Synthesis and antitumor activity of 1-deoxybaccatin III analogs from 1-deoxybaccatin VI

Article abstract of DOI:10.1007/s00706-013-0981-z

Several new 1-deoxybaccatin III analogs were conveniently synthesized from 1-deoxybaccatin VI with the aim of having modified ester groups at C-2 and C-4. The antitumor activity of these compounds was evaluated. The preliminary SAR analysis showed that the electronic properties of the terminal group in the substituent on C4, C9, and C10 constituted important factors to the cytotoxic activities against A 549 and MCF-7 cell lines. The present studies provide a new synthetic basis for development of new 1-deoxypaclitaxel analogs. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-013-0981-z

Monatsh Chem (2013) 144:1573–1582
DOI 10.1007/s00706-013-0981-z
ORIGINAL PAPER
Synthesis and antitumor activity of 1-deoxybaccatin III analogs
from 1-deoxybaccatin VI
•
Yuan-You Qiu Hai-Xia Lin Yong-Mei Cui
•
•
•
Jun-Chao Shao Dan-Hui Jin
Received: 11 October 2012 / Accepted: 24 March 2013 / Published online: 13 August 2013
Ó Springer-Verlag Wien 2013
Abstract Several new 1-deoxybaccatin III analogs were
conveniently synthesized from 1-deoxybaccatin VI with
the aim of having modified ester groups at C-2 and C-4.
The antitumor activity of these compounds was evaluated.
The preliminary SAR analysis showed that the electronic
properties of the terminal group in the substituent on C4,
C9, and C10 constituted important factors to the cytotoxic
activities against A 549 and MCF-7 cell lines. The present
studies provide a new synthetic basis for development of
new 1-deoxypaclitaxel analogs.
with taxinine and sinenxan stimulated several groups to
investigate possible approaches to 1-deoxy analogs, starting
from taxinine or sinenxan [7, 8]. However, these approaches
required constructing an oxetane moiety, leading to long
synthetic sequences and considerably low overall yields. On
the other hand, 1-deoxybaccatin VI (3), which possesses the
typical 6/8/6/4 taxoid ring and lacks 1-hydroxyl group, is
readily available from Taxus chinensis, Rehd. Var. mairei in
good yield [9, 10]. Therefore, 1-deoxybaccatin VI (3) rep-
resents a more efficient starting material than taxinine or
sinenxan for the preparation of selected 1-deoxyanalogs with
potentially greater therapeutic benefits.
Keywords 1-Deoxybaccatin III ꢀ 1-Deoxybaccatin VI ꢀ
Analogs ꢀ Bioactivity
As a result of extensive SAR study at the diterpenoid core,
the northern part of the taxane skeleton, including the C7, C9,
and C10 positions, can survive structural modifications
without great loss of activity as the taxane skeleton retains its
rigid conformation [11]. This leads to the conclusion that this
part of the molecule is not directly involved in the interaction
with tubulin. However, other studies have shown that the
hydrophobic character of C7 and C10 substituents can mod-
ulate the interaction of these drugs with microtubules [12],
and changes in this region of taxanes may affect the specific
binding of paclitaxel to P-glycoprotein. Anticancer taxoids
with high potency against drug-resistant cancer cells have
been prepared based on these observations. Cabazitaxel,
which was approved by the US Food and Drug Administra-
tion (FDA) in 2010 [13], is a semisynthetic taxane that has
different substituents at C7 and C10 compared with docetaxel
and paclitaxel. It has been confirmed that cabazitaxel has poor
binding ability with P-gp and shows activity in both doce-
taxel-sensitive and docetaxel-resistant cancers. And the
functionalities on the bottom part of the molecule (including
C2, C4, oxetane ring, and C13) are involved in the intimate
interaction with the receptor. Several interesting approaches
to C2, C4 modifications have been disclosed [14, 15].
Introduction
The extensive utilization of paclitaxel (TaxolÒ, 1) as an
anticancer agent has stimulated interest in taxoids to find
alternative sources of paclitaxel or related compounds with
improved activities [1, 2]. Structure-activity relationship
(SAR) studies have revealed that the 1-hydroxyl group is not
necessary for the activity of paclitaxel [3]. Deoxygenation of
the 1-hydroxyl group of paclitaxel or baccatin III (2a) had
been reported to be a difficult procedure [4–6]. Thus, devel-
opment of a procedure for synthesis of 1-deoxypaclitaxel
analogs will be very significant. Its structural congruence
Y.-Y. Qiu ꢀ H.-X. Lin (&) ꢀ Y.-M. Cui (&) ꢀ J.-C. Shao ꢀ
D.-H. Jin
Department of Chemistry, College of Sciences, Shanghai
University, Shanghai 200444, People’s Republic of China
e-mail: haixialin@staff.shu.edu.cn
Y.-M. Cui
e-mail: ymcui80@gmail.com
123

1574
Y.-Y. Qiu et al.
Paclitaxel is a complex molecule and is expensive to
derivatives with meta-substituted benzoyl groups 4a–4c,
5a, 5b. As depicted in Scheme 1, 4,7,9,10,13-penta(de-
acetyl)-1-deoxybaccatin VI (6) was prepared by
hydrazinolysis using the procedure previously developed in
our laboratory [20]. Treatment of 6 with 2,2-dimethoxy-
propane (DMP) in the presence of montmorillonite K10
resulted in the formation of 9,10-acetonide 7 in 95 %
isolated yield. Subsequently, 7 was treated with triton B
(trimethylbenzylammonium hydroxide) to give the C2 de-
produce from natural sources. It would be highly desirable
if future generations of this class of drugs were structurally
much simpler than paclitaxel, while retaining the full
activity of the parent compound. It has been reported that
2-(m-azidobenzoyl)baccatin III (2b) has taxol-like activity
[16]. Its exact role, however, remains a matter of debate.
These results suggest that further exploration of the effect
of different acyl groups at the C2 and C4 positions could be
fruitful for the discovery of further candidates for drug
development. In addition, some taxoids without C13 side
chain, which showed MDR (multidrug resistance)-reversal
activities, have also been reported [17]. For the above
reasons, the development of a procedure using 1-deoxybacca-
tin VI as a starting material for the preparation of new bioactive
taxoids would be significant. In continuation of our drug dis-
covery program for anticancer agents [18, 19], we report here
the preparation of a small libraryof 1-deoxybaccatinIII analogs
with the general structures of 4 and 5 from 1-deoxybaccatin VI
and the evaluation of their antitumor activities (Fig. 1).
acylated baccatin
8 in 87 % yield. Selective C13
acetylation of 8 by means of 4-dimethylaminopyridine
(DMAP) and acetic anhydride in tetrahydrofuran afforded
the desired 13-acetyl derivative 9 in 84 % yield, which
reacted with the corresponding m-substituted benzoic acid
in the presence of dicyclohexylcarbodiimide (DCC) and
DMAP at 50 °C to furnish compounds 10a–10c. None of
the C4-acylated baccatin was obtained, probably because
of the much hindered position of the C4 hydroxyl group.
