The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide
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 phenylmagnes...
| Main Authors: | , , , , |
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| Format: | Journal article |
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Elsevier
2019
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| _version_ | 1797067349157740544 |
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| author | Davies, S Fletcher, A Peters, M Roberts, P Thomson, J |
| author_facet | Davies, S Fletcher, A Peters, M Roberts, P Thomson, J |
| author_sort | Davies, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:55:00Z |
| format | Journal article |
| id | oxford-uuid:4c9b50be-56b9-4e30-b96a-b93e38dcb13c |
| institution | University of Oxford |
| last_indexed | 2024-03-06T21:55:00Z |
| publishDate | 2019 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:4c9b50be-56b9-4e30-b96a-b93e38dcb13c2022-03-26T15:50:31ZThe asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromideJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4c9b50be-56b9-4e30-b96a-b93e38dcb13cSymplectic Elements at OxfordElsevier2019Davies, SFletcher, APeters, MRoberts, PThomson, JThe 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. |
| spellingShingle | Davies, S Fletcher, A Peters, M Roberts, P Thomson, J The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide |
| title | The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide |
| title_full | The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide |
| title_fullStr | The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide |
| title_full_unstemmed | The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide |
| title_short | The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide |
| title_sort | asymmetric synthesis of s s methylphenidate hydrochloride via ring opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide |
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