14β-Hydroxy-10-deacetylbaccatin III as a convenient, alternative substrate for the improved synthesis of methoxylated second-generation taxanes

Article abstract of DOI:10.1016/j.bmcl.2006.07.067

This article describes a new, convenient, improved synthesis of the 2-debenzoyl-2-m-methoxybenzoyl-7-triethylsilyl-13-oxo-14β-hydroxybaccatin III 1,14-carbonate, the key intermediate in the synthesis of two new second-generation antitumor taxanes.

Full text of DOI:10.1016/j.bmcl.2006.07.067

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5389–5391
14b-Hydroxy-10-deacetylbaccatin III as a convenient, alternative
substrate for the improved synthesis of methoxylated second-
generation taxanes
Luciano Barboni,a,* Guido Giarlo,a Roberto Ballinia and Gabriele Fontanab
a
`
Dipartimento di Scienze Chimiche, Universita di Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy
bIndena S.p.A. Viale Ortles 12, 20139 Milano, Italy
Received 6 July 2006; revised 19 July 2006; accepted 20 July 2006
Available online 4 August 2006
Abstract—This article describes a new, convenient, improved synthesis of the 2-debenzoyl-2-m-methoxybenzoyl-7-triethylsilyl-13-
oxo-14b-hydroxybaccatin III 1,14-carbonate, the key intermediate in the synthesis of two new second-generation antitumor taxanes.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The antimitotic drugs Taxolꢁ (paclitaxel) and Taxotereꢁ
NHBoc
OAc
9
(docetaxel) are two of the best anticancer agents in clin-
ical use today for the treatment of ovarian cancer, breast
cancer, and nonsmall cell lung cancer. Paclitaxel and
docetaxel suffer from a series of disadvantages, including
poor water solubility and the quick development of
resistance,1 that have fuelled the search for analogues
endowed with a better clinical profile.
O
11
1
O
OH
O
HO
O
14
7
3
O
O
O
5
H
AcO
O
R
O
1: R = OMe
3: R = H
In this context, we recently published the synthesis of
two new biologically active compounds (1 and 2,
Fig. 1),2 the methoxylated analogues of the norstatin
esters IDN5109 and IDN5390 (3 and 4, respectively;
Fig. 1)3 which have recently emerged as interesting clin-
ical candidates to overcome resistance to paclitaxel and
to allow oral administration.
NHBoc
O
O
H
11
1
OH
9
HO
O
OH
14
7
3
R2
R1
5
O
O
AcO
R
O
The synthesis of both compounds 1 and 2 was accom-
plished starting from the naturally occurring 10-deace-
2: R = OMe;R1, R2 = 1,14-carbonate
4: R = H; R1 =OH; R2 = H
tylbaccatin III
intermediate 6.
5 (Scheme 1), through the key
Figure 1.
The synthesis of 6 from 5 proceeded in an unsatisfactory
overall yield (7%), due to the presence of two critical
steps. In fact, since 10-deacetylbaccatin III lacks the b-
oxygen at C-14, the procedure required the diastereo-
selective b-hydroxylation, followed by carbonylation of
the crude 1,14-diol,4 with a low overall yield (30%). This
prompted us to explore an alternative synthesis for the
key compound 6, with the aim of avoiding the diastereo-
selective hydroxylation step and, in this way, to increase
the yield of the synthesis. The new approach started
from the readily available 14b-hydroxy-10-deacetylbacc-
atin III (7), a naturally occurring taxane isolated from
Keywords: 14b-Hydroxy-10-deacetylbaccatin III; Second-generation
taxanes; Natural products; Terpenoids; Antitumor agents.
*
Corresponding author. Tel.: +39 0737402240; fax: +39
0737637345; e-mail: luciano.barboni@unicam.it
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.07.067

5390
L. Barboni et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5389–5391
OAc
OH
OH
OAc
O
O
O
O
10
OH
O
10
OH
OH
6 steps
OTES
O
13
14
HO
HO
O
HO
13
14
HO
HO
b
a
14 1
14 1
1
7
1
7
2
2
O
O
O
HO
BzO
HO
BzO
HO
BzO
H
AcO
H
AcO
H
AcO
O
O
AcO
O
MeO
10-deacetylbaccatin III, 5
14β-hydroxy-
8
O
6
10-deacetylbaccatin III, 7
OAc
O
OAc
O
2 steps
OTES
OTES
O
10
3 steps
13
14
HO
HO
HO
HO
d
2
c
1
7
1
2
HO
HO
Scheme 1. Synthesis of 1 and 2 from 10-deacetylbaccatin III (5); see
Ref. 2.
