Improved synthesis of quinine alkaloids with the Teoc protective group

Article abstract of DOI:10.1016/j.tetlet.2005.06.171

TeocCl (Teoc: C(O)O(CH₂)₂TMS) generated in situ was conveniently used for trans-protection of the N-Bn piperidine intermediate to N-Teoc piperidine. Later, deprotection of the Teoc group and the subsequent quinuclidine ring formation was achieved with CsF in a domino fashion to afford the quinine alkaloids.

Full text of DOI:10.1016/j.tetlet.2005.06.171

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6381–6384
Improved synthesis of quinine alkaloids with the Teoc
protective group
Junji Igarashi and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259,
Midori-ku, Yokohama 226-8501, Japan
Received 12 May 2005; revised 23 June 2005; accepted 30 June 2005
Abstract—TeocCl (Teoc: C(@O)O(CH2)2TMS) generated in situ was conveniently used for trans-protection of the N-Bn piperidine
intermediate to N-Teoc piperidine. Later, deprotection of the Teoc group and the subsequent quinuclidine ring formation was
achieved with CsF in a domino fashion to afford the quinine alkaloids.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently, we have established a synthesis of the quinine
alkaloids (1 and 2 in Fig. 1).1 The synthesis features (1)
stereo- and regioselective installation of the two substitu-
ents on the cyclopentene ring of readily available 3 fol-
lowed by transformation of the cyclopentene into
piperidine 4; (2) assembly of the full carbon structure
from the piperidine aldehyde derived from 4 and the
quinoline phosphonate; and (3) construction of the
quinuclidine ring through an intramolecular epoxide
ring opening by the piperidine nitrogen (Scheme 1).
The high stereoselectivity thus achieved for the first time
allows a secure access to analogues as well, and is advan-
tageous over the recent syntheses of these alkaloids.2
However, two trans-protections of the nitrogen in the
piperidine ring, that is, N-Bn to N-CO2Et and N-CO2Et
to N-COPh at the later stage, make the sequence some-
what lengthy.
PivO
AcO
OH
TBDPSO
N
R
3
4, R = Bn
OMe
OMe
O
*
*
N
N
N
N
R
R
5a, R = CO2Et
5b, R = Teoc
β-epoxide
6a, R = COPh
6b, R = Teoc
α-epoxide 7a, R = COPh
7b, R = Teoc
6, β-epoxide
7, α-epoxide
1 from 6
2 from 7
N-protective group (R):
previous: Bn in 4 → CO2Et → COPh
present: Bn in 4 → CO2(CH2)2TMS (Teoc)
OMe
OMe
Scheme 1. Protective groups of the piperidine nitrogen used previously
(Bn, CO2Et, COPh) and presently (Bn, Teoc) in the synthesis of
quinine and quinidine.
N
HO
N
OH
N
N
quinine (1)
quinidine (2)
To achieve the synthesis in a shorter way, we chose the
Teoc group (CO2(CH2)2TMS) as a new protective group
from those formulated as CO2R3 based on the fact that
the N-Teoc group had been removed under mild condi-
tions.4–6 However, isolation of Teoc-Cl (8) is operation-
ally intricate due to its thermal instability.7,8 Moreover,
the separation of the amine residue(s)9 derived from
Figure 1. The structures of quinine and quinidine.
Keywords: Teoc; Protective group; Nitrogen atom; CsF; Quinine;
Quinidine.
*
Corresponding author. Tel./fax: +81 45 924 5789; e-mail:
ykobayas@bio.titech.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.171

6382
J. Igarashi, Y. Kobayashi / Tetrahedron Letters 46 (2005) 6381–6384
Table 1. Trans-protection of piperidine 9 into 10 with TeocCl (8)
Bu4NF used for deprotection of the N-Teoc group re-
mained unsolved. Herein, we present a convenient pro-
cedure for trans-protection of N-Bn to N-Teoc and
clean deprotection of the N-Teoc group under new con-
ditions. By using these findings, synthesis of the quinine
alkaloids was substantially revised.
prepared in situa
Entry
Base
Equiv
Solvent
Yield of 10 (%)
1
2
3
4
5
6
C5H5N
NaH
K2CO3
K2CO3
K2CO3
K2CO3
3
3
3
10
3
10
THF
THF
THF
THF
Toluene
Toluene
0b
45b
85b
98
90
99
Since the isolation of pure 8 is technically intricate, tri-
phosgene10 and TMS(CH2)2OH was mixed in a 1:3
molar ratio in the presence of a base at room tempera-
ture for 1 h in THF, and 8 thus prepared was used for
trans-protection of the model N-Bn piperidine 9 at room
temperature overnight (Scheme 2 and Table 1). First, 8
generated with pyridine was used for the trans-protec-
tion (entry 1). However, the HCl salt of 9 was formed
probably as a consequence of decomposition of the
reagent 8 under the conditions applied. Next examined
were n-BuLi, NaH, and K2CO3. The latter two bases
afforded the desired product 10 and the HCl salt of 9
(entries 2 and 3). To quench HCl effectively, excess
K2CO3 was used to improve the result substantially
(entry 4). The K2CO3 version was repeated in toluene,
a The reaction was carried out for 12–14 h at rt with TeocCl (8, 3 equiv
in theory), which was prepared in situ from triphosgene (1 equiv) and
TMS(CH2)2OH (3 equiv) with a base specified.
b The HCl salt of 9 was produced.
which produced slightly better results than those in
THF (entries 5 and 6 vs entries 3 and 4).
The best conditions found above (entry 6)11 were ap-
plied to the real 3,4-disubstituted-N-Bn-piperidine 4 to
produce 11 in 92% yield, which was transformed into
aldehyde 14 in good yield (Scheme 3). Wittig-type reac-
tion of 14 with the anion derived from the quinoline
phosphonate and NaH furnished olefin 5b exclusively.12
Dihydroxylation of olefin 5b with AD-mix-b proceeded
at room temperature to obtain diol 15 in 72% yield,12
which was converted into trans epoxide 6b in 86% yield.
In a similar way, diastereomeric epoxide 7b was synthe-
sized from olefin 5b through dihydroxylation with AD-
mix-a.12 During the transformation, the Teoc group
was proven to be stable under acidic, basic, and
oxidative conditions. Particularly, noteworthy is the
compatibility with NaOEt in refluxing EtOH used for
TMS(CH2)2OH
(Cl3CO)2C(=O)
base
ClCO2(CH2)2TMS (8)
N
N
Teoc
Bn
THF or toluene
10
9
Scheme 2. Trans-protection of the N-benzyl piperidine by Teoc-Cl.
PivO
RO
1) 3% HCl
MeOH
o-NO2C6H4SeCN
PBu3
Teoc-Cl
TBDPSO
N
TBDPSO
N
TBDPSO
N
2) PCC
77%
then H2O2
83%
rt, 2 h
92%
Bn
Teoc
Teoc
4
13
11, R = Piv
12, R = OH
NaH / EtOH
reflux
82%
OMe
OMe
P(=O)(OEt)2
OMe
OH
N
AD-mix-β
72%
OHC
N
NaH, THF
95%
Teoc
N
N
N
OH
N
Teoc
Teoc
14
5b
15
OMe
N
OMe
1) MeC(OMe)3
PPTS
CsF
O
O
quinine (1)
DMF-tBuOH
2) TMSCl
3) K2CO3 / MeOH
N
N
N
78% from 6b
Teoc
H
6b
16
86%
OH
O
as above
78%
AD-mix-α
CsF
75%
quinidine (2)
5b
OH
N
N
68%
Teoc
Teoc
7b
Scheme 3. Improved synthesis of the quinine and quinidine.

