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Quinina
Quinina
Quinina
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
of the previous synthetic efforts toward quinine. They go back to the equation 2(C10H13N) + 3O ) C20H24N2O2 + H2O.10
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
† Novartis, Summit, NJ.
molecule was eventually unraveled, largely as the result of the
‡ Deceased February 17, 1989. extensive work of the German chemist Paul Rabe,11 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) Uskoković, 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.; Uskoković, 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) Uskoković, M.; Gutzwiller, J.; Henderson, T. J. Am. Chem. Soc.
16. 1970, 92, 203. (b) Gutzwiller, J.; Uskoković, M. J. Am. Chem. Soc. 1970,
(3) OVer 1 million deaths in 1999; World Health Organization (WHO) 92, 204. (c) Uskoković, 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, Uskoković, M. R. J. Am. Chem. Soc. 1971, 93, 5904. (e) Grethe, G.; Lee,
see: Science 2000, 290, 428ff. H. S.; Mitt, T.; Uskoković, M. R. HelV. Chim. Acta 1973, 56, 1485. (f)
(5) The use of quinine has markedly decreased in recent years, but the Gutzwiller, J.; Uskoković, 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. Uskoković, 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. Uskoković, 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.; Uskoković, 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.; Uskoković, 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.
Scheme 1 Scheme 2
Scheme 3a
a
Conditions: (a) (1) Et2NH/AlMe3, (2) TBS-Cl/lmidazole/DMF.
(b) LDA, -78 °C, ICH2CH2OTBDPS. (c) PPTS (0.3 equiv), EtOH,
12 h, then xylenes, reflux 8-10 h. (d) (1) DIBAL-H, -78 °C, (2)
Ph3PdCHOMe. (e) PH3P/DEAD, (PhO)2P(O)N3. (f) 5 N HCl, THF/
CH2Cl2.
Scheme 4 Scheme 5