Discovery of reactive intermediates via new generic modes of substrate activation is central to the field of asymmetric organocatalysis. Catalytically controlled generation of such intermediates, inspired organic chemists to design a variety of new asymmetric transformations. In this context, there has been a significant expansion of the reactions that catalyzed by tertiary amines. The advent of tertiary amine catalysis introduced two new activation modes of acid chlorides: displacement of the chlorine atom by a tertiary amine generates an electrophilic acylammonium, while subsequent deprotonation at the a-position affords a nucleophilic ammonium enolate intermediate. Despite the utility of saturated acid chlorides, the potential of their unsaturated analogs has been greatly underutilized. Several of these acid chlorides are commodity chemicals in spite of their relatively high reactivity. Recently we have uncovered that the reactivity of these acid chlorides can be modulated by insitu generation of chiral a,�-unsaturated acylammoniums with cinchona alkaloid catalysts. The reaction of these intermediates with bisnucleophiles enabled a one-step, enantioselective strategy to pyrrolidinones, piperid-2-ones and dihydropyridinone through a nucleophile-catalyzed Michael proton transfer-lactamization organocascade. The utility of this method was demonstrated through syntheses of a pyroglutamic acid derivative, which is previously employed for the synthesis of an FDA approved drug baclofen, clinical candidate chlorpheg and a potent a1aadrenergic receptor antagonist. The lecture will highlight these and related reactions

Direct catalytic asymmetric synthesis of N-heterocycles from commodity acid chlorides employing a ,� -unsaturated acylammoniums

247th National Meeting (2014)

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