To install the acetyl group on the C4 position, selective
acetylation of the C7 hydroxy group, followed by further
reaction with lithium bis(trimethylsilyl)amide (LiHMDS),
AcCl afforded 4-O-acetoacetates 4a–4c in total 57–65 %
yields by 5 steps. Deprotection of the acetonide of com-
pounds 4a, 4b under acidic conditions afforded the 9,
10-diol derivatives 5a, 5b in moderate yield.
Results and Discussion
As reported, taxol analogs with meta-substituted benzoyl
groups at C2 such as m-azidobenzoyl and m-methoxyben-
zoyl derivatives can be more active than taxol. Initially, we
The C4 cyclopropyl ester was found to be more potent
than paclitaxel in the bioassays [21]. This trend indicates
that the four-carbon chain at C4 is probably the optimal
synthesized and investigated
a
series of C2-ester
Fig. 1 Taxol and
1-deoxybaccatin VI analogs
OAc
O
O
OH
OAc
O
HO
Ph
NH
O
OH
O
Ph
HO
H
O
OH
O
AcO
HO
BzO
H
AcO
O
O
R
1
2a, R = H
2b, R = N3
OH
O
OH
AcO
1
18
O
OAc
O
10 OAc
17
9
OAc
O
OAc
19
AcO
13
H
16
AcO
AcO
7
2
5
O
4
O
O
O
O
BzO
O
O
R1
AcO
20
R2
O
R1
R2
O
4a, R1 = m-MeO-Ph, R2 = Me
4b, R1 = m-Br-Ph, R2 = Me
4c, R1 = m-N3-Ph, R2 = Me
5a, R1 = m-MeO-Ph, R2 = Me
5b, R1 = m-Br-Ph, R2 = Me
1-Deoxybaccatin VI (3)
4d, R1 = m-MeO-Ph, R2 = cyclopropyl
4e, R1 = Ph, R2 = CF3
4f, R1 = m-MeO-Ph, R2 = CF3
4g, R1 = m-Br-Ph, R2 = CF3
4h, R1 = m-MeO-Ph, R2 = CF2H
123

Synthesis and antitumor activity of 1-deoxybaccatin III analogs
1575
Scheme 1
OH
OAc
O
OH
OAc
OAc
O
OH
O
OH
O
a
b
c
HO
AcO
HO
BzO
BzO
BzO
HO
AcO
O
HO
6
3
7
O
O
O
O
O
O
OH
OH
O
OH
O
d
e
f
AcO
HO
AcO
O
HO
HO
HO
O
HO
HO
R
O
10a, R = OMe
10b, R = Br
10c, R = N3
9
8
O
O
OH
OH
O
O
O
OAc
O
OAc
O
OAc
O
AcO
g
h
AcO
AcO
O
O
HO
AcO
AcO
R
R
O
R
O
O
5a, R = OMe
5b, R = Br
4a, R = OMe
4b, R = Br
4c, R = N3
11a, R = OMe
11b, R = Br
11c, R = N3
Reagents and conditions: (a) NH2NH2, r.t., 71%; (b) 2,2-DMP, Montmorillonite K10,
o
r.t., 95 %; (c) Triton B, r.t., 87%; (d) Ac O, DMAP, THF, 0 C., 84%; (e) appropriate
2
m-substituted benzoic acids, DMAP, DCC/Toluene, 50 oC, 91% (10a), 88% (10b) and
74% (10c); (f) Ac2O, DMAP, DCC, Toluene, 55 C, 82% (11a), 80% (11b) and 82%
o
o
(11c); (g) AcCl, LiHMDS, THF, 0 C, 79% (4a), 78% (4b) and 70% (4c); (h) 0.1 N
HCl, MeOH, r.t., 24 h, 63% (5a) and 74% (5b).
size for the effective receptor binding. In order to further
optimize activity, the cyclopropylcarbonyl group was intro-
duced to the C4 position by treating 11a with LiHMDS,
cyclopropylcarboxyl chloride in THF at 0 °C to give the
desired compound 4d (Scheme 2).
Scheme 2
O
O
O
O
OAc
O
OAc
O
AcO
AcO
a
O
O
O
In the course of our SAR study of taxoids, we set out to
incorporate fluorine into taxoids to study the effects of
fluorine incorporation on the cytotoxicity of the resulting
analogs. Novel taxoids bearing a 2,2,2-trifluoroacetyl
group at the C4 position and modifications at the C2
position were synthesized. From compound 7, the first
acetylation of C7 and C13 hydroxyl groups, followed by
treatment with trifluroacetic anhydride in the presence of
DMAP in toluene at 60 °C, afforded compound 4e. Using
similar methods, compounds 4f and 4g were obtained from
11a and 11b in 80 and 88 % yield, respectively. Compound
4h was obtained from 11a by treatment with 2,2-difluoro-
acetic anhydride, DMAP in toluene at r.t. for 12 h in 86 %
yield (Scheme 3).
HO
O
MeO
O
MeO
O
4d
11a
Reagents and conditions: (a) LiHMDS, cyclopropylcarbonyl
chloride, THF, 0 °C, 77%.
Biological activities of synthesized taxoids 4a–4h, 5a,
5b were evaluated in cytotoxicity assays against two tumor
cell lines including A 549 (human lung carcinoma) and
MCF-7 (breast cancer) cell lines. We employed these
acetonide compounds because the 9,10 positions were
reported not to interact directly with tubulin [2] and the
effectiveness of acetal groups in the 9,10-positions of the
taxane skeleton [22]. Also, the 9,10-deprotected derivatives
123

1576
Y.-Y. Qiu et al.
Scheme 3
O
O
O
O
O
O
OAc
O
OAc
O
OH
O
AcO
b
a
AcO
HO
O
BzO
BzO
O
HO
HO
O
O
F3C
11d
4e
7
O
O
O
O
OAc
OAc
AcO
b
AcO
O
O
HO
O
O
O
O
R
O
R
O
F3C
11a, R = MeO
11b, R = Br
4f, R = MeO
4g, R = Br
O
O
O
O
OAc
OAc
O
AcO
c
AcO
O
O
HO
O
O
MeO
O
MeO
O
O
HF2C
11a
4h
Reagents and conditions: (a) Ac2O, DMAP, THF, r.t., 83%; (b) (CF3CO)2O, DMAP,
toluene, r.t, 83% (4e), 88% (4f) and 80% (4g); (c) (CHF2CO)2O, DMAP, toluene, r.t., 12
h, 86% .
5a, 5b were synthesized for comparison. The results are
presented in Table 1. 1-Deoxybaccatin VI (3) showed no
cytotoxic activities against A 549 and MCF-7 cell lines.
For the acetonide derivatives, compounds with acetyl
(4a–4c), 2,2,2-trifluoroacetyl (4e–4g) or 2,2-difluoroacetyl
group (4i) at the C4 position showed no activity, regardless
of the properties of C2 substituents. On the contrary,
replacement of the 4-acetyl group with the cyclopropyl-
carbonyl group leads to analogs possessing enhanced
cyctotoxicity against the A 549 cell line (compound 4d vs.
4a). On the other hand, the 9,10-diol derivatives 5a, 5b
exhibited improved activity against the A549 tumor cell
line compared to the corresponding 9,10-acetonide com-
pounds 4a, 4b. Obviously, electronic properties of the
terminal group in the substituents on C4, C9, and C10
constitute important factors.
