Rearrangement or gem-difluorination of quinine and 9-epiquinine and their acetates in superacid

Article abstract of DOI:10.1016/j.tet.2004.12.045

In HF-SbF₅, quinine 1a or its dihydrochloride rearranges into compound 3 (89%), the preferred conformation of the substrate favouring the observed cyclization. Under similar conditions epiquinine 2a dihydrochloride yields in equal amounts two 10,10-difluoro derivatives, epimeric at C-3. In this case, the more stable conformation of the substrate in which the benzylic hydroxyl group is 'exo' to the quinuclidyl moiety, prevents the cyclisation. Similarly acetates 1b and 2b give the corresponding 10,10-difluoro derivatives epimeric at C-3. Formation of gem-difluoro compounds implies the formation of chloro intermediates at C-10 followed by an hydride abstraction, yielding an α-chloronium ion. This one is trapped by a fluoride ion and leads to the product by halogen exchange.

Full text of DOI:10.1016/j.tet.2004.12.045

Tetrahedron 61 (2005) 2065–2073
Rearrangement or gem-difluorination of quinine and 9-epiquinine
and their acetates in superacid
a
Sebastien Debarge, Sebastien Thibaudeau, Bruno Violeau, Agnes Martin-Mingot,
a
a
a
´
´
`
Marie-Paule Jouannetaud,a, Jean-Claude Jacquesy and Alain Cousson
a,
b
*
*
a
` ´ ´
Laboratoire ‘Synthese et Reactivite des Substances Naturelles’, UMR 6514, 40, Avenue du Recteur Pineau, F-86022 Poitiers Cedex, France
b
´
Laboratoire Leon Brillouin-CEA Saclay, 91191 Gif-sur-Yvette Cedex, France
Received 20 October 2004; revised 15 December 2004; accepted 21 December 2004
Abstract—In HF-SbF5, quinine 1a or its dihydrochloride rearranges into compound 3 (89%), the preferred conformation of the substrate
favouring the observed cyclization. Under similar conditions epiquinine 2a dihydrochloride yields in equal amounts two 10,10-difluoro
derivatives, epimeric at C-3. In this case, the more stable conformation of the substrate in which the benzylic hydroxyl group is ‘exo’ to the
quinuclidyl moiety, prevents the cyclisation. Similarly acetates 1b and 2b give the corresponding 10,10-difluoro derivatives epimeric at C-3.
Formation of gem-difluoro compounds implies the formation of chloro intermediates at C-10 followed by an hydride abstraction, yielding an
a-chloronium ion. This one is trapped by a fluoride ion and leads to the product by halogen exchange.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
in HF-SbF5 at K30 8C yield almost quantitatively a sole
rearranged product 3 (89%).4 Under similar conditions,
quinine acetate 1b, 9-epiquinine 2a and its corresponding
acetate 2b lead to a complex mixture, whereas in the
presence of chloride ions in the media (CCl4 or 2HCl), these
compounds give gem-difluoro derivatives.
Cinchona alkaloids quinine and quinidine have been used
respectively as antimalaria and antiarrhythmic drugs.1 More
recently these compounds and derivatives have been
reported as catalysts or (co)catalysts in a variety of
enantioselective reactions.2
2.1. Reaction of quinine 1a (or its dihydrochloride
1a$2HCl)
Quinine and quinidine are cleaved in acetic acid to yield
quinicine.1 In our research for new derivatives we were
interested in an original approach using superacidic media.
We have previously reported novel and selective reactions
carried out in superacid HF-SbF5 on various polyfunctional
products.3 Under these superacidic conditions, the reactivity
of the substrates, being (poly)protonated, is dramatically
modified compared to what is observed with conventional
acids. In this paper we would like to report the reactivity of
quinine 1a, 9-epiquinine 2a, and acetates 1b and 2b in
superacid (Fig. 1).
2.1.1. Determination of structure. Mass spectrometry of
compound 3 shows that the molecular weight (324) is
identical to that of quinine 1a. The determination of
structure and conformation of compound 3 was made by
extensive NMR analysis. 1H and 13C resonances were
assigned by DEPT, COSY, NOESY, HMQC and HMBC
data. The long range couplings and NOE interactions have
been observed and are reported in Figure 2.
These data favour an anti conformation with the quinoline
moiety in horizontal position due to the reduced rotation
mobility about the C4–C4, bond as indicated. The structure
of compound 3 has been confirmed by X-ray analysis
(Fig. 2).
2. Results and discussion
Table 1 shows that either quinine 1a or its dihydrochloride
Keywords: Cinchona alkaloids; Superacid; Gem-difluorination;
Rearrangement.