BzO
HO
O
AcO
AcO
9
10
OAc
OAc
Taxus wallichiana Zucc.5 which, compared to 10-deace-
tylbaccatin III, shows an additional b-hydroxyl group at
C-14.
O
O
OTES
OTES
10
10
13
14
13
14
O
f
HO
e
7
7
1
6
1
2
2
O
O
O
O
O
O
HO
HO
The first step of our procedure was the selective acety-
lation of the 10-hydroxyl group, which was carried out
by treatment with Ac2O in the presence of CeCl3Æ7H2O,6
which gave compound 8 with a 98% yield, followed by
the selective silylation of the 7-hydroxyl group7
(Scheme 2) to give 9 (55%). The obtained compound
9 was then debenzoylated at C-2 by treatment with ben-
zyltrimethylammonium hydroxide (Triton B)8 giving
the polyhydroxylated compound 10. The crude 10
was then selectively carbonylated at 1,14 with triphos-
gene9 to yield compound 11 (56% from 9). The latter
was selectively oxidized at C-13 by treating with N-
methylmorpholine-N-oxide and a catalytic amount of
OsO4,10 to yield ketone 12 (93%, Scheme 2). Finally,
12 was benzoylated at C-2 with anisic acid,11 allowing
the target compound 6 to be obtained in an acceptable
yield of 40% (Scheme 2).12 It is worth noting that, as
far as we know, the benzoylation at C-2 of a taxane,
in the presence of the 1,14-carbonate, has never been
reported before. The limited yield of this step is proba-
bly due to the steric hindrance that the 1,14-carbonate
and the 4-acetate are exerting on the C-2 hydroxyl
group.
O
O
AcO
12
AcO
11
Scheme 2. Synthesis of 6 from 14b-hydroxy-10-deacetylbaccatin III
(7). Reagents and conditions: (a) Ac2O, CeCl3Æ7H2O, THF, overnight,
98%; (b) TESCl, pyridine, overnight, 55%; (c) Triton B, DCM,
ꢀ78 ꢂC ! 0 ꢂC, 1.5 h; (d) triphosgene, pyridine, DCM, 0 ꢂC, 10 min,
56%; (e) N-methylmorpholine-N-oxide, OsO4, acetone, 0 ꢂC ! rt, 1 h,
93%; (f) anisic acid, DCC, DMAP, toluene, 60 ꢂC, 2.5 h, 40%.
Acknowledgments
We gratefully acknowledge Giovanni Appendino for his
helpful suggestions and the University of Camerino and
MIUR-Italy for financial support.
References and notes
1. Rowinsky, E. K.; Donehower, R. C. N. Engl. J. Med.
1995, 332, 1004.
2. Barboni, L.; Ballini, R.; Giarlo, G.; Appendino, G.;
Fontana, G.; Bombardelli, E. Bioorg. Med. Chem. Lett.
2005, 15, 5182.
3. (a) Eckstein, J. W. IDrugs 2004, 7, 575; (b) Miller, M. L.;
Ojima, I. Chem. Rec. 2001, 1, 195; (c) Appendino, G.;
Danieli, B.; Jakupovic, J.; Belloro, E.; Scambia, E.;
Bombardelli, E. Tetrahedron Lett. 1997, 38, 4273.
4. Baldelli, E.; Battaglia, A.; Bombardelli, E.; Carenzi, G.;
Fontana, G.; Gambini, A.; Gelmi, M. L.; Guerrini, A.;
Pocar, D. J. Org. Chem. 2003, 68, 9773.
5. Appendino, G.; Gariboldi, P.; Gabetta, B.; Pace, R.;
Bombardelli, E.; Viterbo, D. J. Chem. Soc., Perkin Trans.
1 1992, 2925.
6. Appendino, G.; Belloro, E.; Del Grosso, E.; Minassi, A.;
Bombardelli, E. Eur. J. Org. Chem. 2002, 277.
7. Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.;
Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc.
1995, 117, 624.
