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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. According to William, Bob was able to boil
290:: 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 StorkâWoodward controversy almost a century later.
58:
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 in
654:: Gilbert Stork publishes his stereoselective quinine synthesis. He questions the validity of the Woodward/Doering claim: "the basis of their characterization of Rabeâs claim as âestablishedâ is unclear". M. Jacobs, writing in The
679:
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
531:: 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
1090:
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.
675:: Researcher Jeffrey I. Seeman in a 30-page review concludes that the WoodwardâDoeringâRabeâKindler total synthesis of quinine is a valid achievement. He notes that Paul Rabe was an extremely experienced
65:
sided with Stork, but the controversy was eventually laid to rest once and for all when
Williams and coworkers successfully repeated Woodward's proposed conversion of quinotoxine to quinine in 2007.
478:
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
1465:"Rabe Rest in Peace: Confirmation of the RabeâKindler Conversion of dâ Quinotoxine Into Quinine: Experimental Affirmation of the WoodwardâDoering Formal Total Synthesis of Quinine"
561:
451:
16:
42:
although it has never been produced industrially as a substitute for natural occurring quinine. The subject has also been attended with some controversy:
499:, synthetic quinine was a promising alternative for fighting malaria on the battlefield and both men become instant war heroes making headlines in the
488:
1776:
350:
1443:
1107:
1098:
346:
powder and sodium ethoxide in ethanol and quinine can be identified. Quinotoxine is the first relay molecule in the
Woodward/Doering claim.
361:: Rabe and Kindler re investigate a sample left over from their 1918 experiments and identify and isolate quinine (again) together with
890:
273:
296:
416:
and quinotoxine. Homomeroquinene (the second relay molecule in the
Woodward/Doering claim) is obtained in several steps from the
263:(quinine's chemical formula) and one equivalent of water. His oxidations with other toluidines sets him on the path to discover
109:
centers (the N1 and C4 constituting a single asymmetric unit), making synthesis potentially difficult because it is one of 16
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1428:. The conversion of this compound to quinine is based on the RabeâKindler chemistry discussed in the timelime.
1341:
979:
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38:
drug, was developed over a 150-year period. The development of synthetic quinine is considered a milestone in
1799:
CâH Activation
Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity
1696:
Gilbert Stork, Deqiang Niu, A. Fujimoto, Emil R. Koft, James M. Balkovec, James R. Tata, and
Gregory R. Dake
572:
856:
181:
1773:-Quinotoxine to Quinine: Experimental Affirmation of the WoodwardâDoering Formal Total Synthesis of Quinine
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water but an egg would be a challenge. As many natural quinine resources were tied up in the enemy-held
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994:. This is of no consequence for stereocontrol because in the next step the alcohol is oxidized in a
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1738:
Review: The
Woodward-Doering/Rabe-Kindler Total Synthesis of Quinine: Setting the Record Straight
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576:
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525:: The then 22-year-old Gilbert Stork writes to Woodward asking him if he did repeat Rabe's work.
1290:. Only the cis isomer crystallizes and used in the next reaction step, a ring opening with the
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267:. The commercial importance of mauveine eventually lead to the birth of the chemical industry.
