A one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems

A highly effective method for the synthesis of the core indolo[2,3-a]quinol izidine skeleton found in yohimbine is described. The reaction of N-monosub stituted thioamides with bromoalkenoyl chlorides furnishes thioisomunchnone s as transient 1,3-dipoles that undergo ready intramolecular cycloaddition across the tethered pi-bond to give thio-bicycloannulated products in a one -pot operation. The stereochemical outcome of the intramolecular reaction i s the consequence of an endo cycloaddition of the neighboring-bond across t he transient thioisomunchnone dipole. A major limitation of the method is t hat when a hydrogen is present in the alpha-position of the thioamide the i nitially formed thio-N-acyliminium ion undergoes proton loss to produce a S ,N-ketene acetal at a faster rate than dipole formation. Treatment of tetr ahydro-beta-carboline-1-thione with 2-bromooct-7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the formation of (+/-)-alloyahimbanone. Attempts to cycloadd the thioisomunchnone dipole across several nucleophilic-bonds failed, and instead, products derived fr om cyclization of the pi-bond onto the initially formed thio-N-acyliminium ion were formed. The resulting N,S-ketals were further converted into sever al tetrahydroisoquinoline alkaloids in good yield.