Quinine Total Synthesis - Quinine Total Synthesis Timeline

Quinine Total Synthesis Timeline

• 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: William Henry Perkin attempts quinine synthesis by oxidation of N-allyl toluidine based on the erroneous idea that 2 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 of mauveine which eventually leads to the birth of chemical industry.

• 1907: the correct atom connectivity established by Paul Rabe
• 1918: Paul Rabe and Karl Kindler synthesize quinine from quinotoxine, 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 is sodium hypobromite addition to quinotoxine to an N-bromo intermediate possibly with structure 2. The second step is organic oxidation with sodium ethoxide in ethanol. Because of the basic conditions the initial product quininone interconverts with quinidinone via a common enol intermediate and mutarotation is observed. In the third step the ketone group is reduced with aluminum 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 with diastereomers quinidine, epi-quinine and epi-quinidine
• 1940: Robert Burns Woodward signs on as a consultant for the Polaroid Corporation at the request of Edwin H. Land. Quinine is of interest to Polaroid for its light polarizing properties.
• 1943: Prelog and Proštenik interconvert an allyl piperidine called homomeroquinene and quinotoxine. Homomeroquinene (the second relay molecule in the Woodward/Doering claim) is obtained in several steps from the biomolecule cinchonine (related to quinidine but without the methoxy group):

The key step in the assembly of quinotoxine is a claisen condensation:

• 1944: Bob Woodward and W.E. Doering report the synthesis of quinine starting from 7-hydroxyisoquinoline. Although the title of their 1 page publication is The 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 after chiral 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 post doc Doering (age 26) the bench worker. According to William, Bob was able to boil water but an egg would be a challenge. As many natural quinine resources are tied up in the enemy-held Dutch East Indies synthetic quinine is a promising alternative for fighting malaria on the battlefield and both men become instant war heroes making headlines in the New York Times, Newsweek and Life magazine.

• 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. One of the two referees rejects the manuscript (too much historic material, too much experimental details and poor literary style with inclusion of words like adumbrated and apposite) but it is published without changes nonetheless.
• 1974: Kondo & Mori synthesize racemic vinylic gamma-lactones, a key starting meterial in Stork's 2001 quinine synthesis.:

The starting materials are trans-2-butene-1,4-diol and ethyl orthoacetate and the key step is a Claisen rearrangement

• 1988: Ishibashi & Taniguchy resolve said lactone to enantiopure compounds via chiral resolution:

In this process the racemic lactone reacts in aminolysis with (S)-methylbenzylamine assisted by triethylaluminum to a diastereomeric pair of amides which can be separated by column chromatography. The S-enantiomer is converted back to the S-lactone in two steps by hydrolysis with potassium hydroxide and ethylene glycol followed by azeotropic ring closure.

• 2001: Gilbert Stork publishes his stereoselective quinine synthesis. He questions the validity of the Woodward/Doering claim: "the basis of their characterization of Rabe’s claim as “established” is unclear". The Chemical & Engineering News is equally critical.

• 2007: Researcher Jeffrey I Seeman in a 30 page review concludes that the Woodward–Doering/ Rabe–Kindler total synthesis of quinine is a valid achievement. He notes that Paul Rabe was an extremely experienced alkaloid 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's d-quinotoxine to quinine route