Positional isomerization of quinine and quinidine via rhodium on alumina catalysis: Practical one-step synthesis of Δ3,10-isoquinine and Δ3,10-isoquinidine

Article abstract of DOI:10.1016/S0040-4039(03)01180-8

The synthesis of Δ^3,10-isoquinine (5Z,5E) and Δ^3,10-isoquinidine (6Z,6E) was achieved in one-step through positional isomerization of the terminal alkene in the parent cinchona alkaloids using catalytic amounts of 5% Rh/Al₂O₃ and excess hydrochloric acid in refluxing 50% aqueous EtOH. The products were obtained in good yields as a mixture of E and Z geometric isomers and fully characterized using spectroscopic methods.

Full text of DOI:10.1016/S0040-4039(03)01180-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5365–5368
Positional isomerization of quinine and quinidine via rhodium on
alumina catalysis: practical one-step synthesis of D3,10-isoquinine
and D3,10-isoquinidine
David E. Portlock,a,* Dinabandhu Naskar,b Laura West,a William L. Seibel,a Titan Gu,a
Howard J. Krauss,a X. Sean Peng,a Paul M. Dybas,a Edward G. Soyke,a Stephen B. Ashtona
and Jonathan Burtona
aCombinatorial Chemistry Section, Procter & Gamble Pharmaceuticals, Health Care Research Center,
8700 Mason Montgomery Road, Mason, OH 45040, USA
bChembiotek Research International, Block BN, Sector-V, Salt Lake City, Calcutta 700 091, India
Received 14 April 2003; revised 8 May 2003; accepted 8 May 2003
Abstract—The synthesis of D3,10-isoquinine (5Z,5E) and D3,10-isoquinidine (6Z,6E) was achieved in one-step through positional
isomerization of the terminal alkene in the parent cinchona alkaloids using catalytic amounts of 5% Rh/Al2O3 and excess
hydrochloric acid in refluxing 50% aqueous EtOH. The products were obtained in good yields as a mixture of E and Z geometric
isomers and fully characterized using spectroscopic methods. © 2003 Elsevier Science Ltd. All rights reserved.
Since quinine (1) has historically been prescribed for the
treatment of malaria,1 there has been substantial inter-
est in the isolation, structural characterization, synthe-
sis, and biological profiles of its human metabolites.2
This is also the case for quinidine (3), which has found
clinical utility for many years in the treatment of atrial
fibrillation.3,4 Within this context we wished to develop
a concise synthetic method for the preparation of the
positional isomers of quinine and quinidine, i.e. D3,10
-
isoquinine (5Z,5E)5 and D3,10-isoquinidine (6Z,6E),6 for
their utility as key synthetic intermediates. In this
regard, Carroll and co-workers have elaborated
(6Z,6E) into an important (pharmacologically active)
human metabolite of quinidine.4a,7 Furthermore, much
attention has been drawn to quinine (1), cinchonine (2),
quinidine (3), and cinchonidine (4) analogues for their
useful properties as chiral ligands in the catalytic asym-
metric dihydroxylation8 and aminohydroxylation9 of
olefins, as well as the enantioselective phase transfer
catalyzed alkylation of enolates,10 epoxidation of a,b-
unsaturated ketones,11 and the asymmetric Michael
reaction.12 Therefore, mild synthetic methods which are
effective in modifying these alkaloids are of consider-
able interest for the rational and combinatorial design
of new catalysts.
