The asymmetric synthesis of (S, S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide. Issue 49 (6th December 2019)

• Record Type: Journal Article
• Authors: Davies, Stephen G.; Fletcher, Ai M.; Peters, Matthew E.; Roberts, Paul M.; Thomson, James E.
• Is Part Of: Tetrahedron. Volume 75:Issue 49(2019)
• Publication Date: 2019-12-06
• Subjects: Methylphenidate -- Ritalin -- Asymmetric synthesis -- Lithium amide -- Aziridinium -- α-Aryl-β-amino acid; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2019.130713
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: The key step in our synthetic strategy towards ( S, S )-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N -deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave ( S, S )-methylphenidate hydrochloride, in only 8 steps from 1, 5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues. Graphical abstract: Image 1 Highlights: Asymmetric synthesis of ( S, S )-methylphenidate hydrochloride in 15% overall yield in only 8 steps from 1, 5-pentanediol. Stereospecific and regioselective ring-opening of an in situ formed aziridinium intermediate with phenylmagnesium bromide. Conversion of an α-hydroxy-β-amino ester into an α-phenyl-β-amino ester with overall retention of configuration. Enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds.