A facile one-pot synthesis of 7-triethylsilylbaccatin III

Article abstract of DOI:10.1055/s-2005-863733

A one-pot synthesis of 7-triethylsilylbaccatin III has been delineated. The reaction can easily be extended for the preparation of analogs of baccatin III.

Full text of DOI:10.1055/s-2005-863733

LETTER
817
A Facile One-Pot Synthesis of 7-Triethylsilylbaccatin III
O
E
ne-Pot Synthe
r
sis of 7-
k
Triethylsilyl
a
baccatin IIIn Baloglu,* Michael L. Miller, Emily E. Cavanagh, Tracy P. Marien, Elizabeth E. Roller, Ravi V. J. Chari
ImmunoGen Inc., 128 Sidney Street, Cambridge, MA 02139, USA
Fax +1(617)9952510; E-mail: erkan.baloglu@immunogen.com
Received 23 November 2004
position. In this procedure, an excess amount of chloro-
triethylsilane and pyridine were used. The reaction time
reported for this procedure was 20 hours for protection of
the C-7 hydroxyl as its triethylsilyl ether, and an addition-
al 48 hours for protection of the C-10 hydroxyl as its ace-
tate ester. A similar method was reported by Bastart et al.,5
except this time lower temperature (5 °C) and even longer
reaction time (40 h) was reported for the protection of the
C-7 hydroxyl as its triethylsilyl ether, and for the acylation
of the C-10 hydroxyl (48 h). Another two-step method
uses chlorotriethylsilane and imidazole in dimethylform-
Abstrac: A one-pot synthesis of 7-triethylsilylbaccatin III has been
delineated. The reaction can easily be extended for the preparation
of analogs of baccatin III.
Key words: taxol, taxotere, baccatin, paclitaxel, docetaxel
The taxane diterpenoids, or taxoids, are of great interest
because of the potent anti-tumor activities of two mem-
®
bers of this family, the natural product paclitaxel (Taxol ,
®
1
2
), and its semi-synthetic analog docetaxel (Taxotere ,
1
). Paclitaxel was first isolated from the bark of the Pa-
amide (DMF) at 0 °C in the first step to form the triethyl-6
2
cific Yew tree (Taxus brevifolia), in very low yields.
Subsequently, semi-synthetic routes to paclitaxel from the
more readily available natural product, 10-deacetylbacca-
silyl ether followed by chromatographic purification.
The next acetylation step is conducted at –40 °C, followed
by another chromatographic purification to give 4. Alter-
native methods for the production of 7-triethylsilylbacca-
3
tin III (3) were reported (Figure 1). In these reports, the
C-13 side chain is synthesized separately and coupled to
the baccatin where the C-7 and the C-10 hydroxyl groups
are selectively protected, such that the only location for
coupling would be through the C-13 hydroxyl group. The
protecting group used for the C-7 hydroxyl group is usu-
ally a triethylsilyl (TES) group, while the C-10 position is
protected as its acetate ester to give 7-triethylsilylbaccatin
III (4). In 10-deacetylbaccatin III (3), the sterically hin-
dered tertiary C-1 hydroxyl group is the least reactive, fol-
lowed by the C-13 hydroxyl group. The C-7 hydroxyl
group is easier to access and hence more reactive than the
C-10 hydroxyl group.
7
tin III (4) were also reported by Sisti et al., and Holton et
8
al. In these procedures, the C-10 position is first selec-
tively acylated, followed by protection of the C-7 hydrox-
yl. However, these methods have several disadvantages
including: a) requiring two steps with purifications after
each step, b) longer reaction time, and c) potential of un-
desired acylation simultaneously at both C-7 and C-10
positions. Thus, all the methods for the incorporation of
appropriate protecting groups at the C-7 and C-10
positions of 10-deactylbaccatin III (3), described thus far,
involve long reaction times, strictly controlled tempera-
tures, or multiple reaction and purification steps, and
potential generation of undesired side products, making
the process cumbersome and expensive for scaling up.
2
R O
O
OH
HO
O
OH
O
1
0
R1
7
NH
O
The object of this study is to provide an easy-to-handle,
useful, scalable, and inexpensive method for the conver-
sion of 10-deacetylbaccatin III (3) to 7-triethylsilylbacca-
tin III (4), which can be readily used in commercial
processes for the semi-synthesis of paclitaxel, docetaxel
and other taxoids.
5
4
1
3
1
2
Ph
O
O
HO
O
H
H
OH
OH
OH
OAc
OAc
OBz
OBz
3
1
2
®
1
Figure 1 1: R = Ph, R = Ac, Taxol (paclitaxel); 2: R = t-BuO,
2
®
R = H, Taxotere (docetaxel).
This paper describes a method for the synthesis of 7-tri-
ethylsilylbaccatin III (4) from 10-deacetylbaccatin III (3)
in one step (Scheme 1). The key feature of our study is the
addition of imidazole to the reaction mixture in pyridine,
which greatly accelerates the reaction. The reaction pro-
ceeds with high yields and is usually completed within
four to five hours, but, if desired, can be stirred overnight.
No significant side products are observed. The whole
process is performed at room temperature without the
need for cooling or heating. Although it is preferred to
provide dry conditions, the process described herein does
not require the use of an argon or nitrogen atmosphere.
As a result of the higher reactivity of the hydroxyl group
at the C-7 position, attempts for the conversion of 10-
deacetylbaccatin III (3) to baccatin III (5) or 7-triethyl-
silylbaccatin III (4) have been directed to the protection of
the hydroxyl group at C-7 first, usually in the form of its
4
triethylsilyl ether, followed by acylation of the C-10
SYNLETT 2005, No. 5, pp 0817–0818
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863733; Art ID: S10904ST
©
Georg Thieme Verlag Stuttgart · New York

