Synthesis and biological evaluation of new 4-deacety-1,7,9-trideoxy-10- oxopaclitaxel via sinenxan A

Article abstract of DOI:10.1080/00397910701569767

A new 4-deacety-1,7,9-trideoxy-10-oxopaclitaxel (compound 1) was prepared in 21 steps via sinenxan A, a biosynthetic taxane. The biological evaluation in vitro against human cancer lines showed compound 1 to be devoid of cytotoxicity. Copyright Taylor & F

Full text of DOI:10.1080/00397910701569767

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Synthesis and Biological Evaluation of New
4‐Deacety‐1,7,9‐trideoxy‐10‐oxopaclitaxel
via Sinenxan A
Huixia Du a , Meng Zhang a , Dali Yin a , Yan Li b & Xiaoguang Chen b
a Department of Medicinal Chemistry , Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Science , Beijing,
China
b Department of Pharmacology , Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Science , Beijing, China
Published online: 19 Oct 2007.
To cite this article: Huixia Du , Meng Zhang , Dali Yin , Yan Li & Xiaoguang Chen (2007) Synthesis and
Biological Evaluation of New 4‐Deacety‐1,7,9‐trideoxy‐10‐oxopaclitaxel via Sinenxan A, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:21,
3779-3791, DOI: 10.1080/00397910701569767
To link to this article: http://dx.doi.org/10.1080/00397910701569767
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Synthetic Communicationsw, 37: 3779–3791, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701569767
Synthesis and Biological Evaluation of New
4-Deacety-1,7,9-trideoxy-10-oxopaclitaxel
via Sinenxan A
Huixia Du, Meng Zhang, and Dali Yin
Department of Medicinal Chemistry, Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Science,
Beijing, China
Yan Li and Xiaoguang Chen
Department of Pharmacology, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Science, Beijing,
China
Abstract: A new 4-deacety-1,7,9-trideoxy-10-oxopaclitaxel (compound 1) was
prepared in 21 steps via sinenxan A, a biosynthetic taxane. The biological evaluation
in vitro against human cancer lines showed compound 1 to be devoid of cytotoxicity.
Keywords: biological evaluation, 4-deacety-1,7,9-trideoxy-10-oxopaclitaxel, sinenxan
A, synthesis
The diterpenoid paclitaxel has proven to be one of the most potent antitumor
agents for the treatment of a variety of cancers. They are commonly used
against ovarian cancer, breast cancer, melanoma, and nonsmall cell lung
cancer. However, despite its powerful antitumor activity, this drug often
results in a number of undesired side effects as well as multidrug resistance
(MDR).[1] Therefore, it is essential to develop new anticancer agents with
Received July 19, 2007
Address correspondence to Dali Yin, Department of Medicinal Chemistry, Institute
of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical
College, Beijing 100050, China. E-mail: yindali@imm.ac.cn
3779

3780
H. Du et al.
fewer side effects, improved pharmacological properties, and optimized
activity through synthetic modification of structure.
Ojima et al.[2] reported that appropriate modification at the C10 position
and replacement of the phenyl group with an alkenyl or alkyl group at the C3
position of taxoids provide second-generation taxoids, which exhibit one to
two orders of magnitude more potency against drug-resistant cancer cell
lines. As part of our efforts in this area, we were interested in expanding the
structure–activity relationship (SAR) investigation of the C10 position.
Previous studies at this position have been primarily focused on modification
of the ester group and introduction of alkyl substituents; we were interested in
the oxidation state of C10, which might in theory affect the conformation of
the cyclooctane ring. The synthesis and biological evaluation of 10-oxo
analogs will enrich our knowledge of the structural requirements of the
10-substituted group.
Sinenxan A (SIA) was converted to 3 by the known methods.[3] Selective
deacylation at C10 followed by selective protection of the obtained C10
hydroxyl group as triethylsilyl (TES) ether provided 4. Then the exo olefin
was dihydroxylated, and the newly formed primary hydroxyl group was
acetylated; to give 5. Reduction of the C13 ketone of 5 at 08C provided the
desired a-C13 alcohol; subsequent protection of the 4,5-dihydroxyl groups
of 6 gave 7 as a major product. The acylation of the C13 hydroxyl group of
7 with Ac2O in the presence of 4-dimethylaminopyridine (DMAP) in
pyridine led to acetate 8 and acetylacetate 9, and the ratio of 8 and 9 and
increased from 65/33 (2 equiv DMAP) to 80/15 (0.4 equiv DMAP)
(Scheme 1).
Scheme 1.

