Synthesis and biological evaluation of C-3′NH/C-10 and C-2/C-10 modified paclitaxel analogues

Article abstract of DOI:10.1016/S0968-0896(02)00608-9

Concurrent modifications on the C-3′NH/C-10, and C-2/C-10 positions on paclitaxel were carried out as a way of investigating possible synergistic effects. The biological activities of these analogues were evaluated in both a microtubule assembly assay and

Full text of DOI:10.1016/S0968-0896(02)00608-9

Bioorganic & Medicinal Chemistry 11 (2003) 1557–1568
Synthesis and Biological Evaluation of C-30NH/C-10 and
C-2/C-10 Modified Paclitaxel Analogues
Erkan Baloglu,a Jeannine M. Hoch,a Sabarni K. Chatterjee,b Rudravajhala Ravindra,b
Susan Baneb and David G. I. Kingstona,*
aDepartment of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
bDepartment of Chemistry, State University of New York, Binghamton, NY 13902, USA
Received 6 August 2002; accepted 7 October 2002
Abstract—Concurrent modifications on the C-30NH/C-10, and C-2/C-10 positions on paclitaxel were carried out as a way of
investigating possible synergistic effects. The biological activities of these analogues were evaluated in both a microtubule assembly
assay and human ovarian cancer (A2780) and prostate cancer (PC3) cytotoxicity assay. In some cases the doubly modified analo-
gues were more active than would have been predicted based on the activity of the singly modified analogues, indicating probable
synergistic effects.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
as essential for biological activity, and has been of great
interest to many researchers.5
The complex natural product paclitaxel (Taxol1; 1),
first isolated from Taxus brevifolia,1 is a member of a
large family of taxane diterpenoids.2 Paclitaxel has
excellent clinical activity against ovarian and breast
cancers, and shows promising results in the treatment of
lung, skin and head and neck cancers.3 The structure–
activity relationships (SAR) of paclitaxel have been
extensively studied, and it is well known that key modi-
fications at certain positions may result in significant
differences in its activity.4 Knowledge of the SAR of
paclitaxel will help in the design and synthesis of new
analogues, with improved physical, chemical and biolo-
gical properties. It is already well known that the C-13
side chain with a free hydroxyl group at the C-20 posi-
tion, the ester groups at C-2 and C-4, the oxetane ring,
and the rigid taxane ring system are all important for
activity. Modifications in the northern hemisphere of
the molecule, consisting of C-6–C-12, do not usually
result in drastic changes in activity, but modifications in
the southern hemisphere, consisting of carbons 1-5 and
14, including the oxetane ring, have dramatic effects on
paclitaxel’s anticancer activity. The oxetane ring, for
example, is one of the four structural features regarded
Many derivatives of paclitaxel have been reported, some
of which have been found to be more, and some less
potent than paclitaxel. Most of the SAR studies repor-
ted to date have focused primarily on modifications at
only one position and their effects on activity, although
several have involved in manipulations at more than
one site.6 The questions of interest in this study were
‘How would the activity be affected if paclitaxel was
simultaneously modified at more than one site? Would
the simultaneous modification of two groups that are
known to increase paclitaxel’s activity when used singly
result in analogues that are more active than either sin-
gly modified analogue? Would the increase in activity be
merely additive, or would there be a synergistic effect?’
In order to answer these questions, we prepared various
paclitaxel analogues with modifications at the C-30NH/
C-10, and C-2/C-10 positions.
*Corresponding author. Tel.:+1-540-231-6570; fax: +1-540-231-
7702; e-mail: dkingston@vt.edu; website: http://www.chem.vt.edu/
chem-dept/kingston/DGIK.html
0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00608-9

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E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
Synthesis
10-deacetylbaccatin III (10-DAB, 9) by selective acyla-
tion at C-10 by Holton’s procedure11 (Scheme 1).
Previous SAR studies on the effects of modifications at
the C-30 nitrogen showed that analogues without a C-30-
N-acyl group are significantly less active than pacli-
taxel.7 It is also known that aliphatic and heteroaro-
matic N-acyl analogues are slightly more active than
paclitaxel.8 Therefore, an aliphatic, a heteroaromatic
and a heteroaliphatic group were selected to be sub-
stituted for the phenyl ring of the benzoyl group at the
C-30-NH position.
The b-lactams 14–16 were prepared by previously
described methods,12,13 and the baccatin III analogues
10–13 were coupled with them in the presence of NaH.
The coupled products were finally deprotected with HF-
pyridine to give the desired C-30NH/C-10 modified
paclitaxel analogues 17–28 in good yield (Scheme 2).
The design of the selected C-2/C-10 modified analogues
and choice of the groups to be introduced to these
compounds followed a careful study of the reported
SAR information of paclitaxel. To maximize the prob-
ability of synthesizing a more potent analogue, m-azido
and m-chloro benzoyl groups were selected to replace
the benzoyl group at the C-2 position, since these
groups are known to increase paclitaxel’s activity.14 At
the same time, four different groups with different sizes
were explored for the C-10 position.
In order to evaluate the biological activity of paclitaxel
analogues modified at more than one site, it was logi-
cally necessary to compare their activities with those of
the corresponding monosubstituted analogues. The C-
30-NH and C-10 monosubstituted paclitaxel analogues 2–
8 were thus prepared according to literature procedures
(Fig. 1).9
The doubly modified C-30-NH/C-10 analogues 17–28
were prepared by the Holton-Ojima b-lactam synthon
method10 using appropriately modified baccatin III
analogues and b-lactams as starting materials. The bacca-
tin III analogues 10–13 were prepared from the available
As before, the synthesis started from the easily acces-
sible natural product 10-DAB (9). Selective acylation of
the C-10 hydroxyl group as previously described fol-
lowed by protection of the C-7 and C-13 hydroxyl
groups yielded the four baccatins 29–32. Selective
removal of the C-2 benzoyl group with Red-Al, fol-
lowed by carbodiimide-based reesterification with either
m-azido or m-chlorobenzoic acid in the presence of
EDC, and finally removal of the silyl protecting groups
with HF-pyridine gave the baccatin analogues 33–40
(Scheme 3).
In order to convert these new baccatin analogues to
paclitaxel derivatives, the C-7 hydroxyl groups were
Figure 1. Mono-modified paclitaxel analogues.
Scheme 2. (a) NaH, THF, rt, 4 h, 85–96%; (b) HF-pyridine, THF, rt,
24 h, 85–95%.
Scheme 1. (a) RCOOCOR, CeCl3, THF, rt, 4 h, 95–100%; (b) SiEt3Cl
(5 equiv), Im., DMF, 0 ꢀC, 3 h, 90–95%.

E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
1559
reprotected to give analogues 41–48, which were cou-
pled with the appropriate b-lactam derivative to give the
protected paclitaxel analogues. Simultaneous removal
of the silyl protecting groups with HF/pyridine furn-
ished the new paclitaxel analogues 49–56, modified at
the C-2 and C-10 positions (Scheme 4).
between cytotoxicity and tubulin assembly activity was
observed.14
In the cytotoxicity test of the C-2/C-10 modified com-
pounds using the A2780 human ovarian cancer cell line
compounds 49 and 50 both showed significantly
increased activity. However, compounds 49 and 53 were
the only compounds that showed increased activity
when compared to paclitaxel in the microtubule assem-
bly assay and the PC3 cytotoxicity assay, and com-
pound 49 was the only compound with increased
activity in all three assays (Table 3).
Biological Results and Discussion
Cytotoxicity values were obtained for most of the com-
pounds in two different cell lines; the A2780 human
ovarian cancer and the PC3 cell lines. Compounds 2–5
showed increased cytotoxicity as compared with pacli-
taxel (1) in both cell lines, while only compound 8
showed a diminished cytotoxic activity in both cell lines.
Interestingly, only analogues 2 and 6 showed greater
activity than paclitaxel in the microtubule assembly assay
(Table 1).
Although compound 49 showed improved activity rela-
tive to paclitaxel in both cytotoxicity assays and the
tubulin assembly assay, this improvement is not sig-
nificantly greater than would have been expected from
the C-2 substituent alone. Thus Kingston and colla-
borators have shown that 2-(m-azidobenzoyl)taxol has
increased cytotoxicity in the A2780 cell line compared
with paclitaxel by a factor of 5.6.14 The improvement in
activity of compound 49 in the A2780 cell line is of
comparable magnitude to this value, suggesting that the
effect of the C-10 substituent is not significant. The
activities of compounds 51–56, which are less than those
expected for the C-2 substituents alone, indicate that the
Several of the C-30NH/C-10 modified compounds
showed increased activity in both cytotoxicity assays as
compared with paclitaxel, while other compounds had
better tubulin assembly activity (Table 2). However,
compounds 25, 27, and 28 were the only compounds of
this group that showed increased activity when com-
pared to paclitaxel in all three of the assays. This dis-
connect between improved cytotoxicity and tubulin
assembly activity is not unprecedented, but it is never-
theless unusual; in the case of the 2-acyl analogues of
paclitaxel, for example, a reasonably good correlation
Scheme 3. (a) RCOOCOR, CeCl3, THF, rt, 4 h, 95–100%; (b)
SiEt3Cl, Im., DMF, rt, 5 h, 95–100%; (c) Red-Al, THF, 0 ꢀC, 15 min,
85–90%; (d) m-R2-C6H4CO2H, EDC, DMAP, 55 ꢀC, 4 h, 80–90%; (e)
HF-pyridine, THF, rt, 24 h, 85–95%.
Scheme 4. (a) Et3SiCl, DMF, 0 ꢀC, 3 h, 90–95%; (b) b-lactam 14
(R=Ph), NaH, THF, rt, 4 h, 85–95%; (c) HF-pyridine, THF, rt, 24 h,
85–95%.

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E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
Table 1. Biological evaluation of the singly modified paclitaxel analogues 2–8
Compd
PC3 cytotoxicity
(IC50, mg/mL)
A2780 cytotoxicity
(IC50, mg/mL)
Microtubule assembly activity
(I50, mM)
1
2
3
4
5
6
7
8
0.07
0.05
0.05
0.04
0.04
0.05
ND
1.9
0.02
<0.001
0.005
<0.001
<0.001
0.44ꢁ0.19
0.14ꢁ0.06
0.54ꢁ0.07
0.71ꢁ0.17
0.67ꢁ0.28
0.11ꢁ0.04
3.78ꢁ1.55
2.0ꢁ0.48
0.07, 0.13, 0.19
0.05, 0.04
14.1, 14.9, 16.3
ND, not determined.
Table 2. Biological evaluation of C-30N/C-10 modified Taxol analogues
Compd
PC3 cytotoxicity
(IC50, mg/mL)
A2780 cytotoxicity
(IC50, mg/mL)
Microtubule assembly activity
(I50, mM)
17
18
19
20
21
22
23
24
25
26
27
28
1
0.25, 0.3
0.14, 0.13
0.04
0.19, 0.3
1.3, 1
0.5
0.05
0.2
0.04
0.35
<0.00122
0.01, 0.002
0.04, 0.002
<0.001
0.007ꢁ0.005
0.022, 0.03
<0.001
1.20ꢁ0.31
0.08ꢁ0.036
0.65ꢁ0.31
0.14ꢁ0.06
2.03ꢁ0.17
4.85ꢁ2.44
1.63ꢁ0.44
4.99ꢁ2.32
0.07ꢁ0.02
1.10ꢁ0.52
0.49ꢁ0.08
0.36ꢁ0.13
0.55ꢁ0.10
0.06, 0.02
0.001ꢁ0.001
0.02ꢁ0.01, 0.42
0.004, 0.05
0.002ꢁ0.001
0.02
0.04
0.03
0.07
Table 3. Biological evaluation of C-2/C-10 modified Taxol analogues
Compd
PC3 cytotoxicity
(IC50, mg/mL)
A2780 cytotoxicity
(IC50, mg/mL)
Microtubule assembly activity
(I50, mM)
49
50
51
52
53
54
55
56
1
0.05
0.4
0.4, 0.4
0.3
0.055, 0.045
0.3
0.1, 0.09
0.4
0.07
0.014, <0.00122
0.007, 0.08
2.2
0.32ꢁ0.15
1.50ꢁ0.45
2.47ꢁ1.02
1.09ꢁ0.33
0.29ꢁ0.002
1.08ꢁ0.34
3.90ꢁ0.49
0.78ꢁ0.17
0.55ꢁ0.1
0.24, 0.22
0.17, 0.15
0.17, 0.2
0.07, 0.14
0.19, 0.17
0.02
Table 4. Evidence for positive synergistic effecta
Compd
R1
R2
PC3 cytotoxicity
(IC50, mg/mL)
A2780 cytotoxicity
(IC50, mg/mL)
Microtubule assembly activity
(I50, mM)
1
4
5
8
27
28
Ph
Ph
Ph
2-Furyl
2-Furyl
2-Furyl
Me
Et
Pr
Me
Et
Pr
0.07
0.04
0.04
1.9
0.04
0.03
0.02
0.55ꢁ0.1
N/A
5.70ꢁ1.07
2.10ꢁ0.29
0.49ꢁ0.08
0.36ꢁ0.13
<0.00122
<0.00122
14.1, 14.9
0.004
0.002ꢁ0.001
aPTX, paclitaxel.

