J. Am. Chem. Soc. 2001, 123, 3239-3242 3239 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⊥ Contribution from the Department of Chemistry, Columbia UniVersity, New York, New York 10027 ReceiVed December 22, 2000 Abstract: The first entirely stereoselective total synthesis of (-)-quinine is reported. Introduction Quinine (1)1 has occupied a central place among the many plant alkaloids which are used in medicine. For over three centuries, and until relatively recently, it was the only remedy available to deal with malaria,2 a disease from which millions have died.3-5 Rational attempts to synthesize quinine started early in the first half of the twentieth century6,7 and eventually resulted in total syntheses in which 3 of the 4 asymmetric centers in the molecule were established stereoselectively. 8,9 An entirely Figure 1. stereoselective synthesis of quinine has, however, not yet been achieved. This paper reports our successful efforts to meet this empirical formula of quinine, C20H24N2O2, had only recently challenge. been settled, tried to produce the alkaloid by the oxidation of We first put our work in context with a brief survey of some what was supposedly an N-allyl toluidine (C10H13N) according + ) + 10 of the previous synthetic efforts toward quinine. They go back to the equation 2(C10H13N) 3O C20H24N2O2 H2O. almost a century and a half. One of the early attempts has Although the arithmetic was suggestive, it is hardly surprising become part of the history and legend of chemistry: the well- that Perkin did not obtain quinine. known story of William Henry Perkin who, in 1856, when the The correct connectivity between the atoms of the quinine molecule was eventually unraveled, largely as the result of the † Novartis, Summit, NJ. 11 ‡ Deceased February 17, 1989. extensive work of the German chemist Paul Rabe, who then § Merck & Co, Rahway, NJ. began to consider the possibility of a synthesis of the alkaloid. ⊥ University of British Columbia. This was quite a challenge since the presence of 4 asymmetric (1) (a) Turner, R. B.; Woodward, R. B. The Chemistry of the Cinchona Alkaloids. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New carbons in the quinine molecule means that the correct atom York, 1953; Vol. 3, Chapter 16. (b) Uskokovic´, M. R.; Grethe, G. The connectivity corresponds to 16 possible isomeric structures for Cinchona Alkaloids. In The Alkaloids; Manske, R. H. F., Ed.; Academic the alkaloid. Even without the knowledge of the correct stereo- Press: New York, 1973; Vol. 14, p 181. (c) Grethe, G.; Uskokovic´, M. R. In The Chemistry of Heterocyclic Compounds; Sexton, J. E., Ed.; Wiley- chemistry, Rabe chose to attempt to reconstruct quinine from a Interscience: New York, 1983; Vol. 23, Part 4, p 279. 3,4-disubstituted piperidine, originally named quinicine, and later (2) (a) McGrew, R. E. The most significant disease for world civilization known as quinotoxine (3),1a which had earlier been obtained over the past three centuries. In Encyclopedia of Medical History; McGraw- by Pasteur12 by acid-catalyzed isomerization of quinine (Scheme Hill: New York, 1985; p 166.(b) Casteel, D. A. Quinine may be claimed ‚‚‚ as the drug to have relieved more human suffering than any other in 1). And, indeed, Rabe claimed, in a very terse 1918 com- history. In Burger’s Medicinal Chemistry and Drug DiscoVery, 5th ed.; Wolff, M. E., Ed.; John Wiley: New York, 1997; Vol. 5, Chapter 59, p (8) (a) Uskokovic´, M.; Gutzwiller, J.; Henderson, T. J. Am. Chem. Soc. 16. 1970, 92, 203. (b) Gutzwiller, J.; Uskokovic´, M. J. Am. Chem. Soc. 1970, (3) OVer 1 million deaths in 1999; World Health Organization (WHO) 92, 204. (c) Uskokovic´, M.; Reese, C.; Lee, H. L.; Grethe, J.; Gutzwiller, Report 2000, World Health in Statistics, Annex Table 3. J. J. Am. Chem. Soc. 1971, 93, 5902. (d) Grethe, G.; Lee, H. S.; Mitt, T.; (4) For a very recent discussion of the status of the malaria problem, Uskokovic´, M. R. J. Am. Chem. Soc. 1971, 93, 5904. (e) Grethe, G.; Lee, see: Science 2000, 290, 428ff. H. S.; Mitt, T.; Uskokovic´, M. R. HelV. Chim. Acta 1973, 56, 1485. (f) (5) The use of quinine has markedly decreased in recent years, but the Gutzwiller, J.; Uskokovic´, M. R. HelV. Chim. Acta 1973, 56, 1494. (g) U.S. still imported over 68 tons of quinine and its salts in 1999. Cf. U.S. Uskokovic´, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, J.; Department of Commerce, U.S. imports of organic chemicals for consump- Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571. (h) Gutzwiller, J.; tion; Chapter 29, subheading 293921. Uskokovic´, M. R. J. Am. Chem. Soc. 1978, 100, 576. (i) Grethe, G.; Lee, (6) Rabe, P.; Kindler, K. Chem. Ber. 1918, 51, 466. This extremely H. S.; Mitt, T.; Uskokovic´, M. R. J. Am. Chem. Soc. 1978, 100, 581. (j) abbreviated announcement states that the conditions used 7 years previously Grethe, G.; Lee, H. S.; Mitt, T.; Uskokovic´, M. R. J. Am. Chem. Soc. 1978, for the related conversion of cinchotoxine to cinchoninone (Rabe, P. Ber. 100, 589. 