Although
D
3,10-isoquinine (5Z,5E) and
D
3,10-iso-
quinidine (6Z,6E) have been isolated from a complex
mixture of products formed in the reaction of the
parent alkaloids with boiling concentrated sulfuric acid,
the yields are low and the method is impractical for
synthesis.13 To our knowledge there have not been any
other reported methods for the synthesis of (5Z,5E)
and there is only one synthetically feasible method for
the conversion of quinidine (3) to D3,10-isoquinidine
(6Z,6E). This was developed by Carroll et. al. in
19764a,7 and subsequently improved by Hoffmann et. al.
in 1996.14a This four-step sequence employs the regio-
selective addition of fuming 62% HBr (ca. 6 equiv.) to
the terminal side-chain double bond in 3, followed by
acetylation of the secondary alcohol, elimination of
HBr with DBU, and finally deacetylation to give a
mixture of 6Z and 6E in moderate to good overall
* Corresponding author. Present address: Wright State University,
Department of Chemistry, Dayton, OH 45435, USA. E-mail:
portlockde@aol.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01180-8

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D. E. Portlock et al. / Tetrahedron Letters 44 (2003) 5365–5368
Table 1. Extent of double bond isomerization in quinine by various catalysts
Entry
Catalyst
Reaction times (2 h)
Reaction times (24 h)
% Quinine
% 5Z
% 5E
% Quinine
% 5Z
% 5E
1
2
3
4
5% Pd/C
90
90
79
60
8
8
18
24
2
2
3
81
85
0
14
11
72
72
5
4
28
28
5% Pd/Al2O3
5% Rh/Al2O3
5% Rh/C
16
0
yield. Although this reaction sequence has found exten-
sive application for small scale laboratory work,14 for
our purposes we sought to develop a one-step catalytic
process for the isomerization of both quinine (1) and
quinidine (3).
position. The observations of Cheung et. al.15 are con-
sistent with this expectation, but it was not clear a
priori whether this approach could be used for practical
synthetic application with an inexpensive hydrogenation
catalyst such as 5% Pd–C. For example, it is well
documented that multi heteroatom (basic) substrates
can coordinate to commercial Pd/C and poison the
catalytic activity.20 We have now observed in our labo-
ratory (as predicated by the results of Cheung et. al.15)
that when quinine is solubilized in 50% aqueous etha-
nol with 10 equiv. of hydrochloric acid, treated with 5%
Pd–C catalyst (5% by weight) under an atmosphere of
argon, and then heated to 90°C for 24 h, that it is
slowly but incompletely converted (Table 1, entry 1) to
two new products (as detected by HPLC).21 Preparative
separation of the reaction components followed by
structural characterization revealed that peak one is 5Z
and peak two is 5E.22 Modifying reaction conditions to
include a different catalytic support (i.e. 5% Pd–Al2O3),
did not significantly improve these results (Table 1,
entry 2). Although no efforts were made to drive the
isomerization to completion by longer reaction times,
increased temperature, or variation of solvent, we did
explore additional catalysts. Remarkably, when quinine
was treated with 5% Rh/Al2O3 or 5% Rh/C (5% by
weight), complete conversion to 5Z and 5E was
observed during a 24 h period (Table 1, entries 3 and
4). The reaction was readily performed on a larger scale
(10 g) providing a 95% yield of a mixture of 5Z/5E.
Very similar results were obtained for the isomerization
of quinidine (3) to a mixture of 6Z and 6E.23
In 1968 Cheung et. al.15 observed the presence of two
impurities in dihydroquinine, which were formed dur-
ing the commercial hydrogenation of quinine with Pd–
C in ethanol (2–7% yield). Careful isolation using
1
preparative TLC and structural characterization by H
NMR spectroscopy, demonstrated that these contami-
nants were 5Z and 5E.15 Apparently, they were formed
as a result of double bond migration via transition
metal catalysis and were resistant to subsequent hydro-
genation under these reaction conditions. Based on this
literature precedent we wondered if quinine and
quinidine could be preparatively converted to 5Z,5E
and 6Z,6E in one synthetic step through the positional
isomerization of the terminal alkene in the parent alka-
loids using Pd–C or some other heterogeneous or
homogeneous catalyst. In this paper we describe the
results of these studies. Furthermore, we have qualita-
tively compared Pd versus Rh supported on both alu-
mina and activated carbon for catalytic efficiency.