* Corresponding authors. Tel.: C33 549453702; fax: C33 549453501;
e-mail: marie.paule.jouannetaud@univ-poitiers.fr
2.1.2. Formation of compound 3. In the reaction
conditions, quinine 1a is probably polyprotonated yielding
ion 8 by N-protonation of the quinuclidine group and
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.045

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S. Debarge et al. / Tetrahedron 61 (2005) 2065–2073
Figure 1.
diprotonation of the quinoline moiety at nitrogen and
oxygen atoms, thus minimizing the interaction of the two
positive charges (Scheme 1). Thus diprotonation disfavours
the expected formation of benzylic ion by dehydratation of
the protonated hydroxyl group (probably in equilibrium
with the neutral form).
The following mechanism may be operative to account for
the formation of compound 3. Protonation of the C10–C11
double bond yields ion 9. A rearrangement (9/10/11/
12) implying a 1,2 hydride shift from C3 to C10, concerted
with the migration of C4–C7 bond to C3, is followed by a
1,2 hydride shift to give ion 12. The latter ion is trapped by
the neutral hydroxyl group to give ether 3, diprotonation of
the quinoline moiety and N-protonation of the quinuclidyl
group disfavouring the protonation of the hydroxyl group at
C9. A non-concerted mechanism might lead either to ion 10
or to ion 13, the latter leading to a product which has not
been observed in the reaction.
Table 1
Entry
Substrate
Product(s) (yield %)
1
2
3
4
5
6
7
1a or 1a$2HCl (or CCl4)
1b
1b$2HCl (or CCl4)
2a
2a$2HCl (or CCl4)
2b
2b$2HCl (or CCl4)
3 (89)
Complex mixture
4b (30)C5b (30)
Complex mixture
6a (30)C7a (30)
Complex mixture
6b (30)C7b (30)
Reaction conditions: HF/SbF5, 10 min, K30 8C.

S. Debarge et al. / Tetrahedron 61 (2005) 2065–2073
2067
Figure 2.
Scheme 1.
2.2. Reaction of 9-epiquinine dihydrochloride 2a$2HCl
(JZ240 Hz) for carbon 10 for both compounds. It should be
noted that the 13C NMR for compounds 6a and 7a are
similar except for C5 and C7. For compound 6a, C7 is more
shifted than C5 as previously observed with quinine and its
derivatives, whereas for compound 7a C5 is more shifted
than C7.6 These data imply that compounds 6a and 7a are
epimeric at C3. A Mitsunobu reaction, carried out with
compounds 6a and 7a, gave 4a and 5a, respectively. The
structure of compound 5a has been determined by X-ray
analysis confirming the proposed structure for compounds
4a, 6a and 7a (Fig. 3).
2.2.1. Determination of structure. 9-Epiquinine 2a was
prepared from quinine 1a by the Mitsunobu reaction5 and
exhibits the expected NMR spectrometric data.1c Whereas
9-epiquinine 2a gives a complex mixture in HF-SbF5, the
corresponding dihydrochloride 2a$2HCl yields two new
gem-difluoro derivatives 6a (30%) and 7a (30%).
Structures of 6a and 7a have been determined by NMR
analysis and mass spectrometry. Whereas the quinoline
moiety appears not to be modified when compared to
compound 2a, changes are observed in the upper part:
disappearance of vinylic protons and presence of a
2.2.2. Formation of compound 6a and 7a. Firstly, the
importance of configuration at C9 on the reactivity of the
substrates in superacid should be pointed out. Whereas
quinine 1a yields a single rearranged product 3, 9-epi-
quinine 2a gives, in the presence of chloride ions, two
1
difluorinated ethyl group characterized in H NMR by a
triplet at 1.51 ppm (JZ18.7 Hz) for 6a and at 1.54 ppm (JZ
18.7 Hz) for 7a, and in 13C NMR by a triplet at 125 ppm

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S. Debarge et al. / Tetrahedron 61 (2005) 2065–2073
Figure 3.
gem-difluoro derivatives 6a and 7a. The postulated
mechanism accounting for the formation of compounds 6a
and 7a is similar to that postulated for the synthesis of
gem-difluoroamines, from unsaturated amines such as
anhydrovinblastine, precursor of Vinflunine (Javlorw),
which is a novel anticancer agent.7 This mechanism implies
the formation of a carbenium ion 14 at C10 after protonation
of the C10–C11 double bond (Scheme 2).
hydrogen from C10 to C3 yields ion 14 and ion 16,
epimeric at C3. Another mechanism through a deprotona-
tion–protonation process might also be operative for the
formation of ions 14 and 16. Trapping of these ions by the
complex chloride SbF5ClK involves the formation of
intermediates 17 and 18, chlorinated at C10. Hydride
abstraction at C10 by the superacid HF-SbF5 itself or by
trichloromethyl ion CClC3 in the presence of CCl4,7 gives
mesomeric a-chlorocarbenium 19 and 20, respectively
which react with fluoride ions and lead by halogen exchange
to the difluorinated products 6a and 7a. It has been shown
that a-chloronium ions are stabilized by a chlorine atom
This ion can isomerize by a 1,2-hydride shift to tertiary ion
15 which is destabilized on account of the proximity of the
protonated nitrogen atom. Ion 15, after migration of
Scheme 2.

