New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 2

Article abstract of DOI:10.1016/S0960-894X(02)00628-5

To investigate structure-activity relationships of the 9,10-acetal-9β-dihydro taxoids, we modified the 7-hydroxyl groups of the 9,10-acetonide-3′-(4-pyridyl) analogue to deoxy, methoxy, α-F, and 7β,8β-methano group. As a result of this study, we found that the 7-deoxy analogue was the strongest among these analogues. In addition, we found that the 7-deoxy-3′-(4-pyridyl) and 7-deoxy-3′-(2-pyridyl) analogues showed stronger activity against cell lines expressing P-glycoprotein than the corresponding 3′-phenyl analogue.

Full text of DOI:10.1016/S0960-894X(02)00628-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2815–2819
New Highly Active Taxoids from 9ꢀ-Dihydrobaccatin-
9,10-acetals. Part 2
Takashi Ishiyama, Shin Iimura, Toshiharu Yoshino, Jun Chiba, Kouichi Uoto,
Hirofumi Terasawa and Tsunehiko Soga*
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center,
16-13 Kita-kasai 1-Chome Edogawa-ku, Tokyo 134-8630, Japan
Received 20 May 2002; accepted 24 July 2002
Abstract—To investigate structure–activity relationships of the 9,10-acetal-9b-dihydro taxoids, we modified the 7-hydroxyl groups
of the 9,10-acetonide-30-(4-pyridyl) analogue to deoxy, methoxy, a-F, and 7b,8b-methano group. As a result of this study, we found
that the 7-deoxy analogue was the strongest among these analogues. In addition, we found that the 7-deoxy-30-(4-pyridyl) and
7-deoxy-30-(2-pyridyl) analogues showed stronger activity against cell lines expressing P-glycoprotein than the corresponding
30-phenyl analogue.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
Synthesis of 9,10-acetal-7-deoxy-9b-dihydro-30-(4-pyr-
idyl) taxoid (14) is described in Scheme 2. In the pre-
sence of DMAP, Tf2O was reacted with 8 in DMF to
introduce the formyl group selectively to 10-hydroxyl
group.7 Selective methylthiocarbonylation of the
7-hydroxyl group of 9, radical hydrogenation of the
resulting compound, and deprotection of the formyl
group of 10 gave 11. The following reduction of the
Paclitaxel (1, Taxol1)1 and docetaxel (2, Taxotere1)2
are important drugs used in cancer chemotherapy (Fig.
1). In the previous paper, we reported on 9,10-acetal-
9b-dihydro taxoids (3), which are much more potent
than paclitaxel (1) and docetaxel (2) (Fig. 2).3 To
improve water solubility,4 we synthesized the 30-(4-pyr-
idyl) analogue (4) and utilized it as a standard com-
pound for investigation of structure activity
relationships on 7-position moieties of the 9,10-acetal-
9b-dihydro taxoids.
Chemical Synthesis
Synthesis of 9,10-acetonide-9b-dihydro-30-4-pyridyl)
taxoid (4) is described in Scheme 1. The 7-hydroxyl
group was selectively protected by using TESOTf and
2,6-di-tert-butylpyridine in quantitative yield.3 Intro-
duction of the pyridylisoserine side chain to the
13-position of 6 using protected b-lactam (7)5 in the
presence of NaHMDS and deprotection of the silyl
groups gave 46 (Scheme 1).
Figure 1.
*Corresponding author. Tel.: +81-3-3680-0151; fax: +81-3-5696-
8344; e-mail: sogatf7t@daiichipharm.co.jp
Figure 2.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00628-5

2816
T. Ishiyama et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2815–2819
Scheme 1. Reagents and conditions: (a) TESOTf, THF/CH2Cl2,
ꢀ78 ꢁC (100%); (b) (1) 7, NaHMDS, THF, ꢀ78 ꢁC; (2) HF-pyridine,
pyridine, rt (41% from 6).
Scheme 3. Reagents and conditions: (a) Tf2O (1.5 equiv), pyridine,
CH2Cl2, 0 ꢁC (88%); (b) (1) SiO2, 1,2-dichloroethane, 60 ꢁC; (2) N2H4,
EtOH, rt (79% from 15); (c) BH3–THF, THF, 0 ꢁC (58%); (d) 2,2-
dimethoxypropane, TsOH, acetone, rt (86%); (e) 7, LiHMDS, THF,
0 ꢁC (55%); (f) HF-Py, pyridine, rt (93%).