III analogs (taxoids) modified with 3-oxobutyryl, 2-methyl-
3-oxopentoyl groups, or others instead of the acetyl group at
the C4 position. 1-Deoxybaccatin VI (3) showed no cyto-
toxicity activities against A 549 and MCF-7 cell lines. The
present SAR studies showed that the electronic properties of
the terminal group in the substituent on C4, C9, and C10
constituted important factors in the cytotoxic activities
against A 549 and MCF-7 cell lines. Since 1-deoxybaccatin
III derivatives are very difficult to prepare through deoxy-
genation of baccatin III and paclitaxel, the synthetic
methodology described here and better understanding of the
chemical reactivity of taxoids would be useful for more
efficient syntheses of selected 1-deoxypaclitaxel analogs
with potentially greater therapeutic benefits.
In conclusion, several new 1-deoxybaccatin III analogs
were conveniently synthesized from readily available
1-deoxybaccatin VI, a major taxoid component in Taxus
chinensis, Rehd. Var. mairei. These include 1-deoxybaccatin
Experimental
All reported yields are isolated yields after column chro-
matography or crystallization. Column chromatography
123

Synthesis and antitumor activity of 1-deoxybaccatin III analogs
1577
Table 1 Cytotoxicity of paclitaxel and analogs 4a–4h, 5a, 5b
O
O
OH
OH
OAc
O
OAc
AcO
O
AcO
O
O
O
O
O
O
R1
R1
R2
O
R2
O
4
5
Compounds
R1
R2
Cytotoxic activity IC50/lg cm-3
A 549
MCF-7
Taxol
3
–
–
–
0.00244
[100
0.421
[100
[100
–
4a
CH3
[100
4b
4c
4d
CH3
CH3
[100
[100
23.29
[100
[100
[100
4e
4f
CF3
CF3
[100
[100
[100
[100
4g
CF3
[100
[100
4h
5a
CF2H
CH3
[100
[100
[100
29.68
123

1578
Y.-Y. Qiu et al.
Table 1 continued
Compounds
R1
R2
Cytotoxic activity IC50/lg cm-3
A 549
MCF-7
5b
CH3
63.51
[100
79.6, 75.0, 74.9, 72.1, 70.7, 69.7, 55.4, 46.8, 45.9, 41.9,
37.8, 36.6, 33.1, 27.5, 27.0, 26.8, 24.8, 21.2, 16.9,
12.5 ppm; MS (ESI): m/z = 623.3 [M ? Na]?.
was performed with silica-gel H (Qingdao Haiyang
Chemical Plant, P.R. China). The NMR spectra were
recorded with a Bruker Avance/AV 500. Chemical shifts
are reported in parts per million (ppm), and coupling
constants (J) are reported in hertz (Hz). Chemical shifts in
CDCl3 were reported on a scale relative to CHCl3
4,7-Bis(deacetyl)-2-(3-bromobenzoyl)-9,10-O-isopropyli-
dene-1-deoxybaccatin VI (10b, C32H41BrO9)
(7.26 ppm) for 1H NMR and to CDCl3 (77.23 ppm) for 13
C
10b was prepared from 4,7-deacetyl-2-debenzoyl-9,10-O-
isopropylidene-1-deoxybaccatin VI (9) and m-bromoben-
zoic acid by using the procedure described for preparation
of 10a; yield 88 %; white solid. 1H NMR (500 MHz,
CDCl3): d = 8.17 (t, J = 1.5 Hz, Bz-20-H), 7.98 (dt,
J = 7.5, 1.0 Hz, Bz-60-H), 7.68 (dq, J = 7.5, 1.0 Hz, Bz-
40-H), 7.33 (t, J = 7.5 Hz, Bz-50-H), 5.62–5.66 (m, C2,
C13-H), 5.46 (t, J = 8.5 Hz, C7-H), 4.88 (d, J = 9.5 Hz,
C10-H), 4.81 (dd, J = 8.5, 2.5 Hz, C5-H), 4.42 (q,
J = 2.5 Hz, 2H, C20-H), 4.22 (d, J = 9.5 Hz, C9-H),
2.67–2.71 (m, C6-H), 2.64 (s, C4-OH), 2.46–2.53 (m, C14-
H), 2.36 (d, J = 5.0 Hz, C3-H), 2.13 (s, 3H, C13-OAc-H),
2.09–2.11 (m, C1-H), 2.05 (s, 3H, C7-OAc-H), 1.98 (s, 3H,
C18-H), 1.96–1.95 (m, C6-H), 1.77–1.79 (m, C14-H), 1.75
(s, 3H, C16-H), 1.66 (s, 3H, C17-H), 1.33 (s, 6H, 9,10-
acetonide-H), 1.07 (s, 3H, C19-H) ppm; 13C NMR
(125 MHz, CDCl3): d = 170.2, 169.2, 164.8, 137.6,
136.5, 135.8, 132.9, 132.8, 129.9, 128.5, 122.3, 106.8,
86.3, 81.7, 79.9, 74.8, 74.4, 71.9, 71.4, 69.7, 47.1, 46.0,
42.4, 37.8, 34.4, 32.9, 27.9, 26.9, 25.2, 21.6, 21.2, 16.8,
14.0 ppm; MS (ESI): m/z = 671.2 [M ? Na]?.
NMR as internal references. Chemical shifts in 19F NMR
spectra were reported in ppm downfield from internal flu-
orotrichloromethane (CFCl3). MSs were recorded on a
Thermo Finnigan LCQ Advantage Mass spectrometer. All
chemicals were dried or purified according to standard
procedures prior to use.