S. Debarge et al. / Tetrahedron 61 (2005) 2065–2073
2069
Figure 4.
which becomes p donor.8 Unfortunately, it was not possible
to isolate the assumed chloro intermediates 17 and 18. In
a similar reaction carried out with anhydrovinblastine,
the corresponding chloroderivatives precursors of the gem-
difluoro products, could be isolated and characterized.7a
acetates 4b and 5b, thus establishing the structures of 4b,
5b, 6b and 7b.
3. Biological activity
2.2.3. Interpretation of the results. The different reactivity
of quinine 1a and 9-epiquinine 2a in superacid can be
explained by the two conformations of these substrates
obtained by molecular modelisation, NMR and X-ray
analysis.9
Gem-difluoro derivatives 6a and 7a have been tested in vitro
on Plasmodium falciparum assay. The quinine-sensitive K1
¨
or Thaı clones have been used to determine the influence of
the two fluorine atoms at C10, and of the configuration at C3
on antimalaria activity. The IC50 values of quinine,
chloroquine and gem-difluoro compounds 6a and 7a are
reported in Table 2. The activity of the gem-difluoro
derivatives appears to be comparable to that of quinine and
chloroquinine.
The more stable conformation of quinine 1a and its
hydrochloride is conformation A in which the hydroxyl
group is under the quinuclidyl moiety, favouring the
cyclisation following the rearrangement (Fig. 4). On the
other hand, for 9-epiquinine 2a, the preferred conformation
is B, the hydroxyl group being ‘exo’ to the quinuclidyl
group, thus preventing any cyclisation.
Table 2
Substrate
IC50 (nM)
¨
Thaı
K1
Quinine
Chloroquine
4a
5a
50
22
22.8
24
2.3. Reaction of quinine and 9-epiquinine acetates
dihydrochloride 1b$2HCl or 2b$2HCl
39.2
100
120
25
Taking into account the cyclisation observed in the reaction
of quinine dihydrochloride, we studied the reactivity of
the corresponding acetate 1b and its dihydrochloride in
HF-SbF5. Whereas acetate 1b yields only a complex
mixture, its dihydrochloride gives gem-difluoro derivatives
4b (30%) and 5b (30%), acylation of the hydroxyl
preventing rearrangement and cyclisation. As expected,
reaction of 9-epiquinine acetate dihydrochloride 2b$2HCl
yields the corresponding gem-difluoro compounds 6b and
7b. Reaction of acetates 6b and 7b with K2CO3 in methanol
leads to the corresponding alcohols 6a and 7a, respectively.
These compounds were also obtained by hydrolysis of
4. Conclusion
The study of the reactivity of cinchona alkaloids (quinine,
9-epiquinine) and their acetates in superacid media has
showed the influence of the configuration of C-9.
With quinine 1a, the more stable conformation, in which the
benzylic hydroxyl group is under the quinuclidyl moiety,
favours a new rearrangement not observed in usual acid
conditions leading to an oxazapolycyclic compound.

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S. Debarge et al. / Tetrahedron 61 (2005) 2065–2073
In the case of 9-epiquinine, benzylic hydroxyl is ‘exo’ to the
quinuclidyl moiety in the more stable conformation,
preventing such a rearrangement. In the presence of chloride
ions, two gem-difluoro derivatives, epimeric at C-3, are
obtained.
0.6 mol) maintained at K30 8C in a Teflonw flask, was
added quinine derivatives (3 mmol) with or without chloride
source (2HCl, or CCl4 (2 equiv)). The reaction mixture was
magnetically stirred at the same temperature for 10 min.
The reaction mixture was then neutralized with water/ice
(300 mL) and sodium carbonate (100 g, 1 mol) and worked-
up by usual manner. The products were isolated by column
chromatography over SiO2.
By protection of the hydroxyl group of quinine by acetyl-
ation, no rearrangement is observed, but two gem-difluoro
derivatives are obtained in the presence of chloride ions.
5.3. Reaction on quinine 1a
These results show the generality of this novel gem-
difluorination, previously reported on amines and Vinca
alkaloids.
After reaction of quinine 1a (972 mg, 3 mmol), following
the general procedure, compound 3 (865 mg, 89%) was
obtained as a white solid after flash chromatography eluted
with the mixture CH2Cl2/MeOH/NH3: 95/4.5/0.5 (v/v/v).
