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C-H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity.

  • O' Donovan DH AstraZeneca, Oncology, IMED Biotech Unit, 1 Francis Crick Avenue, Cambridge, CB2 0RE, UK.
  • Aillard P Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
  • Berger M Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
  • de la Torre A Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
  • Petkova D Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
  • Knittl-Frank C Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
  • Geerdink D Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
  • Kaiser M Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.
  • Maulide N Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
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  • 2018-05-16
Published in:
  • Angewandte Chemie (International ed. in English). - 2018
C−H activation
malaria
quinine
total synthesis
Aldehydes
Animals
Antimalarials
Carbon
Catalysis
Crystallography, X-Ray
Hydrogen
Malaria
Mice
Molecular Conformation
Plasmodium berghei
Quinine
Ruthenium
Stereoisomerism
English We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C-H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (-)-quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (-)-quinine both in vitro and in mice infected with Plasmodium berghei.
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  • English
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hybrid
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https://sonar.ch/global/documents/109671
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