4-Deacety-1,7,9-trideoxy-10-oxopaclitaxel
3781
The TES group of 8 was removed with tetrabutylammonium fluoride
(TBAF) in good yield, and the generated hydroxyl group was oxidized with
the catalytic amount of tetrapropylammonium perruthenate (TPAP) in the
presence of 4-methylmorpholine N-oxide (NMO) to furnish 11. Treatment
of 11 with a 4/2/1 mixture of AcOH/H2O/THF at 458C provided 12.[4]
Then the secondary C5 hydroxyl group of 12 was mesylated for 24 h at
room temperature to afford 13 in high yield. Because of intramolecular
acetyl transfer, the C2 and C20 acetyl groups were removed at the same
time to afford 14. The oxetane ring was formed according to Potier’s
procedure,[5] and subsequent benzoylation of the C2 hydroxyl group gave
15.[6a] Although acetylation of the C4 hydroxyl group of 15 under two con-
ditions (1.5 equiv of DMAP, 20 equiv of Ac2O, Py, 508C and 1.5 equiv of
LiHMDS, 08C, 30 min, then 1.3 equiv of AcCl)[6] were examined, 16 was
not achieved, which can be explained by the fact that the C13 acetyl group
and the C2 benzoyl group hinder the C4 hydroxyl group, making it less
reactive. Further studies in acylation of the C4 hydroxyl group are now in
progress in our laboratory (Scheme 2). On the other hand, we currently
evaluate the antitumor activity of the 4-deacety-10-oxo derivative for more
molecular modeling studies at the C10 position. Deacylation of 15 using
Red-Al afforded 17.[7] The coupling product of the C13 hydroxyl group
with side chain 17a was deprotected with 0.5% HCl/ethanol at room tempera-
ture to yield 1[8] (Scheme 3).
Compound 1 was evaluated in vitro for cytotoxicity against several
human cancer cell lines: A549 (nonsmall cell lung carcinoma), A549/taxol
(taxol-resistant lung carcinoma), HT-29 (colon carcinoma), MCF-7
(mammary carcinoma), and BGC823 (gastric carcinoma), and A2780
Scheme 2.

3782
H. Du et al.
Scheme 3.
(ovarian carcinoma) (Table 1). The results showed 1 to be devoid of cytotox-
icity. These findings showed that modification of C10 significantly affected
cytotoxicity.
EXPERIMENTAL
Melting points were obtained on a Yanaco micrometer, and all of the temperatures
are uncorrected. NMR spectra were recorded on Mercury Plus 400 and Varian
Inova 500 spectrometers (400 and 500 MHz for 1H and 100 MHz and 125 MHz
for 13C in CDCl3 unless otherwise noted). Mass spectra were obtained on an
Autospec-Ultima ETOF spectrometer. High resolution electron spray ionization
mass spectra (HRESIMS) spectra were recorded on an Agilent LC/MSD TOF.
Optical rotation was recorded on a Perkin-Elmer 341 polarimeter. Thin-layer
chromatography (TLC) preparation and flash chromatography were performed
on GF254 plates and silica gel (160–200 mesh), respectively. Reactions were
run under an atmosphere of N2. Tetrahydrofuran and toluene were distilled
from sodium prior to use. Dichloromethane was dried with P2O5. Pyridine was
dried with KOH. Commercially available reagents were used as supplied,
unless stated otherwise. Sinenxan A was provided by the Biosynthetic Laboratory
of Institute of Materia Medica.
Table 1. In vitro activity (IC50) of compound 1
Compound 1
A 549
1.68 ꢀ 1025
3.74 ꢀ 1025
2.83 ꢀ 1025
1.34 ꢀ 1025
2.78 ꢀ 1025
3.66 ꢀ 1025
A 549/Taxol
HT-29
MCF-7
BGC 823
A 2780

4-Deacety-1,7,9-trideoxy-10-oxopaclitaxel
3783
2a-Acetoxy-5a,10b-dihydroxy-4(20),11-dien-13-one (3)
At 08C, 1 M K2CO3 (47.4 mL, 47.4 mmol) was added to a solution of 2 (6.6 g,
15.8 mmol) in MeOH (80 mL). After being stirred for 20 h at 08C, the reaction
mixture was neutralized with 1 M HCl, concentrated, and extracted with EtOAc
(4 ꢀ 30 mL). The combined organic phase was washed with brine (50 mL),
dried over Na2SO4, and concentrated to give a crude product, which was
purified by flash chromatography (EtOAc–petroleum ether, 1:4) to afford 3
(2.9 g) and recover 2 (3.0 g) in 89.5% yield based on 54.5% conversion. Mp
1
239–2408C; H NMR (500 MHz) d 5.48 (dd, J ¼ 2 Hz, 6 Hz, 1H), 5.22 (dd,
J ¼ 6 Hz, 12 Hz, 1H), 5.08 (s, 1H), 4.75 (s, 1H), 4.15 (t, J ¼ 3 Hz, 1H), 3.49
(s, 1H), 2.78 (dd, J ¼ 7 Hz, 20 Hz, 1H), 2.43 (dd, J ¼ 12 Hz, 15 Hz, 1H),
2.36 (d, J ¼ 20 Hz, 1H), 2.12 (dd, J ¼ 2 Hz, 7 Hz, 1H), 2.06–2.04 (s þ m,
7H), 1.76 (s, 3H), 1.75–1.70 (m, 3H), 1.58–1.64 (m, 1H, 9-H), 1.25 (m, 1H),
1.19 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz) d 200.3, 169.7, 156.8, 147.9,
134.8, 113.1, 76.1, 71.0, 68.7, 49.2, 46.3, 39.8, 38.8, 38.1, 37.6, 36.2, 33.1,
31.0, 24.7, 22.5, 21.5, 13.9; ESIMS m/z 377 (M þ H)þ.
