an Umpolung strategy as one of the\nα-carbonyl positions has to be inverted into an electrophilic\ncenter to react with a normal enolate. We report herein the highly\nenantio- and diastereoselective addition of silyl ketene acetals toward\nelectrophilic 1-azaallyl cations to furnish chiral 4-hydrazonoesters,\nwhich are masked 1,4-dicarbonyl compounds. The products carrying up\nto 2 new stereogenic centers were obtained in excellent yields across\na broad substrate scope. As precursors to the 1-azaallyl cations,\nα-acetoxy hydrazones were employed and ionized with a strongly\nLewis acidic, chiral silylium imidodiphosphorimidate (IDPi). The resulting\nion pair was characterized with NMR and mass spectroscopy, while DFT\ncalculations provided further insights into the reaction mechanism.\nIn addition, the products were successfully converted into enantiomerically\nhighly enriched b-cyano and b-formyl esters as well as γ-lactams\nand γ-amino acids, as demonstrated by syntheses of the anticonvulsant\nagent pregabalin and a brivaracetam precursor.