8
18
E. Baloglu et al.
LETTER
HO
O
OH
HO
O
OTES
References
1
0
10
7
7
(
1) (a) Voegelein-Gueritte, F.; Guenard, D.; Lavalle, F.; LeGoff,
M.-T.; Mangatal, L.; Potier, P. J. Med. Chem. 1991, 992.
(b) Baloglu, E.; Kingston, D. G. I. J. Nat. Prod. 1999, 1448.
2) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
McPhail, A. T. J. Am. Chem. Soc. 1971, 2325.
Et3SiCl, imidazole
5
4
5
4
13
13
1
2
1
2
HO
O
pyridine, r.t., 5 min HO
O
H
H
OH
OH
(
OAc
OAc
OBz
OBz
3
5
(3) Kingston, D. G. I.; Jagtap, P. G.; Yuan, H.; Samala, L. In
Progress in the Chemistry of Organic Natural Products,
Vol. 84; Herz, W.; Falk, H.; Kirby, G. W., Eds.; Springer-
Verlag: Wien / New York, 2002, and the references cited
therein.
Et3SiCl, imidazole,
Ac2O, pyridine, r.t.
AcO
O
OTES
(
4) (a) Denis, J. N.; Greene, A. E.; Guenard, D.; Voegelein, F.
G.; Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 5917.
(b) Holton, R. A.; Somoza, C. US Patent 5654447, 1997.
10
7
5
4
13
1
2
HO
O
(5) Bastart, J. P.; Pilard, J. PCT Int. Appl. WO 95/26967, 1995.
(6) Bouchard, H.; Bourzat, J. D.; Commercon, A.; Ojima, I. US
Pat. Appl. US2002/0087013 A1, 2002.
H
OH
OAc
OBz
4
(7) Sisti, N. J.; Zygmunt, J.; Brinkman, H. R.; Chander, M. C.;
Liang, X.; McChesney, J. D. US Patent 5914411, 1999.
Scheme 1 Synthesis of 7-triethylsilylbaccatin III.
(8) Holton, R. A.; Zhang, Z.; Clarke, P. A. H. N.; Procter, D. J.
Tetrahedron Lett. 1998, 39, 288.
(
9) Experimental Procedure for 7-Triethylsilylbaccatin III
1
0-Deacetylbaccatin III (3) is dissolved in pyridine (0.5
(
4).
mL of pyridine for every 100 mg of 10-deacetylbaccatin
III) at room temperature. Imidazole (6 equiv) is added to
the reaction mixture at room temperature, followed by
dropwise addition of chlorotriethylsilane (2 equiv). The
reaction mixture is stirred for five minutes at room tem-
perature. Although at this point one could stop the reac-
tion and isolate 7-triethylsilyl-10-deacetylbaccatin III (5)
in high yields, we have found that with the addition of ace-
tic anhydride (20 equiv) the reaction progresses to give
the desired 7-triethylsilylbaccatin III (4) in high yields,
usually within four to five hours, which is purified by
To a stirred solution of 10-deacetylbaccatin III (3, 2.72 g, 5