8. Gunatilaka, A. A. L.; Ramdayal, F. D.; Sarragiotto, M.
H.; Kingston, D. G. I. J. Org. Chem. 1999, 64, 2694.
9. Ojima, I.; Slater, J. C.; Kuduk, S. D.; Takeuchi, C. S.;
Gimi, R. H.; Sun, C.-M.; Park, Y. H.; Pera, P.; Veith, J.
M.; Bernacki, R. J. J. Med. Chem. 1997, 64, 267.
The overall yield of the synthesis was 11%, which repre-
sents a significant increase (>50%) compared to 7% of
the previous procedure. Additionally, the chance to have
two approaches for the synthesis of highly active antitu-
mor taxanes, from different naturally occurring com-
pounds, could be very useful since the restricted
availability of the starting material is, usually, one of
the main limiting factor.13
In summary, a convenient preparation of the key inter-
mediate 6 has been reported; the method includes the
first benzoylation at C-2 of a taxane carrying a 1,14 car-
bonate. This synthetic procedure starts from a different
precursor and involves simpler chemistry compared with
those from 10-deacetylbaccatin III. Moreover, a sub-
stantial increase of the yield (>50%) with respect to
the previous procedure is the crucial advantage of this
method. Further studies on the synthesis of antitumor
taxanes are in progress.

L. Barboni et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5389–5391
5391
10. Appendino, G.; Jakupovic, J.; Cravotto, G.; Enriu, R.;
Varese, M.; Bombardelli, E. Tetrahedron Lett. 1995, 36,
3233.
11. Chordia, M. D.; Kingston, D. G. I. Tetrahedron 1997, 53,
5699.
reaction mixture was diluted with H2O (20 ml), extracted
with CHCl3 (3 · 10 ml), dried over Na2SO4, and the
solvent evaporated, giving compound 12 (613, 93%). 1H
NMR (CDCl3, 200 MHz):d 0.59 (m, 6H), 0.94 (t,
J = 7.57 Hz, 9H), 1.19 (s, 3H), 1.22 (s, 3H), 1.66 (s,
3H), 1.91 (m, 1H), 2.05 (s, 3H), 2.19 (s, 3H), 2.21 (s,
3H), 2.52 (m, 1H), 3.51 (d, J = 6.7 Hz, 1H), 4.41 (d,
J = 6.7 Hz, 1H), 4.45 (dd, J = 10.7, 6.5 Hz, 1H), 4.61 (br
s, 2H), 4.67 (s, 1H), 4.90 (br d, J = 9.9 Hz, 1H), 6.46 (s,
1H); 13C NMR (CDCl3, 100 MHz): d 5.5, 6.9, 10.3, 14.1,
19.3, 20.9, 21.9, 33.1, 37.2, 41.8, 46.0, 59.3, 68.8, 72.3,
74.9, 77.0, 77.7, 81.2, 83.9, 87.9, 139.4, 151.3, 152.5,
168.9, 170.6, 191.7, 200.0; MS (ESI) m/z 659 (M+Na+).
Compound 6: to a dry CH2Cl2 (30 ml) solution of 12
(637 mg, 1 mmol), anisic acid (1.8 g, 12 mmol), DCC
(2.5 g, 12 mmol), and DMAP (1.5 g, 12 mmol) were
added, and the temperature was raised to 60 ꢂC for 4 h.
10 ml of EtOH was then added and, after stirring
overnight, the mixture was diluted with EtOAc (100 ml)
and filtered through Celite and silica gel. Finally, solvent
evaporation and chromatography (hexane/EtOAc 7:3)
12. Experimental procedures for the synthesis of compounds
11, 12 and 6. Compound 11: to a CH2Cl2 (25 ml)
solution of 9 (71 mg, 1 mmol), cooled at ꢀ78 ꢂC, Triton
B (0.91 ml, 2 mmol) was slowly added and the temper-
ature was left to rise to 0 ꢂC. After 1.5 h, HCl 5% (40 ml)
was added and the mixture was extracted with CH2Cl2
(40 ml). The organic layer was washed with NaHCO3 5%
(20 ml), H2O (20 ml), and brine (20 ml), and then dried
over Na2SO4 and the solvent was evaporated. The crude
compound 10 was dissolved in CH2Cl2 (70 ml) and
cooled to 0 ꢂC under N2 atmosphere. Pyridine (1.6 ml,
20 mmol) and triphosgene (297 mg, 1 mmol) were then
added. After 5 min, a saturated solution of NH4Cl
(90 ml) was added. The organic layer was diluted with
EtOAc (40 ml), washed with H2O (20 ml) and brine
(20 ml), dried over Na2SO4, and the solvent evaporated.