5. Experimental
1
5.3.1. Compound 3. H NMR (300 MHz, CDCl3): 0.87 (t,
5.1. General methods
3H, JZ7.5 Hz, H-12), 1.21 (ddd, 1H, JZ12.5, 9.8, 2.8 Hz,
H-2a), 1.40 (m, 2H, H-11), 1.82 (m, 1H, H-9a), 1.84 (m, 1H,
H-2b), 1.93 (dm, 1H, JZ13.7 Hz, H-9b), 2.72 (broad s,
2H, H-10), 2.82 (dm, 1H, JZ14 Hz, H-7a), 3.96 (s, 3H,
O–CH3), 3.99 (dm, 1H, JZ14 Hz, H-7b), 4.10 (dm, 1H, JZ
9.8 Hz, H-3), 4.33 (broad s, 1H, H-6), 5.83 (broad s, 1H,
H-4), 7.20 (d, 1H, JZ2.0 Hz, H-50), 7.36 (dd, 1H, JZ7.7,
2.0 Hz, H-70), 7.66 (d, 1H, JZ4.4 Hz, H-30), 08.03 (d, 1H,
JZ7.7 Hz, H-80), 8.78 (d, 1H, JZ4.4 Hz, H-2 ).
The authors draw the reader’s attention to the dangerous
features of superacidic chemistry. Handling of hydrogen
fluoride and antimony pentafluoride must be done by
experienced chemists with all the necessary safety arrange-
ments in place.
Reactions performed in superacid were carried out in a
sealed Teflonw flask with a magnetic stirring. No further
precautions have to be taken to prevent mixture from
moisture (test reaction worked out in anhydrous conditions
leads as expected to the same results).
13C NMR (75 MHz, CDCl3): 9.8 (s, C-12), 29.6 (s, C-11),
38.4 (s, C-2), 42.2 (s, C-1), 42.3 (s, C-9), 54.4 (s, C-7), 56.1
(s, O–CH3), 63.9 (s, C-3), 68.1 (s, C-10), 68.7 (s, C-4), 70.5
(s, C-6), 101.0 (s, C-50), 119.5 (s, C-30), 121.9 (s, C-70),
126.5 (s, C-90), 1320.1 (s, C-80), 144.2 (s, C-40), 144.4 (s,
C-100), 148.1 (s, C-2 ), 158.2 (s, C-60). MS (70 eV), m/z (%):
324 (64), 309 (31), 295 (50), 282 (41), 252 (37), 83 (100).
HRMS: C20H24N2O2 calculated: 324.1838, found:
324.1843. [a]D: K123.58 (cZ0.2, CHCl3, 20 8C). Mp:
83.6 8C.
Yields refer to isolated pure products. H and 13C NMR
were recorded on a 300 MHz Bruker spectrometer using
CDCl3 as solvent and TMS as internal standard.
1
Melting points were determined in a capillary tube and are
uncorrected.
Mass spectra were measured in the electron impact mode
(EI). High resolution mass spectra were performed on a
Compound 3 was recrystallised in hexane/ether (80:20, v:v)
and the single crystal was selected for X-ray experiment.
´
Micromass ZABSpec TOF by the Centre Regional de
Mesures Physiques de l’Ouest, Universite Rennes.
´
Crystal color: colorless prisms, chemical formula
C20H24N2O5 molecular weight MZ324.18, crystal system:
˚
˚
All separations were done under flash-chromatography
conditions on silica gel (15–40 mm).
orthorhombic, aZ6.1430 (12) A, bZ17.355 (4) A, cZ
3
˚
˚
18.305 (4) A, volume of unit cell VZ1951.5 (7) A .
Crystal data for 3 and 5a were recorded at room temperature
with a Nonius Kappa CDD diffractometer equipped with a
graphite monochromator and an X-ray tube with a Mo
5.4. Reaction on 9-epiquinine 2a
After reaction of 9-epiquinine 2a dihydrochloride (1.2 g,
3 mmol), following the general procedure, compounds 6a
(326 mg, 30%) and 7a (326 mg, 30%) were isolated as oils
after column chromatography eluted with the mixture
AcOEt/petroleum ether/HNEt2: 78/20/2 (v/v/v).
˚
anticathode (lZ0.71069 A). The structure was solved using
direct methods10 and refined using least square calcu-
lation.11 The crystal structure has been deposited at the
Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 252807 for 3 and CCDC 252808
for 5a.
1
5.4.1. Compound 6a. H NMR (300 MHz, CDCl3): 0.87
(m, 1H, H-7 endo), 1.51 (t, 3H, JZ18.7 Hz, H-11), 1.56 (m,
1H, H-7 exo), 1.58 (m, 2H, H-5), 1.98 (m, 1H, H-3), 1.99
(m, 1H, H-4), 2.81 (m, 1H, H-6 exo), 3.14 (m, 2H, H-2),
3.17 (m, 1H, H-6 endo), 3.18 (m, 1H, H-8), 3.94 (s, 3H,
–O–Me), 5.01 (d,0 1H, JZ10.0 Hz, H-9), 7.36 (dd, 1H, JZ
9.2, 2.7 Hz, H-7 ), 7.38 (d, 1H, JZ4.5 Hz, H-30), 7.63
(d, 1H, JZ2.7 Hz, H-50), 8.03 (d, 1H, JZ9.2 Hz, H-80), 8.73
(d, 1H, JZ4.5 Hz, H-20).
