Stereocontrolled synthesis of quinine and quinidine

Article abstract of DOI:10.1016/j.tetlet.2004.03.085

Disubstituted cyclopentene was prepared from cyclopentene monoacetate and transferred into disubstituted piperidine via oxidative cleavage of the olefin moiety followed by piperidine ring formation. The piperidine was then condensed at the side chain with a quinoline part to afford the olefin precursor of quinine. Finally, the olefin was converted into quinine through the corresponding epoxide. Quinidine was synthesized in a similar way.

Full text of DOI:10.1016/j.tetlet.2004.03.085

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3783–3786
Stereocontrolled synthesis of quinine and quinidine
Junji Igarashi, Masahiro Katsukawa, Yong-Gang Wang, Hukum P. Acharya
and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
Received 12 February 2004; revised 10 March 2004; accepted 12 March 2004
Abstract—Disubstituted cyclopentene was prepared from cyclopentene monoacetate and transferred into disubstituted piperidine
via oxidative cleavage of the olefin moiety followed by piperidine ring formation. The piperidine was then condensed at the side
chain with a quinoline part to afford the olefin precursor of quinine. Finally, the olefin was converted into quinine through the
corresponding epoxide. Quinidine was synthesized in a similar way.
Ó 2004 Elsevier Ltd. All rights reserved.
Quinine and quinidine have been used as effective ther-
apeutic agents against malaria for over three centuries,
and, recently, other medicinal applications have been
reported for these alkaloids.1 On the other hand, the
unique structure of these alkaloids has attracted much
attention as chiral catalysts in asymmetric reactions.2
Usually structural modifications, when required, have
been performed at the hydroxyl and/or amino group
sites, providing moderate to high efficiencies in various
reactions. In cases where efficiency is not high, modifi-
cation of the structural backbone would be an alterna-
tive way of attaining higher efficiency. To execute
research work along this line, it is indispensable to
establish a flexible approach to these alkaloids.
The results of the previous investigation over 50 years
into the synthesis of these alkaloids are suggestive of
achieving successful total synthesis. These works are
briefly described in the first and stereoselective total
synthesis of quinine (1) published by Stork et al. in
2001,3 who prepared the 9-deoxy-quinine 3 in a stereo-
selective way through a 2,4,5-trisubstituted piperidine
(Fig. 1). Previously, Uskokovic and co-workers4 and
Gates et al.5 independently synthesized the deoxy-qui-
nine 3 and converted it into 1 by hydroxylation using O2
and t-BuOK with ꢀ5:1 stereoselectivity. This step was
modified by Stork (O2, NaH, DMSO) to afford 1 more
selectively (14:1). However, the synthesis seems hardly
applicable to quinidine synthesis because the method
developed is specialized for production of the key tri-
substituted piperidine. Quite recently, Jacobsen and
co-workers reported synthesis of 1 and 2.6 In his syn-
thesis, the 3,4-disubstituted piperidine, synthesized with
a 3:1 ratio regarding the cis/trans substitutions at C(3)
and C(4), was transformed, after condensation with the
quinoline part, into epoxide 4 (for 1) and the diaste-
reomeric epoxide (for 2), respectively, through the
Sharpless AD reaction, and each epoxide was converted
3
OMe
OMe
4
N
8
OH
N
OH
9
N
N
quinidine (2)
quinine (1)
OMe
OMe
N
O
4
3
N
NH
N
Keywords: Quinine; Quinidine; Piperidine; Cyclopentene-1,3-diol
monoacetate; Epoxide ring opening.
3
4
* Corresponding author. Tel./fax: +81-45-924-5789; e-mail: ykobayas@
bio.titech.ac.jp
Figure 1. The previous intermediates for synthesis of quinine (1).
