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

Abstract

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.

Psychedelic medicines

“…The last contribution in the psychedelic series is an original research article, contributed by one of the Guest Editors, Matthew Piggott, and five of his co-workers from the University of Western Australia. [6] MDMA used recreationally is probably exclusively racemic, but the pharmacology of its enantiomers is distinctly different. Piggott and co-workers outline the synthesis of homochiral R-and S-MDMA from chiral pool amino acids, with a key step being the nucleophilic ring-opening of homochiral N-tosylaziridines.…”