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Concept
Quinine total synthesis
Summary
The total synthesis of quinine, a naturally-occurring antimalarial drug, was developed over a 150-year period. The development of synthetic quinine is considered a milestone in organic chemistry although it has never been produced industrially as a substitute for natural occurring quinine. The subject has also been attended with some controversy: Gilbert Stork published the first stereoselective total synthesis of quinine in 2001, meanwhile shedding doubt on the earlier claim by Robert Burns Woodward and William Doering in 1944, claiming that the final steps required to convert their last synthetic intermediate, quinotoxine, into quinine would not have worked had Woodward and Doering attempted to perform the experiment. A 2001 editorial published in Chemical & Engineering News sided with Stork, but the controversy was eventually laid to rest once and for all when Williams and coworkers successfully repeated Woodward's proposed conversion of quinotoxine to quinine in 2007.
The aromatic component of the quinine molecule is a quinoline with a methoxy substituent. The amine component has a quinuclidine skeleton and the methylene bridge in between the two components has a hydroxyl group. The substituent at the 3 position is a vinyl group. The molecule is optically active with five stereogenic centers (the N1 and C4 constituting a single asymmetric unit), making synthesis potentially difficult because it is one of 16 stereoisomers.
1817: First isolation of quinine from cinchona tree by Pierre Joseph Pelletier and Joseph Caventou.
1853: Louis Pasteur obtains quinotoxine (or quinicine in older literature) by acid-catalysed isomerization of quinine.
1856: Sir William Henry Perkin attempts quinine synthesis by oxidation of N-allyltoluidine based on the erroneous idea that two equivalents of this compound with chemical formula C10H13N plus three equivalents of oxygen yield one equivalent of C20H24N2O2 (quinine's chemical formula) and one equivalent of water. His oxidations with other toluidines sets him on the path to discover mauveine.
Official source
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