Synthesis of R- and S-MDMA via nucleophilic ring-opening of homochiral N-tosylaziridines
Katie D. Lewis, Glenn A. Pullella, Han Chern Loh, Brian W. Skelton, Gavin R. Flematti, Matthew Piggott
Australian Journal of Chemistry July 11, 2023 DOI: 10.1071/ch23064 via OpenAlex
Summary
Homochiral (R)- and (S)-MDMA were synthesized in six steps from d- and l-alanine. A copper-catalyzed regioselective ring-opening of an N-tosylaziridine with an aryl Grignard reagent gave high yields and complete regioselectivity. The synthesis preserved configurational integrity, yielding R- and S-MDMA hydrochlorides with enantiopurities greater than 99.5%, confirmed by enantioselective HPLC with fluorescence detection. Applying the same method to make homochiral enantiomers of the α-phenyl analogue UWA-001 failed due to a switch in regioselectivity in the key step.
Study at a glance
| Characteristics | Synthetic methodology paper Peer reviewed |
|---|---|
| Keywords | Regioselectivity Enantioselective synthesis Enantiomer Ring chemistry Biocatalysis |
| Citations | 2 |
| Key finding | Homochiral R- and S-MDMA were prepared with >99.5% enantiopurity via a copper-catalyzed regioselective ring-opening of an N-tosylaziridine, but the same method failed for the α-phenyl analogue UWA-001 due to a regioselectivity switch. |
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 a-phenyl analogue of MDMA (UWA-001) were thwarted by a switch in regioselectivity in the key step.