Scheme 2. Reagents and conditions: (a) Tf2O, DMAP, DMF, 0 ꢁC
(95%); (b) thiocarbonyldiimidazole, DBU, THF, PhH, rt (75%);
(c) n-Bu3SnH, AIBN, dioxane, 80 ꢁC (46%); (d) N2H4, EtOH, rt
(61%); (e) BH3-THF, THF, 0 ꢁC (58%); (f) 2,2-dimethoxypropane,
CSA, CH2Cl2, rt (87%); (g) (1) 7, LiHMDS, THF, 0 ꢁC, (2) HF-pyri-
dine, pyridine, rt (64% from 13).
Scheme 4. Reagents and conditions: (a) n-BuLi, ZCl, THF, ꢀ40 ꢁC
(95%); (b) TESCl, imidazole, DMF, rt (76%); (c) TsOH, MeOH, rt
(85%); (d) (diethylamino)sulfur trifluoride, CH2Cl2, ꢀ78 ꢁC to rt (42%
for 22, 24% for 23); (e) 10% Pd/C, H2, EtOH, rt (89%); (f) BH3–THF,
THF, 0 ꢁC (88%); (g) 2,2-dimethoxypropane, TsOH, acetone, rt
(91%); (h) HF-Py, pyridine, rt (97%); (i) 7, LiHMDS, THF, 0 ꢁC
(60%); (j) HF-Py, pyridine, rt (95%).
9-carbonyl group of 11 and acetalization of the
9,10-hydroxyl groups of 12 gave 13. Compound 13 was
converted to 148 by reactions similar to those used for
preparation of 4. Configuration of the 9-hydroxyl group
of 13 was identified by comparison of the proton NMR
data between 13 and that of the 9a-hydroxyltaxoids (40)
from Taxus canadenesis.9
Synthesis of 9,10-acetal-7-deoxy-9b-dihydro-7a-fluoro-
30-(4-pyridyl)taxoid (25) is described in Scheme 4. The
key intermediate (24) was synthesized from 20.9,12
Compound 24 was converted to 25.13
Synthesis of 9,10-acetal-7-deoxy-9b-dihydro-7b,8b-
methano-30-(4-pyridyl)taxoid (19) is described in
Scheme 3. The key intermediate (18) was synthesized
from 10 in satisfactory yield.9,10 Compound 18 was
converted to 19.11
Synthesis of 9,10-acetal-9b-dihydro-7-O-methyl-30-
(4-pyridyl) taxoid (28) is described in Scheme 5. Selec-
tive protection of the 7-hydroxyl group of 5 by Troc,
introduction of TES to the 13-hydroxyl group and
deprotection of 7-Troc gave 26 in moderate yield. We

T. Ishiyama et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2815–2819
Table 1. Cytotoxicity of 9-b-dihydro-9,10-acetal taxoidsa
2817
30
7
Cytotoxic activity GI50 (ng/mL) b
PC-6
PC-12
PC-6/VCR
2
4
Docetaxel
1.48
0.380
0.386
7.03
0.266
0.229
0.145
0.332
42.2
0.655
0.038
33.7
0.130
2.26
135
13.5
3.84
>100
3.87
38.1
0.538
2.91
4-Py
4-Py
4-Py
4-Py
OH
Deoxy
Methano
a-F
14
19
25
28
29
30
4-Py
2-Py
Phenyl
OMe
Deoxy
Deoxy
0.116
0.151
aThe in vitro experiments were performed with three different cell
lines: PC-6, a human small cell lung cancer,17 its variant, PC-6/
VCR29–9, a vincristine-resistant cell line expressing P-glycoprotein,18
PC-12, a human non-small cell lung cancer cell line.17 Determination
of GI50 was performed by using the MTT assay.19 The cells were
exposed continuously to the test compounds for 72 h.
Scheme 5. Reagents and conditions: (a) TrocCl, pyridine, 0 ꢁC (47%);
(b) TESOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC (54%); (c) Zn, AcOH–MeOH–
dioxane 1:1:1, rt (80%); (d) MeOTf, 2, 6-di-tert-BuPy, rt (12%);
(e) HF-Py, pyridine, rt (85%); (f) 7, NaHMDS, THF, ꢀ55 ꢁC (56%);
(g) HF-Py, pyridine, rt (76%).
bGrowth inhibition of 50%: the concentration required to obtain half
of the maximal inhibition for cell growth.