2a-Acetoxy-10b-triethylsilyl-5a-hydroxy-4(20),11-taxadien-13-one (4)
A solution of 3 (3.57 g, 9.49 mmol) and imidazole (3.87 g, 56.9 mmol) in dry
CH2Cl2 (30 mL) was mixed with TESCl (4.76 mL, 28.5 mmol) at 2408C for
20 min; the reaction mixture was then quenched with ice water (5 g) and
stirred for 30 min at rt. The mixture was concentrated and extracted with
EtOAc (3 ꢀ 50 mL). The combined organic phase was washed with brine
(50 mL), dried over Na2SO4, and concentrated to give a crude product,
which was purified by flash chromatography (EtOAc–petroleum ether, 1:6)
1
to yield compound 4 (2.8 g, 60.2%). Mp 132–1338C; H NMR (500 MHz)
d 5.48 (dd, J ¼ 2 Hz, 6 Hz, 1H), 5.11 (dd, J ¼ 6 Hz, 11.5 Hz, 1H), 5.07
(s, 1H), 4.72 (s, 1H), 4.14 (s, 1H), 3.50 (d, J ¼ 6 Hz, 1H), 2.76 (dd, J ¼
7 Hz, 20 Hz, 1H), 2.43 (dd, J ¼ 11.5 Hz, 15 Hz, 1H), 2.35 (d, J ¼ 20 Hz,
1H), 2.08 (d, J ¼ 7 Hz, 1H), 2.05–2.01 (s þ m, 7H), 1.74 (s, 3H), 1.71–1.69
(m, 2H), 1.61–1.57 (dd, J ¼ 6 Hz, 15 Hz, 1H), 1.16 (s, 3H), 1.12–1.09
(m, 1H), 0.96 (t, J ¼ 8 Hz, 9H), 0.84 (s, 3H), 0.61 (q, J ¼ 8 Hz, 6H);
13C NMR (100 MHz) d 200.7, 169.6, 158.0, 148.1, 133.1, 112.9, 76.2, 71.1,
68.6, 49.3, 47.6, 39.7, 38.9, 38.1, 37.5, 36.2, 36.1, 31.0, 24.6, 22.6, 21.5, 13.9,
6.8, 5.0. HRESIMS calcd. for C28H47O5Si (M þ H)þ 491.3193; found 491.3199.
2a,20-Diacetoxy-4a,5a-dihydroxy-10b-triethylsilyl-11-taxen-
13-one (5)
.
NMO H2O (2.92 g, 21.6 mmol) and 4% aqueous OsO4 (3.16 mL) were added
to a solution of 4 (2.12 g, 4.33 mmol) in THF (30 mL), acetone (40 mL), and

3784
H. Du et al.
H2O (12 mL). After the reaction mixture was stirred for 4 h at rt, saturated
aqueous NaHSO3 (30 mL) was added, and stirring continued for an additional
4 h. The resultant mixture was concentrated, poured into saturated aqueous
NaHCO3, and extracted with EtOAc (3 ꢀ 50 mL). The combined organic
phase was washed with brine (50 mL), dried (Na2SO4), and concentrated to
give a crude product (2.7 g).