39:
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SYNTHESIS OF Îł-LACTONES BY THE CONDENSATION OF 2-ALKENE-1,4-DIOLS WITH ORTHOCARBOXYLIC ESTERS
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of both the ester and the amide group but it is not the free amine that is isolated but the
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Fumito
Ishibashi and Eiji Taniguchi Bulletin of the Chemical Society of Japan Vol.61 (
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total synthesis of quinine in 2001, meanwhile shedding doubt on the earlier claim by
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and in fact, in the subsequent steps all stereogenic centers are put in place by
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590:: Ishibashi & Taniguchi resolve said lactone to enantiopure compounds via
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Synthesis and
Absolute Configuration of the Acetalic Lignan (+)-Phrymarolin
1506:
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1066:. In the final step the C9 hydroxyl group was introduced by oxidation with
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with correct stereochemistry. Removal of the silyl protecting group with
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based on the erroneous idea that two equivalents of this compound with
78:
30:
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1082:
The 1944 WoodwardâDoering synthesis starts from 7-hydroxyisoquinoline
20:
quinine carbon atom numbering scheme left and asymmetric centers right
1284:
1237:. Further hydrogenation does not take place until the amino group is
1142:
999:
991:
960:
871:
339:
1769:
Rabe Rest in Peace: Confirmation of the RabeâKindler Conversion of
1218:
with already all carbon and nitrogen atoms accounted for. A second
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1314:
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1021:
905:
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310:-bromo intermediate possibly with structure 2. The second step is
82:
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331:
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liberates the piperidine group and leaving the methyl group in
606:
In this process the racemic lactone reacts in aminolysis with (
1801:
D. H. O'Donovan et al Angewandte Chemie International Edition
120:
247:
N plus three equivalents of oxygen yield one equivalent of C
1156:
and the second reaction step is cyclization in concentrated
553:, a key starting material in Stork's 2001 quinine synthesis.
15:
715:, including analogues with improved antimalarial activity
284:: the correct atom connectivity established by Paul Rabe.
1373:
in water at 140 °C. This process is accompanied by
1013:
closes the ring between the ketone and the azide to the
470:
report the synthesis of quinine, starting from 7-hydroxy
1093:
922:
746:
711:
and his team report the total synthesis of quinine via
148:
1650:
Kiyosi Kondo and Fumio Mori Chemistry Letters Vol.3 (
1178:
474:. Although the title of their one-page publication is
322:. Because of the basic conditions the initial product
1694:
The First Stereoselective Total Synthesis of Quinine
1074:
and oxygen with quinine to epiquinine ratio of 14:1.
1627:
R. B. Woodward and W. E. Doering J. Am. Chem. Soc.;
73:
The aromatic component of the quinine molecule is a
1463:Smith, Aaronâ
C.; Williams, Robertâ
M. (2008-02-15).
1172:and the product is isolated as the sodium salt of
539:) but it is published without changes nonetheless.
441:The key step in the assembly of quinotoxine is a
1396:with ethanol and the urea group replaced with a
724:The Stork quinine synthesis starts from chiral (
686:: Smith and Williams revisit and confirm Rabe's
1078:WoodwardâDoering formal quinine total synthesis
1571:P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. B
1317:group. The oxime group is hydrogenated to the
916:and acid hydrolysis yields the azido aldehyde
97:group. The substituent at the 3 position is a
1164:is then alkylated in another condensation by
1039:. The silyl protecting group is removed with
394:. Quinine is of interest to Polaroid for its
8:
1584:ProĹĄtenik, M.; Prelog, V. HelV. Chim. Acta
1545:Rabe, P.; Ackerman, E.; Schneider, W. Ber.
1194:Woodward/Doering quinine synthesis part III
227:attempts quinine synthesis by oxidation of
1496:
1116:Woodward/Doering quinine synthesis part I
1024:group in this compound is reduced to the
638:-lactone in two steps by hydrolysis with
1740:Jeffrey I. Seeman Angew. Chem. Int. Ed.
1438:Quinine Total Syntheses @ SynArchive.com
1420:. The desired enantiomer is obtained by
1062:which enables the third ring closure to
1777:Angewandte Chemie International Edition
1469:Angewandte Chemie International Edition
1455:
202:in older literature) by acid-catalysed
1261:at 150 °C under high pressure to
900:. The hydroxyl group is replaced in a
423:(related to quinidine but without the
867:of 1 met with undisclosed problems).
634:-enantiomer is converted back to the
7:
1704:; 123(14) pp 3239 - 3242; (Article)
646:followed by azeotropic ring closure.