4,7-Bis(deacetyl)-9,10-O-isopropylidene-2-(3-methoxyben-
zoyl)-1-deoxybaccatin VI (10a, C33H44O10)
To a stirred solution of 165.2 mg 4,7-deacetyl-2-deben-
zoyl-9,10-O-isopropylidene-1-deoxybaccatin VI (9, 0.35
mmol) in 4 cm3 toluene was added 161.1 mg m-methoxy-
benzoic acid (1.06 mmol), 130.2 mg DMAP (1.06 mmol),
and 218.7 mg DCC (1.06 mmol). The reaction mixture was
stirred at 50 °C for about 6 h. The solvent was evaporated,
followed by adding 8 cm3 EtOAc. Solids were removed by
filtration, and the filtrate was concentrated in vacuo. The
crude residue was purified by column chromatography on
silica gel using EtOAc and n-hexane (1/2 v/v) to afford 10a
(598 mg, 94 %) as white solid. 1H NMR (500 MHz,
CDCl3): d = 7.59 (d, J = 8.0 Hz, Bz-60-H), 7.54–7.55 (m,
Bz-20-H), 7.35 (t, J = 8.0 Hz, Bz-50-H), 7.09–7.11 (m, Bz-
40-H), 5.81 (dd, J = 5.0, 2.0 Hz, C2-H), 5.71 (dd,
J = 10.0, 2.0 Hz, C13-H), 4.98 (s, 1H, C7-OH), 4.97 (d,
J = 9.5 Hz, C10-H), 4.74 (dd, J = 9.5, 3.0 Hz, C7-H),
4.48 (d, J = 9.5 Hz, C9-H), 4.27 (d, J = 8.0 Hz, C20-H),
4.25 (d, J = 8.0 Hz, C20-H), 4.00 (dd, J = 10.5, 7.0 Hz,
C5-H), 3.84 (s, 3H, Bz-30-OMe-H), 2.65 (m, C6-H), 2.55
(s, 1H, C4-OH), 2.49 (m, C14-H), 2.26 (d, J = 5.0 Hz, C3-
H), 2.18–2.22 (m, C1-H), 2.16 (s, 3H, C13-OAc-H),
1.92–1.98 (m, C6-H), 1.88 (s, 3H, C18-H), 1.85–1.86 (m,
C14-H), 1.71 (s, 3H, C16-H), 1.57 (s, 3H, C17-H), 1.51 (s,
6H, 9,10-acetonide-H), 1.08 (s, 3H, C19-H) ppm; 13C
NMR (125 MHz, CDCl3): d = 169.8, 165.1, 159.6, 138.5,
136.2, 130.8, 129.6, 122.0, 119.6, 114.7, 107.7, 87.7, 83.4,
2-(3-Azidobenzoyl)-4,7-bis(deacetyl)-9,10-O-isopropyli-
dene-1-deoxybaccatin VI (10c, C32H41N3O9)
10c was prepared from 4,7-deacetyl-2-debenzoyl-9,10-O-
isopropylidene-1-deoxybaccatin VI (9) and m-azidobenzo-
ic acid by using the procedure described for preparation of
10a; yield 74 %; white solid. 1H NMR (500 MHz, CDCl3):
d = 7.78 (d, J = 8.0 Hz, Bz-60-H), 7.71 (t, J = 2.0 Hz,
Bz-20-H), 7.44 (t, J = 8.0 Hz, Bz-50-H), 7.23 (ddd,
J = 8.0, 2.0, 1.0 Hz, Bz-40-H), 5.80 (dd, J = 5.0, 2.5 Hz,
C2-H), 5.72 (dd, J = 10.5, 1.5 Hz, C13-H), 4.99 (s, 1H,
C7-OH), 4.97 (d, J = 9.5 Hz, C10-H), 4.75 (dd, J = 9.5,
3.0 Hz, C7-H), 4.47 (d, J = 9.5 Hz, C9-H), 4.26 (d,
J = 8.0 Hz, C20-H), 4.22 (d, J = 8.0 Hz, C20-H), 4.00
(dd, J = 10.5, 7.0 Hz, C5-H), 2.62–2.69 (m, C6-H),
123

Synthesis and antitumor activity of 1-deoxybaccatin III analogs
1579
2.46–2.53 (m, 2H, C14-H, C4-OH), 2.28 (d, J = 5.0 Hz,
C3-H), 2.19–2.22 (m, C6-H), 2.17 (s, 3H, C13-OAc-H),
1.92–1.98 (m, C1-H), 1.88 (s, 3H, C7-OAc-H), 1.86 (dd,
J = 8.0, 2.0 Hz, C14-H), 1.71 (s, 3H, C18-H), 1.67 (s, 3H,
C16-H), 1.57 (s, 3H, C17-H), 1.52 (s, 6H, 9,10-acetonide-
H), 1.09 (s, 3H, C19-H) ppm; 13C NMR (125 MHz,
CDCl3): d = 169.9, 164.4, 141.0, 138.5, 136.4, 131.5,
130.2, 126.1, 124.0, 122.0, 107.9, 88.0, 83.5, 79.6, 75.1,
75.0, 72.2, 71.1, 69.8, 46.9, 46.0, 42.0, 37.9, 36.6, 33.2,
27.6, 27.1, 27.0, 24.9, 21.3, 17.0, 12.6 ppm; MS (ESI):
m/z = 634.3 [M ? Na]?.
C5-H), 4.53 (d, J = 8.0 Hz, C9-H), 4.27 (d, J = 8.0 Hz,
C20-H), 4.24 (d, J = 8.0 Hz, C20-H), 2.76 (d, J = 5.0 Hz,
C3-H), 2.59–2.66 (m, C6-H), 2.42–2.48 (m, C14-H), 2.18
(s, 3H, C13-OAc-H), 2.17 (s, 3H, C7-OAc-H), 2.05 (s, 3H,
C18-H), 1.95–2.03 (m, C1-H), 1.95 (s, 3H, C16-H), 1.84 (s,
3H, C17-H), 1.71 (s, 3H, 9,10-acetonide-H), 1.49–1.54 (m,
C6, C14-H), 1.31 (s, 3H, 9,10-acetonide-H), 1.18 (s, 3H,
C19-H) ppm; 13C NMR (125 MHz, CDCl3): d = 170.7,
169.7, 169.4, 164.5, 138.6, 135.6, 133.8, 133.1, 132.9,
129.8, 128.6, 122.3, 106.3, 84.2, 82.0, 80.6, 76.6, 74.4,
72.1, 71.1, 47.9, 42.4, 38.4, 34.8, 31.3, 26.9, 26.8, 26.6,
22.7, 21.6, 21.3, 15.1, 14.0 ppm; MS (ESI): m/z = 713.2
[M ? Na]?.
4-Deacetyl-9,10-O-isopropylidene-2-(3-methoxybenzoyl)-
1-deoxybaccatin VI (11a, C35H46O11)
2-(3-Azidobenzoyl)-4-deacetyl-9,10-O-isopropylidene-1-
deoxybaccatin VI (11c, C34H43N3O10)
To a stirred solution of 168.0 mg 10a (0.31 mmol) and
190.5 mg DMAP (1.55 mmol) in 3 cm3 dry toluene was
added 0.24 cm3 acetic anhydride (2.48 mmol) in one
portion, and the reaction mixture was stirred at 50 °C for
5 h. After cooling to room temperature, the mixture was
diluted with 50 cm3 EtOAc, washed with saturated aq.
NaHCO3 (20 cm3 9 2) and brine (20 cm3 9 2). The
organic phase was dried over anhydrous Na2SO4 and
concentrated to give the crude residue, which was purified
by column chromatography on silica gel using EtOAc and
hexanes to afford 11a (161.2 mg, 82 %) as white solid. 1H
NMR (500 MHz, CDCl3): d = 7.59 (d, J = 8.0 Hz, Bz-60-
H), 7.54–7.55 (m, Bz-20-H), 7.36 (t, J = 8.0 Hz, Bz-50-H),
7.10–7.13 (m, Bz-40-H), 5.89 (dd, J = 5.0, 2.0 Hz, C2-H),
5.70 (d, J = 9.0 Hz, C10-H), 5.24 (t, J = 8.5 Hz, C13-H),
4.89 (d, J = 9.0 Hz, C9-H), 4.74 (dd, J = 8.5, 2.5 Hz, C7-
H), 4.27–4.31 (m, 3H, C5, C20-H), 3.85 (s, 3H, Bz-30-
OMe-H), 2.65–2.70 (m, 1H, C6-H), 2.63 (s, 1H, C4-OH),
2.40 (d, J = 5.0 Hz, C3-H), 2.35 (m, C14-H), 2.18–2.22
(m, C1-H), 2.15 (s, 3H, C13-OAc-H), 2.05 (s, 3H, C7-
OAc-H), 1.96–2.01 (m, C6-H), 1.94 (s, 3H, C18-H),
1.82–1.84 (m, C14-H), 1.72 (s, 3H, C16-H), 1.64 (s, 3H,
C17-H), 1.46 (s, 3H, 9,10-acetonide-H), 1.36 (s, 3H, 9,10-
acetonide-H), 1.07 (s, 3H, C19-H) ppm; 13C NMR
(125 MHz, CDCl3): d = 170.6, 169.8, 165.0, 159.6,
137.3, 136.8, 130.8, 129.6, 122.0, 119.7, 114.6, 106.6,
87.1, 81.8, 79.5, 74.8, 74.4, 70.7, 70.1, 69.7, 55.4, 47.0,
45.8, 42.2, 37.7, 34.4, 33.0, 27.6, 27.1, 26.9, 25.1, 21.7,
21.1, 16.7, 13.7 ppm; MS (ESI): m/z = 665.3 [M ? Na]?.
