Quinine total synthesis
total synthesis, the Quinine total synthesis describes the efforts in synthesis of quinineover a 150 year period. The development of synthetic quinine is considered a milestone in organic chemistryalthough it has never been produced industrially as a substitute for natural occurring quinine. The subject has also been attended with some controversy: in 2001 Gilbert Storkpublished the first stereoselectivequinine synthesis and he shed doubt (calling it a myth) on the earlier claim in 1944 by Bob Woodward and William Doering on account that they had obtained not quinine but a precursor molecule. In 2001, an editorial in Chemical & Engineering Newssupported Storks claim but according to a critical 30 page review in this matter published in 2007 in Angewandte Chemiethe Woodward/Doering claim is valid.
The aromatic part of the quinine molecule is a
quinolinewith a methoxysubstituent. The aminecomponent has a quinuclidineskeleton and the methylenebridge in between has an hydroxide group. The substituent at the carbon-3 position is a vinylgroup. The molecule is optically activewith four stereogenicgroups making synthesis potentially difficult because it is one of 16 stereoisomers.
Quinine total synthesis timeline
* 1817: First isolation of quinine from
cinchonatree by Pierre Joseph Pelletierand Joseph Caventou
Louis Pasteurobtains quinotoxine (or "quinicine" in older literature) by acid-catalysed isomerizationof quinine [Pasteur, L. Compt. rend. 1853, 37, 110.] :
* 1856: William Henry Perkin attempts quinine synthesis by oxidation of N-allyl
toluidinebased on the amazing but erroneous idea that 2 equivalents of this compound with chemical formulaC10H13N plus three equivalents of oxygen yield one equivalent of C20H24N202 (quinine's chemical formula) and one equivalent of water [Perkin, W. H. J. Chem. Soc. 1896, 69, 596] His oxidations with other toluidines sets him on the path of mauveinewhich eventually leads to the birth of chemical industry.:
* 1907: the correct atom connectivity established by Paul Rabe [Rabe, P.; Ackerman, E.; Schneider, W. Ber. 1907, 40, 3655]
* 1918: Paul Rabe and Karl Kindler synthesize quinine from quinotoxine [Rabe, P.; Kindler, K. Chem. Ber. 1918, 51, 466] , 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 hypobromiteaddition to quinotoxine to an N-bromo intermediate possibly with structure 2. The second step is organic oxidationwith sodium ethoxidein ethanol. Because of the basic conditions the initial product quininone interconverts with quinidinone via a common enolintermediate and mutarotationis observed. In the third step the ketonegroup is reduced with aluminumpowder 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 [P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. B 1939, 72, 263–264.]
Robert Burns Woodwardsigns on as a consultant for the Polaroid Corporationat the request of Edwin H. Land. Quinine is of interest to Polaroid for its light polarizing properties.
* 1943: Prelog and Proštenik interconvert an allyl
piperidinecalled homomeroquinene and quinotoxine [Proštenik, M.; Prelog, V. HelV. Chim. Acta 1943, 26, 1965.] . 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 methoxygroup):
:The key step in the assembly of quinotoxine is a
* 1944: Bob Woodward and
W.E. Doeringreport the synthesis of quinine ["The Total Synthesis of Quinine" R. B. Woodward and W. E. Doering J. Am. Chem. Soc.; 1944; 66(5) pp 849 - 849; DOI|10.1021/ja01233a516] 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 Indiessynthetic 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, Newsweekand 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 ["The Total Synthesis of Quinine" R. B. Woodward and W. E. Doering
J. Am. Chem. Soc.; 1945; 67(5) pp 860 - 874; DOI|10.1021/ja01221a051] . 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
racemicvinylic gamma-lactones, a key starting meterial in Storks 2001 quinine synthesis. ["SYNTHESIS OF γ-LACTONES BY THE CONDENSATION OF 2-ALKENE-1,4-DIOLS WITH ORTHOCARBOXYLIC ESTERS" Kiyosi Kondo and Fumio Mori Chemistry Letters Vol.3 (1974) , No.7 pp.741-742 DOI|10.1246/cl.1974.741] ::The starting materials are trans-2-butene-1,4-dioland ethyl orthoacetateand the key step is a Claisen rearrangement
* 1988: Ishibashi & Taniguchy resolve said lactone to enantiopure compounds via
chiral resolution[" Synthesis and Absolute Configuration of the Acetalic Lignan (+)-Phrymarolin" Fumito Ishibashi and Eiji Taniguchi Bulletin of the Chemical Society of Japan Vol.61 (1988) , No.12 pp.4361-4366 doi|10.1246/bcsj.61.4361] :::In this process the racemic lactone reacts in aminolysis with (S)- methylbenzylamineassisted by triethylaluminumto a diastereomeric pairof 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 hydroxideand ethylene glycolfollowed by azeotropic ring closure.