Geometry optimizations were executed with Chem 3D by
applying the AM1 and PM3 semi-empirical methods in
MOPAC.
5.2. General procedure in superacidic media
To a mixture of SbF5 (18 g, 0.082 mol) and HF (12 g,

S. Debarge et al. / Tetrahedron 61 (2005) 2065–2073
2071
13C NMR (75 MHz, CDCl3): 22.5 (t, JZ3 Hz, C-4), 23.0 (t,
JZ23 Hz, C-11), 25.9 (s, C-7), 28.8 (s, C-5), 40.7 (s, C-6),
42.3 (t, JZ23 Hz, C-3), 50.5 (t, JZ3 Hz, C-2), 055.5 (s,
O–CH3), 61.1 (s, C-8); 71.1 (s, C-9), 102.5 (s, C-5 ), 120.1
(s, C-700), 121.3 (s, C-30), 124.8 (t, JZ240 Hz, C-10), 1280.1
(s, C-9 ), 131.6 (s, C-80), 144.1 (s, C-40), 144.8 (s, C-10 ),
147.6 (s, C-20), 157.4 (s, C-60). MS (70 eV), m/z (%): 362
(28), 189 (49), 174 (77), 146 (69), 82 (100). HRMS:
C20H24N2O2F2 calculated: 362.1806, found: 362.1789.
[a]D: 24.48 (cZ1, MeOH, 20 8C).
H-13), 2.15 (m, 1H, H-5), 2.75 (m, 1H, H-6 exo), 2.89 (m,
2H, H-2), 3.11 (m, 1H, H-6 endo), 3.34 (m, 1H, H-8), 3.96
(s, 3H, –O–Me), 6.55 (d, 1H, JZ6.7 Hz, H-9), 7.33 0(d, 1H,
JZ4.5 Hz, H-30), 7.390 (dd, 1H, JZ9.1, 2.7 Hz, H-7 0), 7.46
(d, 1H, JZ2.7 Hz, H-5 ), 8.02 (d, 1H, JZ9.1 Hz, H-8 ), 8.72
(d, 1H, JZ4.5 Hz, H-20).
13C NMR (75 MHz, CDCl3): 21.4 (s, C-13), 22.6 (s, C-5),
23.3 (t, JZ4 Hz, C-4), 23.4 (t, JZ23 Hz, C-11), 31.0 (s, C-
7), 42.5 (t, JZ23 Hz, C-3), 43.4 (s, C-6), 51.2 (t, JZ4 Hz,
C-2), 56.0 (s, O–CH3), 59.2 (s, C-8), 74.0 (s, C-9), 101.9 (s,
C-50), 118.9 (s, C-30), 122.2 (s, C-70), 125.6 (t, JZ240 Hz,
C-10), 127.30 (s, C-90), 132.2 (s, C-80), 143.9 (s, C-100),
145.1 (s, C-4 ), 147.7 (s, C-20), 158.4 (s, C-60), 170.8 (CO).
HRMS: C22H26N2O3F2 calculated: 404.1911, found:
404.1911. [a]D: K74.98 (cZ1, MeOH, 20 8C).
1
5.4.2. Compound 7a. H NMR (300 MHz, CDCl3): 1.10
(m, 1H, H-7), 1.25 (m, 1H, H-7), 1.26 (m, 1H, H-5), 1.54
(t, 3H, JZ18.7 Hz, H-11), 2.00 (m, 1H, H-5), 1.98 (m, 1H,
H-3), 1.99 (m, 1H, H-4), 2.86 (m, 1H, H-6 exo), 3.10 (m,
2H, H-2), 3.12 (m, 1H, H-8), 3.14 (m, 1H, H-6 endo), 3.92
(s, 3H, –O–Me), 5.04 (d, 1H, JZ10.0 Hz, H-9), 7.36 (dd,
1H, JZ9.2, 2.6 Hz, H-70), 07.40 (d, 1H, JZ4.5 Hz, H-300),
7.67 (d, 1H, JZ2.6 Hz, H-5 ), 8.03 (d, 1H, JZ9.2 Hz, H-8 ),
8.70 (d, 1H, JZ4.5 Hz, H-20).
5.6. Reaction on epiquinine acetate dihydrochloride 2b
After reaction of epiquinine acetate 2b dihydrochloride
(350 mg, 0.8 mmol), following the general procedure,
compounds 6b (97 mg, 30%) and 7b (97 mg, 30%) were
isolated as oils after column chromatography eluted with the
mixture AcOEt/petroleum ether/HNEt2: 28/70/2 (v/v/v).
