Synthetic approaches to Cinchona alkaloids: The C-8/C-9 disconnection strategy

Article abstract of DOI:10.1016/S0040-4039(03)00926-2

When conducted in DMSO, the Hünig's base-promoted condensation of 3-quinuclidinone with quinoline-4-carboxaldehyde gave an equimolar mixture of epimeric aldols 8 with an excellent yield.

Full text of DOI:10.1016/S0040-4039(03)00926-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4187–4190
Synthetic approaches to Cinchona alkaloids: the C-8/C-9
disconnection strategy
Raphae¨l Jankowski,a Delphine Joseph,a Christian Cave´,a Franc¸oise Dumas,a Miche`le Ourevitch,a
Jacqueline Mahuteau,a Georges Morgant,b Nada Bosnjakovic´ Pavlovic´c and Jean d’Angeloa,*
aUnite´ de Chimie Organique, UMR CNRS 8076, Centre d’Etudes Pharmaceutiques, Universite´ Paris-Sud,
5 rue Jean-Baptiste Cle´ment, 92296 Chaˆtenay-Malabry, France
bLaboratoire de Cristallochimie Bioinorganique, Centre d’Etudes Pharmaceutiques, Universite´ Paris-Sud,
5 rue Jean-Baptiste Cle´ment, 92296 Chaˆtenay-Malabry, France
cSPMS, UMR CNRS 8580, Ecole Centrale de Paris, Grande Voie des Vignes, 92296 Chaˆtenay-Malabry, France
Received 17 March 2003; revised 8 April 2003; accepted 8 April 2003
Abstract—When conducted in DMSO, the Hu¨nig’s base-promoted condensation of 3-quinuclidinone with quinoline-4-carboxalde-
hyde gave an equimolar mixture of epimeric aldols 8 with an excellent yield. © 2003 Elsevier Science Ltd. All rights reserved.
Gates–Schreiber,4 Taylor–Martin,5 Brown,6 Wilson7) or
N-1 and C-6 (Stork8). In comparison, the C-8/C-9
disconnection strategy, involving the condensation of a
pre-existing quinuclidine unit with a quinoline moiety,
has been much less studied.
Quinine (1), the most celebrated member of the Cin-
chona alkaloids, has played a dominant role in human
therapeutics for the treatment of malaria (Fig. 1). In
organic chemistry, quinine and related alkaloids have
been widely used as chiral substrates for achieving
chiral discrimination/recognition, e.g. as resolving
agents for acids, as ligands for asymmetric synthesis,1
as chiral solvating agents in NMR spectroscopy and as
selectors in the elaboration of chiral stationary/mobile
phases for chromatographic resolution. After a long
period of exploratory studies, there has been a resur-
gence of interest in developing synthetic routes to the
Cinchona alkaloids, culminating in several successful
approaches to quinine. A consistent theme among these
syntheses was the creation of the quinuclidine system at
the late stages by heterocyclization between N-1 and
C-8 (Woodward–Doering,2 Uskokovic´–Gutzwiller,3
The first investigation in the area was reported by
Coffen who established that the sodium ethoxide-pro-
moted condensation of a mixture of 3-quinuclidinone
(2) and 6-methoxyquinoline-4-carboxaldehyde (3) fur-
nishes in 90% yield (Z)-6%-methoxy-7-oxo-8-rubene (4).9
Thus, in such operating conditions, the (desired) initial
aldol adduct suffered an irreversible dehydration reac-
tion, affording a,b-ethylenic carbonyl compound 4. The
Figure 1. Structure of quinine (1).
Keywords: aldols; alkaloids; amines; quinolines; quinuclidines.
* Corresponding author. Fax: +33 (0)
1 46 83 57 52; e-mail:
jean.dangelo@cep.u-psud.fr
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00926-2

4188
R. Jankowski et al. / Tetrahedron Letters 44 (2003) 4187–4190
and of the solvent of the reaction. In THF, all experi-
ments that employed tertiary amines as a base returned
only unchanged starting materials (Table 1, entries
1–4), while the utilization of the strongly basic quater-
nary ammonium hydroxide Triton® B yielded almost
quantitatively (Z)-7-oxo-8-rubene (Z-9) (entry 5), an
outcome that parallels completely conversion [2+3“4].
