Catalytic Enantioselective Synthesis of 1,4-(Hetero) Dicarbonyl Compounds through α-Carbonyl Umpolung

Abstract

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