In summary, we have developed a mild and efficient
one-step preparative procedure to convert quinine and
quinidine to their D3,10 positional isomers.24 This
method should provide ready access to these useful
synthetic intermediates.5–12
Transition metal reagents have been used extensively to
catalyze the positional isomerization of carbonꢀcarbon
double bonds.16,17 Practical synthetic applications have
most frequently been realized with Wilkinson’s
catalyst17,18 and RhCl3 hydrate.19 This isomerization
approach is predicated empirically upon the preference
for a double bond to migrate into conjugation and/or
to a more highly alkyl substituted position. In this
regard, the conversion of quinine (1) and quinidine (3)
to D3,10-isoquinine (5Z/5E) and D3,10-isoquinidine (6Z/
6E), respectively, should be favored thermodynamically
(Saytzev’s Rule), since a terminal mono-substituted
double bond is isomerizing to an internal tri-substituted
References
1. For leading references related to clinical applications of
quinine, see: Tracy, J. W.; Webster, L. T., Jr. In Goodman
& Gilman’s The Pharmacological Basis of Therapeutics,
9th ed.; Hardman, J. G.; Limbird, L. E.; Molinoff, P. B.;
Ruddon, R. W.; Gilman, A. G., Eds.; McGraw-Hill: New
York, 1996; Chapter 40, pp. 978–981.
2. For examples of work related to metabolites of quinine,
see: (a) Bannon, P.; Yu, P.; Cook, J. M.; Roy, L.;
Villeneuve, J.-P. J. Chromat. B.: Biomed. Sci. Applications
1998, 715, 387; (b) Wanmimolruk, S.; Wong, S.-M.;

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Zhang, H.; Coville, P. F.; Walker, R. J. J. Pharmacy
Pharm. 1995, 47, 957.
Organotransition Metal Chemistry: Applications to
Organic Synthesis; Pergamon Press: Oxford, 1982; Chap-
ter 7.
3. For leading references related to clinical applications of
quinidine, see: Roden, D. M. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 9th ed.; Hardman,
J. G.; Limbird, L. E.; Molinoff, P. B.; Ruddon, R. W.;
Gilman, A. G., Eds.; McGraw-Hill: New York, 1996;
Chapter 35, pp. 869–871.
17. (a) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16,
3775; (b) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973,
38, 3224.
18. Birch, A. J.; Subba Rao, G. S. R. Tetrahedron Lett. 1968,
9, 3797.
4. For examples of work related to metabolites of quinidine,
see: (a) Carroll, F. I.; Abraham, P.; Gaetano, K.; Mas-
carella, S. W.; Wohl, R. A.; Lind, L.; Petzoldt, K. J.
Chem. Soc., Perkin Trans. 1 1991, 3017; (b) Guengerich,
F. P.; Muller-Enoch, D.; Blair, I. A. Mol. Pharm. 1986,
30, 287 and references cited therein.
19. (a) Calabi, L.; Danieli, B.; Lesma, G.; Palmisano, G.
Tetrahedron Lett. 1982, 23, 2139; (b) Andrieux, J.; Bar-
ton, D. H. R.; Patin, H. J. Chem. Soc., Perkin 1 1977,
359; (c) Grieco, P. A.; Nishizawa, M.; Marinovic, N.;
Ehmann, W. J. J. Am. Chem. Soc. 1976, 98, 7102; (d)
Bertele, E.; Schudel, P. Helv. Chim. Acta 1967, 50, 2445;
(e) Harrod, J. F.; Chalk, A. J. J. Am. Chem. Soc. 1964,
86, 1776.
20. For leading references, see: (a) Sajiki, H.; Hattori, K.;
Hirota, H. J. Org. Chem. 1998, 63, 7990; (b) Hattori, K.;
Sajiki, H.; Hirota, K. Tetrahedron Lett. 2000, 41, 5711;
(c) Ulan, J. G.; Maier, W. F.; Smith, D. A. J. Org. Chem.
1987, 52, 3132.