However, when DMSO was employed as solvent a
dramatic increase in reactivity was gained,14 the utiliza-
tion of tertiary amines furnishing now the desired
aldols 8 (obtained as a nearly equimolar mixture of
diastereomers) (entries 7–10); the best catalyst was
found to be the moderately basic Hu¨nig’s base, produc-
ing 8 in 90% yield (entry 7). Somewhat surprisingly,
when the condensation [2+7] was conducted in DMSO,
in the absence of any external base, a substantial
amount of aldols 8 was formed (30%, entry 6). Pre-
sumably, the driving force for this autocatalytic aldol
condensation was the intrinsic basicity of 2 (MeCNpKB
of quinuclidine: 19.5). Although aldols 8 were obtained
as an equimolar mixture of diastereomers, reflecting a
thermodynamic control (while the formation of the
single aldol (erythro)-610 implicates a kinetically-con-
trolled addition process),15 it is noteworthy that addi-
tion [2+7“8] realizes the first aldol-type condensation
between a quinuclidinone and a quinoline–carboxalde-
hyde, thus opening future prospects for a synthetic
approach to Cinchona alkaloids based on the C-8/C-9
disconnection strategy. The identity of aldols 816 was
corroborated by dehydration which led to an equimolar
mixture of enones (Z)-9 and (E)-9 (Burgess’ inner salt:
Et3N+SO2N−COOMe,17 benzene, 80°C, quantitative
yield). Configurational assignment of enone (Z)-918 was
definitively secured by single-crystal X-ray diffraction
analysis (Fig. 2). Incidentally, we have observed that
the irradiation, using visible light, of (Z)-9 in CCl4 in
the presence of a trace of I2 gave a photostationary
mixture of (Z)-9 and (E)-9 containing ca. 40% of
(Z)-9.19,20
Scheme 2.
critical problem of the interception of the intermediary
aldol was partly solved by Stotter some years later, who
preformed the lithium enolate of 3-quinuclidinone (5)
by treating ketone 2 with LDA. Subsequent condensa-
tion of this enolate with benzaldehyde at −78°C pro-
duced stereoselectively aldol (erythro)-6 with a 83%
yield. However, probably because of its reduced elec-
trophilicity, aldehyde 3 proved unsuitable in the con-
densation with enolate 5 (Scheme 1).10 In connection
with our sustained research efforts in the Cinchona
alkaloids series, directed towards their synthesis11 and
their use as chiral ligands in asymmetric catalysis,12 we
recently reinvestigated the above ‘aldol route’, taking
advantage of the recent developments in the field.
Results from this endeavor are reported hereafter.
Condensation between both commercially available 3-
quinuclidinone (2) and quinoline-4-carboxaldehyde
(7)13 was attempted first; selected results are depicted in
Scheme 2 and are listed in Table 1. These results are
strongly dependent upon the nature of the base added
Table 1. Compounds produced via condensation between 2 and 7
Entry
Solvent
Base addeda
SM (%)b
8 (%)c
(Z)-9 (%)d
1
2
3
4
5
6
7
8
9
THF
–
–
–
Hu¨nig’s basee
2,6-Di-tert-butylpyridine
DMAPf
100
100
100
100
0
70
10
50
50
0
0
0
0
0
0
0
0
95
0
0
0
0
0
Proton-Sponge®g
–
Triton® Bh
No base added
Hu¨nig’s base
0
DMSO
30
90
50
50
50
–
–
–
–
2,6-Di-tert-butylpyridine
DMAP
10
Proton-Sponge®
50
a All reactions were performed at 30°C during 2 weeks, employing a stoichiometric ratio of 2 and 7 and 1.5 equiv. of base.
b Recovered starting materials.
c Yield determined by 1H NMR (equimolar mixture of diastereomers).
d Yield determined by 1H NMR (single Z isomer).
e Hu¨nig’s base: N,N-diisopropylethylamine.
f DMAP: 4(dimethylamino)pyridine.
g Proton-Sponge®: 1,8-bis(dimethylamino)naphthalene.
h Triton® B: benzyltrimethylammonium hydroxide (40 wt.% solution in MeOH); in that case the reaction was completed after 2 h at 20°C.

R. Jankowski et al. / Tetrahedron Letters 44 (2003) 4187–4190
4189
Figure 2. ORTEP view of (Z)-9 with labeled heteroatoms.