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.085

3784
J. Igarashi et al. / Tetrahedron Letters 45 (2004) 3783–3786
into the target alkaloid. These epoxides were originally
synthesized and cyclized to these alkaloids by Uskoko-
vic and co-workers,4 though at that time the synthesis of
the epoxide was nonstereoselective.7 Herein, we report
stereoselective synthesis of a 3,4-disubstituted piperidine
and its conversion into 1 and 2.
philes as substituents on the piperidine ring can be in-
stalled on the cyclopentene ring by using reactions
developed by us14;15 and others.16 The strategy based on
these reactions is a synthetic advantage to execute the
study mentioned above. On the other hand, the previous
syntheses of the substituted piperidines seem to lack
such flexibility.
We have chosen epoxide 4 as the key intermediate of 1,
and envisioned a synthesis of 4 as illustrated in Scheme 1
from olefin 58 by using steps consisting of the Sharpless
et al. asymmetric dihydroxylation9 and subsequent
epoxide ring formation.10 On the other hand, we selected
piperidine aldehyde 6 and quinoline phosphonate 7 as
the parts of olefin 5. While a number of synthetic
methods of the 3,4-disubstituted piperidines of this type
(the acid is known as meroquinene) have been
reported,11;12 we investigated an alternative route start-
ing with acetate 813 because a variety of carbon nucleo-
Synthesis of the piperidine aldehyde 6 through key
cyclopentene 11 and its conversion into quinine (1) are
presented in Scheme 2. Monoacetate 8 (>95% ee) was
converted into methyl ester 9. High yield of 98% for
step a was attained by using the conditions recently
developed by us.17 Reduction of the ester and selective
protection of the primary hydroxyl group furnished 10
in 63% yield. Claisen rearrangement with vinyl ether and
Hg(OAc)2 as a catalyst at 190 °C afforded aldehyde,
which upon reduction with NaBH4 and subsequent
1
OHC
OMe
AcO
OH
1
NBz
8
6
(1R)-isomer
+
4
N
NBz
OMe
O
5
P(OEt)2
N
7
Scheme 1. Retrosynthesis of quinine (1).
Scheme 2. Synthesis of quinine (1): (a) CH2(CO2Me)2, t-BuOK, Pd(PPh3)4 (cat.); (b) KI, DMF, 125 °C; (c) LiAlH4; (d) TBDPSCl, imidazole; (e)
CH2@CHOEt, Hg(OAc)2 (cat.), 190 °C; (f) NaBH4; (g) t-BuCOCl, Et3N, CH2Cl2; (h) O3, n-PrOH, )78 °C, then NaBH4; (i) I2, PPh3, imidazole; (j)
BnNH2, dioxane; (k) ClCO2 Et, toluene; (l) NaOEt, EtOH; (m) o-(NO2)C6H4SeCN, PBu3, THF then 35% H2O2, THF; (n) MeLi, 0 °C; (o) BzCl; (p)
TBAF; (q) PCC; (r) 7, NaH, THF, rt; (s) AD-mix-b, 0 °C to rt; (t) MeC(OMe)3, PPTS (cat.), CH2Cl2, TMSCl, K2CO3, MeOH; (u) DIBAL-H,
toluene; (v) DMF, 160 °C.

J. Igarashi et al. / Tetrahedron Letters 45 (2004) 3783–3786
3785
protection of the resulting hydroxyl group as the piva-
loyl ester (Piv ¼ t-BuCO) produced the key cyclopen-
OMe
OH
tene 11 in good overall yield.
a
b
5
With the necessary substituents for piperidine aldehyde
6 being installed as masked forms, construction of the
piperidine ring was then studied. Ozonolysis of cyclo-
pentene 11 in n-PrOH18 at )78 °C followed by reductive
work-up with NaBH4 afforded alcohol 12, which was
converted into iodide 13 in 72% yield from 11. Nucleo-
philic amino cyclization of 13 with BnNH2 in dioxane at
100 °C produced the N-benzyl piperidine 14 quantita-
tively. The N-protection was changed to the ethoxy-
carbonyl group with ClCO2Et to produce the piperidine
carbamate 15 in good yield. Transformation of 15 with
EtONa in refluxing EtOH furnished the alcohol, which
was converted into olefin 16 by the Grieco et al. pro-
tocol.19 The overall yield of 16 from 13 was 75%. The
N-protective group (CO2Et) of 16 was altered to the
benzoyl group at this stage to produce the benzoyl
amine 17 in 61% yield.20;21 Finally, the TBDPS group
was removed with TBAF, and the resulting alcohol was
oxidized with PCC to the key aldehyde 6 in good yield.