J. Igarashi, Y. Kobayashi / Tetrahedron Letters 46 (2005) 6381–6384
6383
conversion of 11 to 12 and with 3% HCl in MeOH at
room temperature used for deprotection of the TBDPS
(SiPh2Bu-t) of 13.
easy isolation of the corresponding amines 23–25 by
chromatography.
In summary, the synthesis of quinine (1) and quinidine
(2) was accomplished with the N-Teoc group in shorter
steps and higher overall yield than those recorded in the
original synthesis: with the Teoc group, nine steps from
N-Bn piperidine 4, 22.1% and 18.2% yields for 1 and 2,
respectively; with the original groups, 12 steps from 4,
17.2% and 12.8% yields. Moreover, the last two reac-
tions (deprotection and cyclization) proceeded in a dom-
ino fashion quite cleanly and efficiently with CsF.
Deprotection of the Teoc group in 6b was first carried
out according to the literature procedure7b with Bu4NF
(3 equiv) in refluxing THF. The deprotection proceeded
quite successfully as expected. However, piperidine 16
thus formed was contaminated with the chromatograph-
ically inseparable amine(s) probably attributed to
amine(s) derived from Bu4NF and/or an impurity in-
volved in the commercial bottle.9 The amine impurity
was not separated even after its conversion to quinine
(1).
Acknowledgements
Inorganic salts such as KF and CsF were next examined
as a reagent for deprotection of the Teoc group using a
model compound 10. Reaction with KF (10 equiv) in
refluxing MeCN and that in refluxing DMF proceeded
marginally in both runs, and 10 was recovered un-
changed. On the other hand, deprotection with CsF
(5 equiv) in refluxing MeCN (bp 81 °C) was observed
to a slight extent. Attempts to speed up the deprotection
in other solvents such as EtCN (bp 97 °C), MeCN/DMF
(9:1), and MeCN/DMI (9:1) under reflux were unsuc-
cessful. In contrast, complete deprotection was realized
with CsF (5 equiv) in DMF at 90 °C.
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
References and notes
1. Igarashi, J.; Katsukawa, M.; Wang, Y.-G.; Acharya, H.
P.; Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783–3786.
2. StorkÕs approach to quinine seems inapplicable to that of
quinidine, and JacobsenÕs synthesis of the quinine alka-
loids suffer from low stereoselectivity in the preparation of
the piperidine ring: (a) 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; (b) Raheem, I.
T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 706–707.
Keeping in mind the above conditions for deprotection
of the N-Teoc group and the conditions for the subse-
quent quinuclidine ring formation by the intramolecular
attack of the nitrogen to the epoxy carbon, reaction of
6b with CsF was conducted in DMF/t-BuOH (9:1) at
110 °C for 12 h. The domino reaction proceeded cleanly,
and quinine (1) was obtained in 78% yield from 6b after
chromatography on silica gel.
3. (a) Cooley, J. H.; Evain, E. J. Synthesis 1989, 1–7; (b)
Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley
& Sons: New
York, 1999; (c) Bhat, R. G.; Ghosh, Y.; Chandrasekaran,
S. Tetrahedron Lett. 2004, 45, 7983–7985.
4. (a) Sieber, P. Helv. Chim. Acta 1977, 60, 2711–2716; (b)
Carpino, L. A.; Tsao, J.-H. J. Chem. Soc., Chem.
Commun. 1978, 358–359; (c) Carpino, L. A.; Sau, A. C.
J. Chem. Soc., Chem. Commun. 1979, 514–515; (d) Meyers,
A. I.; Babiak, K. A.; Campbell, A. L.; Comins, D. L.;
Fleming, M. P.; Henning, R.; Heuschmann, M.; Hudsp-
eth, J. P.; Kane, J. M.; Reider, P. J.; Roland, D. M.;
Shimizu, K.; Tomioka, K.; Walkup, R. D. J. Am. Chem.
Soc. 1983, 105, 5015–5024; (e) Forsch, R. A.; Rosowsky,
A. J. Org. Chem. 1984, 49, 1305–1309; (f) Kim, G.; Chu-
Moyer, M. Y.; Danishefsky, S. J.; Shulte, G. K. J. Am.
Chem. Soc. 1993, 115, 30–39.
Similarly, diastereomeric epoxide 7b furnished quinidine
(2) in 75% yield upon exposure to CsF under the above
reaction conditions (Scheme 3).
Finally, generality of the new protocols for the trans-
protection with 8 synthesized in situ and for the CsF-
promoted deprotection of the N-Teoc group was briefly
studied. As is summarized in Scheme 4, trans-protec-
tion of N-Bn amines 17–19 in toluene at room temper-
ature proceeded in high yields and deprotection of
the N-Teoc amines 20–22 with CsF was cleanly
accomplished in DMF at 90 °C for 1 h, thus allowing
5. (a) Reagents/conditions used for deprotection of N-CO2R
groups
(CO2CH2CCl3
with
Zn
in
AcOH,5a
CO2CH(Cl)CH3 in MeOH,5b–d and CO2CH@CH2 with
Br2 or NBS5e) seemed incompatible with our strategy for
synthesis of the quinine alkaloids due to hard conditions,
instability of the protective group as such, and/or incon-
venience of the reagent Montzka, T. A.; Matiskella, J. D.;
Partyka, R. A. Tetrahedron Lett. 1974, 1325–1327; (b)
Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081–2082; (c)
Ph
N
N
R
R
17, R = Bn
18, R = Bn
21, R = Teoc
24, R = H
85%
90%
78%
89%
20, R = Teoc
23, R = H
´
Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A.
Synthesis 1991, 318–320; (d) Yang, B. V.; OÕRourke, D.;
Li, J. Synlett 1993, 195–196; (e) Olofson, R. A.; Schnur, R.
C.; Bunes, L.; Pepe, J. P. Tetrahedron Lett. 1977, 1567–
1570.
Ph
19, R1 = TBS, R2 = Bn
22, R1 = TBS, R2 = Teoc
25, R1 = R2 = H
73%
99%
R1O
N
R2
6. The Cbz group used in JacobsenÕs synthesis is removed by
Scheme 4.
using Et2AlCl/thioanisole.2b

