The first stereoselective total synthesis of quinine

Article abstract of DOI:10.1021/ja004325r

The first entirely stereoselective total synthesis of (-)-quinine is reported.

Full text of DOI:10.1021/ja004325r

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
stereoselective synthesis of quinine has, however, not yet been
achieved. This paper reports our successful efforts to meet this
challenge.
We first put our work in context with a brief survey of some
of the previous synthetic efforts toward quinine. They go back
almost a century and a half. One of the early attempts has
become part of the history and legend of chemistry: the well-
known story of William Henry Perkin who, in 1856, when the
Figure 1.
empirical formula of quinine, C20H24N2O2, had only recently
been settled, tried to produce the alkaloid by the oxidation of
what was supposedly an N-allyl toluidine (C10H13N) according
to the equation 2(C10H13N) + 3O ) C20H24N2O2 + H2O.10
Although the arithmetic was suggestive, it is hardly surprising
that Perkin did not obtain quinine.
The correct connectivity between the atoms of the quinine
molecule was eventually unraveled, largely as the result of the
extensive work of the German chemist Paul Rabe,11 who then
began to consider the possibility of a synthesis of the alkaloid.
This was quite a challenge since the presence of 4 asymmetric
carbons in the quinine molecule means that the correct atom
connectivity corresponds to 16 possible isomeric structures for
the alkaloid. Even without the knowledge of the correct stereo-
chemistry, Rabe chose to attempt to reconstruct quinine from a
3,4-disubstituted piperidine, originally named quinicine, and later
known as quinotoxine (3),1a which had earlier been obtained
by Pasteur12 by acid-catalyzed isomerization of quinine (Scheme
1). And, indeed, Rabe claimed, in a very terse 1918 com-
† Novartis, Summit, NJ.
‡ Deceased February 17, 1989.
§ Merck & Co, Rahway, NJ.
University of British Columbia.
(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
York, 1953; Vol. 3, Chapter 16. (b) Uskokovic´, M. R.; Grethe, G. The
Cinchona Alkaloids. In The Alkaloids; Manske, R. H. F., Ed.; Academic
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-
Interscience: New York, 1983; Vol. 23, Part 4, p 279.
(2) (a) McGrew, R. E. The most significant disease for world civilization
over the past three centuries. In Encyclopedia of Medical History; McGraw-
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
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
16.
(3) OVer 1 million deaths in 1999; World Health Organization (WHO)
Report 2000, World Health in Statistics, Annex Table 3.
(4) For a very recent discussion of the status of the malaria problem,
see: Science 2000, 290, 428ff.
(5) The use of quinine has markedly decreased in recent years, but the
U.S. still imported over 68 tons of quinine and its salts in 1999. Cf. U.S.
Department of Commerce, U.S. imports of organic chemicals for consump-
tion; Chapter 29, subheading 293921.
(6) Rabe, P.; Kindler, K. Chem. Ber. 1918, 51, 466. This extremely
abbreviated announcement states that the conditions used 7 years previously
for the related conversion of cinchotoxine to cinchoninone (Rabe, P. Ber.
1911, 44, 2088) were those used for the quinotoxine to “quininone” (now
known to be quinidinone) transformation. On the other hand, the procedure
for the aluminum powder reduction, stated to reduce “quininone” to quinine
in 12% yield in the 1918 paper, was only revealed 14 years later (Rabe, P.
Annalen 1932, 492, 242), using as example the reduction of hydrocinchoni-
none to hydrocinchonine (which is, incidentally, known to have the quinidine
stereochemistry at C-8, C-9) because as Rabe understates it, the method
used in his 1918 paper “ist noch nicht eingehend beschrieben worden”.
(7) (a) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1944, 66,
849. (b) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1945, 67,
860.
(8) (a) Uskokovic´, M.; Gutzwiller, J.; Henderson, T. J. Am. Chem. Soc.