N
OH
24
NBz
87%
88%
OMe
N
O
c,d
2
NBz
55%
25
Scheme 4. Synthesis of quinidine (2): (a) AD-mix-a, 0 °C to rt; (b)
MeC(OMe)3, PPTS (cat.), CH2Cl2, TMSCl, K2CO3, MeOH; (c) DI-
BAL-H, toluene; (d) DMF, 160 °C.
1
tical with that obtained from Sigma by H NMR spec-
troscopy and TLC analysis.
In a similar manner, olefin 5 was converted into the
corresponding diol 24 with AD-mix-a, and the same
transformation as described above furnished quinidine
(2) in good yield (Scheme 4).
Phosphonate 7 was synthesized from commercially
available 20 (Scheme 3). At the outset, 20 was converted
into quinoline 21 by the literature procedure.22 The
methyl group on the ring was then oxidatively trans-
formed into the hydroxymethyl group according to the
method of Unno et al. and Isobe.23 Remaining conver-
sion was accomplished under the conditions presented in
Scheme 3, furnishing the key quinoline 7 in 50% yield
from alcohol 22.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
Condensation of the key piperidine 6 with anion derived
from the quinoline 7 and NaH produced olefin 5 in 82%
yield (Scheme 2). Dihydroxylation of 5 with AD-mix-b
proceeded as usual and the resulting diol 18 was con-
verted into epoxide 1924 in 85% yield (two steps) by
using the protocol developed by Sharpless and
co-workers.10 Finally, the N-benzoyl group was
removed and the resulting 4 underwent cyclization with
the nitrogen atom in hot DMF to furnish quinine (1) in
66% yield from 19. Quinine thus synthesized was iden-
References and notes
1. (a) White, N. J.; Looareesuwan, S.; Warrell, D. A.;
Warrell, M. J.; Bunnag, D.; Harinasuta, T. Am. J. Med.
1982, 73, 564–572; (b) List, A. F. Leukemia 1996, 10, 937–
942; (c) Wilairatana, P.; Krudsood, S.; Treeprasertsuk, S.;
Chalermrut, K.; Looareesuwan, S. Arch. Med. Res. 2002,
33, 416–421.
2. Recent and selected reports: (a) Wynberg, H.; Staring, E.
G. J. J. Am. Chem. Soc. 1982, 104, 166–168; (b) Jacobsen,
E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968–
1970; (c) Amberg, W.; Bennani, Y. L.; Chadha, R. K.;
Crispino, G. A.; Davis, W. D.; Hartung, J.; Jeong, K.-S.;
Ogino, Y.; Shibata, T.; Sharpless, K. B. J. Org. Chem.
1993, 58, 844–849; (d) Becker, H.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 448–451; (e) Li, G.; Angert,
H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 2813–2817; (f) Lygo, B.; Wainwright, P. G. Tetrahe-
dron Lett. 1997, 38, 8595–8598; (g) Lygo, B.; Wainwright,
P. G. Tetrahedron Lett. 1998, 39, 1599–1602; (h) Iwabuchi,
Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219–10220; (i) Blake, A. J.;
Friend, C. L.; Outram, R. J.; Simpkins, N. S.; Whitehead,
A. J. Tetrahedron Lett. 2001, 42, 2877–2881; (j) Jew, S.-s.;
Yoo, M.-S.; Jeong, B.-S.; Park, Y., II; Park, H.-g. Org.