Figure 3.
against three cell lines (PC-6, PC-12, and PC-6/VCR).
Among the 7-position modified 30-(4-pyridyl) analogues
(14, 19, 25, 28), deoxy type (14) showed the strongest
activity against two cell lines expressing P-glycoprotein,
PC-12 and PC-6/VCR. 7-O-Methyl and 7-a-fluoro ana-
logues also showed strong activity; however, methano
analogue (19) was less potent than docetaxel. This
structure activity relationship on the 7-position is
almost the same as that of the 10-C-alkyl docetaxel
analogue,14 except for the methano analogue (19). The
7-Deoxy-30-(4-pyridyl) analogue (14) was more potent
than the corresponding 30-phenyl analogue (30) against
PC-12, and the 30-(2-pyridyl) analogue (29) was more
potent than 30 against PC-6/VCR. We think that the
7-deoxy-30-pyridyl analogues are useful for increasing
water solubility and activity against cell lines expressing
P-glycoprotein (Table 1).
Scheme 6. Reagents and conditions: (a) (1) 31,5 NaHMDS, THF,
ꢀ55 ꢁC (75%); (2) HF-Py, pyridine, rt (75%); (b) (1) 32, NaHMDS,
THF, ꢀ55 ꢁC (72%); (2) HF-Py, pyridine, rt (83%).
reported 7-O-methylation of taxoid by using methyl-
thiomethylation and following desulfurylation.14 How-
ever, oxidation of the 7-hydroxyl group to ketone was
mainly observed in the methylthiomethylation step by
DMSO and Ac2O. We tried several conditions and
found that the 7-methylated intermediate is derived by
using 2,6-di-tert-butylpyridine and methyltriflate.
Deprotection of 13-TES of the derived intermediate
gave 27. Compound 27 was converted to 28.15
In conclusion, we synthesized the 7-position- and
30-position-modified 9,10-acetal-9b-dihydro taxoids and
found that the 7-deoxy-30-pyridyl analogues showed
potent activities. We believe that we can report synthesis
of the optimized lead compound in the near future.
As a result of in vitro studies, the 7-deoxy analogue
showed the strongest activity against cancer cell lines.
To investigate the structure–activity relationship on the
30-aryl group, we synthesized a 2-pyridyl analogue (29)
and a phenyl analogue (30)5,16 (Scheme 6). b-Configur-
ation of the 9-position was confirmed by comparison of
the 1H NMR of 30 with the a-isomer of that synthesized
from the 9-a taxoid extracted from T. canadenesis.9
Table 2. Solubility of taxanes
Solubility (mg/mL)
JP1 (pH 1.2)
JP2 (pH 6.8)
Results (Biological Activity) and Discussion
Taxol
Taxotere
4
<4
<4
333
<4
<4
57
Antitumor activities of the 9-b-dihydro-9,10-acetal tax-
oids (4, 14, 19, 25, 28, 29, 30) were evaluated in vitro

2818
T. Ishiyama et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2815–2819
Table 3. NMR data of 9-a and 9-b taxoids
the article: Poujol, H.; Mourabit, A. A., Ahond, A., Poupat,
C. and Potier, P. Tetrahedron 1997, 53, 12575.
10. Johnson, R. A.; Nidy, E. G.; Dobrowolski, P. J.; Geb-
hard, I.; Qualls, S. J.; Wicnienski, N. A.; Kelly, R. C. Tetra-
hedron Lett. 1994, 35, 7893.