11c was prepared from 10c by using the procedure
described for preparation of 11a; yield 82 %; white solid.
1H NMR (500 MHz, CDCl3): d = 7.79 (d, J = 8.0 Hz,
Bz-60-H), 7.71 (t, J = 2.0 Hz, Bz-20-H), 7.45 (t,
J = 8.0 Hz, Bz-50-H), 7.24 (ddd, J = 8.0, 2.0, 1.0 Hz,
Bz-40-H), 5.87 (dd, J = 5.0, 2.0 Hz, C2-H), 5.71 (dd,
J = 10.5, 1.5 Hz, C13-H), 5.24 (d, J = 9.5 Hz, C10-H),
4.89 (d, J = 9.5 Hz, C9-H), 4.74 (dd, J = 8.5, 2.5 Hz, C7-
H), 4.25–4.28 (m, 3H, C5, C20-H), 2.64–2.70 (m, C6-H),
2.42 (d, J = 5.0 Hz, C3-H), 2.32–2.38 (m, C14-H),
2.19–2.23 (m, C6-H), 2.16 (s, 3H, C13-OAc-H), 2.06 (s,
3H, C7-OAc-H), 1.96–2.02 (m, C1-H), 1.94 (s, 3H, C18-
H), 1.82–1.84 (m, C14-H), 1.72 (s, 3H, C16-H), 1.64 (s,
3H, C17-H), 1.46 (s, 3H, 9,10-acetonide-H), 1.36 (s, 3H,
9,10-acetonide-H), 1.07 (s, 3H, C19-H) ppm; 13C NMR
(125 MHz, CDCl3): d = 170.8, 169.9, 164.5, 141.0, 137.5,
137.1, 131.5, 130.2, 126.1, 124.0, 122.4, 106.9, 87.5, 82.0,
79.5, 75.0, 74.6, 71.1, 70.3, 69.9, 47.2, 46.0, 42.4, 37.9,
34.6, 33.2, 27.8, 27.2, 27.1, 25.3, 21.9, 21.3, 16.9,
13.9 ppm; MS (ESI): m/z = 776.3 [M ? Na]?.
9,10-O-Isopropylidene-2-(3-methoxybenzoyl)-1-deoxy-
baccatin VI (4a, C37H48O12)
To a stirred solution of 160.5 mg 11a (0.25 mmol) in
4 cm3 dry THF was added a solution of 0.5 cm3 LiHMDS
(0.5 mmol, 1 M in THF) dropwise. After the reaction
mixture was stirred at 0 °C for 1 h, a diluted solution of
38 mm3 acetyl chloride (0.55 mmol) in 3.8 cm3 THF was
added slowly. The mixture was stirred at 0 °C for another
5 h, quenched with 2 cm3 saturated aq. NH4Cl, diluted
with 60 cm3 EtOAc, and washed with water (20 cm3 9 2).
The organic layer was washed with brine (20 cm3 9 2),
dried over anhydrous Na2SO4, and concentrated to give the
crude residue, which was purified by column chromatog-
raphy on silica gel using EtOAc and n-hexane (2/7 v/v) to
afford 4a (135.1 mg, 79 %) as white solid. 1H NMR
(500 MHz, CDCl3): d = 7.66 (d, J = 8.0 Hz, Bz-60-H),
7.60–7.61 (m, Bz-20-H), 7.38 (t, J = 8.0 Hz, Bz-50-H),
2-(3-Bromobenzoyl)-4-deacetyl-9,10-O-isopropylidene-1-
deoxybaccatin VI (11b, C34H43BrO10)
11b was prepared from 10b by using the procedure
described for preparation of 11a; yield 80 %; white solid.
1H NMR (500 MHz, CDCl3): d = 8.18 (t, J = 1.5 Hz, Bz-
20-H), 7.98 (dt, J = 9.0, 1.5 Hz, Bz-60-H), 7.66 (dq,
J = 9.0, 1.5 Hz, Bz-40-H), 7.31 (t, J = 8.0 Hz, Bz-50-H),
5.95 (t, J = 9.0 Hz, C13-H), 5.67 (t, J = 9.0 Hz, C7-H),
5.58 (dd, J = 5.0, 2.0 Hz, C2-H), 4.95–4.99 (m, 2H, C10,
123

1580
Y.-Y. Qiu et al.
7.12–7.14 (m, Bz-40-H), 5.96 (t, J = 9.0 Hz, C13-H), 5.82
(dd, J = 5.0, 2.0 Hz, C2-H), 5.47 (t, J = 8.5 Hz, C7-H),
4.98 (d, J = 9.5 Hz, C10-H), 4.96 (d, J = 9.5 Hz, C9-H),
4.40 (d, J = 8.0 Hz, C20-H), 4.32 (d, J = 10.0 Hz, C5-H),
4.13 (d, J = 8.0 Hz, C20-H), 3.87 (s, 3H, Bz-30-OMe-H),
2.81 (d, J = 5.0 Hz, C3-H), 2.44–2.55 (m, 2H, C6, C14-
H), 2.25–2.19 (m, C1-H), 2.18 (s, 3H, C13-OAc-H), 2.05
(s, 3H, C7-OAc-H), 1.92 (s, 3H, C4-OAc-H), 1.86–1.89
(m, C6-H), 1.79 (s, 3H, C16-H), 1.75 (s, 3H, C17-H),
1.60–1.65 (m, C14-H), 1.45 (s, 3H, 9,10-acetonide-H), 1.37
(s, 3H, 9,10-acetonide-H), 1.19 (s, 3H, C19-H) ppm; 13C
NMR (125 MHz, CDCl3): d = 170.6, 169.0, 164.9, 159.6,
138.5, 136.6, 130.8, 129.6, 122.1, 119.8, 114.5, 106.2,
84.0, 82.1, 80.9, 76.5, 74.4, 71.5, 70.8, 69.4, 55.3, 48.1,
42.7, 42.4, 38.3, 34.8, 31.3, 27.1, 27.0, 26.9, 26.6, 22.6,
21.9, 21.2, 15.0, 13.8 ppm; MS (ESI): m/z = 707.3
[M ? Na]?.