Lett. 2002, 4, 4245–4248; (k) Lambers, M.; Beijer, F. H.;
Padron, J. M.; Toth, I.; deVries, J. G. J. Org. Chem. 2002,
67, 5022–5024; (l) Rogers, L. M.-A.; Rouden, J.; Lecomte,
L.; Lasne, M.-C. Tetrahedron Lett. 2003, 44, 3047–3050;
(m) Jew, S.-s.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Lee,
Scheme 3. Synthesis of quinoline phosphonate 7: (a) H2SO4; (b)
POCl3; (c) Zn, AcOH; (d) m-CPBA, CH2Cl2, rt; (e) Ac2O, rt; (f)
K2CO3, MeOH; (g) SOCl2, CH2Cl2, reflux; (h) H–P(@O)(OEt)2,
n-BuLi, THF.

3786
J. Igarashi et al. / Tetrahedron Letters 45 (2004) 3783–3786
Y.-J.; Park, B.-s.; Kim, M. G.; Park, H.-g. J. Org. Chem.
2003, 68, 4514–4516, and references cited therein.
3. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.;
Balkovec, J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem.
Soc. 2001, 123, 3239–3242.
4. (a) Gutzwiller, J.; Uskokovic, M. J. Am. Chem. Soc. 1970,
92, 204–205; (b) Gutzwiller, J.; Uskokovic, M. R. J. Am.
Chem. Soc. 1978, 100, 576–581.
5. Gates, M.; Sugavanam, B.; Schreiber, W. L. J. Am. Chem.
Soc. 1970, 92, 205–207.
4832; (c) Matsuumi, M.; Ito, M.; Kobayashi, Y. Synlett
2002, 1508–1510; (d) Kobayashi, Y.; Murugesh, M. G.;
Nakano, M.; Takahisa, E.; Usmani, S. B.; Ainai, T.
J. Org. Chem. 2002, 67, 7110–7123; (e) Ainai, T.; Ito, M.;
Kobayashi, Y. Tetrahedron Lett. 2003, 44, 3983–3986;
(f) Ainai, T.; Matsuumi, M.; Kobayashi, Y. J. Org.
Chem. 2003, 68, 7825–7832; (g) Ainai, T.; Wang, Y.-G.;
Tokoro, Y.; Kobayashi, Y. J. Org. Chem. 2003, 68, 7825–
7832.
16. Deardorff, D. R.; Linde, R. G., II; Martin, A. M.;
Shulman, M. J. J. Org. Chem. 1989, 54, 2759–2762.
17. Acharya, H. P.; Kobayashi, Y. Tetrahedron Lett. 2004, 45,
1199–1202.
18. Ozonolysis in MeOH proceeded with somewhat lower
product selectivity.
19. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485–1486.
20. A model reaction of I(CH2)5I with BzNH2 and NaH
successfully afforded the piperidine benzoyl amide in 64%
yield. However, reaction of 13 with BzNH2 under similar
conditions was unsuccessful.
6. Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 706–707.
7. Similar quinuclidine formations from epoxides have been
reported: (a) Grethe, G.; Gutzwiller, J.; Lee, H. L.;
Uskokovic, M. R. Helv. Chim. Acta 1972, 55, 1044–1047;
(b) Gutzwiller, J.; Uskokovic, M. R. Helv. Chim. Acta
1973, 56, 1494–1503; (c) Taylor, E. C.; Martin, S. F.
J. Am. Chem. Soc. 1972, 94, 6218–6220; (d) Lygo, B.;
Crosby, J.; Lowdon, T.; Wainwright, P. G. Tetrahedron
1999, 55, 2795–2810.
8. Olefin 5 has been reported to afford a mixture of
9-deoxy-quinine 3 and the C(8)-epimer in ꢀ1:1 ratio: (a)
see Refs. 4a,5,7c; (b) Taylor, E. C.; Martin, S. F. J. Am.
Chem. Soc. 1974, 96, 8095–8102.
9. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa,
K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992,
57, 2768–2771; (b) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
10. Kolb, H.; Sharpless, K. B. Tetrahedron 1992, 48, 10515–
10530.
