Synthesis of (+)-Dumetorine and Congeners Using Flow Chemistry Technologies

An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2- (piperidin-2-yl)ethanol 4 with 29 % overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler-Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (-)-sedamine and (+)-sedridine.