21. HPLC analyses were performed on a Waters (Milford,
MA, USA) Alliance HPLC/PDA chromatography system
equipped with a 996 photodiode array UV detector and a
2690 separations module controlled by the Waters Mil-
lennium 2020 data system. All peaks were detected at a
wavelength of 250 nm. For analytical HPLC of the
quinine reaction, a 10 mL sample (1 mg/mL concentration
in MeOH) was injected on a Chiralcel OJ-R (150×4.6
mm, 5 mm) column and the two isomers were separated at
ambient temperature by an isocratic elution with a
mobile phase consisting of MeOH:H2O:HCO2-
H:Et3N:THF (3/95/0.2/0.2/2, v/v/v/v/v). At a flow rate of
1 mL/min, quinine was eluted at 11.0 min, the Z isomer
at 16.5 min, and the E isomer at 17.8 min.
5. (a) (E)-D3,10-Isoquinine (5E) and a-isoquinine are syn-
onyms for (3E,8a,9R)-3,10-didehydro-10,11-dihydro-6%-
methoxy-cinchonan-9-ol (Chemical Abstracts 9CI,
registry number: 16934-08-0); (b) (Z)-D3,10-Isoquinine
(5Z) and b-isoquinine are synonyms for (3Z,8a,9R)-3,10-
didehydro - 10,11 - dihydro - 6% - methoxy - cinchonan - 9 - ol
(Chemical Abstracts 9CI, registry number: 16934-07-9).
6. D3,10-Isoquinidine (6Z,6E) and apoquinidine methyl ether
are synonyms for (9S)-3,10-didehydro-10,11-dihydro-6%-
methoxy-cinchonan-9-ol (Chemical Abstracts 9CI, reg-
istry number: 139237-97-1). The separated 6Z geometric
isomer has also been reported (registry number: 60801-
73-2).
7. Carroll, F. I.; Philip, A.; Coleman, M. C. Tetrahedron
Lett. 1976, 17, 1757.
8. (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483; (b) Becker, H.; Sharpless, K.
B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448.
9. Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1483 and references cited
therein.
10. (a) Corey, E. J.; Bo, Y.; Busch-Peterson, J. J. Am. Chem.
Soc. 1998, 120, 13000; (b) Lygo, B. J. Am. Chem. Soc.
1999, 40, 1389.
22. Milligram samples of pure 5Z and 5E were isolated with
difficulty using a preparative scale chiral stationary phase
HPLC column as described for the analytical method.21
NMR spectra were taken on a Bruker Avance DRX 600
spectrometer at room temperature. Chemical shift values
are reported relative to tetramethylsilane (TMS) as the
external standard. One-dimensional 1H NOE difference,
11. Lygo, B.; Wainwright, G. P. Tetrahedron Lett. 1998, 39,
1599.
12. Alvarez, R.; Hourdin, M.-A.; Cave, C.; d’Angelo, J.;
Chaminade, P. Tetrahedron Lett. 1999, 40, 7091.
13. Henry, T. A.; Solomon, W.; Gibbs, E. M. J. Chem. Soc.
1937, 592. As reviewed in: Turner, R. B.; Woodward, R.
B. In The Alkaloids; Manske, R. H. F.; Holmes, H. L.,
Eds.; Academic Press: New York, 1953; Vol. 3, pp.
20–21.
14. (a) von Riesen, C.; Jones, P. G.; Hoffmann, H. M. R.
Chem. Eur. J. 1996, 2, 673; (b) von Riesen, C.; Hoff-
mann, H. M. R. Chem. Eur. J. 1996, 2, 680; (c) Langer,
P.; Hoffmann, H. M. R. Tetrahedron 1997, 53, 9145; (d)
Frackenpohl, J.; Langer, P.; Hoffmann, H. M. R. Helv.
Chim. Acta 1998, 81, 1429; (e) Braje, W.; Frackenpohl, J.;
Langer, P.; Hoffmann, H. M. R. Tetrahedron 1998, 54,
3495; (f) Langer, P.; Frackenpohl, J.; Hoffmann, H. M.