E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
1561
C-10 substituent has reduced their activity as compared
with the corresponding C-10 acetyl analogues.
Nebraska and in the Department of Chemistry at Vir-
ginia Polytechnic Institute and State University. The
phrase ‘worked-up in the usual way’ refers to diluting
the reaction mixture with an excess amount of organic
solvent, washing with water and brine, drying over
anhydrous sodium sulfate and evaporating the solvent
in vacuo unless otherwise noted. The known inter-
mediates were prepared following the procedures that
are reported in the literature, and NMR data of these
compounds were identical to those in literature.
Given the available data, it was of interest to attempt to
evaluate whether any synergistic effects were observed.
A comparison of selected data for the C-30NH/C-10
analogues is shown in Table 4.
These data indicate that replacement of the C-10 acetyl
group with C-10 propanoyl or butanoyl groups (4 and
5) results in a significant increase in cytotoxicity to the
A2780 cell line, while replacement of the C-30-N benzoyl
group with a 2-furoyl group gave a product (8) with
significantly decreased cytotoxicity and microtubule
assembly activity. Interestingly, replacement of both the
C-30N benzoyl group with a 2-furoyl group and the C-
10 acetate with a butanoate (27) gave a product with
improved cytotoxicity and also improved microtubule
assembly activity. This improvement in the microtubule
assembly activity would not have been predicted, and
indicates a probable positive synergistic effect.
General procedure for the coupling of the baccatin III
derivatives (10–13) with the ꢀ-lactams (14–16). Synthesis
of the silyl protected paclitaxel derivatives. To a stirred
solution of the baccatin derivative (10–13) (0.04 mmol)
in THF (2 mL) at 0 ꢀC was added NaH (2 mmol). The
mixture was stirred for 15 min, and then b-lactam (14–
16; 0.08 mmol) was introduced. The reaction mixture
was allowed to come to room temperature and further
stirred for 4 h. The reaction mixture was cooled down to
0 ꢀC, quenched with acetic acid, and diluted with
EtOAc, washed with dil. NaOH solution (0.1 N) and
worked-up in the usual way. Finally the crude product
was applied on a PTLC plate (30% EtOAc/hexane) and
the desired product was isolated in 85–95% yield.
Conclusion
In conclusion, a series of analogues of paclitaxel have
been synthesized modified at the C-30-NH, C-2 and C-
10 positions. It appears that simultaneously modifying
two substituents on the paclitaxel system produces
effects on the bioactivity of paclitaxel which are not
simply the sum of the effects of the individual modifi-
cations. The reasons for this complex situation are not
currently understood, and additional studies in this area
are needed.
Synthesis of the paclitaxel derivatives 17–28; general
procedure for removal of the silyl protecting groups. To
a stirred solution of every 10 mg of the of protected
paclitaxel derivative THF (0.5 mL) was added 0.15 mL
of pyridine at 0 ꢀC, stirred for 5 min where 0.15 mL of
HF-pyridine was introduced. The reaction mixture was
allowed to come to room temperature and further stir-
red overnight for 24 h. The reaction mixture was then
diluted with EtOAc, washed with satd aq NaHCO3
solution and worked-up in the usual way. Finally the
crude product was applied on a PTLC plate (60%
EtOAc/hexane) and the desired product was isolated in
85–95% yield.
Experimental
General methods
Chemicals were obtained from Aldrich Chemical Co.
and were used without further purification, unless
otherwise noted. All anhydrous reactions were per-
formed in oven-dried glassware under argon. Tetra-
hydrofuran (THF) was distilled over sodium/
benzophenone. All reactions were monitored by E.
Merck analytical thin-layer chromatography (TLC)
plates (silica gel 60 GF, aluminum back) and analyzed
with 254 nm UV light and/or vanillin/sulfuric acid spray
and/or phosphomolybdic acid/ethanol spray. Silica gel
for column chromatography was purchased from E.
Merck (230–400 mesh). Preparative thin layer chroma-
tography (PTLC) plates (silica gel 60 GF) were pur-
30-N-Debenzoyl-30-N-hexanoyl-10-deacetyl-10-isopropanoyl-
paclitaxel (17). H NMR (CDCl3, 399.951 MHz) d 8.11
1
(d, 2H), 7.61 (t, 1H), 7.52–7.33 (m, 7H), 6.26 (s, 1H),
6.19 (t, 1H), 6.16 (d, J=8.8 Hz, 1H), 5.67 (d, J=7.2 Hz,
1H), 5.56 (d, J=9.2 Hz, 1H), 4.93 (d, J=8 Hz, 1H),
4.67 (m, 1H), 4.40 (m, 1H), 4.29 (d, J=8.4 Hz, 1H), 4.18
(d, J=8.4 Hz, 1H), 3.80 (d, J=7.2 Hz, 1H), 3.44 (d,
J=5.2 Hz, 1H), 2.73 (m, 1H), 2.54 (m, 1H), 2.51 (s, 1H),
2.34 (s, 3H), 2.29 (m, 1H), 2.21 (t, 2H), 1.82 (s, 3H), 1.76
(s, 1H), 1.67 (s, 3H), 1.58 (s, 6H), 1.31 (d, 3H), 1.26 (d,
3H), 1.24–1.15 (m, 6H), 0.84 (t, 3H); 13C NMR (CDCl3,
100.578 MHz) d 203.68, 177.20, 172.84, 170.23, 167.00,
141.85, 138.06, 133.71, 133.27, 130.22, 129.09, 128.97,
128.27, 126.96, 84.42, 81.12, 79.04, 76.47, 75.19, 74.94,
73.13, 72.41, 72.22, 58.61, 54.51, 45.60, 43.20, 36.59,
35.55, 34.04, 31.30, 26.83, 25.36, 22.61, 19.19, 18.62,
14.81, 13.84, 9.54. HRFABMS m/z calculated for
C48H62NO14 (M+H)+ 876.4170, found 876.4099, Á
8.1 ppm. LRFABMS m/z found 876.5.
1
chased from Analtech. H and; 13C NMR spectra were
obtained in CDCl3 or CD3OD on Varian Unity 400
spectrometer (operating at 399.951 MHz for 1H and
100.578 MHz for 13C) and were assigned by comparison
of chemical shifts and coupling constants with those of
related compounds. Chemical shifts were reported as
d-values relative to tetramethylsilane (TMS) as internal
reference, and coupling constants were reported in Hertz.
HRFAB and LRFAB mass spectra were obtained at the
Nebraska Center for Mass Spectrometry, University of
30-N-Debenzoyl-30-N-hexanoyl-10-deacetyl-10-(2-butene)-
1
oylpaclitaxel (18). H NMR (CDCl3, 399.951 MHz) d
8.11 (d, 2H), 7.61 (t, 1H), 7.50 (t, 2H), 7.40–7.30 (m,