408:and ProĹĄtenik interconvert an allyl
93:in between the two components has a
1775:Aaron C. Smith, Robert M. Williams
1424:with the chiral dibenzoyl ester of
1412:, which after acidic workup yields
870:The lactone is then reduced to the
818:. The C5 and C6 atoms are added as
338:is observed. In the third step the
302:The first step in this sequence is
891:methoxymethylenetriphenylphosphine
176:: First isolation of quinine from
14:
1600:R. B. Woodward and W. E. Doering
1558:Rabe, P.; Kindler, K. Chem. Ber.
893:(delivering the C8 atom) to form
386:signs on as a consultant for the
1182:
1106:
1097:
935:
926:
859:returns the compound to lactone
759:
750:
740:: the sequence does not contain
695:
663:
599:
560:
487:
450:
432:
349:
295:
272:
211:
125:
117:Quinine total synthesis timeline
1723:Chemical & Engineering News
1206:at 220 °C for 10 hours in
978:of its anion (by reaction with
656:Chemical & Engineering News
62:Chemical & Engineering News
1625:The Total Synthesis of Quinine
1598:The Total Synthesis of Quinine
732:. The compound is obtained by
690:-quinotoxine to quinine route.
476:The total synthesis of quinine
306:addition to quinotoxine to an
140:format but may read better as
1:
1442:Quinine story at Harvard.edu
720:Stork quinine total synthesis
1532:Perkin, W. H. J. Chem. Soc.
545:: Kondo and Mori synthesize
1400:group. The final step is a
1253:is again hydrogenated with
1130:The first reaction step is
982:) to the aldehyde group in
965:6-methoxy-4-methylquinoline
776:Introducing C8 and nitrogen
571:The starting materials are
1849:
879:diisobutylaluminum hydride
626:which can be separated by
1519:Pasteur, L. Compt. rend.
831:nucleophilic substitution
1342:quaternary ammonium salt
1047:and then activated as a
910:diphenylphosphoryl azide
837:(LDA) at â78 °C to
835:lithium diisopropylamide
34:, a naturally-occurring
1677:), No.12 pp.4361-4366
1388:. In the next step the
1365:is then constructed by
857:azeotropic distillation
769:Stork quinine synthesis
728:)-4-vinylbutyrolactone
573:trans-2-butene-1,4-diol
182:Pierre Joseph Pelletier
149:converting this article
1810:10.1002/anie.201804551
1788:10.1002/anie.200705421
1750:10.1002/anie.200601551
1631:; 67(5) pp 860 - 874;
1608:; 66(5) pp 849 - 849;
1481:10.1002/anie.200705421
1283:in acetic acid to the
1232:tetrahydroisoquinoline
1141:with (formally) the di
658:, is equally critical.
579:and the key step is a
342:group is reduced with
21:
1408:with ethyl quininate
1347:and subsequently the
1263:decahydroisoquinoline
1136:3-hydroxybenzaldehyde
1132:condensation reaction
976:nucleophilic addition
846:-toluenesulfonic acid
628:column chromatography
581:Claisen rearrangement
464:Robert Burns Woodward
384:Robert Burns Woodward
52:Robert Burns Woodward
19:
1683:10.1246/bcsj.61.4361
1654:), No.7 pp.741-742
1402:Claisen condensation
1354:after reaction with
1309:with a newly formed
1279:is then oxidized by
855:and ring-closure by
787:is ring-opened with
482:) that is described.
443:Claisen condensation
388:Polaroid Corporation
225:William Henry Perkin
184:and Joseph Caventou.
46:published the first
1660:10.1246/cl.1974.741
1637:10.1021/ja01221a051
1614:10.1021/ja01233a516
1367:Hofmann elimination
1007:Staudinger reaction
952:Second ring closure
823:-butyldiphenylsilyl
640:potassium hydroxide
620:diastereomeric pair
326:interconverts with
1033:sodium borohydride
1015:tetrahydropyridine
1011:triphenylphosphine
945:First ring closure
902:Mitsunobu reaction
881:and its liberated
833:of acidic C4 with
825:(TBDPS) protected
577:ethyl orthoacetate
390:at the request of
304:sodium hypobromite
151:, if appropriate.