Thermal ellipsoids are scaled to 50% probability level. Hydro-
gen atom shown is drawn to an arbitrary scale.
Scheme 4.
pared with the unsubstituted parent ketone 2. However,
exposure of a stoichiometric mixture of 7 and 12 to
Triton® B in THF led to enone (Z)-1322 in 70% yield.
Upon irradiation of (Z)-13 with visible light, a photo-
stationary state was reached in which the (Z)-13/(E)-13
ratio is about 1:3 (Scheme 4).
In conclusion, our original objective was to develop a
new synthetic approach to Cinchona alkaloids based on
the C-8/C-9 disconnection strategy. The results thus far
obtained show that the addition of 3-quinuclidinone (2)
with aldehyde 7 proceeded smoothly when conducted in
DMSO in the presence of Hu¨nig’s base, producing the
desired aldols 8 with an excellent yield. Although our
initial purpose was found to be thwarted by the failure
of the aldol condensation between functionalized quin-
uclidinone 12 and aldehyde 7, the experience gained
during this study may have paved the way for an
eventual, hopefully highly successful, solution.
Scheme 3.
Another interesting outcome was obtained when a stoi-
chiometric mixture of 2 and 7 was pressurized at 1.1
GPa in THF at 50°C during 3 days: dimer 10 was
isolated in 40% yield, along with aldols 8 (60% yield).
Compound 10,21 a cream solid almost insoluble in usual
solvents, was assigned
a
molecular formula of
C34H36N4O4, established by elemental analysis and
mass spectroscopy (MALDI), corresponding to the
condensation of two molecules of aldols 8, and its
bis-hemiacetal structure (of unidentified stereochem-
istry) was deduced from its IR spectrum which revealed
the absence of CꢀO absorption. When stirred in
CD3OD at 65°C, dimer 10 progressively dissolved, a
process which, in fact, involved a cycloreversion of the
bis-hemiacetal core of the molecule, restoring an
equimolar epimeric mixture of progenitors 8. On the
other hand, treatment of 10 with Burgess’ inner salt17 in
benzene at 80°C gave an equimolar mixture of enones
(Z)-9 and (E)-9 (40% combined yield), together with
aldehyde 7 (40% yield), the latter issuing from a con-
comitant retro-aldol type cleavage of the transient
aldols 8 (Scheme 3).
Acknowledgements
Dr. O. Lapre´vote (ICSN, CNRS, Gif sur Yvette) is
gratefully acknowleged for his invaluable advice in
mass spectroscopy.
References
1. For a recent review, see: Kacprzak, K.; Gawron´ski, J.
Synthesis 2001, 961–998.
2. Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc.
Encouraged by our success with the synthesis of aldols
8, we have also investigated the condensation of func-
tionalized quinuclidinone (3R,4S)-12 (quinine number-
ing) (synthesized with a 80% de and a 90% ee through
asymmetric bridging annulation of enamino ester (S)-
11)11 with aldehyde 7. Unfortunately, all experiments
performed in DMSO in the presence of a tertiary amine
proved unsatisfactory, since returning invariably
unchanged starting materials, a failure which may be
attributed to the marked steric hindrance of 12, com-
1945, 67, 860–874.
3. Uskokovic´, M. R.; Henderson, T.; Reese, C.; Lee, H. L.;
Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100,
571–576.
4. Gates, M.; Sugavanan, B.; Schreiber, W. L. J. Am. Chem.
Soc. 1970, 92, 205–207.
5. Taylor, E. C.; Martin, S. F. J. Am. Chem. Soc. 1972, 94,
6218–6220.
6. Brown, R. T.; Curless, D. Tetrahedron Lett. 1986, 27,
6005–6008.

4190
R. Jankowski et al. / Tetrahedron Letters 44 (2003) 4187–4190
7. Wilson, S. R.; Di Grandi, M. J. J. Org. Chem. 1991, 56,
for 2-(quinolin-4-ylmethylene)-1-aza-bicyclo[2.2.2] octan-
3-one: Yellow crystal of 0.25×0.31×0.35 mm, C17H16N2O,
Mw=264.32; orthorhombic, space group Pbn21, Z=8,
4766–4772.
8. Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec,
J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001,
123, 3239–3242.
9. Bender, D. R.; Coffen, D. L. J. Org. Chem. 1968, 33,
2504–2509.