13C NMR (75 MHz, CDCl3): 22.4 (s, C-5), 22.8 (t, JZ4 Hz,
C-4), 23.1 (t, JZ23 Hz, C-11), 31.5 (s, C-7), 41.2 (s, C-6),
42.3 (t, JZ23 Hz, C-3), 50.2 (t, JZ4 Hz, C-2), 55.5 (s,
–O–CH3), 61.2 (s, C-8), 71.6 (s, C-9), 102.6 (s, C-50), 120.2
(s, C-700), 121.4 (s, C-30), 125.2 (t, JZ240 Hz, C-10), 1280.0
(s, C-9 ), 131.6 (s, C-80), 144.2 (s, C-40), 144.5 (s, C-10 ),
147.5 (s, C-20), 157.4 (s, C-60). MS (70 eV), m/z (%): 362
(28), 189 (49), 174 (85), 146 (70), 82 (100). HRMS:
C20H24N2O2F2 calculated: 362.1806, found: 362.1789.
[a]D: K13.88 (cZ1, MeOH, 20 8C).
1
5.6.1. Compound 6b. H NMR (300 MHz, CDCl3): 0.75
(m, 1H, H-7), 1.52 (t, 3H, JZ18.7 Hz, H-11), 1.53 (m, 3H,
2H-5, H-7), 1.93 (m, 2H, H-4, H-3), 2.08 (s, 3H, H-13), 2.77
(m, 1H, H-6), 3.13 (m, 2H, H-2), 3.33 (m, 1H, H-6), 3.61
(m, 1H, H-8), 3.97 (s, 3H, –O–Me), 6.41 (d, 1H, JZ10 Hz,
H-9), 7.40 (m, 2H, H-30, H-70), 07.58 (d, 1H, JZ2.7 Hz,
H-500), 8.03 (d, 1H, JZ9.2 Hz, H-8 ), 8.76 (d, 1H, JZ4.5 Hz,
H-2 ).
5.5. Reaction on quinine acetate dihydrochloride 1b
After reaction of quinine acetate 1b dihydrochloride
(880 mg, 2 mmol), following the general procedure, com-
pounds 4b (240 mg, 30%) and 5b (240 mg, 30%) were
isolated as oils after column chromatography eluted with the
mixture AcOEt/petroleum ether/HNEt2: 28/70/2 (v/v/v).
13C NMR (75 MHz, CDCl3): 21.6 (s, C-13), 23.0 (s, C-4),
23.4 (t, JZ28 Hz, C-11), 26.4 (s, C-7), 29.2 (s, C-5), 41.6
(s, C-6), 43.1 (t, JZ23.4 Hz, C-3), 51.1 (s, C-2), 056.0 (s,
–O–CH3), 59.1 (s, C-8); 71.5 (s, C-9), 102.1 (s, C-5 ), 121.0
(s, C-70), 122.2 (s, C-30),0 128.1 (t, JZ240 Hz, C-10), 1280.2
(s, C-100), 132.2 (s, C-8 ), 141.3 (s, C-40), 145.2 (s, C-9 ),
147.9 (s, C-20), 158.5 (s, C-60), 170.8 (s, C]O).
1
5.5.1. Compound 4b. H NMR (300 MHz, CDCl3): 1.50
(m, 1H, H-7 endo), 1.52 (m, 1H, H-5), 1.56 (t, 3H, JZ
18.7 Hz, H-11), 1.74 (m, 1H, H-5), 1.99 (m, 1H, H-3), 2.03
(m, 1H, H-7 exo), 2.11 (s, 3H, H-13), 2.16 (m, 1H, H-4),
2.67 (m, 1H, H-6 exo), 2.93 (m, 2H, H-2), 3.16 (m, 1H, H-6
endo), 3.55 (m, 1H, H-8), 3.96 (s, 3H, –O–Me), 6.480(d, 1H,
JZ7.5 Hz, H-9), 7.35 0(dd, 1H, JZ9.2, 2.5 Hz, H-7 0), 7.38
(d, 1H, JZ4.5 Hz, H-3 ), 7.43 (d, 1H, JZ2.5 Hz, H-5 ),08.01
(d, 1H, JZ9.2 Hz, H-80), 8.73 (d, 1H, JZ4.5 Hz, H-2 ).
1
5.6.2. Compound 7b. H NMR (300 MHz, CDCl3): 0.99
(m, 1H, H-7), 1.25 (m, 3H, H-7, 2H-5), 1.55 (t, 3H, JZ
18.7 Hz, H-11), 1.94 (m, 2H, H-3, H-4), 2.09 (s, 3H, H-13),
2.84 (m, 1H, H-6), 3.10 (m, 2H, H-2), 3.24 (m, 1H, H-6),
3.46 (m, 1H, H-8), 3.97 (s, 3H, –O–Me), 6.43 (d, 1H, JZ
10 Hz, H-9), 7.40 (m, 2H, H-30, H-80), 7.59 (d, 1H, 2.7 Hz,
H-500), 8.03 (d, 1H, JZ9.2 Hz, H-80), 8.75 (d, 1H, JZ4.5 Hz,
H-2 ).
