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C−H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity
Author(s) -
O' Donovan Daniel H.,
Aillard Paul,
Berger Martin,
de la Torre Aurélien,
Petkova Desislava,
KnittlFrank Christian,
Geerdink Danny,
Kaiser Marcel,
Maulide Nuno
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201804551
Subject(s) - quinine , natural product , total synthesis , chemistry , plasmodium berghei , stereoselectivity , stereochemistry , aldol reaction , aryl , combinatorial chemistry , in vitro , plasmodium falciparum , antimalarial agent , malaria , biochemistry , biology , organic chemistry , catalysis , alkyl , immunology
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.