Thetotal synthesis ofquinine, a naturally-occurringantimalarial drug, was developed over a 150-year period. The development of synthetic quinine is considered a milestone inorganic 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 firststereoselective total synthesis of quinine in 2001, meanwhile shedding doubt on the earlier claim byRobert Burns Woodward andWilliam 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 inChemical & Engineering News sided with Stork, but the controversy was eventually laid to rest once and for all when Robert Williams and coworkers successfully repeated Woodward's proposed conversion of quinotoxine to quinine in 2007.^[1]

The aromatic component of the quinine molecule is aquinoline with amethoxy substituent. Theamine component has aquinuclidine skeleton and themethylene bridge in between the two components has ahydroxyl group. The substituent at the 3 position is avinyl group. The molecule isoptically active with fivestereogenic centers (the N1 and C4 constituting a single asymmetric unit), making synthesis potentially difficult because it is one of 16stereoisomers.

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• 1817: First isolation of quinine fromcinchona tree byPierre Joseph Pelletier and Joseph Caventou.
• 1853:Louis Pasteur obtainsquinotoxine (orquinicine in older literature) by acid-catalysedisomerization of quinine.^[2]

• 1856: SirWilliam Henry Perkin attempts quinine synthesis by oxidation ofN-allyltoluidine based on the erroneous idea that two equivalents of this compound withchemical formula C₁₀H₁₃N plus three equivalents of oxygen yield one equivalent of C₂₀H₂₄N₂O₂ (quinine's chemical formula) and one equivalent of water.^[3] His oxidations with other toluidines sets him on the path to discovermauveine. The commercial importance of mauveine eventually lead to the birth of the chemical industry.

• 1907: the correct atom connectivity established by Paul Rabe.^[4]
• 1918: Paul Rabe and Karl Kindler synthesize quinine from quinotoxine,^[5] reversing the Pasteur chemistry. The lack of experimental details in this publication would become a major issue in the Stork–Woodward controversy almost a century later.

The first step in this sequence issodium hypobromite addition to quinotoxine to anN-bromo intermediate possibly with structure 2. The second step isorganic oxidation withsodium ethoxide inethanol. Because of the basic conditions the initial productquininone interconverts withquinidinone via a commonenol intermediate andmutarotation is observed. In the third step theketone group is reduced withaluminum powder and sodium ethoxide in ethanol and quinine can be identified. Quinotoxine is the first relay molecule in the Woodward/Doering claim.

• 1939: Rabe and Kindler re investigate a sample left over from their 1918 experiments and identify and isolate quinine (again) together withdiastereomersquinidine,epi-quinine andepi-quinidine.^[6]
• 1940:Robert Burns Woodward signs on as a consultant for thePolaroid Corporation at the request ofEdwin H. Land. Quinine is of interest to Polaroid for itslight polarizing properties.
• 1943:Prelog and Proštenik interconvert an allylpiperidine calledhomomeroquinene and quinotoxine.^[7] Homomeroquinene (the second relay molecule in the Woodward/Doering claim) is obtained in several steps from thebiomoleculecinchonine (related to quinidine but without themethoxy group):

The key step in the assembly of quinotoxine is aClaisen condensation:

• 1944:Robert Burns Woodward andW. E. Doering report the synthesis of quinine,^[8] starting from 7-hydroxyisoquinoline. Although the title of their one-page publication isThe total synthesis of quinine it is oddly not the synthesis of quinine but that of the precursor homomeroquinene (racemic) and then with groundwork already provided by Prelog a year earlier to quinotoxine (enantiopure afterchiral resolution) that is described.

Woodward and Doering argue that Rabe in 1918 already proved that this compound will eventually give quinine but do not repeat Rabe's work. In this project 27-year-old assistant professor Woodward is the theorist and postdoc Doering (age 26) the bench worker. As many natural quinine resources were tied up in the enemy-heldDutch East Indies, synthetic quinine was a promising alternative for fighting malaria on the battlefield and both men become instant war heroes making headlines in theNew York Times,Newsweek andLife.

• 1944: The then 22-year-old Gilbert Stork writes to Woodward asking him if he did repeat Rabe's work.
• 1945: Woodward and Doering publish their second lengthy quinine paper.^[9] One of the two referees rejects the manuscript (too much historic material, too much experimental details and poor literary style with inclusion of words likeadumbrated andapposite) but it is published without changes nonetheless.
• 1974: Kondo and Mori synthesizeracemic vinylic gamma-lactones, a key starting material in Stork's 2001 quinine synthesis.^[10]

The starting materials aretrans-2-butene-1,4-diol andethyl orthoacetate and the key step is aClaisen rearrangement

• 1988: Ishibashi & Taniguchi resolve said lactone to enantiopure compounds viachiral resolution:^[11]

In this process the racemic lactone reacts in aminolysis with (S)-methylbenzylamine assisted bytriethylaluminum to adiastereomeric pair ofamides which can be separated bycolumn chromatography. TheS-enantiomer is converted back to theS-lactone in two steps by hydrolysis withpotassium hydroxide andethylene glycol followed by azeotropic ring closure.

