Asymmetric Syntheses of Aziridine-2-carboxylates via Reductive Kinetic Resolution of 2H-Azirines

03 July 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Enantioenriched aziridine-2-carboxylates are valuable organic compounds thanks to their versatility as chiral building blocks. Several syntheses of bioactive molecules employ aziridine-2-carboxylates as a crucial synthetic intermediate, e.g. the total synthesis of dynobacin A. However, traditional strategies only access N-protected aziridines, which are poorly stable and can undergo unwanted side reactions as ring-opening. Herein, we present the first copper hydride kinetic resolution of racemic 2H-azirines for the asymmetric preparation of N-H aziridine-2-carboxylates and the corresponding enantioenriched 2H-azirines. This is relevant as N-H aziridine-2-carboxylates are a generally bench stable and easily diversifiable building block. After an extensive catalyst screening and reaction optimization, the N-H aziridines were obtained with excellent diastereoselectivity (>20:1) and high enantioselectivity (up to 94%). Additionally, we conducted a Hammett study and we observed a linear free energy relationship between the ΔΔG⧧ of the diastereomeric transition states and the σp- values.

Keywords

kinetic resolution
asymmetric catalysis
copper
aziridine

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Supporting Information
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Supplemental figures, experimental procedures, and characterization of substrates are available within this article Supplementary Information. CCDC 2343244 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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