1970, 92, 203. (b) Gutzwiller, J.; Uskokovic´, M. J. Am. Chem. Soc. 1970,
92, 204. (c) Uskokovic´, M.; Reese, C.; Lee, H. L.; Grethe, J.; Gutzwiller,
J. J. Am. Chem. Soc. 1971, 93, 5902. (d) Grethe, G.; Lee, H. S.; Mitt, T.;
Uskokovic´, M. R. J. Am. Chem. Soc. 1971, 93, 5904. (e) Grethe, G.; Lee,
H. S.; Mitt, T.; Uskokovic´, M. R. HelV. Chim. Acta 1973, 56, 1485. (f)
Gutzwiller, J.; Uskokovic´, M. R. HelV. Chim. Acta 1973, 56, 1494. (g)
Uskokovic´, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, J.;
Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571. (h) Gutzwiller, J.;
Uskokovic´, M. R. J. Am. Chem. Soc. 1978, 100, 576. (i) Grethe, G.; Lee,
H. S.; Mitt, T.; Uskokovic´, M. R. J. Am. Chem. Soc. 1978, 100, 581. (j)
Grethe, G.; Lee, H. S.; Mitt, T.; Uskokovic´, M. R. J. Am. Chem. Soc. 1978,
100, 589.
(9) (a) Gates, M.; Sugavanam, B.; Schreiber, W. L. J. Am. Chem. Soc.
1970, 92, 205. (b) Taylor, E. C.; Martin, S. F. J. Am. Chem. Soc. 1974, 96,
8095. See also: (c) Speckamp, W. N.; Dijkink, J. Heterocycles 1974, 2,
291. (d) Brown, R. T.; Curless, D. Tetrahedron Lett. 1986, 27, 6005. (e)
Wilson, S. R.; DiGrandi, M. J. J. Org. Chem. 1991, 56, 4766.
(10) Cf. the account presented much later, in his Hofmann Memorial
Lecture, by Perkin: Perkin, W. H. J. Chem. Soc. 1896, 69, 596.
(11) Rabe, P.; Ackerman, E.; Schneider, W. Ber. 1907, 40, 3655, and
numerous previous and later papers; cf. ref 1a.
(12) (a) Pasteur, L. Compt. rend. 1853, 37, 110. (b) Pasteur, L. Ann.
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
the piperidine ring of homomeroquinene had been established,15
but the Woodward-Doering half of the synthesis was not
stereoselective, and produced the precursors of their homome-
roquinene target as a mixture of cis and trans stereoisomers, in
roughly equal amounts.16
The first successful efforts toward a stereoselective quinine
synthesis were reported 55 years ago.17 The synthesis of the
ethyl ester of (()-cis-3-ethyl-4-piperidineacetic acid (dihy-
dromeroquinene, also known as cincholoipon) illustrated a
possible path to the creation of the substituted piperidine stereo-
chemistry required for a “Rabe route” to the quinine alkaloids,
but although the synthesis deserves some notice as one of the
earliest successful examples of stereorational planning related
to natural product synthesis, there was still no solution to the
problem of stereocontrol of the crucial asymmetric centers at
C-8 and C-9.
A quarter of a century passed before further progress toward
a stereoselective total synthesis of quinine was achieved by
Uskokovic´, Gutzwiller, and their collaborators at Hoffmann-
La Roche.8 That impressive achievement was illustrated by a
number of syntheses of quinine in which the quinuclidine ring
was created by forming the bond between N-1 and C-8. That
strategy, which may be called the Rabe connection, was
endorsed by the workers who followed Rabe, starting with
Woodward and Doering,7-9 presumably because of the attractive
structural simplification it seemed to offer.
munication,6 that he had succeeded in accomplishing that partial
synthesis.
Twenty-five years later, Prelog and Prosˇtenik13 showed that
the 3-vinyl-4-piperidinepropionic acid, known as homomero-
quinene (4), which they had obtained as the proper enantiomer
by degradation of quinotoxine, could be reconverted into the
latter, thereby completing a route from homomeroquinene back
to quinine, assuming the validity of Rabe’s claim. A formal
total synthesis of quinine was completed when Woodward and
Doering announced in 19447 that they had succeeded in
synthesizing homomeroquinene itself. As a synthetic route to
quinine, it suffered from the lack of stereocontrol in the
ingenious Woodward-Doering sequence to homomeroquinene,
and from the low yields and the difficult separations of the 4
isomers anticipated from the Rabe scheme for the conversion
of quinotoxine to quinine because that half of the construction
did not involve any stereocontrol.14
The Stereochemical Problem
Stereocontrol was not a concern of synthetic organic chemists
before 1940 or so, largely because the mechanistic and con-
formational underpinnings of modern organic chemistry were
not yet part of synthesis design. In fact, the configuration of
the C-8 and C-9 asymmetric centers of quinine was not yet
known in 1918, when Rabe announced the reconstruction of
(13) Prosˇtenik, M.; Prelog, V. HelV. Chim. Acta 1943, 26, 1965.