1562
E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
5H), 7.10 (m, 1H), 6.34 (s, 1H), 6.23 (d, NH, 1H), 6.21
(t, 1H), 5.99 (d, J=15.6 Hz, 1H), 5.67 (d, J=7.2 Hz,
1H), 5.57 (dd, 1H), 4.93 (d, 1H), 4.67 (m, 1H), 4.42 (m,
1H), 4.28 (d, J=8.8 Hz, 1H), 4.18 (d, J=8.8 Hz, 1H),
3.80 (d, J=7.2 Hz, 1H), 3.51 (d, J=5.6 Hz, 1H), 2.64
(d, 1H), 2.53 (m, 1H), 2.34 (s, 3H), 2.30 (t, 2H), 2.18 (t,
2H), 1.94 (d, 3H), 1.91 (s, 1H), 1.85 (dt, 1H), 1.81 (s,
3H), 1.68 (s, 3H), 1.67 (s, 3H), 1.56 (m, 2H), 1.27 (s,
3H), 1.25–1.20 (m, 5H), 1.16 (s, 3H), 0.83 (t, 3H); 13C
NMR (CDCl3, 100.578 MHz) d 203.75, 173.00, 172.80,
170.23, 166.95, 166.23, 147.26, 142.06, 138.05, 133.68,
133.26, 130.20, 129.13, 128.95, 128.68, 128.26, 126.95,
121.59, 84.43, 81.13, 78.98, 76.48, 75.28, 74.98, 73.11,
72.41, 72.24, 58.59, 54.51, 45.58, 43.20, 36.58, 35.63,
35.55, 31.29, 26.87, 25.35, 22.59, 22.28, 21.99, 18.23,
14.81, 13.84, 9.52. HRFABMS m/z calculated for
C47H60NO14 (M+H)+ 874.4017, found 874.4013, Á
3.5 ppm. LRFABMS m/z found 874.2.
7H), 6.26 (s, 1H), 6.25 (t, 1H), 5.66 (d, J=7.2 Hz, 1H),
5.52 (d, J=9.2 Hz, 1H), 5.30 (d, 1H), 4.94 (d, J=8 Hz,
1H), 4.64 (s, 1H), 4.41 (m, 1H), 4.28 (d, J=8.4 Hz, 1H),
4.13 (d, J=8.4 Hz, 1H), 3.80 (d, J=7.2 Hz, 1H), 2.73
(m, 1H), 2.54 (m, 2H), 2.36 (s, 3H), 2.23 (m, 1H), 1.87
(t, 2H), 1.83 (s, 3H), 1.72 (d, 1H), 1.67 (s, 3H), 1.63 (d,
2H), 1.48 (m, 2H), 1.32 (d, 3H), 1.26 (d, 3H), 1.25–1.15
(m, 6H), 0.84 (t, 3H); 13C NMR (CDCl3, 100.578 MHz)
d 203.63, 197.00, 193.84, 177.20, 170.31, 133.73, 130.20,
129.07, 128.90, 128.68, 128.21, 126.73, 84.42, 79.17,
76.47, 75.17, 72.22, 65.36, 58.59, 45.65, 43.17, 35.55,
34.04, 30.88, 26.86, 22.60, 19.19, 18.62, 14.85, 13.62,
9.56. HRFABMS m/z calculated for C47H60NO15
(M+H)+ 878.3963, found 878.3975,
Á 1.2 ppm.
LRFABMS m/z found 878.4.
30-N-Debenzoyl-30-N-butoxycarbonyl-10-deacetyl-10-but-
1
2-enoylpaclitaxel (22). H NMR (CDCl3, 399.951 MHz)
d 8.11 (d, 2H), 7.61 (t, 1H), 7.50 (t, 2H), 7.40--7.30 (m,
5H), 7.10 (m, 1H), 6.34 (s, 1H), 6.26 (t, 1H), 5.99 (d,
J=15.6 Hz, 1H), 5.66 (dd, 1H), 5.56 (d, 1H), 5.30 (d,
1H), 4.93 (d, 1H), 4.64 (bs, 1H), 4.43 (m, 1H), 4.28 (d,
J=8.4 Hz, 1H), 4.18 (d, J=8.4 Hz, 1H), 3.94 (d, 1H),
3.93 (m, 1H), 3.80 (d, J=7.2 Hz, 1H), 3.40 (d, J=5.2
Hz, 1H), 2.66 (d, 1H), 2.54 (m, 1H), 2.36 (s, 3H), 2.24
(m, 1H), 1.95 (d, 3H), 1.88 (dt, 1H), 1.82 (s, 3H), 1.79 (s,
1H), 1.67 (s, 6H), 1.48 (m, 2H), 1.27 (s, 3H), 1.16 (s,
3H), 0.82 (t, 3H); 13C NMR (CDCl3, 100.578 MHz) d
203.72, 173.00, 172.80, 170.32, 167.03, 166.23, 147.29,
133.71, 130.20, 129.07, 128.88, 128.66, 128.19, 126.73,
121.58, 84.44, 81.14, 79.17, 76.47, 75.26, 74.97, 72.23,
65.34, 58.59, 45.62, 43.16, 35.54, 30.87, 26.91, 22.57,
18.84, 18.22, 14.83, 13.60, 9.52. HRFABMS m/z calcu-
lated for C47H58NO15 (M+H)+ 876.3806, found
876.3806 LRFABMS m/z found 876.1.
30-N-Debenzoyl-30-N-hexanoyl-10-deacetyl-10-propanoyl-
paclitaxel (19). H NMR (CDCl3, 399.951 MHz) d 8.11
1
(d, 2H), 7.61 (t, 1H), 7.50 (t, 2H), 7.40–7.30 (m, 5H),
6.29 (s, 1H), 6.23 (d, NH, 1H), 6.21 (t, 1H), 5.67 (d,
J=7.2, 1H), 5.57 (dd, 1H), 4.93 (d, 1H), 4.67 (m, 1H),
4.40 (m, 1H), 4.28 (d, J=8.8 Hz, 1H), 4.18 (d, J=8.8
Hz, 1H), 3.78 (d, J=7.2 Hz, 1H), 3.52 (d, J=5.6 Hz,
1H), 2.61–2.44 (m, 4H), 2.33 (s, 3H), 2.30 (t, 2H), 2.18
(t, 2H), 1.93 (s, 1H), 1.88 (dt, 1H), 1.81 (s, 3H), 1.70 (s,
3H), 1.67 (s, 3H), 1.56 (m, 2H), 1.25–1.22 (m, 11H), 1.14
(s, 3H), 0.83 (t, 3H); 13C NMR (CDCl3, 100.578 MHz) d
203.73, 174.62, 173.03, 172.84, 170.23, 166.93, 141.89,
138.05, 133.68, 133.22, 130.20, 129.12, 128.95, 128.68,
128.26, 126.94, 84.40, 81.11, 78.94, 76.47, 75.36, 74.95,
73.11, 72.40, 72.18, 58.57, 54.52, 45.58, 43.20, 36.58,
35.63, 31.28, 27.55, 26.79, 25.35, 22.59, 22.28, 21.90,
14.79, 13.84, 9.55, 9.00. HRFABMS m/z calculated for
C47H60NO14 (M+H)+ 862.4014, found 862.4013, Á
2.3 ppm. LRFABMS m/z found 862.2.
30-N-Debenzoyl-30-N-butoxycarbonyl-10-deacetyl-10-pro-
1
panoylpaclitaxel (23). H NMR (CDCl3, 399.951 MHz)
d 8.11 (d, 2H), 7.61 (t, 1H), 7.50 (t, 2H), 7.40–7.30 (m,
5H), 6.29 (s, 1H), 6.26 (t, 1H), 5.66 (d, 1H), 5.54 (d, 1H),
5.30 (d, 1H), 4.93 (d, 1H), 4.64 (bs, 1H), 4.41 (m, 1H),
4.28 (d, J=8.4 Hz, 1H), 4.17 (d, J=8.4 Hz, 1H), 3.95
(d, 1H), 3.94 (m, 1H), 3.80 (d, J=7.2 Hz, 1H), 3.37 (d,
J=5.2 Hz, 1H), 2.60–2.44 (m, 4H), 2.36 (s, 3H), 2.24
(m, 2H), 1.88 (dt, 1H), 1.83 (s, 3H), 1.77 (s, 1H), 1.67 (s,
3H), 1.63 (s, 3H), 1.48 (m, 2H), 1.27 (s, 3H), 1.23 (t,
3H), 1.14 (s, 3H), 0.82 (t, 3H); 13C NMR (CDCl3,
100.578 MHz) d 203.69, 174.61, 172.80, 170.31, 167.03,
166.23, 133.71, 130.16, 130.19, 129.08, 128.89, 128.66,
128.19, 126.73, 84.40, 79.14, 76.47, 75.34, 74.94, 72.19,
65.35, 58.57, 45.62, 43.16, 35.52, 30.87, 27.54, 26.83,
22.58, 18.85, 14.83, 13.61, 9.55, 9.00. HRFABMS m/z
calculated for C46H58NO15 (M+H)+ 864.3806, found
864.3806 LRFABMS m/z found 864.1.
30-N-Debenzoyl-30-N-hexanoyl-10-deacetyl-10-butanoyl-
paclitaxel (20). H NMR (CDCl3, 399.951 MHz) d 8.11
1
(d, 2H), 7.61 (t, 1H), 7.50 (t, 2H), 7.40–7.33 (m, 5H),
6.28 (s, 1H), 6.22 (d, NH, 1H), 6.21 (t, 1H), 5.67 (d,
J=7.2 Hz, 1H), 5.57 (dd, 1H), 4.93 (d, 1H), 4.67 (m,
1H), 4.40 (m, 1H), 4.28 (d, J=8.8 Hz, 1H), 4.18 (d,
J=8.8 Hz, 1H), 3.78 (d, J=7.2 Hz, 1H), 3.51 (d, J=5.2
Hz, 1H), 2.58–2.40 (m, 4H), 2.34 (s, 3H), 2.29 (t, 2H),
2.18 (t, 2H), 1.90 (s, 1H), 1.84 (dt, 1H), 1.81 (s, 3H),
1.73 (m, 3H), 1.69 (s, 3H), 1.67 (s, 3H), 1.56 (m, 2H),
1.25 (s, 3H), 1.22 (m, 5H), 1.14 (s, 3H), 1.02 (t, 3H), 0.83
(t, 3H); 13C NMR (CDCl3, 100.578 MHz) d 203.68,
173.85, 172.84, 170.23, 166.94, 141.90, 138.05, 133.68,
133.26, 130.20, 129.12, 128.96, 128.68, 128.26, 126.95,
84.41, 81.11, 78.96, 76.47, 75.30, 74.95, 73.11, 72.40,
72.19, 58.57, 54.51, 45.57, 43.19, 36.58, 36.07, 35.63,
35.54, 31.29, 26.81, 25.35, 22.59, 22.28, 21.93, 18.41,
14.79, 13.84, 13.65, 9.55. HRFABMS m/z calculated for
C48H62NO14 (M+H)+ 876.4170, found 876.4170, Á
0 ppm. LRFABMS m/z found 876.3.
30-N-Debenzoyl-30-N-butoxycarbonyl-10-deacetyl-10-but-
1
anoylpaclitaxel (24). H NMR (CDCl3, 399.951 MHz) d
8.11 (d, 2H), 7.61 (t, 1H), 7.50 (t, 2H), 7.40–7.30 (m,
5H), 6.29 (s, 1H), 6.26 (t, 1H), 5.66 (d, 1H), 5.54 (d, 1H),
5.30 (d, 1H), 4.93 (d, 1H), 4.64 (bs, 1H), 4.41 (m, 1H),
4.28 (d, J=8.4 Hz, 1H), 4.17 (d, J=8.4 Hz, 1H), 3.95
(d, 1H), 3.94 (m, 1H), 3.80 (d, J=7.2 Hz, 1H), 3.37 (d,
J=5.2 Hz, 1H), 2.55–2.40 (m, 5H), 2.36 (s, 3H), 2.24
30-N-Debenzoyl-30-N-butoxycarbonyl-10-deacetyl-10-iso-
propanoylpaclitaxel
(21).
1H
NMR
(CDCl3,
399.951 MHz) d 8.11 (d, 2H), 7.60 (t, 1H), 7.51–7.32 (m,