mmol) in pyridine (13.5 mL) was added imidazole (2.04 g,
30 mmol) and chlorotriethylsilane (1.6 mL, 10 mmol) at r.t.
The reaction mixture was stirred for 5 min where acetic
anhydride (9.5 mL, 100 mmol) was introduced dropwise.
The reaction mixture was stirred for additional 4–5 h and
when the completion of the reaction is confirmed by MS the
reaction was diluted with EtOAc, washed with aq sat.
NaHCO , H O and brine. The organic phase was dried over
3
2
Na SO and the concentrated crude product was purified by
2
4
column chromatography (EtOAc–hexane, 60:40) to give the
desired product (82% yield for two steps).
1
9
Analytical data: H NMR (CDCl ): d = 8.08 (d, 2 H), 7.58 (t,
silica chromatography after work-up. The reaction works
3
1
4
H), 7.45 (t, 2 H), 6.44 (s, 1 H), 5.61 (d, 1 H), 4.94 (d, 1 H),
.80 (m, 1 H), 4.48 (m, 1 H), 4.28 (d, 1 H), 4.11 (d, 1 H), 3.86
smoothly when 2 equivalents of chlorotriethylsilane are
used. When less than 2 equivalents of chlorotriethylsilane
are used, we observed that the C-7 protection does not go
to completion. When more than 2 equivalents of chloro-
triethylsilane are used, multi-silylation products are ob-
served.
(
d, 1 H), 2.49 (m, 1 H), 2.23 (s, 3 H), 2.22 (t, 3 H), 2.10 (s, 6
H), 1.82 (m, 1 H), 1.68 (d, 1 H), 1.66 (s, 3 H), 1.17 (s, 3 H),
13
1
.01 (s, 3 H), 0.89 (t, 9 H), 0.49–0.63 (m, 6 H). C NMR
(CDCl ): d = 202.57, 171.01, 169.67, 167.39, 144.38,
3
133.91, 132.96, 130.40, 129.74, 128.90, 84.54, 81.15, 79.03,
76.83, 76.13, 75.08, 72.67, 68.21, 58.97, 47.58, 43.09,
In conclusion, our methodology describes the conversion
of 10-deacetylbaccatin III (3) to 7-triethylsiylylbaccatin
III (4) in one step, without the need of any intermediary
purification. The reaction proceeds at room temperature,
without a dry atmosphere, and in considerably shorter
time than any of the previously reported methods. The
present method has been found to produce high yields of
3
8.66, 37.56, 27.11, 22.96, 21.24, 20.42, 15.24, 10.26, 7.05,
+
5.60. LRMS [MNa] : m/z calcd for C H O SiNa: 723.32;
37 52 11
found: 723.20.
7
-triethylsilylbaccatin III (4) directly from 10-deacetyl-
baccatin III (3) in a process that is readily scalable.
Synlett 2005, No. 5, 817–818 © Thieme Stuttgart · New York