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Synthesis 2022; 54(02): 355-368
DOI: 10.1055/a-1638-2478
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Kinetic Resolution by Lithiation: Highly Enantioselective Synthesis of Substituted Dihydrobenzoxazines and Tetrahydroquinoxalines

Ashraf El-Tunsi
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
,
Nicholas Carter 
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
,
Song-Hee Yeo
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
,
Joshua D. Priest
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
,
Anthony Choi
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
,
Carolin M. Kobras
b   The Florey Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK
,
Soneni Ndlovu
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
,
Ilaria Proietti Silvestri
c   Liverpool ChiroChem, Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
,
Andrew K. Fenton
b   The Florey Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK
,
Iain Coldham∗
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
› Author AffiliationsThis work was supported by the Engineering and Physical Sciences Research Council (EPSRC, grant EP/R024294/1), the University of Sheffield, the Ministry of Higher Education and Scientific Research Libya, the Royal Society (Short Industry Fellowship SIF\R2\202031), and the Medical Research Council (MRC, grant MR/S009280/1).
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Abstract

Kinetic resolution provided a highly enantioselective method to access a range of 3-aryl-3,4-dihydro-2H-1,4-benzoxazines using n-butyllithium and the chiral ligand sparteine. The enantioenrichment remained high on removing the tert-butoxycarbonyl (Boc) protecting group. The intermediate organolithium undergoes ring opening to an enamine. The kinetic resolution was extended to give enantiomerically enriched substituted 1,2,3,4-tetrahydroquinoxalines and was applied to the synthesis of an analogue of the antibiotic levofloxacin that was screened for its activity against the human pathogen Streptococcus pneumoniae.

Key words

ring opening - lithiation - kinetic resolution - heterocycles - enantioselectivity - elimination - antibiotics

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1638-2478.
  • Supporting Information


Publication History

Received: 20 August 2021

Accepted: 06 September 2021

Accepted Manuscript online:
06 September 2021

Article published online:
26 October 2021

© 2021. Thieme. All rights reserved

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