6384
J. Igarashi, Y. Kobayashi / Tetrahedron Letters 46 (2005) 6381–6384
7. (a) Shute, R. E.; Rich, D. H. Synthesis 1987, 346–349; (b)
(283 mg, 2.05 mmol) in toluene (0.7 mL) at 0 °C was
added triphosgene (61 mg, 0.21 mmol) in toluene (0.7 mL)
dropwise. The mixture was stirred at room temperature
for 1 h, and re-cooled to 0 °C. To this was added a
solution of 9 (36 mg, 0.21 mmol) in toluene (0.7 mL) at
À20 °C. The mixture was stirred at room temperature for
2 h. The reaction mixture was poured into saturated
NaHCO3, and the mixture was extracted with EtOAc
twice. The combined extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Chromatography of
the residue (hexane/EtOAc = 10:1) afforded the desired
product 10 (47 mg, 99%).
Campbell, A. L.; Pilipauskas, D. R.; Khanna, I. K.;
Rhodes, R. A. Tetrahedron Lett. 1987, 28, 2331–2334.
8. In practice, temperatures below +40 °C are recom-
mended7a for the preparation of 8 from phosgene and
TMS(CH2)2OH and isolation of 8 was carried out by
distillation into a liquid nitrogen trap without heating.7b
9. Kobayashi, Y.; Shimazaki, T.; Taguchi, H.; Sato, F. J.
Org. Chem. 1990, 55, 5324–5335.
10. While a solution of phosgene in toluene was used
previously,7a solid triphosgene was studied to carry out
the reaction in a safer way.
11. General procedure: To a solution of 2-trimethylsilyletha-
nol (0.088 lL, 0.62 mmol) and potassium carbonate
12. The stereoisomer and the starting compound were not
1
detected by H NMR spectroscopy and TLC analysis.