(14) Woodward and Doering did not claim to have confirmed Rabe’s
1918 report, in a few lines, that he had succeeded in converting quinotoxine
to quinine (although the basis of their characterization of Rabe’s claim as
“established” is unclear), nor is there any evidence that they produced any
quinine in their own laboratories. But this was wartime, and the U.S. had
been cut off from the Dutch East Indies, its major source of cinchona bark.
The resulting anxiety may explain press accounts, notable for enthusiasm
rather than for sober analysis, which created the quasiuniversal impression
that the construction of homomeroquinene in 1944 meant that quinine had
been synthesized: cf. inter alia: (a) Laurence, W. M. The New York Times,
1944, May 4, 1: “The duplication of the highly complicated chemical
architecture of the quinine molecule, hailed by leading scientists at Harvard
and other institutions as one of the greatest scientific achievements in a
century”. (b) Manchester, H. Sci. News Lett. 1944, June 10, 378ff: “Starting
with five pounds of chemical they obtained the equivalent [?] of 40
milligrams of quinine”. Remarkably, the confusion produced by these and
hundreds of other contemporary reports has persisted to this day: inter
alia: (c) The Columbia Encyclopedia, 6th ed.; Columbia University Press:
New York, 2000; p 2344: “Chemical synthesis [of quinine] was achieved
in 1944 by Woodward, R. B; Doering, W. E. ...”. (d) The Encyclopaedia
Britannica, 15th ed.; Chicago, 1997; Vol. 9, p 862: “[quinine’s] total
laboratory synthesis in 1944 is one of the classical achievements of synthetic
organic chemistry”. (e) The Grolier Library of Scientific Biography; Grolier
Educational: Danbury, 1997; Vol. 10, p 167: “In 1944 Woodward, with
William von Eggers Doering, synthesized quinine from the basic elements.
This was a historic moment ...”.
The problem with that approach, however, turned out to be
the difficulty of achieving stereospecificity, or at least high
stereoselectivity, involving the C8 and C9 centers, with the result
that even the largely stereocontrolled Hoffmann-La Roche
synthesis produced quinine together with an equal amount of
quinidine (2), that isomer which is epimeric with quinine at
both of these centers.
A very important observation was made, however, by the
Hoffmann-La Roche chemists who discovered8h that the 1:1
mixture of deoxyquinine (5) and its C-8 epimer, deoxyquinidine
(6), which results from one of their syntheses (cf Scheme 2),
could be oxidized to a mixture consisting largely of only two
of the four possible secondary alcohols, one of them quinine
and the other quinidine. They verified the implication of that
(15) Prelog, V.; Zalan, E. HelV. Chim. Acta 1944, 27, 535.
(16) The ingenious, carefully documented,7b separation of the mixture
of the cis- and trans-hydroisoquinolone precursors of homomeroquinene is
a tribute to the experimental acumen that is also displayed in the further
details of the experimental work on the synthesis of homomeroquinene.
(17) Stork, G.; McElvain, S. M. J. Am. Chem. Soc. 1946, 68, 1053. The
cis-stereochemistry claimed for that 3,4-disubstituted piperidine has been
confirmed: Sundberg, R. J.; Holcomb, F. D. J. Org. Chem. 1969, 34, 3273.

The First StereoselectiVe Total Synthesis of Quinine
J. Am. Chem. Soc., Vol. 123, No. 14, 2001 3241
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.
control of the stereochemistry at C-8, and to our stereospecific
construction of deoxyquinine.
