Quaternized α,α′-Amino Acids via Curtius Rearrangement of Substituted Malonate–Imidazolidinones

An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate–i...

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Bibliographic Details
Published in:Journal of organic chemistry 2017-10, Vol.82 (19), p.10650-10658
Main Authors: Gokada, Maheswara Rao, Hunter, Roger, Andrijevic, Ana, Petersen, Wade F, Samanta, Sauvik, Venter, Gerhard, Rees-Jones, Sophie
Format: Article
Language:English
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Summary:An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate–imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89–99% for eight cases) for quaternizing a range of proteinogenic α-amino acids. The stereogenicity in targets 5a–i supports previous conclusions that the diastereoselective alkylation step proceeds via an α-substituted malonate–imidazolidinone enolate in its Z-configuration, with the auxiliary in an s-trans C–N conformation.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.7b01684