9-H (ppm)
10-H (ppm)
J (Hz)
9a:
9b
40
13
18
24
27
4.39
4.18
4.49
4.61
4.57
4.72
5.62
5.49
5.59
5.53
9.5
7.3
7.8
8.8
7.8
11. Analytical data of 19 is as follows: mp 152–157 ꢁC; FAB-
MS m/z 833 (M+1)+; 1H NMR (400 MHz, CDCl3) d 0.78
(broad s, 1H), 1.15–1.45 (m, 2H), 1.22 (s, 3H), 1.35 (s, 12H),
1.49 (s, 3H), 1.57 (s, 3H), 1.70–1.80 (m, 1H), 1.70 (s, 3H), 1.85
(s, 1H), 2.26 (s, 3H), 2.29 (dd, J=8.3, 15.6 Hz, 1H), 2.57 (dd,
J=9.0, 15.6 Hz, 1H), 2.65–2.77 (m, 1H), 3.17 (d, J=7.8 Hz,
1H), 3.83 (broad s, 1H), 4.18 (d, J=7.8 Hz, 9-H, 1H), 4.38 (d,
J=8.3 Hz, 1H), 4.48 (d, J=7.5 Hz, 1H), 4.55 (broad t, J=8.8
Hz, 1H), 4.64 (broad, s 1H), 5.31 (broad t, J=9.3 Hz, 1H),
5.44 (d, J=7.5 Hz, 10-H, 1H), 5.54 (d, J=8.3 Hz, 1H), 5.58 (d,
J=9.3 Hz, 1H), 6.24 (broad t, J=8.5 Hz, 1H), 7.33 (d, J=6.1
Hz, 2H), 7.48 (d, J=7.3 Hz, 2H), 7.57 (t, J=7.3 Hz, 1H), 8.07
(d, J=7.3 Hz, 2H), 8.59 (d, J=6.1 Hz, 2H).
Acknowledgements
The authors are greatly indebted to Dr. M. Iwahana,
organizer, M. Minami, M. Mochizuki, and S. Imagawa
for performing the in vitro study. Also we greatly
appreciate Dr. K. Akimoto and co-workers for the
solubility study.
12. Chen, S.-H.; Huang, S.; Farina, V. Tetrahedron Lett.
1994, 35, 41.
13. Analytical data of 25 are as follows: mp 154–158 ꢁC; H
1
NMR (400 MHz, CDCl3) d 1.19 (s, 3H, Me), 1.41 (s, 9H, tert-
Bu), 1.42 (s, 3H, Me), 1.56 (s, 3H, Me), 1.61 (s, 3H, Me), 1.62
(s, 3H, Me), 1.63 (s, 3H, Me), 1.87 (s, 1H, OH), 2.32 (s, 3H,
acetyl), 2.08–2.47 (m, 4H, 6-H, 14-H), 3.46 (d, J=5.4 Hz, 1H,
3-H), 4.28–4.40 (br, 1H), 4.31 (d, J=8.5 Hz, 1H, 20-H), 4.36
(d, J=8.5 Hz, 1H, 20-H), 4.59 (d, J=8.6 Hz, 1H, 9-H), 4.63
(br, 1H, 20-H), 4.87 (ddd, J=3.9, 7.8, 45.9 Hz, 1H, 7-H), 4.93–
4.97 (m, 1H, 5-H), 5.31 (broad d, J=9.6 Hz, 1H, 30-H), 5.52
(d, J=8.6 Hz, 1H, 10-H), 5.69 (broad d, J=9.6 Hz, 1H, NH),
5.92 (d, J=5.4 Hz, 1H, 2-H), 6.12 (broad t, J=8.3 Hz, 1H, 13-
H), 7.35 (d, J=6.2 Hz, 2H, pyridine), 7.48 (t, J=7.6 Hz, 2H,
Bz), 7.62 (t, J=7.6 Hz, 1H, Bz), 8.10 (d, J=7.6 Hz, 2H, Bz),
8.60 (d, J=6.2 Hz, 2H, pyridine).
References and Notes
1. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
Mcphail, A. J. Am. Chem. Soc. 1971, 93, 2325.
2. Gueritte-Voegelein, F.; Guenard, D.; Lavelle, F.; Le Goff,
M.-T.; Mangatal, L.; Potier, P. J. Med. Chem. 1991, 34, 992.
3. Ishiyama, T.; Iimura, S.; Yoshino, T.; Chiba, J.; Uoto, K.;
Terasawa, H.; Soga, T. Bioorg. Med. Chem. Lett. In press.
4. Analogue 4 showed the better water solubility than Taxol
and Taxotere (Table 2).
5. Georg, G. I.; Harriman, G. C. B.; Hepperle, M.; Himes,
R. H. Bioorg. Med. Chem. Lett. 1994, 4, 1381.
14. Iimura, S.; Uoto, K.; Ohsuki, S.; Chiba, J.; Yoshino, T.;
Iwahana, M.; Jimbo, T.; Terasawa, H.; Soga, T. Bioorg. Med.