Ac2O (1.9 mL, 20.1 mmol) was added to a solution of this crude triol
compound in dry pyridine (40 mL). After the reaction mixture was stirred
for 10 h at rt, MeOH (3 mL) was added to quench the reaction. The
resulting mixture was neutralized with 1 M HCl and extracted with EtOAc
(3 ꢀ 40 mL). The organic phase was washed with saturated aqueous
NaHCO3 and brine (40 mL), dried over Na2SO4, concentrated, and purified
by flash chromatography (EtOAc–petroleum ether, 1:8) to give compound
1
5 (2.18 g, 64.7%). [a]2D0 þ 688 (c 2.2, CHCl3); H NMR (500 MHz) d 5.53
(d, J ¼ 3.5 Hz, 1H), 5.02 (dd, J ¼ 5.5 Hz, 11 Hz, 1H), 4.53 (d, J ¼ 11.5 Hz,
1H), 4.06 (d, J ¼ 12 Hz, 1H), 3.79 (s, 1H), 3.03 (d, J ¼ 20 Hz, 1H), 2.98
(d, J ¼ 5 Hz, 1H), 2.71 (dd, J ¼ 7 Hz, 19.5 Hz, 1H), 2.41 (dd, J ¼ 11.5 Hz,
15 Hz, 1H), 2.18 (s, 3H), 2.12–2.01 (2s þ m, 9H), 1.99–1.91 (m, 2H),
1.76–1.74 (m, 1H), 1.73 (s, 3H), 1.44 (dd, J ¼ 6 Hz, 15 Hz, 1H), 1.20
(s, 3H), 0.97 (t, J ¼ 8 Hz, 9H), 0.88 (s, 3H), 0.60 (q, J ¼ 8 Hz, 6H);
13C NMR (100 MHz) d 201.1, 171.3, 169.8, 157.4, 133.5, 72.8, 69.5, 68.3,
65.6, 49.1, 48.6, 41.3, 38.4, 37.6, 37.3, 35.8, 31.2, 29.3, 24.6, 24.4, 24.2,
21.6, 20.8, 13.4, 6.8, 5.0. HRESIMS calcd. for C30H51O8Si (M þ H)þ
567.3347; found 567.3357.
2a,20-Diacetoxy-10b-triethylsilyl-4a,5a,13a-trihydroxy-11-taxene (6)
.
A solution of 5 (2.18 g, 3.85 mmol) and CeCl3 7H2O (3.58 g, 9.62 mmol) in
THF (20 mL) and MeOH (40 mL) was mixed with NaBH4 (1.46 g,
38.5 mmol) at 08C. The reaction mixture was stirred for 2 h at 08C and then
quenched with saturated aqueous NH4Cl (30 mL). After dilution with EtOAc
(60 mL), the organic phase was washed with brine (30 mL), dried over
Na2SO4, concentrated, and purified by flash chromatography (EtOAc–
petroleum ether, 1:6) to give 6 (1.6 g, 73%). [a]2D0 þ 498 (c 0.7, CHCl3);
1H NMR (400 MHz) d 5.31 (dd, J ¼ 1 Hz, 4 Hz, 1H), 4.95 (dd, J ¼ 5.2 Hz,
11.2 Hz, 1H), 4.49 (d, J ¼ 12 Hz, 1H), 4.31 (d, J ¼ 9.2 Hz, 1H), 4.30
(d, J ¼ 12 Hz, 1H), 3.93 (d, J ¼ 2.4 Hz, 1H), 3.14 (d, J ¼ 5.2 Hz, 1H), 2.88
(s, br, 1H), 2.64–2.55 (m, 1H), 2.20 (dd, J ¼ 11.2 Hz, 15 Hz, 1H), 2.17–2.02
(3s þ m, 10H), 2.02–1.99 (m, 1H), 1.76–1.74 (m, 2H), 1.62 (s þ m, 4H),
1.33 (dd, J ¼ 5.2 Hz, 15 Hz, 1H), 1.02 (m, 1H), 0.94 (t, J ¼ 8 Hz, 9H), 0.93
(s, 3H), 0.84 (s, 3H), 0.58 (q, J ¼ 8 Hz, 6H); 13C NMR (100 MHz) d 171.3,
169.6, 138.8, 135.2, 74.0, 69.7, 69.6, 67.6, 67.5, 66.0, 49.3, 47.6, 41.8, 37.4,
33.2, 32.9, 31.3, 30.7, 25.1, 24.7, 24.6, 21.7, 20.9, 15.9, 6.9, 5.0. HRESIMS
calcd. for C30H52O8NaSi (M þ Na)þ 591.3323; found 591.3323.