13C NMR (75 MHz, CDCl3): 21.4 (s, 3H, C-13), 23.0 (t, JZ
3 Hz, C-4), 23.4 (t, JZ22 Hz, C-11), 25.6 (s, C-7), 28.9 (s,
C-5), 42.7 (s, C-6), 43.0 (t, JZ22 Hz, C-3), 51.6 (t, JZ3 Hz,
C-2), 56.1 (s, –O–CH3), 59.1 (s, C-8); 74.2 (s, C-9), 101.9 (s,
C-50), 119.6 (s, C-700), 122.3 (s, C-30), 125.2 (t, JZ240 Hz,
C-10), 127.4 (s, C-9 ), 1320.1 (s, C-80), 145.20 (s, C-40), 143.6
(s, C-100), 147.7 (s, C-2 ), 158.4 (s, C-6 ), 170.4 (CO).
HRMS: C22H26N2O3F2 calculated: 404.1911, found:
404.1911. [a]D: K28.78 (cZ0.9, MeOH, 20 8C).
13C NMR (75 MHz, CDCl3): 21.6 (s, C-13), 22.7 (s, C-5),
23.1 (c, C-4) 23.2 (t, JZ28 Hz, C-11), 32.1 (s, C-7), 41.7
(s, C-6), 42.5 (t, JZ23 Hz, C-3), 50.8 (s, C-2), 56.0 (s,
O–CH3), 59.1 (s, C-8); 71.6 (s, C-9), 102.1 (s, C-50), 120.9
(s, C-70), 122.2 (s, C-30),0 125.6 (t, JZ240 Hz, C-10), 1280.1
(s, C-100), 132.2 (s, C-8 ), 142.1 (s, C-40), 145.3 (s, C-9 ),
147.8 (s, C-20), 158.5 (s, C-60), 170.7 (c, C]O).
5.7. Hydrolysis of compounds 4b and 5b
1
5.5.2. Compound 5b. H NMR (300 MHz, CDCl3): 1.48
(m, 1H, H-5), 1.54 (t, 3H, JZ18.7 Hz, H-11), 1.70 (m, 2H,
H-7), 1.95 (m, 1H, H-4), 1.96 (m, 1H, H-3), 2.14 (s, 3H,
Compounds 4b (or 5b) was treated with K2CO3 (1.2 equiv)
in a solution of MeOH/H2O (7%). After being stirred for

2072
S. Debarge et al. / Tetrahedron 61 (2005) 2065–2073
2 h, the resulting mixture was concentrated under reduced
pressure. The residue was diluted with AcOEt, washed,
dried over anhydrous MgSO4, and concentrated in vacuo to
give compounds 4a as an oil (or 5a as a yellow solid) (90%).
to warm to room temperature and stirred for 2 h. The solvent
was removed in vacuo, and the residue was diluted with
ether. The white precipitate was filtered, and the filtrate was
washed with saturated aqueous NaHCO3. The organic
extract was dried over anhydrous MgSO4 and concentrated
under reduced pressure.
1
5.7.1. Compound 4a. H NMR (300 MHz, CDCl3): 1.44
(m, 1H, H-5), 1.49 (t, 3H, JZ18.7 Hz, H-11), 1.54 (m, 1H,
H-7 endo), 1.69 (m, 1H, H-7 exo), 1.74 (m, 1H, H-5), 1.89
(m, 1H, H-3), 2.05 (m, 1H, H-4), 2.57 (m, 1H, H-6 exo),
2.90 (m, 2H, H-2), 3.21 (m, 1H, H-8), 3.48 (m, 1H, H-6
endo), 3.87 (s, 3H, –O–Me), 5.44 (d, 1H, JZ4.2 Hz, H-9),
7.24 (d, 1H, JZ2.5 Hz, H-50), 7.26 (dd, 1H, JZ8.7, 2.6 Hz,
H-700), 7.38 (d, 1H, JZ4.5 Hz, H-30), 7.84 (d, 1H, JZ8.7 Hz,
H-8 ), 8.36 (d, 1H, JZ4.5 Hz, H-20).
The crude was treated with K2CO3 (1.2 equiv) in a solution
of MeOH/H2O (7%). Then the reaction mixture was stirred
for 2 h and concentrated under reduced pressure. The
residue was diluted with AcOEt, washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo.
Purification by flash chromatography (AcOEt/HNEt2:
98/2, v/v) gave 9-epiquinine 2a (2.63 g, 65%) as an oil.