R. J. Chem. Soc., Perkin 1 1998, 801.
1
1
two-dimensional H COSY and NOESY, as well as H–
13C HMQC experiments were performed to assign proton
and carbon resonances. (Z)-D3,10-Isoquinine (5Z): 1H
NMR (600 MHz, CDCl3): l 1.21 (m, H7a, 1H), 1.48 (d,
J=7 Hz, H11, 3H), 1.87 (m, H5a, 1H), 2.24 (m, H5b,
1H), 2.31 (m, H7b, 1H), 2.59 (m, H4, 1H), 3.20 (m, H6a,
1H), 3.37 (m, H8, 1H), 3.82 (s, H11%, 3H), 3.86 (m, H2,
2H), 4.58 (m, H6b, 1H), 5.40 (m, J=7 Hz, H10, 1H), 6.43
(s, H9, 1H), 6.84 (d, J=2 Hz, H5%, 1H), 7.04 (dd, J=2, 9
Hz, H7%, 1H), 7.67 (d, J=4 Hz, H3%, 1H), 7.74 (d, J=9
Hz, H8%, 1H), 8.60 (broad s, H12, 1H), 8.71 (s, H2%, 1H).
Important NOE: H-10 with H-4 (strong), H-2 with H-11
(strong), and no NOE observed between H-2 and H-10.
13C NMR (150 MHz, CDCl3): l 13.3 (1°, C-11), 24.6 (2°,
C-7), 25.5 (2°, C-5), 32.7 (3°, C-4), 45.9 (2°, C-6), 56.8 (2°,
C-2), 57.5 (1°, C-11%), 62.7 (3°, C-8), 68.1 (3°, C-9), 99.0
(3°, C-5%), 118.5 (3°, C-3%), 120.0 (3°, C-10), 122.2 (3°,
C-7%), 131.8 (3°, C-8%), 147.6 (3°, C-2%).
15. Cheung, A. P.; Benitez, A.; Lim, P. J. Org. Chem. 1968,
33, 3005.
16. For reviews, see: (a) Crabtree, R. H. The Organometallic
Chemistry of the Transition Metals; John Wiley & Sons:
New York, 1988; p. 188; (b) Yamamoto, A. Organotran-
sition Metal Chemistry: Fundamental Concepts and Appli-
cations; Wiley: New York, 1986; p. 372; (c) Davies, S. G.
1
(E)-D3,10-Isoquinine (5E). H NMR (600 MHz, CDCl3): l
1.16 (m, H7a, 1H), 1.54 (d, J=7 Hz, H11, 3H), 1.83 (m,

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D. E. Portlock et al. / Tetrahedron Letters 44 (2003) 5365–5368
H5a, 1H), 2.24 (m, H5b, 1H), 2.33 (m, H7b, 1H), 2.97 (m,
an atmosphere of argon. Aliquot samples were removed
periodically and syringe filtered through a disposable
LC13 PVDF Acrodisc (pore size 0.45 mm filter, diameter
13 mm) to remove catalyst prior to HPLC analysis. The
reaction was monitored by analytical HPLC.21,23 (b)
Preparative scale: A stirred mixture of quinine dihy-
drochloride or quinidine dihydrochloride salt (10.0 g,
25.2 mmol) and 5% rhodium/Al2O3 catalyst (500 mg) in
50% aqueous ethanol (500 mL) was refluxed under an
atmosphere of nitrogen. In a typical experiment isomer-
ization was shown by HPLC to be complete after 24 h.