4-Deacety-1,7,9-trideoxy-10-oxopaclitaxel
3785
2a,20-Diacetoxy-10b-triethylsilyl-13a-hydroxy-4a,5a-
(dimethylmethylenedioxy)-11-taxene (7)
A solution of 6 (1.45 g, 2.55 mmol) and PPTS (320 mg, 1.28 mmol) in dry
CH2Cl2 (50 mL) mixed with 2,2-dimethoxypropane (4.7 mL) was stirred for
8 h at rt and then quenched by saturated aqueous NaHCO3 (5 mL). The
mixture was extracted with EtOAc (3 ꢀ 30 mL), and the combined extracts
were washed with brine (30 mL), dried (Na2SO4), concentrated and purified
by flash chromatography (EtOAc–petroleum ether, 1:10) to give desired 7
(1.25 g, 80.6%). Mp 172–1748C; [a]2D0 þ198 (c 0.3, CHCl3); 1H NMR
(400 MHz) d 5.26 (dd, J ¼ 2 Hz, 6.8 Hz, 1H), 4.90 (dd, J ¼ 5.6 Hz,
11.2 Hz, 1H), 4.52 (dd, J ¼ 6 Hz, 7.6 Hz, 1H), 4.46 (d, J ¼ 13.2 Hz, 1H),
4.46 (m, 1H), 3.91 (d, J ¼ 13.2 Hz, 1H), 2.61–2.57 (dd, J ¼ 6 Hz, 9.2 Hz,
1H), 2.54 (d, J ¼ 6.8 Hz, 1H), 2.28 (dd, J ¼ 11.2 Hz, 15 Hz, 1H), 2.18–
1.94 (3s þ m, 10H), 2.02–2.00 (m, 1H), 1.80–1.72 (m, 2H), 1.64 (s, 3H),
1.64–1.62 (m, 1H), 1.55 (s, 3H), 1.39 (dd, J ¼ 5.6 Hz, 15 Hz, 1H), 1.30
(s, 3H), 1.25–1.18 (m, 1H), 0.99 (s, 3H), 0.94 (t, J ¼ 8 Hz, 9H), 0.83
(s, 3H), 0.57 (q, J ¼ 8 Hz, 6H); 13C NMR (100 MHz) d 170.5, 170.3, 138.4,
133.5, 108.5, 85.1, 75.7, 72.5, 71.7, 67.8, 67.6, 49.3, 48.5, 48.2, 37.1, 35.6,
32.3, 32.2, 31.2, 29.4, 28.0, 27.0, 25.5, 25.0, 22.1, 21.0, 15.2, 6.9,
5.0. HRESIMS calcd. for C33H56O8NaSi (M þ Na)þ 631.3636; found
631.3647.
13a,2a,20-Triacetoxy-10b-triethylsilyl-4a,5a-(dimethylmethyl
enedioxy)-11-taxene(8) and 2a,20-Diacetoxy-13a-acetylacetoxy-
10b-triethylsilyl-4a,5a-(dimethylmethylenedioxy)-11-taxene (9)
A mixture of 7 (1.25 g, 2.06 mmol) and Ac2O (3.5 mL, 37.26 mmol) in dry
pyridine (25 mL) was stirred in the presence of DMAP (100 mg,
0.83 mmol) for 10 h at rt and then quenched with MeOH (5 mL). The
resulting mixture was neutralized with 1 M HCl and extracted with EtOAc
(3 ꢀ 20 mL). The organic phase was washed with saturated aqueous
NaHCO3 and brine (20 mL), dried over Na2SO4, concentrated, and purified
by flash chromatography (EtOAc–petroleum ether, 1:15–1:12) to recover 7
(102 mg) and give the desired compound 8 (980 mg) and side product
9 (200 mg) in 79.7% and 15.3% yields based on 91.8% conversion,
respectively.
Compound 8
1
[a]2D0 þ 168 (c 0.6, CHCl3); H NMR (400 MHz) d 5.89 (t, J ¼ 8.8 Hz, 1H),
5.30 (d, J ¼ 6.8 Hz, 1H), 4.88 (dd, J ¼ 5.6 Hz, 11.2 Hz, 1 H), 4.50
(t, J ¼ 4 Hz, 1H), 4.44 (d, J ¼ 12.4 Hz, 1H), 3.89 (d, J ¼ 12.8 Hz,1H),
2.43–2.41 (m, 2H), 2.23 (m, 1H), 2.16–2.01 (3s þ m, 11H), 1.86–1.80

3786
H. Du et al.
(s þ m, 5H), 1.72 (s, 3H), 1.65 (s, 3H), 1.60–1.56 (m, 3H), 1.39 (dd,
J ¼ 5.6 Hz, 15.2 Hz, 1H), 1.31–1.16 (s þ m, 5H), 0.94 (t, J ¼ 8 Hz, 9H),
0.84 (s, 3H), 0.56 (q, J ¼ 8 Hz, 6H); 13C NMR (100 MHz) d 170.5, 170.3,
139.7, 129.4, 107.3, 83.8, 74.5, 73.3, 70.8, 70.3, 67.1, 50.3, 49.2, 48.8, 38.1,
36.5, 34.0, 31.5, 28.6, 27.0, 26.5, 26.2, 24.7, 23.9, 22.2, 21.0, 20.9, 14.4,
6.9, 5.0. HRESIMS calcd. for C35H58O9NaSi (M þ Na)þ 673.3742; found
673.3745.