E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
1563
(m, 2H), 1.88 (dt, 1H), 1.83 (s, 3H), 1.72 (m, 3H), 1.67
(s, 3H), 1.65 (s, 3H), 1.48 (m, 2H), 1.27 (s, 3H), 1.14 (s,
3H), 1.02 (t, 3H), 0.82 (t, 3H); 13C NMR (CDCl3,
100.578 MHz) d 203.63, 173.83, 172.80, 170.30, 167.03,
166.23, 133.70, 133.20, 130.19, 129.07, 128.87, 128.66,
128.19, 126.71, 84.40, 81.12, 79.14, 76.46, 75.27, 74.94,
73.59, 72.18, 65.35, 58.57, 45.61, 43.16, 36.04, 35.53,
30.87, 26.84, 22.58, 18.83, 18.39, 14.83, 13.64, 13.60,
9.55. HRFABMS m/z calculated for C47H60NO15
13C NMR (CDCl3, 100.578 MHz) d 203.94, 174.87,
172.67, 170.61, 167.2, 165.05, 158.1, 147.36, 144.58,
142.09, 138.07, 133.98, 130.46, 129.38, 128.95, 128.61,
127.26, 115.46, 112.58, 84.64, 81.39, 79.26, 75.59, 75.16,
73.57, 72.54, 58.83, 54.55, 45.86, 43.38, 35.86, 27.78,
27.09, 22.84, 22.05, 15.06, 9.79, 9.23. HRFABMS m/z
calculated for C46H52NO15 (M+H)+ 858.3337, found
858.3380, Á 5.1 ppm. LRFABMS m/z found 858.3.
(M+H)+ 878.3963, found 878.3962
Á
3.0 ppm
30-N-Debenzoyl-30-N-(2-furoyl)-10-deacetyl-10-butanoyl-
1
LRFABMS m/z found 878.2.
paclitaxel (28). H NMR (CDCl3, 399.951 MHz) d 8.18
(d, 2H), 7.62 (tt, 1H), 7.53–7.33 (m, 8H), 7.16 (d, J=9.2
Hz, 1H, NH), 7.01 (d, J=3.6 Hz, 1H), 6.46 (m, 1H),
6.27 (s, 1H), 6.23 (t, 1H), 5.72 (d, J=8.4 Hz, 1H), 5.66
(d, J=7.2 Hz, 1H), 4.93 (d, 1H), 4.76 (s, 1H), 4.4 (m,
1H), 4.29 (d, J=8.4 Hz, 1H), 4.19 (d, J=8.4 Hz, 1H),
3.79 (d, J=7.2 Hz, 1H), 2.53 (m, 1H), 2.47 (m, 2H), 2.36
(s, 3H), 2.28 (m, 2H), 1.87 (m, 2H), 1.79 (s, 3H), 1.73
(m, 2H), 1.67 (s, 3H), 1.23 (s, 3H), 1.13 (s, 3H), 1.01 (t,
3H); 13C NMR (CDCl3, 100.578 MHz) d 203.64, 201.42,
198.87, 181.29, 173.85, 172.43, 170.36, 166.94, 157.86,
151.81, 147.6, 147.1, 144.35, 141.98, 141.83, 138.67,
137.82, 133.73, 133.27, 130.22, 122.15, 128.99, 128.36,
127.02, 115.22, 112.34, 84.4, 81.15, 79.01, 75.3, 74.92,
73.32, 72.31, 58.58, 54.31, 45.6, 43.14, 36.06, 35.64,
33.48, 26.86, 22.6, 21.85, 20.41, 18.4, 14.81, 13.64, 9.55.
HRFABMS m/z calculated for C47H54NO15 (M+H)+
872.3493, found 872.3508, Á 1.5 ppm. LRFABMS m/z
found 872.3.
30-N-Debenzoyl-30-N-(2-furoyl)-10-deacetyl-10-isopropa-
noylpaclitaxel (25). H NMR (CDCl3, 399.951 MHz) d
1
8.14 (d, 2H), 7.6 (tt, 1H), 7.53–7.33 (m, 8H), 7.16 (d,
J=9.2, 1H, NH), 7.01 (d, J=3.2 Hz, 1H), 6.46 (m, 1H),
6.28 (s, 1H), 6.23 (t, 1H), 5.74 (d, J=9.2 Hz, 1H), 5.66
(d, J=7.2 Hz, 1H), 4.94 (d, J=7.6 Hz, 1H), 4.76 (s,
1H), 4.40 (m, 1H), 4.29 (d, J=8.4 Hz, 1H), 4.19 (d,
J=8.4 Hz, 1H), 3.79 (d, J=7.2, 1H), 3.60 (bs, 1H), 2.54
(m, 2H), 2.52 (m, 2H), 2.37 (s, 3H), 1.85 (m, 1H), 1.83
(s, 1H), 1.80 (s, 3H), 1.67 (s, 3H), 1.23 (s, 3H), 1.22 (s,
3H), 1.13 (s, 3H); 13C NMR (CDCl3, 100.578 MHz) d
203.94, 174.87, 172.67, 170.61, 167.2, 1650, 158.1,
147.36, 144.58, 142.09, 138.07, 133.98, 133.46, 130.46,
129.38, 129.23, 128.95, 127.26, 115.46, 111.58, 84.64,
81.39, 79.26, 75.59, 75.16, 73.57, 72.54, 72.44, 58.83,
54.55, 45.86, 43.38, 35.86, 27.78, 27.09, 22.84, 22.05,
15.06, 9.79, 9.23. HRFABMS m/z calculated for
C47H54NO15 (M+H)+ 872.3493, found 872.3433, Á
6 ppm. LRFABMS m/z found 872.3.
Synthesis of the baccatin derivatives 33–40; general pro-
cedure for esterification of the C-2 hydroxyl group of
7,13-di(triethylsilyl)baccatin III derivatives. To a stirred
suspension of either m-azido- or m-chlorobenzoic acid
in anhydrous toluene (2 mL for every 30 mg of acid) was
added EDC (1-[3-(dimethylamino)propyl-3-ethylcarbo-
diimide hydrochloride) (1 equiv) at room temperature
and the reaction mixture was stirred for 15 min. DMAP
[4-(dimethylamino)pyridine] (catalytic amount) was
then added and the reaction mixture was stirred for
another 5 min. The 2-debenzoyl baccatin derivative (1/
15 equiv) was then introduced at room temperature and
the reaction mixture was warmed up to 55 ꢀC and fur-
ther stirred for 24 h. The reaction mixture was cooled
down to room temperature, diluted with EtOAc,
washed with water, satd aq NaHCO3 solution and
worked up in the usual way. Finally the crude product
was applied on a PTLC place (10% EtOAc/hexane) and
the desired products was isolated in 80–90% yield.
30-N-debenzoyl-30 -N-(2-furoyl)-10-deacetyl-10-(2-bute-
ne)oylpaclitaxel (26). H NMR (CDCl3, 399.951 MHz)
1
d 8.12 (d, 2H), 7.62 (tt, 1H), 7.53–7.32 (m, 8H), 7.16 (d,
J=8.8 Hz, 1H, NH), 7.10 (m, 1H), 7.01 (d, J=3.2 Hz,
1H), 6.46 (m, 1H), 6.32 (s, 1H), 6.23 (t, 1H), 6.00 (d,
J=15.6 Hz, 1H), 5.74 (d, J=9.6 Hz, 1H), 5.67 (d,
J=7.2 Hz, 1H), 4.94 (d, J=7.6 Hz, 1H), 4.76 (s, 1H),
4.43 (m, 1H), 4.29 (d, J=8.4 Hz, 1H), 4.19 (d, J=8.4
Hz, 1H), 3.81 (d, J=7.2 Hz, 1H), 2.55 (m, 1H), 2.37 (s,
3H), 2.3 (m, 2H), 1.95 (d, 3H), 1.86 (m, 2H), 1.8 (s, 3H),
1.68 (s, 3H), 1.25 (s, 3H), 1.15 (s, 3H); 13C NMR
(CDCl3, 100.578 MHz) d 203.71, 172.37, 170.37, 167.01,
166.23, 157.81, 147.28, 144.31, 142.04, 137.83, 133.74,
133.26, 130.23, 129.13, 128.99, 128.71, 128.36, 127.03,
121.58, 115.18, 112.33, 84.44, 81.17, 79.11, 76.5, 75.27,
74.95, 73.37, 72.3, 58.64, 54.3, 45.61, 43.14, 35.63, 26.95,
22.61, 21.89, 18.23, 14.85, 9.51. HRFABMS m/z calcu-
lated for C47H51NO15Na (M+Na)+ 892.3156, found
892.3153, Á 0.3 ppm. LRFABMS m/z found (M+Na)+
892.
General procedure for removal of the triethylsilyl pro-
tecting groups. To a stirred solution of the baccatin
derivative in THF was added pyridine at 0 ꢀC, stirred
for 5 min where HF-pyridine was introduced. The reac-
tion mixture was allowed to come to room temperature
and further stirred overnight for 24 h. The reaction
mixture was then diluted with EtOAc, washed with satd
aq NaHCO3 solution and worked-up in the usual way.
Finally the crude product was applied on a PTLC plate
(40% EtOAc/hexane) and the desired products was iso-
lated in 85–95% yield. For every 10 mg of the baccatin
derivative 0.5 mL THF, 0.15 mL of pyridine and 0.15 mL
of HF-pyridine was used.
30 -N-Debenzoyl-30 -N-(2-furoyl)-10-deacetyl-10-propa-
1
noylpaclitaxel (27). H NMR (CDCl3, 399.951 MHz) d
8.18 (d, 2H), 7.62 (tt, 1H), 7.53–7.33 (m, 8H), 7.16 (d,
J=9.2 Hz, 1H, NH), 7.01 (d, J=3.6 Hz, 1H), 6.46 (m,
1H), 6.27 (s, 1H), 6.23 (t, 1H), 5.72 (d, J=8.4 Hz, 1H),
5.66 (d, J=7.2 Hz, 1H), 4.93 (d, 1H), 4.76 (s, 1H), 4.4
(m, 1H), 4.29 (d, J=8.4 Hz, 1H), 4.19 (d, J=8.4 Hz,
1H), 3.79 (d, J=7.2 Hz, 1H), 2.53 (m, 1H), 2.47 (m,
2H), 2.36 (s, 3H), 2.28 (m, 2H), 1.87 (m, 2H), 1.79 (s,
3H), 1.67 (s, 3H), 1.23 (s, 3H), 1.13 (s, 3H), 1.01 (t, 3H);