At this time the reaction mixture was cooled, the catalyst
filtered through Celite, and the filtrate evaporated to a
residue, which was dissolved in water (250 mL). The pH
was adjusted to 9 with conc. NH4OH and the resulting
white precipitate washed well with water and dried to a
constant weight in a vacuum desiccator. Purification of
this crude product isomer mixture by preparative HPLC
eluting with THF gave a mixture of the E and Z isomers
as a white solid in both cases (7.8 g, 95%). Final purifica-
tion to the pure individual E or Z isomers can be
H4, 1H), 3.23 (m, H6a, 1H), 3.34 (m, H8, 1H), 3.64 (s,
H11%, 3H), 3.82 (m, H2, 2H), 4.60 (m, H6b, 1H), 5.30 (m,
J=7 Hz, H10, 1H), 6.42 (s, H9, 1H), 6.85 (d, J=2 Hz,
H5%, 1H), 7.04 (dd, J=2, 9 Hz, H7%, 1H), 7.67 (d, J=4
Hz, H3%, 1H), 7.75 (d, J=9 Hz, H8%, 1H), 8.60 (broad s,
H12, 1H), 8.71 (d, J=4 Hz, H2%, 1H). Important NOE:
H-11 with H-4 (strong), H-10 with H-2 (strong). 13C
NMR (150 MHz, CDCl3): l 13.4 (1°, C-11), 23.5 (2°,
C-7), 24.3 (2°, C-5), 25.3 (3°, C-4), 44.7 (2°, C-6), 56.4 (1°,
C-11%), 57.5 (2°, C-2), 61.1 (3°, C-8), 66.9 (3°, C-9), 100.5
(3°, C-5%), 119.2 (3°, C-3%), 120.9 (3°, C-10), 122.7 (3°,
C-7%), 132.0 (3°, C-8%), 147.9 (3°, C-2%).
23. For analytical HPLC of the quinidine reaction, a 10 mL
sample (1 mg/mL concentration in MeOH) was injected
on a Waters Symmetry Shield RP 18 (3.9×150 mm, 5 mm)
column and the two isomers were separated at ambient
temperature by an isocratic elution with a mobile phase
consisting of CH3CN:H2O:HCO2H:Et3N (5/95/0.2/0.2, v/
v/v/v). At a flow rate of 1 mL/min, quinidine was eluted
at 22.2 min, the Z isomer at 21.0 min, and the E isomer
at 24.0 min. For preparative HPLC of the quinidine
isomerization mixture, 100 mL of sample (50 mg/mL in
MeOH) was injected on a Waters Symmetry Prep C18
(7.8×300 mm, 7 mm) column with a flow rate of 6
mL/min. Using 5% Rh/Al2O3, the result obtained at 2 h
for the isomerization of quinidine (3) to a mixture of 6Z
and 6E were 49, 17 and 34%, respectively, while after 24
h, 0% quinidine (3), 36% 6Z and 64% 6E were obtained.
24. Representative procedure for double bond isomerization:
(a) analytical scale: A magnetically stirred mixture of
quinine or quinidine free base (1.0 g, 3.08 mmol, 1.0
equiv.), 50% aqueous EtOH (50 mL), concentrated (37%,
12N) HCl (2.56 mL, 30.8 mmol, 10.0 equiv.), and the
catalyst (50 mg) was heated with an oil bath (90°) under
achieved with difficulty as described.22,23
D
3,10-Isoquinine
(5Z/5E mixture): CHN calcd for C20H24N2O2: C, 74.05;
H, 7.46; N, 8.63; Found: C, 73.85; H, 7.49; N, 8.53; MS
(EI): 324 (M+); NMR data.22
D
3,10-isoquinidine (6Z/6E
1
mixture): H NMR (MeOH-d4): l 1.57 (m, 1H), 1.67 (d,
J=7 Hz, 3H), 1.92 (m, 1H), 1.98 (m, 2H), 2.40 (m, 1H),
2.70 (s, 1H), 3.10–3.63 (m, 3H), 3.96 (m, 1H), 4.12 (m,
3H), 5.02 (m, 1H), 5.58 (m, 1H), 6.30 (s, 1H), 7.63 (d,
1H), 7.74 (dd, 1H), 8.11 (d, 1H), 8.16 (d, 1H), 8.94 (d,
1H). 13C NMR (MeOH-d4): 13.1, 24.2, 25.0, 33.3, 50.3,
51.9, 53.6, 57.5, 68.9, 103.2, 119.6, 121.4, 127.5, 128.8,
132.2, 133.1, 139.3, 144.8, 153.9, 163.3; HRMS:
325.191911 [calcd for C20H24N2O2 325.191603 (M+H)+].