Purification by column chromatography (hexane/EtOAc
1:1) afforded compound 11 (357 mg, 56% from 9). 1H
NMR (CDCl3, 400 MHz): d 0.52 (m, 6 H), 0.87 (t,
J = 7.6 Hz, 9H), 1.11 (s, 6H), 1.59 (s, 3H), 1.82 (m, 1H),
2.08 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.46 (m, 1H), 3.33
(d, J = 7.1 Hz, 1H), 4.24 (d, J = 7.1 Hz, 1H), 4.41 (dd,
J = 10.6, 6.5 Hz, 1H), 4.52 (d, J = 9.0 Hz, 1H), 4.57 (d,
J = 9.0 Hz, 1H), 4.60 (d, J = 5.6 Hz, 1H), 4.86 (br d,
J = 5.6 Hz, 1H), 4.90 (br d, J = 9.8 Hz, 1H), 6.34 (s, 1H);
13C NMR (CDCl3, 100 MHz): d 5.3, 6.8, 10.5, 14.9, 20.9,
21.7, 22.5, 26.2, 37.1, 41.2, 47.5, 58.6, 68.6, 71.5, 72.2,
75.4, 77.8, 81.2, 83.8, 84.3, 90.0, 132.2, 143.2, 154.5,
169.1, 170.7, 202.2; MS (ESI) m/z 661 (M+Na+).
Compound 12: to a dry acetone solution (1 ml) of N-
methylmorpholine-N-oxide (293 mg, 2.5 mmol), cooled at
0 ꢂC under N2, OsO4 (0.2 M in toluene, 0.5 ml,
0.1 mmol) was added. After stirring for 10 min, com-
pound 11 (1 mmol) was added, dissolved in dry acetone
(12 ml). After 30 min at 0 ꢂC, the temperature was left to
rise to rt and, after stirring for further 30 min, sodium
m-bisulfite (1.9 g, 10 mmol) was added. After 1 h, the
gave compound
300 MHz): 0.56 (q, J = 7.8 Hz, 6H), 0.90 (t,
6
(308, 40%). 1H NMR (CDCl3,
d
J = 7.8 Hz, 9H), 1.16 (s, 3H), 1.34 (s, 3H), 1.70 (s,
3H), 1.89 (m, 1H), 2.17 (s, 3H), 2.21 (s, 6H), 2.52 (m,
1H), 3.77 (d, J = 6.9 Hz, 1H), 3.83 (s, 3H), 4.18 (d,
J = 8.7 Hz, 1H), 4.35 (d, J = 8.7 Hz, 1H), 4.44 (m, 1H),
4.75 (s, 1H), 4.89 (br d, J = 7.8 Hz, 1H), 6.08 (d,
J = 6.9 Hz, 1H), 6.49 (s, 1H), 7.14 (br d, J = 8.7 Hz, 1H),
7.37 (t, J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.54 (d,
J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 5.2,
6.7, 9.8, 13.9, 19.3, 20.7, 21.7, 32.7, 36.9, 41.6, 45.4, 55.4,
59.2, 68.3, 72.0, 74.6, 75.8, 77.1, 80.5, 83.8, 86.4, 114.7,
120.7, 122.0, 128.9, 130.0, 139.3, 151.1, 151.3, 159.8,
164.3, 168.7, 170.2, 190.8, 199.0; MS (ESI) m/z 793
(M+Na+).
13. See for example: (a) Kingston, D. G. I. J. Nat. Prod. 2000,
´
63, 726; (b) Gueritte, F. Curr. Pharm. Des. 2001, 7, 1229;
(c) Tabata, H. D. Curr. Drug Targets 2006, 7, 453; (d)
´
´
Cusido, B. R. M.; Palazon, J.; Bonfill, M.; Navia-Osorio,
A.; Morales, C.; Pin˜ol, M. T. Biotechnol. Prog. 2002, 18,
418.