2.44–2.50 (m, C14-H), 2.26 (s, C4-OH), 2.19 (s, 3H,
C13-OAc-H), 2.06 (s, 3H, C7-OAc-H), 1.93 (s, 3H, C4-
OAc-H), 1.91–1.92 (m, C1-H), 1.86–1.89 (m, C6-H), 1.79
(s, 3H, C18-H), 1.59–1.64 (m, C14-H), 1.46 (s, 3H, 9,10-
acetonide-H), 1.37 (s, 3H, 9,10-acetonide-H), 1.19 (s, 3H,
C19-H) ppm; 13C NMR (125 MHz, CDCl3): d = 170.7,
170.5, 169.1, 164.1, 140.8, 138.6, 133.6, 131.3, 130.1,
126.3, 124.2, 119.8, 106.3, 84.1, 82.1, 80.9, 76.4, 74.4,
72.0, 70.8, 69.3, 48.2, 42.7, 42.4, 38.3, 34.8, 31.3, 27.2,
27.1, 26.9, 26.6, 22.6, 21.9, 21.2, 15.1, 13.8 ppm; MS
(ESI): m/z = 718.2 [M ? Na]?.
4-(Cyclopropanecarbonyl)-9,10-O-isopropylidene-2-(3-
methoxybenzoyl)-1-deoxybaccatin VI (4d, C39H50O12)
4d was prepared from 11a and cyclopropanecarboxyl
chloride by using the procedure described for preparation
of 4a; yield 77 %; white solid. 1H NMR (500 MHz,
CDCl3): d = 7.60 (d, J = 8.0 Hz, Bz-60-H), 7.57 (dd,
J = 2.5, 1.0 Hz, Bz-20-H), 7.37 (t, J = 8.0 Hz, Bz-50-H),
7.13 (ddd, J = 8.0, 2.5, 1.0 Hz, Bz-40-H), 5.74 (dd,
J = 10.5, 1.5 Hz, C2-H), 5.26 (t, J = 8.5 Hz, C13-H),
4.90 (d, J = 8.0 Hz, C10-H), 4.75 (dd, J = 8.5, 3.0 Hz,
C7-H), 4.32 (d, J = 8.0 Hz, C9-H), 4.27–4.29 (m, 2H,
C20-H), 3.85 (s, 3H, Bz-30-OMe-H), 2.61–2.68 (m, C6-H),
2.43 (d, J = 5.0 Hz, C3-H), 2.38 (s, 3H, C13-OAc-H), 2.22
(dd, J = 16.0, 3.5 Hz, cyclopropane-10-H), 2.06 (s, 3H,
C7-OAc-H), 1.97–2.02 (m, C14-H), 1.94 (s, 3H, C18-H),
1.83–1.86 (m, C1-H), 1.72 (s, 3H, C16-H), 1.64 (s, 3H,
C17-H), 1.58–1.63 (m, C6-H), 1.46 (s, 3H, 9,10-acetonide-
H), 1.36 (s, 3H, 9,10-acetonide-H), 1.08–1.13 (m, 2H,
cyclopropane-H), 1.06 (s, 3H, C19-H), 0.94–0.98 (m, 2H,
cyclopropane-H) ppm; 13C NMR (125 MHz, CDCl3):
d = 173.9, 170.8, 166.9, 165.2, 159.8, 137.9, 136.7,
131.0, 129.8, 122.1, 119.9, 114.7, 106.8, 87.3, 82.0, 79.7,
75.0, 74.6, 70.9, 70.3, 69.6, 55.6, 47.2, 45.9, 42.4, 37.9,
34.6, 33.1, 27.7, 27.2, 27.1, 25.3, 22.8, 21.9, 16.8, 14.0,
13.3, 9.1, 8.9 ppm; MS (ESI): m/z = 733.3 [M ? Na]?.
2-(3-Bromobenzoyl)-9,10-O-isopropylidene-1-deoxybacca-
tin VI (4b, C36H45BrO11)
4b was prepared from 11b by using the procedure
described for preparation of 4a; yield 78 %; white solid.
1H NMR (500 MHz, CDCl3): d = 8.23–8.24 (m, Bz-20-H),
7.79 (d, J = 8.0 Hz, Bz-60-H), 7.73 (t, J = 8.0 Hz, Bz-40-
H), 7.36 (t, J = 8.0 Hz, Bz-50-H), 5.96 (t, J = 9.0 Hz,
C13-H), 5.79 (dd, J = 5.5, 2.0 Hz, C2-H), 5.46 (t,
J = 8.5 Hz, C7-H), 4.96–4.98 (m, C9, C10-H), 4.34 (d,
J = 8.0 Hz, C20-H), 4.30 (d, J = 9.5 Hz, C5-H), 4.11 (d,
J = 8.0 Hz, C20-H), 2.82 (d, J = 5.5 Hz, C3-H),
2.45–2.56 (m, 2H, C6, C14-H), 2.28 (s, 3H, C13-OAc-
H), 2.19 (s, 3H, C7-OAc-H), 2.05 (s, 3H, C4-OAc-H), 1.93
(s, 3H, C18-H), 1.91–1.92 (m, C1-H), 1.86–1.89 (m, C6-
H), 1.78 (s, 3H, C16-H), 1.75 (s, 3H, C17-H), 1.58–1.63
(m, C14-H), 1.45 (s, 3H, 9,10-acetonide-H), 1.36 (s, 3H,
9,10-acetonide-H), 1.18 (s, 3H, C19-H) ppm; 13C NMR
(125 MHz, CDCl3): d = 170.6, 170.4, 168.9, 163.6, 138.5,
136.4, 133.6, 132.9, 131.5, 130.2, 128.3, 122.6, 106.2,
84.0, 82.0, 80.8, 76.3, 74.4, 71.9, 70.8, 69.2, 48.2, 42.7,
42.4, 38.2, 34.7, 31.3, 27.1, 27.0, 26.9, 26.6, 22.5, 21.9,
21.2, 15.1, 13.8 ppm; MS (ESI): m/z = 755.2 (95 %),
757.2 (100 %) [M ? Na]?.
