Chemoselective flow hydrogenation approaches to diversify the cytotoxic tetrahydroepoxyisoindole carboxamide scaffold

An Intramolecular Diels-Alder cycloaddition reaction between a furan diene and an alkynic dienophile was performed within a flow hydrogenator fitted with an inert titanium column at 150 °C, no H ₂, under 100 bar pressure. A single column pass (t _R=1.6 min) afforded ≈55% conversion to the tetrahydroepoxyisoindole carboxamide scaffold with a product turnover of ≈0.035 g/h, a 95% improvement over batch procedures. The cycloaddition protocol is performed in water and ethanol, and does not require catalysts or other additives. Quantitative hydrogenation of the resulting dual π-bonds within the oxabicyclo system was effected with either a 10% Pd/Al ₂O ₃ or 10% Pd/CaCO ₃ catalyst at 20 °C, 20 bar, with full H ₂ whereas utilisation of a Raney Ni catalyst under these conditions resulted in a quantitative mono-olefin reduction of the C4-C5 double-bond. With regard to di-olefin reduction, a degree of stereoselectivity was observed with the aforementioned palladium-based catalysts yielding exclusive formation of (R) configuration at C7 while utilisation of a 5% Pt/C (sulfided) catalyst at temperatures below 60 °C promoted the formation of the (S)-isomer at C7. Hence this work further highlights that flow-hydrogenation provides unprecedented convenience for establishing robust protocols to effect chemoselective transformations. (Figure presented.).