The total synthesis of quinine details the research and synthetic methods required to produce the alkaloid quinine artificially, 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.Pasteur, L. Compt. rend. 1853, 37, 110. 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, W. H. J. Chem. Soc. 1896, 69, 596 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.Rabe, P.; Ackerman, E.; Schneider, W. Ber. 1907, 40, 3655 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.Rabe, P.; Kindler, K. Chem. Ber. 1918, 51, 466 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.Proštenik, M.; Prelog, V. HelV. Chim. Acta 1943, 26, 1965.
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.The Total Synthesis of Quinine R. B. Woodward and W. E. Doering J. Am. Chem. Soc.; 1944; 66(5) pp 849 - 849; The Total Synthesis of Quinine R. B. Woodward and W. E. Doering J. Am. Chem. Soc.; 1945; 67(5) pp 860 - 874; 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 First Stereoselective Total Synthesis of Quinine Gilbert Stork, Deqiang Niu, A. Fujimoto, Emil R. Koft, James M. Balkovec, James R. Tata, and Gregory R. Dake J. Am. Chem. Soc.; 2001; 123(14) pp 3239 - 3242; (Article) . 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.
Minor controversy In addition to being the first stereoselective total synthesis of the molecule, Stork's work also called into question Woodward and Doering's synthesis, particularly the final conversion from quinotoxine to quinine using Paul Rabe's 1918 method. Stork claimed that this final conversion had not been verified experimentally by Woodward and Doering, nor Rabe himself, aside from a "terse" announcement. At the time, it remained unknown if this particular quinotoxine-to-quinine step was feasible. The minor controversy was eventually laid to rest when Robert Williams and co-workers successfully repeated Woodward's proposed conversion of quinotoxine to quinine in 2007.
Maulide's synthesis Another unique pathway towards the synthesis of quinine was put forth by Nuno Maulide and co-workers. In 2018, the Maulide group reported the total synthesis of quinine through a key C–H activation step.C–H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity D. H. O'Donovan et al Angewandte Chemie International Edition 2018 Their synthesis began with the quinuclidine system already established, using commercially available 3-aminoquinuclidine as their starting material. The unique C–H activation step functionalized the C3 position, installing a vinyl group through a series of transformations starting from an aryl functional group.
The synthesis was a stereoselective one, producing (–)-quinine in a 5.4% overall yield over the course of ten steps. In addition to the natural product, Maulide and co-workers also synthesized the enantiomer (+)-quinine, as well as two C3-substituted aryl derivatives. The (+)-quinine and related derivatives were screened for antimalarial activity, with the aryl compounds showing enhanced activity compared to the natural product.
Synthetic pathways of selected syntheses Woodward and Doering (1944) The formal synthesis by Woodward and Doering began with the simple building block 3-hydroxybenzaldehyde 1a, which was reacted with the aminoacetal component 1b in a straightforward condensation reaction to give imine 2. Acid-mediated cyclization of 2 produced the 7-hydroxyisoquinoline 3, which Woodward and Doering cited as their starting point towards quinine. A condensation between the reagents formaldehyde, piperidine, and 3 gave intermediate 4, which was then converted to 5 via a base-mediated removal of the piperidine moiety using sodium methoxide in methanol. A hydrogenation reaction completes the first precursor, 7-hydroxy-8-methylisoquinoline 6.
The synthesis continued with the succession of the following steps. With 6 in hand, the free amine is acetyl-protected, and the remaining aromatic ring system is hydrogenated to give tetrahydroisoquinoline 8, which was obtained as the trans isomer via distillation and crystallization. Direct oxidation of 8 gave ketone 9, which was obtained now as the cis isomer from its crystalline hydrate. Reaction of 9 with sodium ethoxide and ethyl nitrite opened the six-membered ring containing the ketone to give intermediate 10. Hydrogenation of the ketoxime group furnished amine 11. Reaction with methyl iodide gave the trimethylammonium salt 12, which was converted free amine 13 though a Hofmann elimination and simultaneous acetyl hydrolysis. Attempts to directly purify amine 13 were unsuccessful, and so reaction with potassium cyanate followed by acidification gave amide 14. This was converted to 15 which was obtained as a colorless oil.
Reaction of 15 with excess ethyl quininate (15a) gave the β-keto ester 16, the result of a condensation reaction between the two. The crude ester 16 was subsequently hydrolyzed to dl-quinotoxine 17. Chiral resolution with dibenzoyl-d-tartaric acid yielded the enantiomerically pure d-quinotoxine-d-tartrate derivative (not pictured). From here, Woodward and Doering considered the work to be complete, citing Rabe's conversion of quinotoxine to quinine as being the final step to reach their synthetic target.
Uskokovic and Gutzwiller (1970) The chemists working at Hoffmann-La Roche began their synthetic endeavor with the "easily accessible" N-benzoyl-hexahydroisoquinolone 1. Schmidt reaction of the starting material gave lactam 2 and its related compound 2a. Hydrogenation of the alkene in 2 using rhodium on alumina gave cis-lactam 3. This intermediate was reacted with dinitrogen tetroxide to give N-nitrosolactam 4. Heating of this unstable intermediate led to an intramolecular rearrangement, forming compound 5, which upon further heating expelled molecular nitrogen, giving lactone 5a and carboxylic acid N-benzoylmeroquinene 6. As reported by Uskokovic and co-workers, lactone 5a could be converted to the desired 6 over the course of four additional steps.
In the next half of the synthesis, carboxylic acid 6 was converted to the methyl ester 7. This was directly coupled to 6-methoxylepidyllithium compound 7a to give N-benzoyl ketone 8.