Photodecarboxylative Ring Annulation of - and -Functionalized Phthaloyl-GABA Derivatives: Bioactive Pyrroloisoindolinones with High Quantum Efficiency

The triplet-sensitized (by the solvent acetone) as well as the direct (lambda ex=300-320 nm) photochemical decarboxylation of N-phthaloylated gamma-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 7 a-7 g, respectively, were applied as substrates. Decarboxylative photocyclization yielded hydroxy benzopyrrolizidines 8 a-8 g in high chemical yields and with moderate diastereoselectivities from the ss-monosubstituted substrates. The analogous alpha-substituted GABA derivatives 11 a-11 c 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 7 h and 11 a 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 8 a and 8 d to exhibit a hyperbolic mode of inhibition with moderate IC50 values of about 60-80 mu M. Reagent and catalyst-free conversion of numerous GABA derivatives into biologically active pyrroloisoindolinones is achieved by direct or triplet-sensitized photolyses in aqueous solvent mixtures with high quantum yields. image