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

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...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2018-08, Vol.57 (33), p.10737-10741
Main Authors: O' Donovan, Daniel H., Aillard, Paul, Berger, Martin, de la Torre, Aurélien, Petkova, Desislava, Knittl‐Frank, Christian, Geerdink, Danny, Kaiser, Marcel, Maulide, Nuno
Format: Article
Language:English
Subjects:
Activation
Aldehydes
Aldehydes - chemistry
Animals
Antimalarial activity
Antimalarial agents
Antimalarials - chemical synthesis
Antimalarials - pharmacology
Antimalarials - therapeutic use
Aromatic compounds
Carbon - chemistry
Catalysis
Chemical synthesis
Communication
Communications
Crystallography, X-Ray
C−H activation
Hydrogen - chemistry
malaria
Malaria - drug therapy
Malaria - veterinary
Mice
Molecular Conformation
Natural products
Plasmodium berghei - drug effects
Quinine
Quinine - analogs & derivatives
Quinine - pharmacology
Quinine - therapeutic use
Ruthenium - chemistry
Stereoisomerism
Stereoselectivity
total synthesis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Revisiting an old friend: A novel approach to the classical natural product quinine is based on two stereoselective key steps, namely a C(sp3)−H activation and an aldol reaction. This strategy enables the preparation of both antipodes of the target as well as novel synthetic analogues that display enhanced in vivo antimalarial activity.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201804551