2-Benzoyl-9,10-O-isopropylidene-4-(trifluoroacetyl)-1-de-
oxybaccatin VI (4e, C36H43F3O11)
A solution of 64.2 mg 11a (0.10 mmol), 122.0 mg DMAP
(1.0 mmol), and 168.0 mg trifluoroacetic anhydride
(0.80 mmol) in 8 cm3 dry toluene was stirred at room
temperature for 12 h. After being quenched with 2 cm3
saturated aq. NaHCO3, the mixture was diluted with
60 cm3 EtOAc, washed with water (20 cm3 9 2) and brine
(20 cm3 9 2). The organic phase was dried over anhydrous
Na2SO4 and concentrated to give the crude residue, which
was purified by column chromatography on silica gel using
EtOAc and n-hexane (2/7 v/v) to afford 4e (62.6 mg, 83 %)
2-(3-Azidobenzoyl)-9,10-O-isopropylidene-1-deoxybacca-
tin VI (4c, C36H45N3O11)
4c was prepared from 11c by using the procedure described
1
for preparation of 4a; yield 70 %; white solid. H NMR
(500 MHz, CDCl3): d = 7.85 (d, J = 8.0 Hz, Bz-60-H),
7.75 (t, J = 2.0 Hz, Bz-20-H), 7.47 (t, J = 8.0 Hz, Bz-50-
H), 7.24 (ddd, J = 8.0, 2.0, 1.0 Hz, Bz-40-H), 5.97 (t,
J = 8.5 Hz, C13-H), 5.83 (dd, J = 5.0, 2.5 Hz, C2-H),
5.48 (t, J = 8.5 Hz, C7-H), 4.98 (d, J = 9.5 Hz, C10-H),
4.96 (d, J = 8.5 Hz, C5-H), 4.37 (d, J = 8.0 Hz, C20-H),
4.32 (d, J = 9.5 Hz, C9-H), 4.12 (d, J = 8.0 Hz, C20-H),
2.82 (d, J = 5.0 Hz, C3-H), 2.51–2.55 (m, C6-H),
1
as white solid. H NMR (500 MHz, CDCl3): d = 8.03 (t,
J = 7.5 Hz, 2H, Bz-20,60-H), 7.60 (t, J = 7.5 Hz, Bz-40-
H), 7.47 (t, J = 7.5 Hz, 2H, Bz-30,50-H), 5.94 (t,
J = 8.0 Hz, C13-H), 5.86 (dd, J = 5.0, 2.0 Hz, C2-H),
123

Synthesis and antitumor activity of 1-deoxybaccatin III analogs
1581
5.45 (t, J = 8.0 Hz, C7-H), 4.97 (d, J = 9.5 Hz, C10-H),
4.92 (d, J = 9.5 Hz, C9-H), 4.42 (d, J = 8.5 Hz, C20-H),
4.34 (d, J = 8.5 Hz, C20-H), 4.21 (d, J = 9.0 Hz, C5-H),
2.83 (d, J = 5.0 Hz, C3-H), 2.48–2.59 (m, 2H, C6, C14-
H), 2.12 (s, 3H, C13-OAc-H), 2.06 (s, 3H, C7-OAc-H),
1.98–1.97 (m, C1-H), 1.96–1.94 (m, C6-H), 1.91 (s, 3H,
C18-H), 1.78 (s, 6H, C16, C17-H), 1.47–1.45 (m, C14-H),
1.46 (s, 3H, 9,10-acetonide-H), 1.37 (s, 3H, 9,10-acetonide-
H), 1.18 (s, 3H, C19-H) ppm; 19F NMR (470.5 MHz,
CDCl3): d = -74.42 ppm; MS (ESI): m/z = 731.3
[M ? Na]?.
H), 1.18 (s, 3H, C19-H) ppm; 19F NMR (470.5 MHz,
CDCl3): d = -74.26 ppm; MS (ESI): m/z = 809.2
[M ? Na]?.
4-(Difluoroacetyl)-9,10-O-isopropylidene-2-(3-methoxy-
benzoyl)-1-deoxybaccatin VI (4h, C37H46F2O12)
4h was prepared from 11a and difluoroacetic anhydride by
using the procedure described for preparation of 4e; yield
1
86 %; white solid. H NMR (500 MHz, CDCl3): d = 7.66
(d, J = 8.0 Hz, Bz-60-H), 7.56 (dd, J = 2.5, 1.5 Hz, Bz-20-
H), 7.37 (t, J = 8.0 Hz, Bz-50-H), 7.14 (ddd, J = 8.0, 2.5,
2
1.0 Hz, Bz-40-H), 6.08 (t, JH–C–F = 53.5 Hz, difluoroace-
9,10-O-Isopropylidene-2-(3-methoxybenzoyl)-4-(trifluoro-
acetyl)-1-deoxybaccatin VI (4f, C37H45F3O12)
tyl-H), 5.96 (t, J = 9.0 Hz, C13-H), 5.86 (dd, J = 5.5,
2.0 Hz, C2-H), 5.47 (t, J = 8.5 Hz, C7-H), 4.97 (d,
J = 9.5 Hz, C10-H), 4.94 (d, J = 8.5 Hz, C5-H), 4.47
(d, J = 8.5 Hz, C20-H), 4.33 (d, J = 9.5 Hz, C9-H), 4.19
(d, J = 8.5 Hz, C20-H), 3.85 (s, 3H, Bz-30-OMe-H), 2.82
(d, J = 5.5 Hz, C3-H), 2.52–2.84 (m, C6-H), 2.45–2.51
(m, C14-H), 2.14 (s, 3H, C13-OAc-H), 2.06 (s, 3H, C7-
OAc-H), 1.93–1.95 (m, C1-H), 1.90 (s, 3H, C18-H), 1.78
(s, 3H, C16-H), 1.77 (s, 3H, C17-H), 1.53 (dd, J = 15.5,
7.0 Hz, C14-H), 1.45 (s, 3H, 9,10-acetonide-H), 1.36 (s,
3H, 9,10-acetonide-H), 1.17 (s, 3H, C19-H) ppm; 13C
NMR (125 MHz, CDCl3): d = 170.8, 170.6, 165.0, 160.6,
159.9, 138.6, 134.0, 130.7, 129.8, 122.4, 120.6, 113.9,
106.9, 104.9, 84.0, 83.5, 82.0, 76.1, 74.5, 71.3, 70.5, 69.3,
55.5, 48.0, 42.9, 42.6, 38.4, 34.7, 31.3, 27.3, 27.2, 27.0,
26.7, 22.0, 20.9, 15.2, 14.0 ppm; 19F NMR (470.5 MHz,
CDCl3): d = -126.50 (dd, J = 51.7, 9.4 Hz, 2F) ppm; MS
(ESI): m/z = 743.3 [M ? Na]?.
4f was prepared from 11a and trifluoroacetic anhydride by
using the procedure described for preparation of 4e; yield
1
88 %; white solid. H NMR (500 MHz, CDCl3): d = 7.65
(t, J = 7.5 Hz, Bz-60-H), 7.53–7.54 (m, Bz-20-H), 7.38 (t,
J = 8.0 Hz, Bz-50-H), 7.15 (dd, J = 8.0, 2.5 Hz, Bz-40-H),
5.95 (t, J = 8.5 Hz, C13-H), 5.88 (d, J = 4.0 Hz, C2-H),
5.47 (t, J = 9.0 Hz, C7-H), 4.97 (d, J = 9.0 Hz, C5-H),
4.92 (d, J = 8.5 Hz, C10-H), 4.48 (d, J = 8.5 Hz, C9-H),
4.34 (d, J = 9.0 Hz, C20-H), 4.22 (d, J = 9.0 Hz, C20-H),
3.84 (s, 3H, Bz-30-OMe-H), 2.84 (d, J = 5.5 Hz, C3-H),
2.54–2.59 (m, C6-H), 2.47–2.53 (m, C14-H), 2.14 (s, 3H,
C13-OAc-H), 2.06 (s, 3H, C7-OAc-H), 1.96–1.98 (m,
C1-H), 1.93–1.94 (m, C6-H), 1.91 (s, 3H, C18-H), 1.79 (s,
3H, C16-H), 1.78 (s, 3H, C17-H), 1.50 (dd, J = 15.5,
7.0 Hz, C14-H), 1.46 (s, 3H, 9,10-acetonide-H), 1.37
(s, 3H, 9,10-acetonide-H), 1.18 (s, 3H, C19-H) ppm; 13C
NMR (125 MHz, CDCl3): d = 171.2, 170.6, 165.0, 159.9,
155.4, 138.8, 133.9, 130.6, 129.9, 122.4, 120.9, 114.5,
113.7, 106.6, 85.6, 83.3, 81.9, 76.1, 74.5, 71.2, 70.3, 69.0,
55.4, 48.1, 43.0, 42.6, 38.4, 34.6, 31.3, 27.3, 27.2,
27.0, 26.7, 22.0, 20.8, 15.3, 14.0 ppm; 19F NMR (470.5
MHz, CDCl3): d = -74.33 ppm; MS (ESI): m/z = 761.3
[M ? Na]?.