1911, 44, 2088) were those used for the quinotoxine to “quininone” (now (9) (a) Gates, M.; Sugavanam, B.; Schreiber, W. L. J. Am. Chem. Soc. known to be quinidinone) transformation. On the other hand, the procedure 1970, 92, 205. (b) Taylor, E. C.; Martin, S. F. J. Am. Chem. Soc. 1974, 96, for the aluminum powder reduction, stated to reduce “quininone” to quinine 8095. See also: (c) Speckamp, W. N.; Dijkink, J. Heterocycles 1974, 2, in 12% yield in the 1918 paper, was only revealed 14 years later (Rabe, P. 291. (d) Brown, R. T.; Curless, D. Tetrahedron Lett. 1986, 27, 6005. (e) Annalen 1932, 492, 242), using as example the reduction of hydrocinchoni- Wilson, S. R.; DiGrandi, M. J. J. Org. Chem. 1991, 56, 4766. none to hydrocinchonine (which is, incidentally, known to have the quinidine (10) Cf. the account presented much later, in his Hofmann Memorial stereochemistry at C-8, C-9) because as Rabe understates it, the method Lecture, by Perkin: Perkin, W. H. J. Chem. Soc. 1896, 69, 596. used in his 1918 paper “ist noch nicht eingehend beschrieben worden”. (11) Rabe, P.; Ackerman, E.; Schneider, W. Ber. 1907, 40, 3655, and (7) (a) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1944, 66, numerous previous and later papers; cf. ref 1a. 849. (b) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1945, 67, (12) (a) Pasteur, L. Compt. rend. 1853, 37, 110. (b) Pasteur, L. Ann. 860. 1853, 88, 209. For the structure, see: Rabe, P. Ann. 1909, 365, 366. 10.1021/ja004325r CCC: $20.00 © 2001 American Chemical Society Published on Web 03/17/2001 3240 J. Am. Chem. Soc., Vol. 123, No. 14, 2001 Stork et al. Scheme 1 Scheme 2 quinine from quinotoxine. By 1944, the cis relationship of the vinyl and propionic acid substituents at positions 3 and 4 of munication,6 that he had succeeded in accomplishing that partial the piperidine ring of homomeroquinene had been established,15 synthesis. but the Woodward-Doering half of the synthesis was not Twenty-five years later, Prelog and Prosˇtenik13 showed that stereoselective, and produced the precursors of their homome- the 3-vinyl-4-piperidinepropionic acid, known as homomero- roquinene target as a mixture of cis and trans stereoisomers, in quinene (4), which they had obtained as the proper enantiomer roughly equal amounts.16 by degradation of quinotoxine, could be reconverted into the The first successful efforts toward a stereoselective quinine latter, thereby completing a route from homomeroquinene back synthesis were reported 55 years ago.17 The synthesis of the to quinine, assuming the validity of Rabe’s claim. A formal ethyl ester of (()-cis-3-ethyl-4-piperidineacetic acid (dihy- total synthesis of quinine was completed when Woodward and dromeroquinene, also known as cincholoipon) illustrated a Doering announced in 19447 that they had succeeded in possible path to the creation of the substituted piperidine stereo- synthesizing homomeroquinene itself. As a synthetic route to chemistry required for a “Rabe route” to the quinine alkaloids, quinine, it suffered from the lack of stereocontrol in the but although the synthesis deserves some notice as one of the ingenious Woodward-Doering sequence to homomeroquinene, earliest successful examples of stereorational planning related and from the low yields and the difficult separations of the 4 to natural product synthesis, there was still no solution to the isomers anticipated from the Rabe scheme for the conversion problem of stereocontrol of the crucial asymmetric centers at of quinotoxine to quinine because that half of the construction C-8 and C-9. did not involve any stereocontrol.14 A quarter of a century passed before further progress toward a stereoselective total synthesis of quinine was achieved by The Stereochemical Problem Uskokovic´, Gutzwiller, and their collaborators at Hoffmann- 8 Stereocontrol was not a concern of synthetic organic chemists La Roche. That impressive achievement was illustrated by a before 1940 or so, largely because the mechanistic and con- number of syntheses of quinine in which the quinuclidine ring formational underpinnings of modern organic chemistry were was created by forming the bond between N-1 and C-8. That not yet part of synthesis design. In fact, the configuration of strategy, which may be called the Rabe connection, was endorsed by the workers who followed Rabe, starting with the C-8 and C-9 asymmetric centers of quinine was not yet 7-9 known in 1918, when Rabe announced the reconstruction of Woodward and Doering, presumably because of the attractive structural simplification it seemed to offer.