,
a=7.864(3), b=14.946(3), c=22.960(3) A, h=i=k=90°,
3
V=2698.7(12) A , dc=1.301 g cm−3, F(000)=1120, u=
,
0.710693 A (MoKa), v=0.082 mm−1; 3826 reflections
,
measured (05h510, 05k519, −305l5 30) on a Non-
ius CAD4 diffractometer. The structure was solved with
SIR9223 and refined with CRYSTALS 2000.24 Hydrogen
atoms riding. Refinement converged to R(gt)=0.0545 for
the 3636 observed reflections having I]3|(I), and
wR(gt)=0.0595, goodness-of-fit S=1.0893. Residual
10. Stotter, P. L.; Friedman, M. D.; Minter, D. E. J. Org.
Chem. 1985, 50, 29–31.
11. Da Silva Goes, A. J.; Cave´, C.; d’Angelo, J. Tetrahedron
Lett. 1998, 39, 1339–1340.
12. Alvarez, R.; Houdin, M.-A.; Cave´, C.; d’Angelo, J.;
Chaminade, P. Tetrahedron Lett. 1999, 40, 7091–7094.
13. In a preliminary experiment we have established that, in
complete analogy with aldehyde 3,10 aldehyde 7 proved
unsuitable in the condensation with enolate 5, revealing
its reduced electrophilicity.
14. For a crucial role of DMSO as a solvent in the uncata-
lyzed aldol addition of trimethylsilyl ketene acetals, see:
Ge´nisson, Y.; Gorrichon, L. Tetrahedron Lett. 2000, 41,
4881–4884.
electron density: −0.55 and 0.58 e A−3. Full crystallo-
,
graphic results have been deposited as Supplementary
Material (CIF file) at the Cambridge Crystallographic
Data Centre, UK (CCDC 205474).
19. Enone (E)-9: 1H NMR (400 MHz, CDCl3): l 8.90 (d,
J=4.4 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.12 (d, J=4.5
Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.69 (dt, J=8.1, 1.2
Hz, 1H), 7.54 (dt, J=7.9, 1.2 Hz, 1H), 7.19 (s, 1H), 3.23
(m, 4H), 2.57 (t, J=2.9 Hz, 1H), 2.02 (m, 4H); 13C NMR
(50 MHz, CDCl3): l 202.6 (CꢀO), 149.5 (CH), 148.3 (C),
148.0 (C), 147.6 (CH), 139.3 (C), 130.0 (CH), 127.5 (C),
126.5 (CH), 126.1 (C), 123.7 (CH), 121.0 (CH), 48.8
(2CH2), 41.7 (CH), 25.0 (2CH2).
15. However, Stotter pointed out that a facile subsequent
equilibration of aldol (erythro)-6 took place in the pres-
ence of a trace of DCl, producing an equimolar mixture
of erythro and threo isomers.10
16. Aldols 8 (1.2:1 mixture of diastereomers): White solid,
mp 145–152°C (Bu¨chi apparatus) 157–158°C (Kofler
bench); IR (neat, cm−1) w: 3300–2500, 1724. Major
diastereomer: 1H NMR (400 MHz, CDCl3): l 8.81 (d,
J=4.9 Hz, 1H), 8.09–7.96 (m, 2H), 7.68–7.56 (m, 2H),
7.54–7.45 (m, 1H), 5.83 (d, J=6.5 Hz, 1H), 4.84 (br. s,
OH), 3.58–3.46 (m, 2H), 3.00–2.70 (m, 3H), 2.49–2.42 (m,
1H), 2.25–2.13 (m, 1H), 2.03–1.81 (m, 3H); 13C NMR (50
MHz, CDCl3) l 217.9 (CꢀO), 150.0 (CH), 148.1 (C),
147.6 (C), 130.2 (CH), 128.8 (CH), 126.4 (CH), 125.7 (C),
122.8 (CH), 119.7 (CH), 72.9 (CH), 67.5 (CH), 49.4
(CH2), 43.3 (CH2), 40.3 (CH), 26.5 (CH2), 25.0 (CH2).