Chem. Lett. 2001, 11, 407.
6. Analytical data of 4 are as follows: 4: mp 160–163 ꢁC; FAB-
MS m/z 851 (M+1)+; 1H NMR (400 MHz, CDCl3) d 1.29,
1.40, 1.59, 1.63, 1.68, and 1.81 (each s, each 3H, Meꢂ6), 1.40
(s, 9H, tert-Bu), 1.92 (broad s, 1H, OH), 2.05–2.42 (m, 4H),
2.19 (s, 3H, Ac), 2.93 (d, 1H, J=4.9 Hz, H-3), 3.83 (d, J=7.3
Hz, 1H, H-9), 4.03–4.13 (m, 1H, H-7), 4.32 and 4.39 (ABq,
J=8.3 Hz, each 1H, H-20, H-200), 4.51 (broad s, 1H), 4.73 (d,
J=7.3 Hz, 1H), 5.18 (s, 1H), 5.30 (broad d, J=8.4 Hz, 1H),
5.46–5.61 (m, 2H), 6.06 (d, J=4.9 Hz, 1H, H-2), 6.23 (m, 1H,
H-13), 7.42 (d, J=6.8 Hz, 2H, Py), 7.46 (t, J=7.6 Hz, 2H, Bz),
7.60 (t, J=7.6 Hz, 1H, Bz), 8.10 (d, J=7.6 Hz, 2H, Bz), 8.62
(d, J=6.8 Hz, 2H, Py).
15. Analytical data of 28 are as follows: mp 155–158 ꢁC; FAB-
1
MS m/z 865 (M+1)+; H NMR (400 MHz, CDCl3) d 1.22 (s,
3H), 1.40 (s, 3H), 1.41 (s, 9H), 1.51 (s, 3H), 1.57 (s, 3H), 1.59
(s, 6H), 1.80–2.40 (m, 5H), 2.31 (s, 3H), 3.00 (d, J=4.9 Hz,
1H), 3.33 (s, 3H), 3.40 (d, J=4.0 Hz, 1H), 4.08 (d, J=7.8 Hz,
1H), 4.19 (d, J=7.8 Hz, 1H, 9-H), 4.55 (d, J=7.8 Hz, 1H),
4.63 (s, 1H), 4.86 (s, 1H), 5.30 (d, J=9.3 Hz, 1H), 5.47 (d,
J=7.8 Hz, 1H, 10-H), 5.73 (d, J=9.3 Hz, 1H), 5.94 (d, J=4.9
Hz, 1H), 6.13 (t, J=8.3 Hz, 1H), 7.35 (d, J=5.9 Hz, 2H), 7.46
(t, J=7.3 Hz, 2H), 7.58 (t, J=7.3 Hz, 1H), 8.10 (d, J=7.3 Hz,
1H), 8.58 (d, J=5.9 Hz, 2H).
7. Selective 10-acetylation of 10-deacetylbaccatin III was
reported in the following article: Damen, E. W. P.; Braamer,
L.; Scheeren, H. W. Tetrahedron Lett. 1998, 39, 6081.
8. Analytical data of 14 are as follows: mp 163–168 ꢁC; 1H
NMR (400 MHz, CDCl3) d 1.23 (s, 3H, Me), 1.43 (s, 9H, tert-
Bu), 1.51 (s, 3H, Me), 1.55 (s, 3H, Me), 1.57 (s, 3H, Me), 1.61
(s, 3H, Me), 1.71 (s, 3H, Me), 1.60–2.10 (m, 5H, 6-Hꢂ2,
7-Hꢂ2 and 14-H), 1.97 (broad s, 1H, OH), 2.28 (s, 3H, Ac),
2.34 (dd, J=10.2, 15.2 Hz, 1H, 14-H), 2.91 (d, J=4.9 Hz, 1H,
3-H), 4.12 (d, J=7.1 Hz, 1H, 9-H), 4.27 (d, J=8.3 Hz, 1H,
20-H), 4.32 (d, J=8.3 Hz, 1H, 20-H), 4.63 (broad s, 1H, 20-H),
4.82 (broad s, 1H, OH), 4.93 (broad s, 1H, 5-H), 5.30 (d,
J=9.1 Hz, 1H, 30-H), 5.56 (d, J=7.1 Hz, 1H, 10-H), 5.81 (d,
J=9.3 Hz, 1H, NH), 6.00 (d, J=4.9 Hz, 1H, 2-H), 6.09 (broad
t, J=7.8 Hz, 1H, 13-H), 7.36 (d, J=5.9 Hz, 2H, Py), 7.47 (t,
J=7.3 Hz, 2H, Bz), 7.60 (t, J=7.3 Hz, 1H, Bz), 8.12 (d, J=7.3
Hz, 2H, Bz), 8.59 (d, J=5.9 Hz, 2H, Py).