101:. The molecule is
69:Chemical structure
22:
1710:10.1021/ja004325r
1698:J. Am. Chem. Soc.
1602:J. Am. Chem. Soc.
1422:chiral resolution
1386:potassium cyanate
1384:by reaction with
1268:. The mixture of
1222:takes place with
1201:
1200:
1147:aminoacetaldehyde
1128:
1127:
1072:dimethylsulfoxide
1054:by reaction with
1041:hydrogen fluoride
1037:stereospecificity
1035:with the correct
957:
956:
781:
780:
734:chiral resolution
612:methylbenzylamine
592:chiral resolution
497:Dutch East Indies
480:chiral resolution
334:intermediate and
312:organic oxidation
170:
169:
89:skeleton and the
81:substituent. The
40:organic chemistry
1840:
1812:
1796:
1790:
1782:, 47, 1736â1740
1765:
1759:
1744:, 46, 1378â1413
1735:
1729:
1728:, 79 (May 7), 5.
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1500:
1475:(9): 1736â1740.
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1371:sodium hydroxide
1311:carboxylic ester
1243:acetic anhydride
1212:sodium methoxide
1186:
1179:
1110:
1101:
1094:
990:as a mixture of
970:is sufficiently
939:
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738:chiral induction
699:
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616:triethylaluminum
603:
564:
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396:light polarizing
353:
299:
276:
237:chemical formula
215:
165:
162:
156:
147:You can help by
129:
128:
121:
103:optically active
91:methylene bridge
85:component has a
1848:
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1828:Total synthesis
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1390:carboxylic acid
1299:sodium ethoxide
1160:. Isoquinoline
1080:
996:Swern oxidation
887:Wittig reaction
810:-butyldimethyl
722:
644:ethylene glycol
414:homomeroquinene
316:sodium ethoxide
262:
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56:William Doering
48:stereoselective
27:total synthesis
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1767:Communication
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1432:External links
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1224:Adams catalyst
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1295:ethyl nitrite
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1292:alkyl nitrite
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1204:Hydrogenation
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1158:sulfuric acid
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1052:leaving group
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392:Edwin H. Land
389:
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375:
374:epi-quinidine
371:
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364:
363:diastereomers
360:
357:
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330:via a common
329:
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155:is available.
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134:This article
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1417:
1416:quinotoxine
1409:
1405:
1381:
1360:
1356:silver oxide
1351:
1344:
1321:
1306:
1294:
1287:
1281:chromic acid
1274:
1270:
1265:
1262:
1255:Raney nickel
1250:
1249:but by then
1234:
1231:
1215:
1202:
1193:
1173:
1166:formaldehyde
1161:
1153:
1138:
1129:
1122:
1115:
1088:quinuclidine
1083:
1081:
1063:
1044:
1028:
1017:
1002:
987:
983:
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964:
958:
951:
944:
917:
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897:
885:reacts in a
874:
869:
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820:
815:
807:
795:
789:diethylamine
782:
775:
768:
729:
725:
723:
709:Nuno Maulide
704:
687:
683:
680:derivatives.
672:
651:
635:
631:
614:assisted by
607:
587:
542:
536:
532:
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506:
500:
475:
472:isoquinoline
459:
413:
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336:mutarotation
327:
323:
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199:
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187:
173:
158:
153:Editing help
135:
87:quinuclidine
72:
60:
36:antimalarial
25:
23:
1721:M. Jacobs,
1588:, 26, 1965.
1363:vinyl group
1338:iodomethane
1330:acetic acid
1228:acetic acid
1043:to alcohol
908:group with
827:iodoethanol
812:silyl ether
418:biomolecule
398:properties.
370:epi-quinine
328:quinidinone
206:of quinine.