• 2001: Gilbert Stork publishes his stereoselective quinine synthesis.^[12] He questions the validity of the Woodward/Doering claim: "the basis of their characterization of Rabe’s claim as “established” is unclear". M. Jacobs, writing in TheChemical & Engineering News, is equally critical.^[13]

• 2007: Researcher Jeffrey I. Seeman in a 30-page review^[14] concludes that the Woodward–Doering–Rabe–Kindler total synthesis of quinine is a valid achievement. He notes that Paul Rabe was an extremely experiencedalkaloid chemist, that he had ample opportunity to compare his quinine reaction product with authentic samples and that the described 1918 chemistry was repeated by Rabe although not with quinotoxine itself but still with closely related derivatives.
• 2008: Smith and Williams revisit and confirm Rabe'sd-quinotoxine to quinine route.^[15]

• 2018:Nuno Maulide and his team report the total synthesis of quinine viaC–H activation, including analogues with improved antimalarial activity^[16]

The Stork quinine synthesis starts from chiral (S)-4-vinylbutyrolactone1. The compound is obtained bychiral resolution and in fact, in the subsequent steps all stereogenic centers are put in place bychiral induction: the sequence does not containasymmetric steps.

Stork quinine synthesis		Introducing C8 and nitrogen

Thelactone is ring-opened withdiethylamine toamide2 and itshydroxyl group isprotected as atert-butyldimethylsilyl ether (TBS) in3. The C5 and C6 atoms are added astert-butyldiphenylsilyl (TBDPS) protectediodoethanol in anucleophilic substitution of acidic C4 withlithium diisopropylamide (LDA) at −78 °C to4 with correct stereochemistry. Removal of the silyl protecting group withp-toluenesulfonic acid toalcohol4b and ring-closure byazeotropic distillation returns the compound to lactone5 (directalkylation of 1 met with undisclosed problems).

The lactone is then reduced to thelactol5b withdiisobutylaluminum hydride and its liberatedaldehyde reacts in aWittig reaction withmethoxymethylenetriphenylphosphine (delivering the C8 atom) to formenol ether6. The hydroxyl group is replaced in aMitsunobu reaction by anazide group withdiphenylphosphoryl azide in7 and acid hydrolysis yields the azido aldehyde8.

First ring closure		Second ring closure

Themethyl group in6-methoxy-4-methylquinoline9 is sufficientlyacidic fornucleophilic addition of its anion (by reaction withLDA) to the aldehyde group in8 to form10 as a mixture ofepimers. This is of no consequence for stereocontrol because in the next step the alcohol is oxidized in aSwern oxidation toketone11. AStaudinger reaction withtriphenylphosphine closes the ring between the ketone and the azide to thetetrahydropyridine12. Theimine group in this compound is reduced to theamine13 withsodium borohydride with the correctstereospecificity. The silyl protecting group is removed withhydrogen fluoride to alcohol14 and then activated as amesylleaving group by reaction withmesyl chloride inpyridine which enables the third ring closure to15. In the final step the C9 hydroxyl group was introduced by oxidation withsodium hydride,dimethylsulfoxide and oxygen with quinine to epiquinine ratio of 14:1.

The 1944 Woodward–Doering synthesis starts from 7-hydroxyisoquinoline3 for thequinuclidine skeleton which is somewhat counter intuitive because one goes from a stable heterocyclic aromatic system to a completely saturated bicyclic ring. This compound (already known since 1895) is prepared in two steps.

Woodward/Doering quinine synthesis part I		Part II

The first reaction step iscondensation reaction of3-hydroxybenzaldehyde1 with (formally) the diacetal ofaminoacetaldehyde to theimine2 and the second reaction step is cyclization in concentratedsulfuric acid. Isoquinoline3 is then alkylated in another condensation byformaldehyde andpiperidine and the product is isolated as the sodium salt of4.

Woodward/Doering quinine synthesis part III

Hydrogenation at 220 °C for 10 hours inmethanol withsodium methoxide liberates the piperidine group and leaving the methyl group in5 with already all carbon and nitrogen atoms accounted for. A secondhydrogenation takes place withAdams catalyst inacetic acid totetrahydroisoquinoline6. Further hydrogenation does not take place until the amino group isacylated withacetic anhydride inmethanol but by then7 is again hydrogenated withRaney nickel inethanol at 150 °C under high pressure todecahydroisoquinoline8. The mixture ofcis andtrans isomers is then oxidized bychromic acid in acetic acid to theketone9. Only the cis isomer crystallizes and used in the next reaction step, a ring opening with thealkyl nitriteethyl nitrite withsodium ethoxide inethanol to10 with a newly formedcarboxylic ester group and anoxime group. The oxime group is hydrogenated to theamine11 withplatinum inacetic acid andalkylation withiodomethane gives thequaternary ammonium salt12 and subsequently thebetaine13 after reaction withsilver oxide.

Quinine'svinyl group is then constructed byHofmann elimination withsodium hydroxide in water at 140 °C. This process is accompanied byhydrolysis of both the ester and the amide group but it is not the free amine that is isolated but theurea14 by reaction withpotassium cyanate. In the next step thecarboxylic acid group isesterified with ethanol and the urea group replaced with abenzoyl group. The final step is aClaisen condensation of15 with ethyl quininate16, which after acidic workup yieldsracemic quinotoxine17. The desired enantiomer is obtained bychiral resolution with the chiral dibenzoyl ester ofTartaric acid. The conversion of this compound to quinine is based on the Rabe–Kindler chemistry discussed in the timelime.

• Quinine Total Syntheses @ SynArchive.com
• Quinine story at Harvard.eduLink

• Total synthesis
• Quinine

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