Stereospecific Construction of Deoxyquinine
As starting material for the construction of the 2,4,5-
trisubstituted piperidine 7, we chose the known (S)-4-vinylbu-
tyrolactone (8)18,19 (Scheme 3). We selected a protected
iodoethanol for the required introduction, trans to the vinyl
group, of a substituent that would eventually become the
4-substituent of piperidine 17. We had initially used a mesitoate
ester for that protection, but base-catalyzed reactions at a later
stage of our synthesis led to serious difficulties resulting from
the unwanted deprotonation of the mesitoate methyls, and we
eventually turned to the tert-butyldiphenylsilyl (TBDPS) pro-
tecting group.
Direct alkylation of 4-vinylbutyrolactone (8) with protected
iodoethanol derivatives was not as satisfactory as the somewhat
more involved, but efficient, process involving opening of the
vinyl lactone with diethylamine, protection of the resulting
primary hydroxyl as its TBS derivative 9, and alkylation of the
resulting diethylamide to give 10. The desired (>20:1) trans-
3,4-disubstituted butyrolactone 11 was then readily obtained by
selective removal of the TBS group with p-toluenesulfonic acid
in ethanol, at room temperature, followed by refluxing the
resulting hydroxyamide in xylene. Elaboration of 11 toward our
trisubstituted piperidine intermediate now required the addition
of a carbon atom and replacement of the ring oxygen by a
nitrogen. The first of these goals was achieved by reduction of
11 with diisobutylaluminum hydride to the corresponding lactol,
followed by Wittig reaction with methoxymethylene triph-
enylphosphorane to give 12. Reaction of the latter with
diphenylphosphoryl azide20 now converted the liberated primary
hydroxyl to an azido group to form 13, from which aqueous
acid hydrolysis, in a two-phase system, at room temperature,
led to the azido aldehyde 14, in ∼60% overall yield from lactone
11.
Figure 2.
result by showing that pure deoxyquinine (obtained from natural
quinine by C-9 deoxygenation) regenerated quinine under their
oxidation conditions. It followed that a stereoselective synthesis
of quinine would finally be achieved if a stereospecific synthesis
of deoxyquinine could be effected. Such a synthesis became our
goal.
We first noted that the formation of the ∼1:1 mixture of
deoxyquinine (5) and its C-8 epimer (6) mentioned above
followed construction of the quinuclidine ring by intramolecular
conjugate addition to a 4-alkenylquinoline. In the absence of
the vinyl group on the incipient quinuclidine, the two adducts
would be mirror images, as would the transition states to their
formation. Practically the same situation obtains in the presence
of the vinyl group because it can adopt a conformation in which
it would have only a minor effect on the relative energies of
the transition states to either 5 or 6, thus resulting in equal
amounts of these C-8 isomers. A totally different situation
would, however, be expected if the C-8 asymmetry arose from
closure to a piperidine, rather than to a quinuclidine. Such a
scheme would require abandoning the time-honored Rabe
connection (shown as a in Figure 2) in favor of the closure
shown by b. Adoption of the latter construction would lead to
the corollary that the vicinal substituents on the piperidine
precursor would now have to be trans. This is not a serious
problem, but it leads to the further corollary that the piperidine
ring in such a scheme would now have to be trisubstituted
because it would bear an additional, and stereodefined, sub-
stituent (cf. 7). At first sight, the increase in complexity hardly
seemed a step in the right direction.
With the azidoaldehyde 14, we had reached a suitable
intermediate for the construction of the required piperidine. That
construction (Scheme 4) started with the addition of the lithium
salt of 6-methoxy-4-methylquinoline to the carbonyl group of
14 to produce the expected secondary alcohol 15 in ∼70% yield.
Alcohol 15 was obtained as a mixture of two epimers, a fact of
no consequence because the mixture was converted by Swern
oxidation to the corresponding azidoketone, the intermediate
We concluded, however, that the benefits would be substan-
tial. A major problem with the cis-3,4-disubstituted piperidine
intermediates of previous quinine syntheses is that their two
possible chair conformations would be similar in energy. Such
a situation would make control of stereochemistry difficult to
achieve in further transformations. In contrast, trans vicinal
substituents on a piperidine intermediate suitable for our purpose
would ensure the specific chair conformation in which those
substituents are equatorial (cf. 7, Figure 2).
(18) Kondo, K.; Mori, E. Chem. Lett. 1974, 741.
(19) Ishibashi, F.; Taniguchi, E. Bull. Chem. Soc. Jpn. 1988, 61, 4361.