I
BzNH2
NaH
I
NBz
64%
DMF, 70 C
˚
.
21. An attempted conversion of the N-benzoyl piperidine
alcohol i, prepared from 13 by the sequence shown below,
into selenide ii was unsuccessful in our hand.
11. (a) Brown, R. T.; Leonard, J. J. Chem. Soc., Chem.
Commun. 1978, 725–726; (b) Hanessian, S.; Faucher,
ꢀ
A.-M.; Leger, S. Tetrahedron 1990, 46, 231–243; (c)
Danieli, B.; Lesma, G.; Mauro, M.; Palmisano, G.;
Passarella, D. Tetrahedron: Asymmetry 1990, 1, 793–800;
(d) Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;
Romagnoli, R.; Spalluto, G.; Zanirato, V. Tetrahedron
1994, 50, 2583–2590.
TBDPSO
ArSeCN
PBu3
OH
1) PMBNH2
2) BzCl
12. (a) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc.
1945, 67, 860–874; (b) Uskokovic, M.; Reese, C.; Lee, H.
L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1971, 93,
5902–5904; (c) Uskokovic, M.; Gutzwiller, J.; Henderson,
T. J. Am. Chem. Soc. 1970, 92, 203–204; (d) Grethe, G.;
Lee, H. L.; Mitt, T.; Uskokovic, M. R. Helv. Chim. Acta
1973, 56, 1485–1494; (e) Augustine, R.; Koletar, G. Synth.
Commun. 1974, 4, 161–165; (f) Uskokovic, M. R.; Hen-
derson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller,
J. J. Am. Chem. Soc. 1978, 100, 571–576; (g) Takano, S.;
Takahashi, M.; Hatakeyama, S.; Ogasawara, K. J. Chem.
Soc., Chem. Commun. 1979, 556–557; (h) Imanishi, T.;
Inoue, M.; Wada, Y.; Hanaoka, M. Chem. Pharm. Bull.
1982, 30, 1925–1928; (i) Funk, R. L.; Munger, J. D., Jr.
J. Org. Chem. 1984, 49, 4319–4322; (j) Yoo, S.-e.; Yi, K.
Y.; Lee, S.-H.; Jeong, N. Synlett 1990, 575–576.
13
NBz
3) t-BuOK, H2O
i
TBDPSO
SeAr
16
NBz
ii
.
22. Campbell, K. N.; Tipson, R. S.; Elderfield, R. C.;
Campbell, B. K.; Clapp, M. A.; Gensler, W. J.; Morrison,
D.; Moran, W. J. J. Org. Chem. 1946, 11, 803–811.
23. Unno, R.; Michishita, H.; Inagaki, H.; Suzuki, Y.; Baba,
Y.; Jomori, T.; Moku, M.; Nishikawa, T.; Isobe, M.
Bioorg. Med. Chem. 1997, 5, 903–919.
13. (a) Sugai, T.; Mori, K. Synthesis 1988, 19–22; (b) Laumen,
K.; Schneider, M. P. J. Chem. Soc., Chem. Commun. 1986,
1298–1299.
14. Reviews: (a) Kobayashi, Y. Curr. Org. Chem. 2003, 7, 133–
147; (b) Kobayashi, Y. Trends Org. Chem. 1998, 7, 27–43.
15. (a) Ito, M.; Matsuumi, M.; Murugesh, M. G.; Kobayashi,
Y. J. Org. Chem. 2001, 66, 5881–5889; (b) Kobayashi, Y.;
Ito, M.; Igarashi, J. Tetrahedron Lett. 2002, 43, 4829–
24. Characteristic 1H NMR signals (300 MHz, CDCl3) for
epoxide 19 and its diastereomer synthesized through
oxidation with AD-mix-a are d 4.15 (d, J ¼ 1:8 Hz)
and 4.17 (d, J ¼ 1:8 Hz), respectively, for proton at
C(9).