Synthesis of R- and S-MDMA via nucleophilic ring-opening of homochiral N-tosylaziridines
Katie D. Lewis A , Glenn A. Pullella A , Han Chern Loh A , Brian W. Skelton A , Gavin R. Flematti A and Matthew J. Piggott
A *
+ Author Affiliations
- Author Affiliations
A Chemistry, School of Molecular Sciences, University of Western Australia, Perth, WA 6009, Australia.
Australian Journal of Chemistry 76(5) 299-310 https://doi.org/10.1071/CH23064
Submitted: 20 April 2023 Accepted: 20 June 2023 Published: 12 July 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)
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.
Keywords: aziridine, chiral pool, enantiopurity determination, HPLC with fluorescence detection, nucleophilic ring-opening, organic chemical synthesis, (R)- and (S)-3,4-methylenedioxymethamphetamine, R- and S-MDMA, X-ray crystal structure.
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