1564
E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-isopropa-
1
129.97, 128.23, 121.68, 84.45, 80.71, 79.2, 76.25, 75.87,
75.35, 72.4, 67.87, 58.61, 46.10, 42.61, 38.52, 35.51,
26.99, 22.46, 20.98, 18.21, 15.59, 9.33. HRFABMS m/z
calculated for C33H40ClO11 (M+H)+ 647.2259, found
647.2233, Á 4.1 ppm. LRFABMS m/z found 647.2.
noylbaccatin III (33). H NMR (CDCl3, 399.951 MHz)
d 7.87 (d, 1H), 7.78 (s, 1H), 7.46 (t, 1H), 7.24 (dd, 1H),
6.30 (s, 1H), 5.6 (d, J=6.8 Hz, 1H), 4.99 (d, J=7.6 Hz,
1H), 4.88 (t, 1H), 4.46 (m, 1H), 4.3 (d, J=8.4 Hz, 1H),
4.12 (d, J=8.4 Hz, 1H), 3.89 (d, J=7.2 Hz, 1H), 2.73
(m, 1H), 2.56 (m, 1H), 2.29 (d, 2H), 2.27 (s, 3H), 2.04 (s,
3H), 1.86 (m, 1H), 1.65 (s, 3H), 1.61 (bs, 1H), 1.32 (d,
3H), 1.25 (d, 3H), 1.10 (s, 6H); 13C NMR (CDCl3,
100.578 MHz) d 204.09, 177.21, 170.67, 166.06, 146.27,
140.76, 131.82, 131.05, 130.11, 126.62, 124.24, 120.05,
84.49, 80.71, 79.07, 75.79, 75.3, 72.3, 67.85, 58.66, 46.1,
42.64, 38.55, 35.52, 34.03, 26.95, 22.58, 20.86, 19.16,
18.62, 15.71, 9.37. HRFABMS m/z calculated for
C33H42N3O11 (M+H)+ 656.2819, found 656.2843, Á
3.6 ppm LRFABMS m/z found 656.3.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-benzoyl-
baccatin III (37). 1H NMR (CDCl3, 399.951 MHz) d
8.10 (s, 1H), 8.08 (d, 1H), 7.88 (dt, 1H), 7.79 (t, 1H),
7.61 (tt, 1H), 7.47 (m, 3H), 7.23 (dd, 1H), 6.58 (s, 1H),
5.65 (d, J=6.8 Hz, 1H), 5.02 (d, J=7.6 Hz, 1H), 4.92 (t,
1H), 4.55 (m, 1H), 4.32 (d, J=8 Hz, 1H), 4.15 (d, J=8
Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 2.61 (m, 2H), 2.33 (d,
2H), 2.29 (s, 3H), 2.1 (s, 3H), 1.89 (m, 1H), 1.68 (s, 3H),
1.21 (s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3,
100.578 MHz) d 203.93, 170.71, 166.43, 166.08, 146.72,
140.78, 133.61, 131.70, 131.05, 130.12, 129.94, 129.18,
128.50, 126.64, 124.26, 120.07, 84.5, 80.72, 79.10, 76.55,
76.33, 75.34, 72.34, 67.88, 58.73, 46.19, 42.71, 38.58,
35.63, 27.14, 22.59, 21.12, 15.66, 9.39. HRFABMS m/z
calculated for C36H40N3O11 (M+H)+ 690.2663, found
690.2669, Á 0.6 ppm. LRFABMS m/z found 690.2.
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-isopropa-
noylbaccatin III (34). 1H NMR (CD3OD, 399.951 MHz)
d 8.13 (s, 1H), 8.03 (d, 1H), 7.65 (d, 1H), 7.52 (t, 1H),
6.49 (s, 1H), 5.6 (d, J=8 Hz, 1H), 5.03 (d, J=10 Hz,
1H), 4.85 (t, 1H), 4.38 (m, 1H), 4.17 (q, 2H), 3.93 (d,
J=7.2 Hz, 1H), 2.71 (m, 1H), 2.48 (m, 1H), 2.38 (d,
1H), 2.34 (d, 1H), 2.28 (s, 3H), 2.07 (s, 3H), 1.79 (m,
1H), 1.64 (s, 3H), 1.27 (d, J=6.8 Hz, 3H), 1.24 (d,
J=6.8 Hz, 3H), 1.13 (s, 3H), 1.07 (s, 3H); 13C NMR
(CD3OD, 100.578 MHz) d 205.54, 177.19, 171.88,
166.20, 147.5, 135.64, 134.33, 133.53, 132.8, 131.36,
130.98, 129.37, 85.85, 81.97, 79.33, 77.32, 76.79, 72.48,
68.07, 59.27, 43.97, 40.49, 37.52, 35.29, 27.17, 22.66,
21.59, 19.42, 19.36, 15.49, 10.30. HRFABMS m/z cal-
culated for C33H42ClO11 (M+H)+ 649.2416, found
649.2390, Á 4.0 ppm. LRFABMS m/z found 649.2.
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-benzoyl-
baccatin III (38). 1H NMR (CDCl3, 399.951 MHz) d
8.12 (d, 1H), 8.08 (s, 2H), 7.98 (d, 1H), 7.62 (m, 2H),
7.48 (m, 3H), 6.58 (s, 1H), 5.61 (d, J=7.2 Hz, 1H), 5.03
(d, J=8.8 Hz, 1H), 4.91 (t, 1H), 4.55 (m, 1H), 4.30 (d,
J=8.4 Hz, 1H), 4.14 (d, J=8.4, 1H), 3.95 (d, J=7.2 Hz,
1H), 2.6 (m, 1H), 2.32 (d, 2H), 2.30 (s, 3H), 2.10 (s, 3H),
1.88 (m, 1H), 1.68 (s, 3H), 1.11 (s, 3H), 1.18 (s, 3H); 13C
NMR (CDCl3, 100.578 MHz) d 203.88, 170.57, 166.43,
165.63, 146.73, 134.72, 133.61, 131.63, 131.11, 130.16,
129.99, 129.93, 129.17, 128.5, 128.24, 84.44, 80.72, 79.2,
76.53, 76.26, 75.36, 72.38, 67.85, 58.65, 46.24, 42.68,
38.58, 35.65, 27.12, 22.46, 21.16, 15.65, 14.16, 9.39.
HRFABMS m/z calculated for C36H40ClO11 (M+H)+
683.2259, found 683.2267, Á 1.1 ppm. LRFABMS m/z
found 683.2.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-but-2-en-
1
oylbaccatin III (35). H NMR (CDCl3, 399.951 MHz) d
7.88 (dt, 1H), 7.78 (t, 1H), 7.47 (t, 1H), 7.23 (d, 1H),
7.15 (m, 1H), 6.38 (s, 1H), 6.00 (d, J=15.6 Hz, 1H),
5.61 (d, J=7.2 Hz, 1H), 5.00 (d, J=7.6 Hz, 1H), 4.89 (t,
1H), 4.48 (m, 1H), 4.30 (d, J=8 Hz, 1H), 4.13 (d, J=8
Hz, 1H), 3.9 (d, J=7.6 Hz, 1H), 2.68 (bs, 1H), 2.57 (m,
1H), 2.29 (d, 2H), 2.28 (s, 3H), 2.18 (bs, 1H), 2.05 (s,
3H), 1.94 (d, J=6.8 Hz, 3H), 1.86 (m, 1H), 1.66 (s, 3H),
1.18 (s, 6H); 13C NMR (CDCl3, 100.578 MHz) d 204.17,
170.68, 166.3, 166.08, 147.06, 146.5, 140.78, 131.82,
131.07, 130.12, 126.64, 124.24, 121.7, 120.06, 84.51,
80.74, 79.10, 75.89, 75.35, 72.36, 67.9, 58.7, 46.07,
42.65,38.53, 35.53, 29.68, 27.02, 22.59, 20.95, 18.21,
15.60, 9.35. HRFABMS m/z calculated for
C33H40N3O11 (M+H)+ 654.2663, found 654.2666, Á
0.3 ppm. LRFABMS m/z found 654.3.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-pentanoyl-
baccatin III (39). 1H NMR (CDCl3, 399.951 MHz) d
7.86 (d, 1H), 7.77 (s, 1H), 7.45 (t, 1H), 7.24 (dd, 1H),
6.31 (s, 1H), 5.59 (d, J=6.8 Hz, 1H), 4.99 (d, J=7.6 Hz,
1H), 4.87 (t, 1H), 4.46 (m, 1H), 4.29 (d, J=8 Hz, 1H),
4.12 (d, J=8 Hz, 1H), 3.87 (d, J=7.2 Hz, 1H), 2.53 (m,
1H), 2.28 (m, 2H), 2.28 (d, 2H), 2.27 (s, 3H), 2.03 (s,
3H), 1.85 (m, 1H), 1.68 (m, 2H), 1.65 (s, 3H), 1.36 (m,
2H), 1.18 (s, 3H), 1.09 (s, 3H), 0.93 (s, 3H); 13C NMR
(CDCl3, 100.578 MHz) d 204.11, 174.06, 170.64, 166.03,
146.43, 140.75, 131.74, 131.05, 130.09, 126.6, 124.22,
120.04, 84.48, 80.67, 79.03, 76.31, 75.9, 75.33, 72.28,
67.79, 58.62, 46.06, 42.61, 38.58, 35.49, 33.9, 26.92,
26.86, 22.55, 22.17, 20.87, 15.55, 13.69, 9.36.
HRFABMS m/z calculated for C34H44N3O11 (M+H)+
670.2976, found 670.2994, Á 2.6 ppm. LRFABMS m/z
found 670.3.
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-but-2-enoyl-
baccatin III (36). 1H NMR (CDCl3, 399.951 MHz) d
8.11 (t, 1H), 7.98 (d, 1H), 7.58 (d, 1H), 7.42 (t, 1H), 7.1
(m, 1H), 6.38 (s, 1H), 6.00 (d, J=15.6 Hz, 1H), 5.85 (d,
J=6.8 Hz, 1H), 5.00 (d, J=7.6 Hz, 1H), 4.88 (t, 1H),
4.48 (m, 1H), 4.28 (d, J=8.4 Hz, 1H), 4.12 (d, J=8.4
Hz, 1H), 3.89 (d, J=6.8 Hz, 1H), 2.57 (m, 1H), 2.28 (s,
3H), 2.26 (m, 2H), 2.05 (s, 3H), 1.93 (d, J=6.8 Hz, 3H),
1.86 (m, 1H), 1.66 (s, 3H), 1.19 (s, 6H); 13C NMR
(CDCl3, 100.578 MHz) d 204.12, 170.55, 166.29, 165.63,
147.07, 146.49, 134.71, 133.60, 131.75, 131.11, 130.15,
2-Debenzoyl-2-m-cholorobenzoyl-10-deacetyl-10-penta-
1
noylbaccatin III (40). H NMR (CDCl3, 399.951 MHz)
d 8.09 (s, 1H), 7.96 (d, 1H), 7.56 (dd, 1H), 7.4 (t, 1H),
6.30 (s, 1H), 5.55 (d, J=6.8 Hz, 1H), 4.98 (d, J=8 Hz,
1H), 4.86 (t, 1H), 4.45 (m, 1H), 4.27 (d, J=8.4 Hz, 1H),