Compound 9
1
[a]2D0 þ 88 (c 0.06, CHCl3); H NMR (400 MHz) d 5.97 (t, J ¼ 8.8 Hz, 1H),
5.30 (d, J ¼ 7.2 Hz, 1H), 4.88 (dd, J ¼ 5.6 Hz, 11.2 Hz, 1H), 4.48
(t, J ¼ 4 Hz, 1H), 4.43 (d, J ¼ 12.8 Hz, 1H), 3.88 (d, J ¼ 12.8 Hz, 1H),
3.42 (s, 2H), 2.46–2.40 (m, 2H), 2.32–2.25 (s þ m, 4H), 2.18–2.06
(2s þ m, 8H), 1.96–1.79 (s þ m, 5H), 1.72 (s, 3H), 1.60–1.55 (s þ m, 4H),
1.39 (dd, J ¼ 5.6 Hz, 15.2 Hz, 1H), 1.30–1.16 (2s þ m, 7H), 0.94
(t, J ¼ 8 Hz, 9H), 0.84 (s, 3H), 0.56 (q, J ¼ 8 Hz, 6H); 13C NMR
(100 MHz) d 200.1, 170.5, 170.3, 166.8, 140.0, 128.9, 107.2, 83.8, 74.5,
73.2, 71.6, 70.7, 67.0, 50.3, 49.9, 49.3, 48.7, 38.0, 36.5, 34.0, 31.5, 30.2,
29.7, 28.6, 27.0, 26.5, 26.2, 24.6, 22.1, 20.9, 14.4, 6.9, 5.0. HRESIMS
calcd. for C37H60O10NaSi (M þ Na)þ 715.3847; found 715.3863.
13a,2a,20-Triacetoxy-10b-hydroxy-4a,5a-
(dimethylmethylenedioxy)-11-taxene (10)
.
A solution of 8 (880 mg, 1.35 mmol) and TBAF 3H2O (1.27 mg, 4.05 mmol)
in THF (50 mL) was stirred for 10 h at rt and then quenched with ice water
(5 mL). The mixture was concentrated, and extracted with EtOAc
(3 ꢀ 30 mL). The organic phase was washed with brine (20 mL), dried over
Na2SO4, concentrated, and purified by flash chromatography (EtOAc–
petroleum ether, 1:4) to give 10 (580 mg, 79.9%). [a]2D0 þ 108 (c 0.9,
CHCl3); 1H NMR (400 MHz)
d
5.91 (t, J ¼ 8.8 Hz, 1H), 5.30
(d, J ¼ 5.6 Hz, 1H), 5.50 (dd, J ¼ 5.6 Hz, 12 Hz, 1H), 4.49 (t, J ¼ 4 Hz,
1H), 4.45 (d, J ¼ 12.4 Hz, 1H), 3.88 (d, J ¼ 12.8 Hz, 1H), 2.63 (s, 1H),
2.48–2.39 (m, 2H), 2.73–2.24 (m, 1H), 2.18–2.03 (3s þ m, 11H), 1.99–
1.82 (s þ m, 6H), 1.74 (s, 3H), 1.67 (s, 3H), 1.51 (dd, J ¼ 5.6 Hz, 15 Hz,
1H), 1.31 (s, 3H), 1.20 (s þ m, 4H), 0.87 (s, 3H); 13C NMR (100 MHz)
d 170.5, 170.3, 138.9, 132.3, 107.3, 83.7, 74.4, 73.2, 70.6, 70.2, 67.2, 53.8,
49.2, 48.7, 38.0, 36.7, 34.0, 31.9, 29.3, 28.5, 26.9, 26.7, 26.1, 24.2, 23.6,
22.1, 20.9, 14.6. HRESIMS calcd. for C29H44O9Na (M þ Na)þ 559.2877;
found 559.2874.

4-Deacety-1,7,9-trideoxy-10-oxopaclitaxel
3787
13a,2a,20-Triacetoxy-4a,5a-(dimethylmethylenedioxy)-11-taxen-
10-one (11)
.
A mixture of 10 (500 mg, 0.93 mmol), NMO H2O (251 mg, 1.86 mmol), and
TPAP (32 mg, 0.09 mmol) in THF (10 mL) was stirred for 10 h at rt. The
reaction mixture was concentrated and purified by flash chromatography
(EtOAc–petroleum ether, 1:4) to give 12 (405 mg, 81.3%). Mp 47–488C;
[a]2D0 þ 38 (c 1.1, CHCl3); 1H NMR (400 MHz) d 5.86 (t, J ¼ 8.8 Hz,
1H),5.47 (d, J ¼ 6.4 Hz, 1H), 4.48–4.45 (d þ m, J ¼ 12.4 Hz, 2H), 3.90
(d, J ¼ 12.4 Hz, 1H), 2.58 (d, J ¼ 5.6 Hz, 1H), 2.55–2.41 (m, 2H), 2.33–
2.26 (m, 1H), 2.10–1.98 (3s þ m, 11H), 1.81 (s, 3H), 1.72–1.63 (m, 3H),
1.74 (s, 3H), 1.67 (s, 3H), 1.51 (dd, J ¼ 5.6 Hz, 15 Hz, 1H), 1.31 (s, 3H),
1.20 (s þ m, 4H), 0.87 (s, 3H); 13C NMR (100 MHz) d 205.6, 170.5, 170.3,
170.2, 142.1, 135.0, 107.9, 84.4, 75.1, 72.7, 69.1, 68.9, 59.9, 48.8, 48.0,
39.0, 36.8, 36.2, 29.3, 28.1, 27.3, 26.9, 26.0, 25.1, 23.8, 22.0, 21.0,
20.8, 15.8. HRESIMS calcd. for C29H43O9 (M þ H)þ 535.2901; found
535.2905.