* 2001: Gilbert Stork publishes his stereoselective quinine synthesis ["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) DOI|10.1021/ja004325r.] . 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 Newsis equally critical [M. Jacobs, Chemical & Engineering News2001, 79 (May 7), 5.] .:
* 2007: Researcher Jeffrey I Seeman in a 30 page review ["Review: The Woodward-Doering/Rabe-Kindler Total Synthesis of Quinine: Setting the Record Straight" Jeffrey I. Seeman
Angew. Chem. Int. Ed.2007, 46, 1378 – 1413 DOI|10.1002/anie.200601551] concludes that the Woodward–Doering/ Rabe–Kindler total synthesis of quinine is a valid achievement. He notes that Paul Rabe was an extremely experienced alkaloidchemist, 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 [Communication "Rabe Rest in Peace: Confirmation of the Rabe-Kindler Conversion of d-Quinotoxine to Quinine: Experimental Affirmation of the Woodward-Doering Formal Total Synthesis of Quinine" Aaron C. Smith, Robert M. Williams
Angewandte Chemie International EditionPublished Online: 31 Jan 2008 DOI|10.1002/anie.200705421 ] :
tork quinine total synthesis
The Stork quinine synthesis starts from chiral (S)-4-vinylbutyrolactone 1. The compound is obtained by
chiral resolutionand in fact, in the subsequent steps all stereogenic centers are put in place by chiral induction: the sequence does not contain asymmetric steps.
The first reaction step is
condensation reactionof 3-hydroxybenzaldehyde1 with (formally) the di acetalof aminoacetaldehyde to the imine2 and the second reaction step is cyclization in concentrated sulfuric acid. Isoquinoline 3 is then alkylated in another condensation by formaldehydeand piperidineand the product is isolated as the sodium salt of 4. Hydrogenationat 220°C for 10 hours in methanolwith sodium methoxideliberates the piperidine group and leaving the methyl group in 5 with already all carbon and nitrogen atoms accounted for. A second hydrogenationtakes place with Adams catalystin acetic acidto "tetrahydroisoquinoline" 6. Further hydrogenation does not take place until the amino group is acylated with acetic anhydridein methanolbut by then 7 is again hydrogenated with Raney nickelin ethanolat 150°C under high pressure to "decahydroisoquinoline" 8. The mixture of cis and trans isomers is then oxidized by chromic acidin acetic acid to the ketone9. Only the cis isomer crystallizes and used in the next reaction step, a ring opening with the alkyl nitrite"ethyl nitrite" with sodium ethoxidein ethanolto 10 with a newly formed carboxylic estergroup and an oximegroup. The oxime group is hydrogenated to the amine11 with platinumin acetic acidand alkylationwith iodomethanegives the quaternary ammonium salt12 and subsequently the betaine13 after reaction with silver oxide.
vinylgroup is then constructed by Hofmann eliminationwith sodium hydroxidein water at 140°C. This process is accompanied by hydrolysisof both the ester and the amide group but it is not the free amine that is isolated but the urea14 by reaction with potassium cyanate. In the next step the carboxylic acidgroup is esterified with ethanol and the urea group replaced with a benzoylgroup. The final step is a claisen condensationof 15 with ethyl quininate 16, which after acidic workup yields racemicquinotoxine 17. The desired enantiomer is obtained by chiral resolutionwith the chiral dibenzoyl ester of Tartaric acid. The conversion of this compound to quinine is based on the Rabe/Kindler chemistry discussed in the timelime.
* Quinine story at harvard.edu [http://daecr1.harvard.edu/pdf/smnr_2001-2002_Reynolds_Dominic.pdf Link]
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