The total synthesis of quinine details the research and synthetic methods required to produce the alkaloid quinine artifically, the steps of which were developed over the course of a century and a half, beginning with the molecule's formal discovery in 1820 by Pierre Joseph Pelletier and Joseph Caventou. Quinine, an alkaloid isolated from the bark of the cinchona, a tree native to South America, has been historically used as a medication to treat malaria as well as babesiosis. In addition to its antimalarial properties, quinine is also commonly found in tonic water, and is responsible for the bitter taste. Although the total synthesis of quinine has been accomplished a number of times, it has never been produced on an industrial scale as a substitute for the naturally-occurring alkaloid. Nevertheless, the total synthesis of quinine is regarded as a milestone in organic chemistry, ushering in a new era of organic synthesis with a purpose outside of structure elucidation.
The structure of quinine
Quinine is a fairly simple natural product, a chiral molecule containing four stereocenters within the quinuclidine bicyclic amine group. With four stereocenters present in the structure, 16 possible stereoisomers of quinine can exist. The correct configuration of these centers (i.e. the correct orientation of these stereocenters and their bonds), is critical to a successful total synthesis. Other structural features of quinine include an aromatic quinoline system, containing a methoxy group present on the carbon ring. A methylene bridge (C9) connects the quinuclidine amine and the quinoline system; on this bridge is a hydroxyl group. A vinyl group occupies the C3 position.
Historical overview of selected syntheses
Early attempts
The synthetic groundwork towards the synthesis of quinine was first laid down in 1853 with French chemist Louis Pasteur. He was able to produce a derivative of quinine (known as quinotoxine) by using an acid-catalyzed isomerization reaction. Around this time, Sir William Henry Perkin attempted a quinine synthesis of his own, by trying to oxidize N-allyltoluidine to the target molecule. Perkin's synthesis had its basis in the molecular formula of his starting material, believing that two equivalents of N-allyltoluidine (formula C10H13N) reacted with three equivalents of atomic oxygen (O) would give one quinine equivalent (formula C20H24N2O2) with water as a byproduct. Although Perkin's assumption turned out to be incorrect, this effort coincidentally led him to discover mauveine, one of the first synthetic dyes. In 1907, German chemist Paul Rabe was able to determine the correct atom connectivity of quinine. By 1918, Rabe and fellow chemist Karl Kindler were able to reverse Pasteur's isomerization step, and announced in a very brief communication that they had obtained quinine from the quinotoxine derivative. Notably, this chemical transformation would later be the cause of minor controversy in the decades to come. In 1943, Milhovil Proštenik and Vladimir Prelog published a report in which they prepared quinotoxine by the condensation of an intermediate called homomeroquinene with ethyl quininate. The homomeroquinene was obtained through the degradation of another natural product, the alkaloid cinchonine.
Woodward and Doering's synthesis
In 1944, Harvard chemists Robert Burns Woodward and William von Eggers Doering put forth the first major synthesis of quinine to date, while working as consultants for the Polaroid Corporation. During World War II, this work was celebrated as a possible new source of quinine, with Japan's occupation of Java in 1942 cutting off the United States from the main source of quinine, then the go-to treatment for malaria. Although Woodward and Doering's work was significant, it constituted a formal synthesis of the alkaloid; the synthesis of a precursor that can then be converted to quinine using previously-known chemistry. Woodward and Doering had in fact, provided a synthetic route to quinotoxine, which they surmised could be converted to quinine using Rabe's method. They did not experimentally verify if Rabe's method indeed could convert quinotoxine to quinine, instead writing that the method was "established".
Uskoković–Gutzwiller–Henderson synthesis In 1970, Milan Uskoković, Jürg Gutzwiller, and Thomas Henderson, chemists working for Hoffmann-La Roche, reported a nine-step synthesis of quinine. The first of its kind in nearly four decades, the synthesis was stereocontrolled throughout the production of the first precursor, an intermediate referred to as N-benzoylmeroquinine. Despite this, their synthesis produced a diastereomic mixture of quinine and quinidine. The main difference between the two products being opposite stereochemistry at the C8 and C9 centers, in particular.
Stork's synthesis Although synthetic quinine had been accomplished, producing quinine with the correct, natural stereochemistry had yet to be reported. In 2001, Gilbert Stork of Columbia University published the first stereoselective total synthesis of quinine. The primary focus of the synthesis was to address the stereochemistry at the C8 and C9 centers, in light of the results published by Hoffmann-La Roche in 1973. Stork and co-workers began their synthesis with the stereoselective construction of an intermediate that would eventually be used as the basis for the quinuclidine amine system. The stereochemistry of the C8 center was set in a hydride addition reaction; a prediction of the reaction site ring being in a half-chair configuration with all substituents positioned equatorially turned out to be correct, with hydride addition resulting in the correct stereochemistry at C8. In the final step of Stork's synthesis, oxidation in the presence of sodium hydride set the correct stereochemistry of the C9 center, completing the synthesis and resulting in a quinine product that, by NMR and mass spectrometry analysis, was identical to a commercial sample.
… excerpt ends here. Continue reading the full article.
