Synthesis of R- and S-MDMA via nucleophilic ring-opening of homochiral N-tosylaziridines

Homochiral (R)- and (S)-3,4-methylenedioxymethamphetamine (MDMA) were prepared in six steps (each) from the chiral pool precursors d- and l-alanine, respectively. The key step, copper-catalysed regioselective ring-opening of an N-tosylaziridine with an aryl Grignard reagent, proceeded in high yield with complete regioselectivity. Elaboration was achieved with preservation of configurational integrity, affording R- and S-MDMA hydrochlorides with enantiopurities of >99.5%, as determined by enantioselective HPLC with fluorescence detection. Attempts to apply the synthetic methodology to the synthesis of the homochiral enantiomers of the α-phenyl analogue of MDMA (UWA-001) were thwarted by a switch in regioselectivity in the key step.