20. Equilibration of (Z)-4 into Z/E mixture under acidic
conditions was reported by Coffen. Furthermore, this
author established that (E)-4 slowly rearranged to (Z)-4
on standing.9
21. Dimer 10: Cream solid, mp 142–146°C (Bu¨chi apparatus)
192°C (Kofler bench) (note the amazing difference in mp,
ca. 50°C, between the ‘instantaneous’ mp determined by
sprinkling the substance on a hot bench, and the one
measured on a capillary tube apparatus, due to the rapid
rearrangement of 10 to 8 upon gradual heating); IR
(neat, cm−1): w 3300–2500; MS (MALDI, direct laser
desorption) m/z: 565 (M+1), 564 (M), 563 (M−1), 519
(M−CO2). Anal. calcd: C, 72.32; H, 6.43; N, 9.92. Found:
C, 71.80; H, 5.86; N, 9.35.
22. Enone (Z)-13 (9:1 mixture of diastereomers at C-3): IR
(neat, cm−1): w 1728 (br). Major diastereomer (3R): 1H
NMR (200 MHz, CDCl3): l 8.88 (d, J=4.7 Hz, 1H), 8.07
(m, 2H), 7.80–7.54 (m, 3H), 7.19 (s, 1H), 4.22 (q, J=7.0
Hz, 2H), 3.59 (s, 3H), 3.52–3.44 (m, 1H), 3.18–297 (m,
3H), 2.70–2.42 (m, 2H), 2.25–1.97 (m, 3H), 1.27 (t, J=7.0
Hz, 3H); 13C NMR (50 MHz, CDCl3): l 198.1 (CꢀO),
172.4 (O-CꢀO), 169.5 (O-CꢀO), 150.0 (CH), 148.5 (C),
146.8 (C), 137.2 (C), 134.2 (CH), 130.4 (CH), 129.4 (CH),
127.2 (CH), 126.9 (C), 123.2 (CH), 120.7 (CH), 61.4
(CH2), 55.4 (CH2), 55.1 (C), 51.7 (CH3), 47.5 (CH2), 38.5
(CH2), 36.4 (CH), 29.4 (CH2), 14.1 (CH3).
1
Minor diastereomer: H NMR (400 MHz, CDCl3, perti-
nent data): l 8.83 (d, J=4.9 Hz, 1H), 5.71 (d, J=4.6 Hz,
1H), 4.97 (br. s, OH), 3.40–3.30 (m, 1H); 13C NMR (50
MHz, CDCl3) l: 221.5 (C=O), 150.1 (CH), 148.0 (C),
147.3 (C), 130.2 (CH), 129.0 (CH), 126.7 (CH), 125.6 (C),
123.0 (CH), 118.6 (CH), 72.7 (CH), 70.5 (CH), 48.6
(CH2), 43.1 (CH2), 40.8 (CH), 27.1 (CH2), 24.5 (CH2).
17. Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org.
Chem. 1973, 38, 26–31.
18. Enone (Z)-9: Yellow crystals, mp 148°C (Bu¨chi appara-
tus) 155°C (Kofler bench); IR (neat, cm−1) w 1710; 1H
NMR (400 MHz, CDCl3): l 8.95 (d, J=4.5 Hz, 1H), 8.15
(d, J=7.8 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 8.12 (d,
J=4.5 Hz, 1H), 7.77 (s, 1H), 7.74 (dt, J=7.5, 1.2 Hz,
1H), 7.60 (dt, J=7.8, 1.1 Hz, 1H), 3.21 (dt, J=13.8, 7.8
Hz, 2H), 3.03 (dt, J=13.2, 7.6 Hz, 2H), 2.73 (t, J=2.7
Hz, 1H), 2.09 (dt, J=8.2, 2.7 Hz, 4H); 13C NMR (50
MHz, CDCl3): l 204.9 (C=O), 149.8 (CH), 148.3 (2C),
137.5 (C), 130.0 (CH), 129.0 (CH), 126.8 (CH), 126.7 (C),
123.1 (CH), 122.6 (CH), 118.7 (CH), 47.4 (2CH2), 39.9
(CH), 25.3 (2CH2). Anal. Calcd: C, 77.25; H, 6.10; N,
10.60. Found: C, 77.13; H, 6.19; N, 10.59. Crystal data
23. SIR92. A program for automatic solution of crystal
structures by direct methods Altomare, A.; Cascarano,
G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.;
Polidori, G.; Camalli, M. J. Appl. Cryst. 1994, 27, 435.
24. Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge,
P. W.; Cooper R. I. CRYSTALS Issue 11. Chemical
Crystallography Laboratory, Oxford, UK, 2001.