Photo-catalyzed, β-selective hydrocarboxylation of α,β-unsaturated esters with CO2 under flow for β-lactone synthesis; natural product derivatization with β-lactones, β-lactams toward ‘infinite’ binders; enantioselective synthesis of medium-sized lactams employing chiral α,β-unsaturated acylammonium salts.

Abstract

β-Lactones and β-lactams are privileged structural motifs found in both therapeutics and natural products. The annulation of relatively small-sized β-lactones and β-lactams onto alkenes are expected to exert minimal steric and conformational perturbations to the overall structure of the natural products, while introducing useful electrophilic moieties for activity-based proteome profiling. We have therefore investigated methods for annulation of β-lactones from simple alkene-containing substrates. In 1978, Lapidus described the first hydrocarboxylation of alkenes leading to a remarkable synthesis of propionic acid from ethylene and CO2. Since then, great progress has been made. Inspired by Jamison's work on the hydrocarboxylation of styrenes, we developed the first photo-catalyzed, β-selective hydrocarboxylation of α,β-unsaturated esters employing CO2 radical anion generated under flow conditions. A range of substrates bearing a variety of functional groups were tolerated, demonstrating chemoselectivity. A series of quaternary carboxylic acids were obtained from sterically demanding β, β-disubstituted alkenes including those derived from natural products. Mechanistic studies suggest a Giese-type CO2 radical anion conjugate addition followed by hydrogen atom transfer by (TMS)3SiH as the principal reaction pathway. Finally, a telescoped process involving the described β-carboxylation followed by α-bromination/β-lactonization sequence provides a strategy for β-lactone synthesis. We also described application of our previously described organocatalytic β-lactone annulation methods, and known β-lactam forming methods for a different purpose; namely, to convert non-covalent bioactive NPs to covalent (‘infinite’) inhibitors. Besides, based on the ready accessibility and divergent reactivity of chiral α,β-unsaturated acylammonium salts, we developed a Michael-proton transfer lactamization organocascade process for the asymmetric synthesis of medium-sized heterocycles including azepanones, benzazepinones, azocanones and benzazocinones in high enatiopurity. An unexpected indoline synthesis was also uncovered and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives including spiroglutarimides, isoquinolinones and δ-lactones.

Description

Keywords

Photocatalysis. Hydrocarboxylation. Medium-sized lactam.

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