13a,2a,20-Triacetoxy-4a,5a-dihydroxy-11-taxen-10-one (12)
A solution of 11 (270 mg, 0.51 mmol) in AcOH (16 mL), THF (4 mL), and
H2O (8 mL) was stirred at for 8 h 458C. The mixture was neutralized with
saturated aqueous NaHCO3 and extracted with EtOAc (3 ꢀ 20 mL). The
organic phase was washed with brine (20 mL), dried over Na2SO4, and
purified by flash chromatography (EtOAc–petroleum ether, 1:3) to give 12
1
(212 mg, 84.8%). [a]2D0 2198 (c 1.5, CHCl3); H NMR (400 MHz) d 5.67
(dd, J ¼ 3.6 Hz, 11.6 Hz, 1H), 5.53 (d, J ¼ 5.2 Hz, 1H), 4.52 (d, J ¼ 12 Hz,
1H), 4.08 (d, J ¼ 12 Hz, 1H), 3.90 (s, 1H), 3.16 (d, J ¼ 5.2 Hz, 1H), 2.88
(d, J ¼ 16 Hz, 1H), 2.70–2.62 (m, 2H), 2.34 (dd, J ¼ 4 Hz, 15.6 Hz, 1H),
2.23–2.08 (3s þ m, 11H), 1.91 (s, 3H), 1.80–1.69 (m, 2H), 1.44 (s, 3H),
1.16–1.12 (m, 1H), 1.06 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz)
d 203.1, 171.3, 170.1, 169.7, 144.3, 136.0, 73.5, 69.6, 68.6, 65.4, 58.7, 46.3,
41.9, 39.2, 35.7, 33.1, 31.0, 29.2, 27.8, 26.0, 24.4, 23.8, 21.6, 21.0,
20.8, 14.6. HRESIMS calcd. for C26H39O9 (M þ H)þ 495.2588; found
495.2598.
5a-Methanesulfonyloxy-4a-hydroxy-2a,13a,20-triacetoxy-11-
taxen-10-one (13)
Methanesulfonyl chloride (200 mL, 2.59 mmol) was added dropwise to a
solution of 12 (212 mg, 0.43 mmol) in dry pyridine (4 mL). The reaction
mixture was stirred for 24 h at rt and then quenched with ice water (2 g).
The resulting mixture was neutralized with 1 M HCl and extracted with

3788
H. Du et al.
EtOAc (3 ꢀ 30 mL). The organic phase was washed with saturated aqueous
NaHCO3 and brine (20 mL), dried over Na2SO4, concentrated, and purified
by flash chromatography (EtOAc–petroleum ether, 1:5) to give 12 (198 mg,
80.8%). 1H NMR (400 MHz) d 5.89 (t, J ¼ 8.8 Hz, 1H), 5.60 (d,
J ¼ 5.2 Hz, 1H), 4.78 (s, 1H), 4.64 (d, J ¼ 12.4 Hz, 1H), 4.00
(d, J ¼ 12.4 Hz, 1H), 3.19 (s, 1H), 3.07 (s, 3H), 3.00–2.94 (m, 2H), 2.56–
2.50 (dt, J ¼ 9.6 Hz, 15.2 Hz, 1H), 2.37 (dd, J ¼ 6.8 Hz, 15.2 Hz, 1H),
2.28–2.11 (3s þ m, 11H), 2.08–1.88 (s þ m, 4H), 1.75 (m, 1H), 1.49
(s, 3H), 1.35–1.28 (m, 1H), 1.17 (s, 3H), 0.94 (s, 3H); 13C NMR
(100 MHz) d 202.5, 171.3, 170.1, 169.7, 142.9, 138.0, 80.8, 74.1, 68.8,
65.3, 59.0, 47.2, 44.2, 38.8, 38.0, 36.2, 33.1, 30.7, 27.8, 27.0, 26.9, 26.0,
25.3, 24.1, 21.6, 20.8, 14.3. HRESIMS calcd. for C27H41O11S (M þ H)þ
573.2364; found 573.2367.