16. Analytical data of 29 and 30 are as follows. 29: mp 145–
148 ꢁC; FAB-MS m/z 835 (M+1)+; 1H NMR (400 MHz,
CDCl3) d 1.26 (s, 3H), 1.43 (s, 3H), 1.44 (s, 9H), 1.52 (s, 3H),
1.56 (s, 3H), 1.61 (s, 3H), 1.71 (s, 3H), 1.80–2.20 (m, 4H),
2.22–2.31 (m, 2H), 2.35 (s, 3H), 2.94 (d, J=4.9 Hz, 1H), 4.17
(d, J=7.3 Hz, 1H), 4.23 (d, J=8.3 Hz, 1H), 4.32 (d, J=8.3
Hz, 1H), 4.88 (d, J=2.5 Hz, 1H), 4.92 (s, 1H), 5.34 (d, J=9.3
Hz, 1H), 5.56 (d, J=7.3 Hz, 1H), 5.94 (d, J=9.4 Hz, 1H), 5.96
(d, J=4.9 Hz, 1H), 6.09 (t, J=8.3 Hz, 1H), 7.22 (dd, J=7.3
Hz, 4.9 Hz, 1H), 7.38–7.50 (m, 3H), 7.59 (t, J=7.8 Hz, 1H),
7.72 (t, J=7.3 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.54 (d,
J=4.4 Hz, 1H). 30: mp 145–148 C; FAB-MS m/z 834
(M+1)+; 1H NMR (400 MHz, CDCl3) d 1.28 (s, 3H), 1.29 (s,
3H), 1.42 (s, 9H), 1.45 (s, 3H), 1.50 (s, 3H), 1.60 (s, 3H), 1.66 (s,
3H), 1.80–2.10 (m, 4H), 2.30 (s, 3H, Ac), 2.48 (dd, J=10.0 Hz,
15.0 Hz, 1H), 2.91 (d, J=4.8 Hz, 1H), 4.14 (d, J=7.3 Hz, 1H, 9-
H), 4.25 (d, J=8.3 Hz, 1H), 4.30 (d, J=8.3 Hz, 1H), 4.39 (brs,
1H), 4.61 (brs, 1H), 4.91 (s, 1H), 5.30 (d, J=9.0 Hz, 1H), 5.56 (d,
J=7.3 Hz, 1H, 10-H), 5.70 (d, J=9.0 Hz, 1H), 6.00 (d, J=4.9
Hz, 1H), 6.07 (m, 1H), 7.27–7.37 (m, 5H), 7.40–7.46 (m, 2H), 7.57
(t, J=7.4 Hz, 1H), 8.11 (d, J=7.5 Hz, 2H).
9. Proton NMR data of 9a-10b-taxoids (40) and 9b-10b-tax-
oids (13, 18, 24, 27, Fig. 3) were compared as follows (Table
3), and these data seemed to support the 9-b configuration.
Proton NMR data of the 9a-10b-taxoid were obtained from

T. Ishiyama et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2815–2819
2819
17. Mitsui, I.; Kumazawa, E.; Hirota, Y.; Aonuma, M.;
Sugimori, M.; Ohsuki, S.; Uoto, K.; Ejima, A.; Terasawa, H.;
Sato, K. Jpn. J. Cancer Res. 1995, 86, 776.
18. Joto, N.; Ishii, M.; Minami, M.; Kuga, H.; Mitsui, I.;
Tohgo, A. Int. J. Cancer 1997, 72, 680.
19. Alley, M. C.; Scudiero, D. A.; Monks, A.; Hursey,
M. L.; Czerwinski, M. J.; Fine, D. L.; Abbott, B. J.;
Mayo, J. G.; Shoemaker, R. H.; Boyd, M. R. Cancer Res.
1988, 48, 589.