E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
1565
4.11 (d, J=8.4 Hz, 1H), 3.86 (d, J=6.8 Hz, 1H), 2.53
(m, 2H), 2.48 (m, 2H), 2.27 (d, 2H), 2.26 (s, 3H), 2.03 (s,
3H), 1.85 (m, 1H), 1.68 (m, 2H), 1.65 (s, 3H), 1.42 (m,
2H), 1.18 (s, 3H), 1.09 (s, 3H), 0.93 (s, 3H); 13C NMR
(CDCl3, 100.578 MHz) d 204.33, 174.33, 170.77, 165.84,
146.72, 134.96, 133.83, 131.92, 131.38, 130.39, 130.22,
128.46, 84.68, 80.90, 79.39, 76.5, 76.16, 75.62, 72.59,
68.01, 58.8, 46.36, 42.84, 38.87, 35.76, 34.16, 27.17,
27.12, 22.68, 22.43, 21.17, 15.81, 13.96, 9.62.
HRFABMS m/z calculated for C34H44ClO11 (M+H)+
663.2572, found 663.2541, Á 4.6 ppm. LRFABMS m/z
found 663.2.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-but-2-en-
oyl-7-triethylsilylbaccatin III (43). 1H NMR (CDCl3,
399.951 MHz) d 7.88 (d, 1H), 7.80 (s, 1H), 7.46 (t, 1H),
7.22 (d, 1H), 7.08 (m, 1H), 6.50 (s, 1H), 5.98 (d, J=15.6
Hz, 1H), 5.63 (d, J=6.8 Hz, 1H), 4.97 (d, J=8 Hz, 1H),
4.83 (t, 1H), 4.5 (m, 1H), 4.3 (d, J=8.4 Hz, 1H), 4.13 (d,
J=8.4 Hz, 1H), 3.9 (d, J=7.2 Hz, 1H), 2.5 (m, 1H),
2.28 (s, 3H), 2.22 (m, 1H), 2.13 (s, 3H), 1.90 (d, J=6.8
Hz, 3H), 1.87 (m, 1H), 1.64(s, 3H), 1.21 (s, 3H), 1.09 (s,
3H), 0.91 (t, 9H), 0.57 (m, 6H); 13C NMR (CDCl3,
100.578 MHz) d 202.21, 170.81, 166.16, 164.71, 145.73,
143.95, 140.75, 132.7, 131.14, 130.09, 126.67, 124.21,
122.29, 120.09, 84.28, 80.31, 78.77, 76.44, 75.5, 75.15,
72.32, 67.93, 58.65, 47.26, 42.75, 38.18, 37.22, 26.76,
22.71, 20.11, 18.15, 14.96, 9.9, 6.74, 5.25. LRFABMS
m/z calculated for (M+H)+ C39H54N3O11Si 768.3528,
found 768.3.
General procedure for the selective triethylsilylation of
the C-7 hydroxyl of the baccatin III derivatives 33–40.
Synthesis of the baccatin derivatives 41–48. To a stirred
solution of the baccatin derivative (33–40) (0.02 mmol)
in DMF (0.5 mL) was added imidazole (0.06 mmol) and
the reaction mixture was cooled down to 0 ꢀC.
0.022 mmol of chlorotriethylsilane was then introduced
and the reaction mixture was stirred at this tempera-
ture for 3–4 h. The reaction mixture was allowed to
come to room temperature, diluted with 5% NaHCO3
in MeOH, stirred for 15 min where further diluted
with EtOAc, washed with satd aq NaHCO3 solution
and worked-up in the usual way. Finally the crude
product was applied on a PTLC plate (30% EtOAc/
hexane) and the desired product was isolated in
90–95% yield.
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-but-2-en-
oyl-7-triethylsilylbaccatin III (44). 1H NMR (CDCl3,
399.951 MHz) d 8.12 (s, 1H), 7.97 (d, 1H), 7.57 (d, 1H),
7.42 (t, 1H), 7.07 (m, 1H), 6.50 (s, 1H), 5.98 (d, J=15.6
Hz, 1H), 5.57 (d, J=6.8 Hz, 1H), 4.98 (d, J=7.6 Hz,
1H), 4.82 (t, 1H), 4.49 (m, 1H), 4.28 (d, J=8 Hz, 1H),
4.12 (d, J=8 Hz, 1H), 3.90 (d, J=7.2 Hz, 1H), 2.5 (m,
1H), 2.28 (s, 3H), 2.21 (m, 1H), 2.22 (s, 3H), 1.90 (d,
J=7.2 Hz, 3H), 1.84 (m, 1H), 1.68 (s, 3H), 1.21 (s, 3H),
1.02 (s, 3H), 0.92 (t, 9H), 0.57 (m, 6H); 13C NMR
(CDCl3, 100.578 MHz) d 202.17, 170.67, 165.69, 164.7,
145.73, 143.94, 134.69, 133.55, 132.63, 131.19, 130.19,
129.93, 128.25, 122.27, 84.21, 80.80, 78.88, 76.36, 75.48,
75.14, 72.36, 67.9, 58.58, 47.29, 42.7, 38.16, 37.2, 26.74,
22.56, 20.13, 18.14, 14.94, 9.89, 6.74, 5.24. LRFABMS
m/z calculated for (M+H)+ C39H54ClO11Si 761.3124,
found 761.3.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-isopropa-
1
noyl-7-triethylsilylbaccatin III (41). H NMR (CDCl3,
399.951 MHz) d 7.87 (d, 1H), 7.79 (s, 1H), 7.46 (t, 1H),
7.26 (dd, 1H), 6.45 (s, 1H), 5.61 (d, J=6.8 Hz, 1H), 4.97
(d, J=8 Hz, 1H), 4.83 (t, 1H), 4.49 (m, 1H), 4.30 (d,
J=8.4 Hz, 1H), 4.12 (d, J=8.4 Hz, 1H), 3.9 (d, J=6.8
Hz, 1H), 2.71 (m, 1H), 2.55 (m, 1H), 2.28 (s, 3H), 2.26
(d, 2H), 2.21 (s, 3H), 1.87 (m, 1H), 1.67 (s, 3H), 1.25 (d,
3H), 1.23 (d, 3H), 1.19 (s, 3H), 1.09 (s, 3H), 0.92 (t, 9H),
0.58 (m, 6H); 13C NMR (CDCl3, 100.578 MHz) d
202.19, 175.28, 170.79, 166.15, 143.92, 140.74, 132.69,
131.13, 130.09, 126.66, 124.21, 120.07, 84.26, 80.81,
78.77, 76.43, 75.35, 75.13, 72.28, 67.9, 58.61, 47.23,
42.72, 38.17, 37.19, 34.13, 26.78, 22.70, 20.06, 19.06,
18.89, 14.96, 9.91, 6.77, 5.25. LRFABMS m/z calculated
for (M+H)+ C39H56N3O11Si 770.3684, found 770.3.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-benzoyl-7-
triethylsilylbaccatin III (45). 1H NMR (CDCl3,
399.951 MHz) d 8.15 (s, 1H), 8.13 (d, 1H), 7.89 (dt, 1H),
7.79 (t, 1H), 7.59 (tt, 1H), 7.46 (m, 3H), 7.22 (d, 1H),
6.69 (s, 1H), 5.68 (d, J=7.2 Hz, 1H), 4.99 (d, J=8 Hz,
1H), 4.85 (t, 1H), 4.57 (m, 1H), 4.32 (d, J=8 Hz, 1H),
4.15 (d, J=8 Hz, 1H), 3.96 (d, J=7.2 Hz, 1H), 2.5 (m,
1H), 2.3 (s, 3H), 2.28 (m, 1H), 2.27 (s, 3H), 1.89 (m,
1H), 1.71 (s, 3H), 1.32 (s, 3H), 1.18 (m, 1H), 1.04 (s,
3H), 0.89 (t, 9H), 0.58 (m, 6H); 13C NMR (CDCl3,
100.578 MHz) d 202.08, 170.82, 166.15, 165.02, 144.39,
140.75, 133.16, 132.58, 131.13, 130.09,129.88, 129.81,
128.49, 126.66, 124.22, 122.09, 84.29, 80.83, 78.80,
76.43, 76.19, 75.17, 72.38, 67.93, 58.70, 47.29, 42.8,
38.25, 37.22, 26.83, 22.71, 20.35, 15.07, 9.92, 6.72, 5.27.
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-isopropa-
1
noyl-7-triethylsilylbaccatin III (42). H NMR (CDCl3,
399.951 MHz) d 8.11 (s, 1H), 7.97 (d, 1H), 7.57 (d, 1H),
7.41 (t, 1H),6.44 (s, 1H), 5.58 (d, J=7.2 Hz, 1H), 4.97
(d, J=8.8 Hz, 1H), 4.81 (t, 1H), 4.47 (m, 1H), 4.27 (d,
J=8 Hz, 1H), 4.11 (d, J=8 Hz, 1H), 3.88 (d, J=6.8 Hz,
1H), 2.69 (m, 1H), 2.52 (m, 1H), 2.28 (s, 3H), 2.25 (d,
2H), 2.20 (s, 3H), 1.87 (m, 1H), 1.66 (s, 3H), 1.25 (d,
3H), 1.23 (d, 3H), 1.19 (s, 3H), 1.09 (s, 3H), 0.91 (t, 9H),
0.57 (m, 6H); 13C NMR (CDCl3, 100.578 MHz) d
202.17, 175.28, 170.63, 165.67, 143.95, 134.68, 133.54,
132.58, 131.17, 130.16, 129.93, 128.23, 84.18, 80.76,
78.87, 76.34, 75.33, 75.13, 72.31, 67.84, 58.53, 47.26,
42.66, 38.17, 37.16, 34.12, 26.73, 22.52, 20.08, 19.05,
18.87, 14.94, 9.89, 6.76, 5.23. LRFABMS m/z calculated
for (M+H)+ C39H56ClO11Si 763.3280, found 763.3.
LRFABMS
C42H54N3O11Si 804.3528, found 804.4.
m/z
calculated
for
(M+H)+
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-benzoyl-
7-triethylsilylbaccatin III (46). 1H NMR (CDCl3,
399.951 MHz) d 8.15 (s, 1H), 8.13 (d, 2H), 7.97 (d, 1H),
7.56 (d, 2H), 7.44 (m, 3H), 6.69 (s, 1H), 5.64 (d, J=6.8
Hz, 1H), 5.0 (d, J=7.6 Hz, 1H), 4.84 (t, 1H), 4.56 (m,
1H), 4.30 (d, J=8.4 Hz, 1H), 4.14 (d, J=8.4 Hz, 1H),
3.95 (d, J=7.6 Hz, 1H), 2.55 (m, 1H), 2.31 (s, 3H), 2.26
(m, 1H), 2.25 (s, 3H), 2.04 (s, 1H), 1.87 (m, 1H), 1.71 (s,
3H), 1.31 (s, 3H), 1.11 (s, 3H), 1.01 (t, 9H), 0.58 (m,