196:quinotoxine
107:stereogenic
99:vinyl group
1822:Categories
1549:, 40, 3655
1523:, 37, 110.
1450:References
1394:esterified
1375:hydrolysis
1361:Quinine's
1340:gives the
1334:alkylation
1170:piperidine
895:enol ether
865:alkylation
742:asymmetric
533:adumbrated
421:cinchonine
410:piperidine
105:with five
1562:, 51, 466
1536:, 69, 596
1489:1433-7851
1392:group is
963:group in
814:(TBS) in
804:protected
802:group is
366:quinidine
324:quininone
233:toluidine
200:quinicine
75:quinoline
1757:17294412
1507:18236503
1326:platinum
1247:methanol
1239:acylated
1208:methanol
1086:for the
1060:pyridine
986:to form
883:aldehyde
863:(direct
800:hydroxyl
798:and its
677:alkaloid
551:lactones
537:apposite
508:Newsweek
344:aluminum
265:mauveine
194:obtains
180:tree by
178:cinchona
95:hydroxyl
1833:Quinine
1498:3085927
1414:racemic
1398:benzoyl
1349:betaine
1303:ethanol
1277:isomers
1259:ethanol
1149:to the
1123:Part II
992:epimers
850:alcohol
785:lactone
744:steps.
547:racemic
427:group):
425:methoxy
412:called
320:ethanol
79:methoxy
77:with a
31:quinine
1755:
1505:
1495:
1487:
1285:ketone
1143:acetal
1020:. The
1000:ketone
972:acidic
961:methyl
904:by an
872:lactol
630:. The
624:amides
406:Prelog
340:ketone
231:-allyl
223:: Sir
136:is in
1369:with
1336:with
1324:with
1319:amine
1315:oxime
1297:with
1275:trans
1241:with
1210:with
1151:imine
1049:mesyl
1031:with
1026:amine
1022:imine
1009:with
906:azide
889:with
877:with
829:in a
806:as a
793:amide
618:to a
314:with
142:prose
83:amine
1803:2018
1780:2008
1753:PMID
1742:2007
1726:2001
1702:2001
1675:1988
1652:1974
1629:1945
1606:1944
1586:1943
1573:1939
1560:1918
1547:1907
1534:1896
1521:1853
1503:PMID
1485:ISSN
1444:Link
1379:urea
1332:and
1273:and
1168:and
1005:. A
974:for
959:The
821:tert
808:tert
783:The
705:2018
684:2008
673:2007
652:2001
642:and
588:1988
575:and
543:1974
535:and
529:1945
523:1944
514:Life
511:and
466:and
460:1944
402:1943
380:1940
372:and
359:1939
332:enol
288:1918
282:1907
221:1856
198:(or
188:1853
174:1817
138:list
54:and
24:The
1806:doi
1784:doi
1746:doi
1706:doi
1679:doi
1656:doi
1633:doi
1610:doi
1493:PMC
1477:doi
1404:of
1328:in
1305:to
1301:in
1271:cis
1257:in
1245:in
1230:to
1226:in
1145:of
1134:of
1058:in
998:to
980:LDA
912:in
848:to
791:to
622:of
318:in
29:of
1824::
1700:;
1604:;
1501:.
1491:.
1483:.
1473:47
1471:.
1467:.
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1358:.
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1307:10
1176:.
1070:,
1064:15
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1029:13
1018:12
1003:11
988:10
920:.
875:5b
853:4b
707::
610:)-
505:,
462::
404::
382::
368:,
253:24
249:20
245:13
241:10
190::
113:.
1808::
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1771:d
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1708::
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1479::
1288:9
1266:8
1251:7
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1216:5
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1139:1
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844:p
839:4
816:3
796:2
730:1
726:S
688:d
636:S
632:S
608:S
594::
517:.
445::
376:.
308:N
261:2
259:O
257:2
255:N
251:H
243:H
239:C
229:N
163:)
159:(
145:.
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