Clarke, Paul Andrew orcid.org/0000-0003-3952-359X, Ermanis, Kristaps and Maddocks, Christopher (2020) Asymmetric ‘Clip-Cycle’ Synthesis of Pyrrolidines and Spiropyrrolidines. Organic Letters. pp. 8116-8121. ISSN 1523-7052
Abstract
The development of an asymmetric ‘clip-cycle’ synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by ‘clipping’ them to thioacrylate via an al-kene metathesis reaction. Enantioselective intramolecular aza-Michael cyclisation onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reac-tion accommodated a range of substitution to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ke-tone and oxoester-containing substrates. DFT studies sup-ported the aza-Michael cyclisation as the rate and stereo-chemical determining step, and correctly predicted the for-mation of the major enantiomer. The catalytic asymmetric syntheses of N-methyl pyrrolidine alkaloids (R)-irnidine and (R)-bgugaine, which possess DNA binding and antibacterial properties were achieved using the ‘clip-cycle’ methodology.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 30 Sep 2020 10:10 |
Last Modified: | 14 Mar 2025 00:09 |
Published Version: | https://doi.org/10.1021/acs.orglett.0c03090 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1021/acs.orglett.0c03090 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:166173 |
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Description: Final Revised spiropyrrolidine 24_9_20