Photodecarboxylative ring annulation of α‐ and β‐functionalized phthaloyl‐GABA derivatives: bioactive pyrroloisoindolinones with high quantum efficiency

Abstract

The triplet‐sensitized (by the solvent acetone) as well as the direct (λex = 300 ‐ 320 nm) photochemical decarboxylation of N‐phthaloylated γ‐aminobutyric acid (GABA) derivatives are versatile and high‐yielding routes to benzopyrrolizidines via intramolecular electron transfer initiated decarboxylation followed by radical coupling. The ß‐mono‐ and ß,ß´‐disubstituted N‐phthaloyl GABA derivatives 7a‐7g, respectively, were applied as substrates. Decarboxylative photocyclization yielded hydroxy benzopyrrolizidines 8a‐8g in high chemical yields and with moderate diastereoselectivities from the ß‐monosubstituted substrates. The analogous α‐substituted GABA derivatives 11a‐11c were also applied as potential substrates for memory of chirality effects. The reaction quantum yields of the photodecarboxylation reactions for the parent GABA derivative 13 and for the new substrates 7h and 11a were determined by the quantum yield determination system (QYDS) and showed a remarkable concentration dependency indicating aggregation at higher substrate concentrations. Inhibition studies on the atherogenic human serine hydrolase cholesterol esterase showed derivatives 8a and 8d to exhibit a hyperbolic mode of inhibition with moderate IC50 values of about 60‐80 µM.