13C NMR (75 MHz, CDCl3): 23.0 (t, JZ3 Hz, C-4), 23.1
(t, JZ23 Hz, C-11), 22.6 (s, C-7), 28.5 (s, C-5), 42.7 (t,
JZ22 Hz, C-3), 43.1 (s, C-6), 51.4 (t, JZ3 Hz, C-2), 550.6
(s, –O–CH3), 59.6 (s, C-8); 71.9 (s, C-9), 101.6 (s, C-5 ),
118.6 (s, C-30), 121.4 (s, C-70), 125.0 (t, JZ240 Hz, C-10),
126.6 (s, C-90), 131.0 (s, C-80), 143.9 (s, C-100), 148.3
(s, C-40), 147.1 (s, C-20), 157.6 (s, C-60). HRMS:
C20H24N2O2F2 calculated: 362.1806, found: 362.1789.
[a]D: K102.88 (cZ1.8, MeOH, 20 8C).
Acknowledgements
´
We thank CNRS for financial support and Region Poitou-
Charentes for a grant (to S.D.). We are also grateful to
Professor Schrevel (Museum National d’Histoire Naturelle,
Paris) for performing the tests on Plasmodium falciparum.
1
5.7.2. Compound 5a. H NMR (300 MHz, CDCl3): 1.10
References and notes
(m, 1H, H-7), 1.53 (t, 3H, JZ18.7 Hz, H-11), 1.58 (m, 1H,
H-5), 1.91 (m, 1H, H-3), 1.92 (m, 1H, H-5), 1.97 (m, 1H,
H-7), 2.06 (m, 1H, H-4), 2.76 (m, 1H, H-6 exo), 2.95 (m,
1H, H-8), 3.71 (s, 3H, –O–Me), 2.96 (m, 2H, H-2), 3.67 (m,
1H, H-6 endo),05.58 (d, 1H, JZ4.2 Hz, H-9), 6.98 (d, 1H,
JZ2.7 Hz, H-5 ), 7.200 (dd, 1H, JZ9.2, 2.7 Hz, H-700), 7.59
(d, 1H, JZ4.5 Hz, H-3 ), 7.84 (d, 1H, JZ9.2 Hz, H-8 ), 8.56
(d, 1H, JZ4.5 Hz, H-20).
1. (a) Verpoorte, R.; Schripsema, J.; V. Der Leer, T. In Brossi, A.,
Ed.; Cinchona Alkaloids in the Alkaloids, Chemistry and
Pharmacology; Academic: San Diego, 1988; Vol. 34,
pp 331–398. (b) Bruneton, J. Pharmacognosie, Phytochimie,
´
Plantes medicinales; Lavoisier: Paris, 1987.
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Asymmetry 1996, 7, 571–580. (b) Augustine, R. L.; Tanielyan,
S. K. J. Mol. Catal. A: Chem. 1996, 112, 93–104. (c) Wang,
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2133–2140. (d) Blaser, H. U.; Jalett, H. P.; Lottenbach, W.;
Studer, M. J. Am. Chem. Soc. 2000, 122, 12675–12682.
13C NMR (75 MHz, CDCl3): 21.7 (s, C-5), 23.3 (t, JZ
23 Hz, C-11), 23.4 (t, JZ4 Hz, C-4), 26.6 (s, C-7), 42.2 (t,
JZ23 Hz, C-3), 43.9 (s, C-6), 51.0 (t, JZ4 Hz, C-2), 550.5
(s, –O–CH3), 59.1 (s, C-8); 70.6 (s, C-9), 100.7 (s, C-5 ),
118.2 (s, C-70), 121.7 (s, C-30), 125.3 (t, JZ240 Hz, C-10),
126.1 (s, C-90), 130.9 (s, C-80), 143.5 (s, C-100), 147.1
(s, C-20), 148.3 (s, C-40), 157.7 (s, C-60). HRMS:
C20H24N2O2F2 calculated: 362.1806, found: 362.1789.
Mp: 214 8C [a]D: K157.08 (cZ1, MeOH, 20 8C).
¨
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(20/80, v/v) and the single crystal was selected for X-ray
experiment.
Crystal color: colorless prisms, chemical formula
C20H24N2O2F2, molecular weight MZ362.42, crystal
˚
system: orthorhombic, aZ7.14224 (3) A, bZ10.8005
˚
˚
(11) A, cZ23.583 (2) A, volume of unit cell VZ1819.2
3
(3) A .
˚
5.8. Synthesis of 9-epiquinine 2a by Mitsunobu reaction
A double-necked, round-bottomed flask was filled with
quinine (4.05 g, 12.5 mmol) in anhydrous THF (70 mL)
with 4-nitrobenzoic acid (4.18 g, 25 mmol) and PPh3
(6.55 g, 25 mmol). The flask was cooled to 0 8C, and
DEAD (3.93 mL, 25 mmol) was slowly added to maintain
the temperature below 10 8C. Then the mixture was allowed

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