(20) Lal, B.; Pramanik, B. M. I.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977.
As we will see presently, it was, indeed, the selection of the
trisubstituted tetrahydropyridine 7 as our goal that led to the

3242 J. Am. Chem. Soc., Vol. 123, No. 14, 2001
Stork et al.
Scheme 4
Scheme 5
we planned to use for cyclization to a piperidine system via an
intramolecular Staudinger reaction.21,22 In the event, the azi-
doketone 16 was smoothly converted to the anticipated tetrahy-
dropyridine 17 by refluxing with 1 equiv of triphenylphosphine
in tetrahydrofuran.
In fact, treatment of 19 with 1 equiv of mesyl chloride in
methylene chloride, in the presence of pyridine, followed by
refluxing of the crude product in acetonitrile, afforded, after
liberation from the methanesulfonate salt, deoxyquinine (5) in
∼70% yield after Flash chromatography.
We approached the next step with some apprehension because
the success of what we intended as a stereospecific synthesis
of deoxyquinine depended on the assumption that the specific
half-chair conformation which places the vinyl group and the
protected hydroxyethyl chain in equatorial orientations (cf.
Figure 2) would result, via the anticipated23 axial addition of
hydride to an imminium intermediate, in placing the quinolyl-
methyl substituent in the equatorial orientation corresponding
to the specific C-8 configuration required for the eventual
deoxyquinine. This proved to be the case: spectral data,
especially 13C NMR, showed that the piperidine 18 (7, X )
OTBDPS) was produced as a single compound, in 91% yield,
by addition of sodium borohydride to a solution of 17 in a 1:1
mixture of tetrahydrofuran and methanol. That the resulting
trisubstituted piperidine 18 was the expected correct epimer at
C-8 followed from its further conversion to deoxyquinine.
The conversion started (Scheme 5) with the quantitative
removal of the silyl protecting group with aqueous hydrogen
fluoride in acetonitrile to form 19. We were now ready to close
the quinuclidine ring, an operation that required changing the
primary hydroxyl into a suitable departing group. On the face
of it, that transformation might be expected to require temporary
protection of the piperidine amino group, but our previous
experience with a somewhat related situation suggested that
mesylation-cyclization, directly on 19, could well succeed.24
Completion of the Quinine Synthesis
The formation of quinine by oxidation of deoxyquinine with
oxygen in tert-butyl alcohol-DMSO, in the presence of
potassium tert-butoxide, proceeded selectively, as had been
found by the Hoffmann-La Roche group. In our hands, a
somewhat higher stereoselectivity (quinine:epiquinine ∼14:1)
was obtained by effecting the oxidation in the presence of
sodium hydride in anhydrous DMSO. The synthetic quinine,
1
thus obtained in 78% yield, had high-resolution mass and H
and 13C NMR spectra essentially identical with those of an
authentic sample from Sigma. The melting point and specific
rotation of the monotartrate of our synthetic quinine also agreed
with the reported values: mp 211.0-212.0 °C (lit.8f mp 211.0-
21.3
212.5 °C); [R]D
-154.7 (c 0.67, methanol) (lit.8f [R]25
D
-156.4 (c 0.97, methanol).
Acknowledgment. We thank Richard Isaacs and Shino
Manabe for their contributions to some aspects of this problem.
Financial support was provided by the National Institutes of
Health.
Supporting Information Available: Detailed experimental
1
procedures and copies of the H NMR and 13C NMR spectra
(21) Inter alia: Knouzi, N.; Vaultier, M.; Carrie, R. Bull. Soc. Chim.
Fr. 1985, 815.
(22) For a related sequence, cf.: Pearson, W. H.; Bergmeier, S. C.;
Williams, J. P. J. Org. Chem. 1992, 57, 3977.
(23) (a) Valls, J.; Toromanoff, E. Bull. Soc. Chim. Fr. 1961, 758. (b)
Toromanoff, E. Bull. Soc. Chim. Fr. 1966, 3357. (c) Deslongchamps, P.
Stereoelectronic Effects in Organic Chemistry; Pergamon: New York, 1983;
p 211.
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA004325R
(24) See also: Narasaka, K.; Yamazaki, S.; Ukaji, Y. Chem. Lett. 1985,
1177.