1566
E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
6H); 13C NMR (CDCl3, 100.578 MHz) d 202.05, 170.69,
165.71, 165.35, 144.37, 134.71, 133.57, 133.17, 132.53,
131.19, 130.19, 129.96, 129.87, 129.81, 128.49, 128.26,
84.23, 80.81, 78.92, 76.17, 75.17, 72.42, 67.91, 58.64,
47.34, 42.76, 38.24, 27.20, 26.82, 22.56, 20.38, 15.06,
9.92, 6.72, 5.27. LRFABMS m/z calculated for
(M+H)+ C42H54ClO11Si 797.3124, found 797.3.
and 0.15 mL of HF-pyridine was used and the desired
products were isolated in 85–95% yield.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-isopropa-
1
noylpaclitaxel (49). H NMR (CDCl3, 399.951 MHz) d
7.91 (d, 1H), 7.82 (s, 1H), 7.71 (d, 2H), 7.51–7.23 (m,
10H), 6.90 (d, J=8.8 Hz, 1H, NH), 6.25 (s, 1H), 6.20 (t,
1H), 5.76 (d, J=8.8 Hz, 1H), 5.66 (d, J=7.2 Hz, 1H),
4.95 (d, J=8.8 Hz, 1H), 4.76 (m, 1H), 4.41 (m, 1H), 4.31
(d, J=8.4 Hz, 1H), 4.17 (d, J=8.4 Hz, 1H), 3.82 (d,
J=6.8 Hz, 1H), 3.51 (d, J=5.2 Hz, 1H), 2.72 (m, 1H),
2.56 (m, 1H), 2.51 (d, 1H), 2.36 (s, 3H), 2.34 (m, 2H),
1.9 (m, 1H), 1.8 (s, 3H), 1.68 (s, 1H), 1.67 (s, 3H),
1.32(d, 3H), 1.24 (s, 3H), 1.22 (d, 3H), 1.14 (s, 3H); 13C
NMR (CDCl3, 100.578 MHz) d 203.59, 177.19, 172.84,
170.34, 167.01, 166.03, 141.91, 140.78, 137.98, 133.63,
133.19, 131.95, 130.85, 130.24, 129.04, 128.68, 128.40,
127.11, 127.01, 126.82, 124.40, 120.13, 84.47, 81.13,
79.09, 76.40, 75.35, 75.17, 73.03, 72.47, 72.20, 58.59,
55.07, 45.59, 43.14, 35.65, 35.53, 34.03, 26.85, 22.68,
21.82, 19.19, 18.61, 14.84, 9.52. HRFABMS m/z calcu-
lated for C49H55N4O14 (M+H)+ 923.3715, found
923.3752, Á 4 ppm. LRFABMS m/z found 923.4.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-pentanoyl-
7-triethylsilylbaccatin III (47). 1H NMR (CDCl3,
399.951 MHz) d 7.87 (d, 1H), 7.78 (s, 1H), 7.45 (t, 1H),
7.23 (m, 1H), 6.47 (s, 1H), 5.61 (d, J=6.8 Hz, 1H), 4.96
(d, J=8 Hz, 1H), 4.82 (t, 1H), 4.48 (m, 1H), 4.29 (d,
J=8 Hz, 1H), 4.11 (d, J=8 Hz, 1H), 3.88 (d, J=6.8 Hz,
1H), 2.51 (m, 1H), 2.43 (m, 2H), 2.27 (s, 3H), 2.26 (d,
2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.86 (m, 1H), 1.66 (s,
3H), 1.63 (m, 2H), 1.4 (m, 2H), 1.18 (s, 3H), 1.09 (s,
3H), 0.93 (s, 3H), 0.92 (t, 9H), 0.58 (m, 6H); 13C NMR
(CDCl3, 100.578 MHz) d 202.19, 172.09, 170.76, 166.12,
143.94, 140.72, 132.67, 131.13, 130.06, 126.64, 124.18,
120.06, 84.24, 80.78, 78.72, 76.42, 75.45, 75.14, 72.28,
67.85, 58.61, 47.19, 42.7, 38.21, 37.18, 34.02, 27.04,
26.75, 22.67, 22.17, 20.04, 14.94, 13.69, 9.89, 6.74, 5.24.
LRFABMS
C40H58N3O11Si 784.3841, found 784.4.
m/z
calculated
for
(M+H)+
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-isopropa-
1
noylpaclitaxel (50). H NMR (CDCl3, 399.951 MHz) d
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-pentanoyl-
7-triethylsilylbaccatin III (48). 1H NMR (CDCl3,
399.951 MHz) d 8.11 (s, 1H), 7.97 (d, 1H), 7.56 (d, 1H),
7.41 (t, 1H), 6.47 (s, 1H), 5.57 (d, J=7.2 Hz, 1H), 4.96
(d, J=7.6 Hz, 1H), 4.81 (t, 1H), 4.48 (m, 1H), 4.27 (d,
J=7.6 Hz, 1H), 4.11 (d, J=7. Hz6, 1H), 3.87 (d, J=6.8
Hz, 1H), 2.50 (m, 1H), 2.43 (m, 2H), 2.28 (s, 3H), 2.22
(m, 2H), 2.18 (s, 3H), 1.85 (m, 1H), 1.68 (m, 2H), 1.65
(s, 3H), 1.4 (m, 2H), 1.18 (s, 3H), 1.2 (s, 3H), 0.93 (s,
3H), 0.92 (t, 9H), 0.57 (m, 6H); 13C NMR (CDCl3,
100.578 MHz) d 202.16, 172.08, 170.61, 165.64, 143.93,
134.67, 133.52, 132.6, 131.17, 130.15, 129.92, 128.21,
84.16, 80.74, 78.82, 76.34, 75.43, 75.14, 72.32, 67.81,
58.53, 47.23, 42.64, 38.19, 37.15, 34.01, 27.03, 26.72,
22.51, 22.16, 20.06, 14.91, 13.68, 9.88, 6.74, 5.23.
8.11 (s, 1H), 8.01 (d, 1H), 7.72 (d, 2H), 7.58 (d, 1H),
7.53–7.32 (m, 9H), 6.97 (d, J=8.8 Hz, 1H, NH), 6.24 (s,
1H), 6.19 (t, 1H), 5.75 (dd, 1H), 5.61 (d, J=6.8 Hz, 1H),
4.95 (d, J=8 Hz, 1H), 4.76 (t, 1H), 4.38 (m, 1H), 4.27
(d, J=8.4 Hz, 1H), 4.15 (d, J=8.4 Hz, 1H), 3.80 (d,
J=7.6 Hz, 1H), 3.64 (d, J=5.2 Hz, 1H), 2.72 (m, 1H),
2.55 (m, 1H), 2.52 (m, 1H), 2.35 (s, 3H), 2.30 (d, 2H),
1.86 (m, 1H), 1.78 (s, 3H), 1.74 (s, 1H), 1.66 (s, 3H), 1.31
(d, 3H), 1.24 (s, 3H), 1.22 (d, 3H), 1.13 (s, 3H); 13C
NMR (CDCl3, 100.578 MHz) d 203.49, 177.16, 172.70,
170.25, 167.09, 165.55, 141.85, 137.7, 134.72, 133.67,
133.61, 133.12, 131.95, 130.95, 130.22, 130.12, 129.03,
128.66, 128.39, 127.10, 127.01, 84.39, 81.11, 79.1, 76.33,
75.32, 75.14, 73.18, 72.29, 72.22, 58.51, 55.18, 45.66,
43.08, 35.61, 35.54, 34.01, 26.79, 22.48, 21.76, 19.16,
18.59, 14.82, 9.4. HRFABMS m/z calculated for
C49H55ClNO14 (M+H)+ 916.3311, found 916.3315, Á
0.4 ppm. LRFABMS m/z found 916.3.
LRFABMS
C40H58ClO11Si 777.3437, found 777.4.
m/z
calculated
for
(M+H)+
Synthesis of the paclitaxel derivatives 49–56. General
procedure for the coupling of the baccatin III derivatives
(41–48) with the ꢀ-lactam. To a stirred solution of the
baccatin derivative (41–48) (0.04 mmol) in THF (2 mL)
at 0 ꢀC was added NaH (2 mmol). The mixture was
stirred for 15 min, and then b-lactam (0.08 mmol) was
introduced. The reaction mixture was allowed to come
to room temperature and further stirred for 4 h. The
reaction mixture was cooled down to 0 ꢀC, quenched
with acetic acid, and diluted with EtOAc, washed with
dil. NaOH solution (0.1 N) and worked-up in the usual
way. Finally the crude product was applied on a PTLC
plate (30% EtOAc/hexane) and the desired product was
isolated in 90–95% yield.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-but-2-en-
1
oylpaclitaxel (51). H NMR (CDCl3, 399.951 MHz) d
7.91 (d, 1H), 7.82 (t, 1H), 7.71 (d, 2H), 7.52–7.23 (m,
10H), 7.10 (m, 1H), 6.91 (d, J=8.8 Hz, 1H, NH), 6.33
(s, 1H), 6.20 (t, 1H), 6.00 (d, J=14.8 Hz, 1H), 5.75 (d,
J=8.8 Hz, 1H), 5.67 (d, J=8.8 Hz, 1H), 4.96 (d, J=9.2
Hz, 1H), 4.77 (m, 1H), 4.38 (m, 1H), 4.32 (d, J=8 Hz,
1H), 4.18 (d, J=8 Hz, 1H), 3.82 (d, J=6.8 Hz, 1H),
3.48 (d, J=5.6 Hz, 1H), 2.61 (d, 1H), 2.56 (m, 1H), 2.37
(s, 3H), 2.33 (d, 1H), 1.93 (d, 3H), 1.86 (m, 1H), 1.79 (s,
3H), 1.67 (s, 3H), 1.56 (s, 3H), 1.24 (s, 3H); 13C NMR
(CDCl3, 100.578 MHz) d 203.68, 195.74, 190.8, 186.66,
175.14, 172.79, 170.35, 168.67, 166.05, 147.34, 143.56,
142.16, 138.58, 137.95, 134.62, 133.62, 131.95, 130.24,
129.04, 128.41, 127.11, 126.82, 124.4, 121.55, 120.37,
84.48, 81.15, 79.14, 76.41, 75.25, 73.03, 72.25, 69.82,
58.61, 55.08, 45.55, 43.14, 35.64, 26.92, 22.67, 21.88,
18.93, 14.88, 9.49. HRFABMS m/z calculated for
General procedure for removal of the silyl protecting
groups. All reactions were performed as described for
the synthesis of baccatin III derivatives. For every 10 mg
of the starting material 0.5 mL THF, 0.15 mL of pyridine

E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
1567
C49H52N4O14Na (M+Na)+ 943.3378, found 943.3370,
Á 0.8 ppm. LRFABMS m/z found 943.3.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-pentanoyl-
1
paclitaxel (55). H NMR (CDCl3, 399.951 MHz) d 7.92
(d, 1H), 7.81 (t, 1H), 7.71 (d, 2H), 7.51–7.23 (m, 10H),
6.92 (d, J=8.8 Hz, 1H, NH), 6.27 (s, 1H), 6.21 (t, 1H),
5.76 (d, J=9.2 Hz, 1H), 5.67 (d, J=6.8 Hz, 1H), 4.95
(d, J=7.6 Hz, 1H), 4.76 (m, 1H), 4.41 (m, 1H), 4.31 (d,
J=8 Hz, 1H), 4.18 (d, J=8 Hz, 1H), 3.81 (d, J=6.8 Hz,
1H), 3.54 (d, J=5.6 Hz, 1H), 2.51 (m, 2H), 2.42 (m,
2H), 2.37 (s, 3H), 2.33 (d, 2H), 1.86 (m, 1H), 1.79 (s,
3H), 1.73 (s, 1H), 1.7 (m, 2H), 1.67 (s, 3H), 1.66 (s, 1H),
1.43 (m, 2H), 1.24 (s, 3H), 1.14 (s, 3H), 0.94 (t, 3H); 13C
NMR (CDCl3, 100.578 MHz) d 203.60, 174.02, 172.82,
170.35, 167.03, 166.02, 141.99, 140.77, 137.98, 133.62,
133.17, 131.95, 130.87, 130.24, 129.03, 128.68, 128.39,
127.11, 127.01, 126.82, 124.39, 120.13, 84.46, 81.12,
79.07, 76.40, 75.36, 73.03, 72.44, 72.19, 58.58, 55.09,
45.55, 43.13, 35.64, 35.51, 33.8, 26.87, 22.66, 21.81,
14.84, 13.71, 9.52. HRFABMS m/z calculated for
C50H57N4O14 (M+H)+ 937.3871, found 937.3843, Á
3 ppm. LRFABMS m/z found 937.4.
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-but-2-en-
1
oylpaclitaxel (52). H NMR (CDCl3, 399.951 MHz) d
8.12 (s, 1H), 8.02 (d, 1H), 7.72 (d, 2H), 7.59 (dt, 1H),
7.50–7.23 (m, 9H), 7.10 (m, 1H), 6.95 (d, J=8.8 Hz, 1H,
NH), 6.32 (s, 1H), 6.2 (t, 1H), 5.98 (d, J=15.6 Hz, 1H),
5.75 (dd, 1H), 5.62 (d, J=7.2 Hz, 1H), 4.96 (d, J=8 Hz,
1H), 4.76 (m, 1H), 4.42 (m, 1H), 4.38 (d, J=8.4 Hz,
1H), 4.16 (d, J=8.4, 1H), 3.81 (d, J=6.8 Hz, 1H), 3.55
(d, J=5.2 Hz, 1H), 2.63 (d, 1H), 2.56 (m, 1H), 2.36 (s,
3H), 2.31 (d, 2H), 1.95 (d, 3H), 1.87 (m, 1H), 1.78 (s,
3H), 1.69 (s, 1H), 1.67 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H);
13C NMR (CDCl3, 100.578 MHz) d 203.59, 172.65,
170.26, 167.00, 166.21, 165.61, 147.34, 142.13, 137.93,
134.74, 133.69, 133.60, 133.11, 131.95, 130.94, 130.22,
130.12, 129.05, 128.68, 128.42, 127.10, 127.01, 121.54,
84.42, 81.13, 79.18, 76.35, 75.34, 75.24, 73.19, 72.31,
58.57, 55.18, 45.62, 43.08, 35.61, 35.53, 36.89, 22.49,
21.83, 18.24, 14.88, 9.47. HRFABMS m/z calculated for
C49H53ClNO14 (M+H)+ 914.3155, found 914.3143, Á
1.2 ppm. LRFABMS m/z found 914.3.
2 - Debenzoyl - 2 - m - chlorobenzoyl - 10 - deacetyl - 10 -
1H
pentanoylpaclitaxel
(56).
NMR
(CDCl3,
399.951 MHz) d 8.11 (s, 1H), 8.01 (d, 1H), 7.71 (d, 2H),
7.57 (d, 1H), 7.53–7.25 (m, 9H), 6.98 (d, J=8.8 Hz, 1H,
NH), 6.26 (s, 1H), 6.19 (t, 1H), 5.74 (d, J=9.6 Hz, 1H),
5.61 (d, J=7.2 Hz, 1H), 4.96 (d, J=8.4 Hz, 1H), 4.76
(m, 1H), 4.38 (m, 1H), 4.27 (d, J=8 Hz, 1H), 4.15 (d,
J=8 Hz, 1H), 3.79 (d, J=7.2 Hz, 1H), 3.66 (d, J=5.2
Hz, 1H), 2.55 (m, 2H), 2.47 (m, 2H), 2.35 (s, 3H), 2.30
(d, 2H), 1.86 (m, 1H), 1.79 (s, 1H), 1.77 (s, 3H), 1.71 (m,
2H), 1.66 (s, 3H), 1.4 (m, 2H), 1.22 (s, 3H), 1.12 (s, 3H),
0.94 (t, 3H); 13C NMR (CDCl3, 100.578 MHz) d 203.51,
173.99, 172.68, 170.25, 167.09, 165.55, 141.94, 137.96,
134.72, 133.67, 133.11, 131.94, 130.95, 130.11, 129.02,
128.65, 128.39, 127.01, 84.38, 81.1, 79.1, 76.34, 75.33,
75.25, 73.19, 72.27, 72.22, 58.11, 55.21, 45.62, 43.07,
35.61, 26.8, 22.47, 21.76, 14.83, 13.7, 9.49. HRFABMS
m/z calculated for C50H57ClNO14 (M+H)+ 930.3468,
found 930.3452, Á 1.6 ppm. LRFABMS m/z found
930.3.
2-Debenzoyl-2-m-azidobenzoyl-10-deacetyl-10-benzoylpa-
clitaxel (53). 1H NMR (CDCl3, 399.951 MHz) d 8.08 (d,
2H), 7.93 (d, 1H), 7.83 (t, 1H), 7.71 (d, 2H), 7.62 (t, 1H),
7.52–7.23 (m, 12H), 6.92 (d, J=8.8 Hz, 1H, NH), 6.53
(s, 1H), 6.24 (t, 1H), 5.76 (d, J=7.2 Hz, 1H), 5.72 (d,
J=7.2 Hz, 1H), 4.96 (d, J=9.6 Hz, 1H), 4.77 (m, 1H),
4.50 (m, 1H), 4.33 (d, J=8.4 Hz, 1H), 4.10 (d, J=8.4
Hz, 1H), 3.89 (d, J=7.2 Hz, 1H), 3.5 (d, J=5.2 Hz,
1H), 2.6 (d, 1H), 2.57 (m, 1H), 2.38 (s, 3H), 2.37 (d, 2H),
1.91 (m, 1H), 1.84 (s, 3H), 1.72 (s, 1H), 1.70 (s, 3H), 1.33
(s, 3H), 1.26 (s, 3H); 13C NMR (CDCl3, 100.578 MHz) d
203.42, 172.79, 170.39, 167.00, 166.38, 166.05, 142.35,
140.78, 137.93, 133.71, 133.08, 131.95, 130.84, 130.25,
129.97, 128.68, 128.55, 128.42, 127.11, 126.82, 124.41,
120.14, 84.47, 81.14, 79.12, 76.41, 75.9, 75.36, 73.02,
72.24, 58.66, 55.1, 45.67. 43.21, 35.69, 27.27, 22.68,
22.03, 14.92, 9.53. HRFABMS m/z calculated for
C52H53N4O14 (M+H)+ 957.3558, found 957.3562, Á
0.4 ppm. LRFABMS m/z found 957.3.
Acknowledgements
2-Debenzoyl-2-m-chlorobenzoyl-10-deacetyl-10-benzoyl-
1
paclitaxel (54). H NMR (CDCl3, 399.951 MHz) d 8.13
This work was supported by a research grant from the
National Institutes of Health (CA-69571), and this sup-
port is gratefully acknowledged. We thank William
Bebout (Virginia Polytechnic Institute and State Uni-
versity) and the Nebraska Center for Mass Spectrometry
for mass spectra.
(s, 1H), 8.07 (d, 2H), 8.02 (d, 1H), 7.72 (d, 2H), 7.61–7.58
(m, 2H), 7.50–7.23 (m, 11H), 6.97 (d, J=8.8 Hz, 1H, NH),
6.52 (s, 1H), 6.22 (t, 1H), 5.78 (d, J=7.6 Hz, 1H), 5.66 (d,
J=6.8 Hz, 1H), 4.97 (d, J=9.2 Hz, 1H), 4.77 (m, 1H), 4.48
(m, 1H), 4.30 (d, J=8.4 Hz, 1H), 4.17 (d, J=8.4 Hz, 1H),
3.87 (d, J=7.2 Hz, 1H), 3.59 (d, J=5.6 Hz, 1H), 2.63 (d,
1H), 2.59 (m, 1H), 2.37 (s, 3H), 2.34 (d, 2H), 1.90 (m, 1H),
1.82 (s, 3H), 1.76 (s, 1H), 1.69 (s, 3H), 1.65 (s, 1H), 1.32 (s,
3H), 1.25 (s, 3H); 13C NMR (CDCl3, 100.578MHz) d
203.34, 172.65, 170.3, 167.05, 166.37, 165.61, 142.31,
137.92, 134.75, 133.72, 133.6, 133.02, 131.95, 130.93,
130.24, 130.14, 129.97, 129.05, 129.06, 128.68, 128.55,
128.43, 128.39, 127.1, 84.41, 81.13, 79.18, 76.35, 75.89,
75.33, 73.19, 72.3, 58.61, 55.21, 45.75, 43.16, 35.66, 26.99,
22.49, 21.99, 14.93, 9.51. HRFABMS m/z calculated for
C52H52ClNO14Na (M+Na)+ 972.2975, found 972.2994,
Á 1.1 ppm. LRFABMS m/z found 972.3.
References and Notes
1. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325.
2. Baloglu, E.; Kingston, D. G. I. J. Nat. Prod. 1999, 62, 1448.
3. For a review on clinical utility, see: Rowinsky, E. K. Annu.
Rev. Med. 1997, 48, 353.
4. (a) For general reviews on the chemistry of paclitaxel, see:
Kingston, D. G. I.; Jagtap, P. G.; Yuan, H.; Samala, L. In
Progress in the Chemistry of Organic Natural Products; Herz,
W., Falk, H., Kirby, G. W., Eds.; Springer: Wien, Austria,