9,10-Bis(deacetyl)-2-(3-methoxybenzoyl)-1-deoxybaccatin
VI (5a, C34H44O12)
To a stirred solution of 11.6 mg 4a (0.017 mmol) in
2 cm3 methanol was added dil. HCl (0.1 N) to maintain
pH 3–4. The reaction mixture was stirred at room
temperature for 18–24 h and then quenched with 1 cm3
saturated aq. NaHCO3, diluted with 40 cm3 EtOAc, and
washed with water (10 cm3 9 2). The organic layer was
washed with brine (10 cm3 9 2), dried over anhydrous
Na2SO4, and concentrated to give a crude residue, which
was purified by column chromatography on silica gel
using EtOAc and n-hexane (1/2 v/v) to afford 5a (8.1 mg,
74 %) as white solid. 1H NMR (500 MHz, CDCl3):
d = 7.65 (m, Bz-60-H), 7.61–7.60 (m, Bz-20-H), 7.37 (t,
J = 8.0 Hz, Bz-50-H), 7.14–7.12 (m, Bz-40-H), 6.16 (d,
J = 9.0 Hz, C10-H), 5.93 (t, J = 9.0 Hz, C13-H), 5.72
(dd, J = 5.5, 2.0 Hz, C2-H), 5.00 (d, J = 9.0 Hz, C9-H),
4.45–4.46 (m, C7-H), 4.43–4.44 (m, C5-H), 4.40 (d,
J = 8.5 Hz, C20-H), 4.16 (d, J = 8.5 Hz, C20-H), 3.86
(s, 3H, Bz-30-OMe-H), 2.87 (d, J = 5.5 Hz, C3-H),
2.53–2.59 (m, C6-H), 2.38–2.47 (m, C14-H), 2.26 (s,
3H, C13-OAc-H), 2.18 (s, 3H, C7-OAc-H), 2.13 (s, 3H,
C4-OAc-H), 1.96 (s, 1H, C16-H), 1.95 (s, 3H, C17-H),
2-(3-Bromobenzoyl)-9,10-O-isopropylidene-4-(trifluoro-
acetyl)-1-deoxybaccatin VI (4g, C36H42BrF3O11)
4g was prepared from 11b and trifluoroacetic anhydride by
using the procedure described for preparation of 4e; yield
1
80 %; white solid. H NMR (500 MHz, CDCl3): d = 8.18
(s, 1H, Bz-20-H), 7.96 (d, J = 8.0 Hz, Bz-60-H), 7.74 (d,
J = 8.0 Hz, Bz-40-H), 7.36 (t, J = 8.0 Hz, Bz-50-H), 5.94
(t, J = 8.0 Hz, C13-H), 5.84 (dd, J = 5.5, 2.0 Hz, C2-H),
5.46 (t, J = 8.5 Hz, C7-H), 4.97 (d, J = 9.5 Hz, C10-H),
4.93 (d, J = 8.0 Hz, C5-H), 4.42 (d, J = 8.5 Hz, C20-H),
4.32 (d, J = 9.5 Hz, C9-H), 4.19 (d, J = 8.5 Hz, C20-H),
2.83 (d, J = 5.5 Hz, C3-H), 2.54–2.59 (m, C6-H),
2.48–2.60 (m, C14-H), 2.13 (s, 3H, C13-OAc-H),
1.98–1.97 (m, C1-H), 1.95–1.94 (m, C6-H), 1.92 (s, 3H,
C18-H), 1.78 (s, 6H, C16, C17-H), 1.53–1.46 (m, C14-H),
1.45 (s, 3H, 9,10-acetonide-H), 1.37 (s, 3H, 9,10-acetonide-
123

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Y.-Y. Qiu et al.
1.91–1.93 (m, C6-H), 1.80 (s, 3H, C18-H), 1.63–1.67 (m,
C14-H), 1.14 (s, 3H, C19-H) ppm; 13C NMR (125 MHz,
CDCl3): d = 170.7, 170.5, 169.3, 165.1, 159.8, 137.6,
134.6, 131.0, 129.7, 122.1, 120.0, 114.6, 84.1, 82.0, 74.2,
74.1, 71.8, 69.1, 55.5, 47.1, 45.0, 44.3, 38.2, 31.5, 29.8,
27.2, 26.7, 22.9, 21.5, 21.3, 14.9, 12.7 ppm; MS (ESI):
m/z = 667.3 [M ? Na]?.
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for preparation of 5a; yield 63 %; white solid. H NMR
(500 MHz, CDCl3): d = 8.24 (d, J = 2.0 Hz, Bz-20-H),
7.98–7.99 (m, Bz-60-H), 7.72–7.74 (m, Bz-40-H), 7.36 (t,
J = 8.0 Hz, Bz-50-H), 6.14 (d, J = 9.0 Hz, C10-H),
5.91–5.94 (m, C2-H), 5.68–5.69 (m, C13-H), 5.02 (d,
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J = 6.0 Hz, C3-H), 2.54–2.61 (m, C6-H), 2.40–2.47 (m,
C14-H), 2.28 (s, 3H, C13-OAc-H), 2.19 (s, 3H, C7-OAc-
H), 2.13 (s, 3H, C4-OAc-H), 1.96 (s, 3H, C18-H),
1.93–1.94 (m, C1-H), 1.86–1.89 (m, C6-H), 1.80 (s, 3H,
C16-H), 1.73 (s, 3H, C17-H), 1.61–1.66 (m, C6-H), 1.15 (s,
3H, C19-H) ppm; 13C NMR (125 MHz, CDCl3):
d = 170.7, 170.4, 169.2, 163.7, 137.7, 136.6, 134.4,
133.1, 131.7, 130.4, 128.5, 122.8, 120.0, 84.0, 81.9, 77.3,
76.7, 74.2, 74.1, 72.2, 69.0, 47.2, 45.0, 44.3, 38.2, 38.1,
31.5, 27.2, 26.7, 22.8, 21.5, 21.3, 15.0, 12.7 ppm; MS
(ESI): m/z = 715.2 (95 %), 717.2 (100 %) [M ? Na]?.
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Acknowledgments The authors are grateful for support from the
National Natural Science Foundation of China (Project No.
21272154, 81202402, and 30672506), Leading Academic Discipline
Project of Shanghai Municipal Education Commission (Project No.
J50102), and Shanghai Pujiang Program (No. 10PJ1403700). The
authors also thank Dr. H. Deng and The Instrumental Analysis &
Research Center of Shanghai University for structural analysis.
123