1568
E. Baloglu et al. / Bioorg. Med. Chem. 11 (2003) 1557–1568
2002; p 53. (b) Georg, G. I., Chen, T. T., Ojima, I., Vyas,
D. M., Eds. Taxane Anticancer Agents: Basic Science and
Current Status; ACS Symposium Series 583. American Che-
mical Society: Washington, DC, 1995. (c) Suffness, M., Ed.
Taxol: Science and Applications. CRC: Boca Raton, 1995. (d)
Kingston, D. G. I. J. Nat. Prod. 2000, 63, 726. (e) Kingston,
D. G. I. Chem. Comm. 2001, 867.
Kingston, D. G. I. Bioorg. Med. Chem. 2001, 9, 171. (e) Ojima,
I.; Slater, J. C.; Michaud, E.; Kuduk, S. C.; Bounaud, P.-Y.;
Vrignaud, P.; Bissery, M.-C.; Veith, J. M.; Pera, P.; Bernacki,
R. J. J. Med. Chem. 1996, 39, 3889. (f) Uoto, K.; Ohsuki, S.;
Takenoshita, H.; Ishiyama, T.; Iimura, S.; Hirota, Y.; Mitsui,
I.; Terasawa, H.; Soga, T. Chem. Pharm. Bull. 1997, 45, 1793.
7. Gueritte-Voegelein, F.; Guenard, D.; Lavelle, F.; Le Goff,
M.-T.; Mangatal, L.; Potier, P. J. Med. Chem. 1991, 34, 992.
8. (a) Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Clowers,
J. S.; Harriman, G. C. B.; Hepperle, M.; Park, H. In Taxol:
Science and Applications; Suffness, M., Ed.; CRC: Boca
Raton, 1995; p 317. (b) Georg, G. I.; Harriman, G. C. B.;
Vander Velde, D. G.; Boge, T. C.; Cheruvallath, Z. S.; Datta,
A.; Hepperle, M.; Park, H.; Himes, R. H.; Jayasinghe, L. In
Taxane Anticancer Agents: Basic Science and Current Status;
ACS Symposium Series 583; Georg, G. I., Chen, T. T., Ojima,
I., Vyas, D. M., Eds.; American Chemical Society: Washing-
ton, DC, 1995; p 217.
5. (a) Wang, M.; Cornett, B.; Nettles, J.; Liotta, D. C.; Sny-
der, J. P. J. Org. Chem. 2000, 65, 1059. (b) Fenoglio, I.; Nano,
G. M.; Vander Velde, D. G.; Appendino, G. Tetrahedron Lett.
1996, 37, 3203. (c) Marder-Karsenti, R.; Dubois, J.; Bricard,
L.; Guenard, D.; Gueritte-Voegelein, F. J. Org. Chem. 1997,
62, 6631. (d) Gunatilaka, A. A. L.; Ramdayal, F. D.; Sarra-
giotto, M. H.; Kingston, D. G. I.; Sackett, D. L.; Hamel, E. J.
Org. Chem. 1999, 64, 2694. (e) Kingston, D. G. I.; Magri,
N. F.; Jitrangsri, C. Studies in Org. Chem. 1986, 26, 219. (f)
Samaranayake, G.; Magri, N. F.; Jitrangsri, C.; Kingston,
D. G. I. J. Org. Chem. 1991, 56, 5114. (g) Wahl, A.; Gueritte-
Voegelein, F.; Guenard, D.; Le Goff, M.; Potier, P. Tetra-
hedron 1992, 48, 6965. (h) Chen, S.; Huang, S.; Wei, J.; Farina,
V. Tetrahedron 1993, 49, 2805. (i) Gueritte-Voegelein, F.;
Guenard, D.; Potier, P. J. Nat. Prod. 1987, 50, 9. (j) Appen-
dino, G.; Danieli, B.; Jakupovic, J.; Belloro, E.; Scambia, G.;
Bombardelli, E. Tetrahedron Lett. 1997, 38, 4273. (k) Nico-
laou, K. C.; Claiborne, C. F.; Nantermet, P. G.; Couladouros,
E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1994, 116, 1591. (l)
Shintani, Y.; Tanaka, T.; Nozaki, Y. Cancer Chemother.
Pharmacol. 1997, 40, 513. (m) Klar, U.; Graf, H.; Schenk, O.;
Rohr, B.; Schulz, H. Bioorg. Med. Chem. Lett. 1998, 8, 1397.
6. (a) Ojima, I.; Lin, S.; Slater, J. C.; Wang, T.; Pera, P.; Ber-
nacki, R. J.; Ferlini, C.; Scambia Bioorg. Med. Chem. 2000, 8,
1619. (b) Yuan, H.; Fairchild, C. R.; Liang, X.; Kingston,
D. G. I. Tetrahedron 2000, 56, 6407. (c) Ali, S. M.; Hoemann,
M. Z.; Aube, J.; Georg, G. I.; Mitscher, L. A. J. Med. Chem.
1997, 40, 236. (d) Chordia, M. D.; Yuan, H. Q.; Jagtap, P. G.;
Kadow, J. F.; Long, B. H.; Fairchild, C. R.; Johnston, K. A.;
9. For the synthesis of these analogues, see ref 4b and the
references cited therein.
10. (a) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.;
Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985. (b) Holton,
R. A.; Biediger, R. J.; Boatman, P. D. In Taxol: Science and
Applications; Suffness, M., Ed.; CRC: Boca Raton, 1995; p 97.
11. Holton, R. A.; Zhang, Z.; Clarke, P. A. H. N.; Procter,
D. J. Tetrahedron Lett. 1998, 39, 2883.
12. Brieva, R.; Crich, J. Z.; Sih, C. J. J. Org. Chem. 1993, 58,
1068.
13. Palomo, C.; Arrieta, A.; Cossio, F.; Aizpurua, J. M.;
Mielgo, A.; Aurrekoetxea, N. Tetrahedron Lett. 1990, 31,
6429.
14. Kingston, D. G. I.; Chaudhary, A. G.; Chordia, M. D.;
Gharpure, M.; Gunatilaka, A. A. L.; Higgs, P. I.; Rimoldi,
J. M.; Samala, L.; Jagtap, P. G.; Giannakakou, P.; Jiang,
Y. Q.; Lin, C. M.; Hamel, E.; Long, B. H.; Fairchild, C. R.;
Johnston, K. A. J. Med. Chem. 1998, 41, 3715.