13a-Acetoxy-2a,4a,20-trihydroxy-5a-methanesulfonyloxy-11-
taxen-10-one (14)
1 M K2CO3 (500 mL, 0.50 mmol) was added to a solution of 13 (190 mg,
0.33 mmol) in MeOH (6 mL) and THF (3 mL). The reaction mixture was
stirred at 2108C for 30 min and then neutralized with 1 M HCl. The
resulting mixture was concentrated and extracted with EtOAc
(3 ꢀ 20 mL). The organic phase was washed with saturated aqueous
NaHCO3 and brine (20 mL), dried over Na2SO4, concentrated, and purified
by flash chromatography (EtOAc–petroleum ether, 1:2) to give 14
1
(100 mg, 61.7%). Mp 47.9–48.28C; [a]2D0 2198 (c 0.5, CHCl3); H NMR
(400 MHz) d 5.75 (dd, J ¼ 6.8 Hz, 9.2 Hz, 1H), 4.71 (s, 1H), 4.38 (s, br,
1H), 4.29 (d, J ¼ 11.6 Hz, 1H), 4.23 (d, J ¼ 4.8 Hz, 1H), 3.66
(d, J ¼ 11.2 Hz, 1H), 3.09 (s, 3H), 2.88 (d, J ¼ 16 Hz, 1H), 2.75
(d, J ¼ 5.6 Hz, 1H), 2.65–2.56 (m, 1H), 2.21 (s, 3H), 2.17–2.11 (s þ m,
5H), 1.97–1.94 (m, 3H), 1.71–1.63 (m, 1H), 1.42 (s, 3H), 1.30–1.26
(m, 1H), 1.17 (s, 3H), 0.96 (s, 3H); 13C NMR (100 MHz) d 203.3, 171.2,
143.4, 137.2, 81.2, 72.3, 69.0, 65.6, 59.0, 50.2, 43.5, 38.5, 38.2, 34.2,
30.5, 27.3, 27.0, 25.6, 24.4, 23.5, 21.1, 14.3. HRESIMS calcd. for
C23H37O9S (M þ H)þ 489.2152; found 489.2147.
13a-Acetoxy-2a-benzoy-5b,20-epoxy-4a-hydroxy-11-taxen-
10-one (15)
A solution of 14 (112 mg, 0.23 mmol) and DBU (40 mL) in dry toluene was
warmed to 1058C for 2 h; the crude mixture was purified by TLC (EtOAc–
petroleum ether, 6:1).
The obtained product and DMAP (298 mg, 2.44 mmol) in dry CH3CN
(4 mL) were cooled to 08C, and then DCC (529 mg, 2.562 mmol), in dry

4-Deacety-1,7,9-trideoxy-10-oxopaclitaxel
3789
CH3CN (5 mL) was added slowly. The reaction mixture was stirred at 08C for
24 h, quenched with MeOH (2 mL), and concentrated. After purification of the
crude product by TLC (EtOAc–petroleum ether, 3:1), the ester 15 was
obtained as a yellow oil (40 mg, 39.2%). [a]2D0 2408 (c 0.4, CHCl3);
1H NMR (400 MHz) d 7.94 (d, J ¼ 8 Hz, 2H), 7.603 (t, J ¼ 7.6 Hz, 1H),
7.48 (t, J ¼ 7.6 Hz, 2H), 5.93 (d, J ¼ 4 Hz, 1H), 5.69 (dd, J ¼ 3.6 Hz,
10.4 Hz, 1H), 4.77 (d, J ¼ 5.2 Hz, 1H), 4.33 (d, J ¼ 8 Hz, 1H), 4.22
(d, J ¼ 8 Hz, 1H), 2.79–2.70 (m, 1H), 2.66–2.60 (m, 2H), 2.34 (dd,
J ¼ 4.4 Hz, 15.6 Hz, 1H), 2.19–2.15 (s þ m, 4H), 1.98–1.83 (m, 4H), 1.79
(s, 3H), 1.46 (s, 3H), 1.40 (s, 3H), 1.36–1.33 (m, 1H), 1.10 (s, 3H);
13C NMR (100 MHz) d 202.3, 170.3, 165.5, 144.8, 136.8, 133.5, 129.8,
128.7, 81.4, 72.7, 68.1, 67.8, 64.1, 58.4, 46.5, 43.8, 39.6, 35.7, 33.6, 31.2,
29.7, 27.9, 27.7, 26.4, 23.6, 21.2, 14.7. HRESIMS calcd. for C29H37O7
(M þ H)þ 497.2533; found 497.2531.
2a-Benzoy-4a,13a-dihydroxy-5b,20-epoxy-11-taxen-10-one (17)
At 08C, ester 15 (23 mg, 0.046 mmol) in dry toluene (1 mL) and Red-Al
(3.5 M in toluene, 79 mL, 0.28 mmol) were stirred for 2 h and then
quenched with ice water (2 g). The resulting mixture was concentrated and
extracted with EtOAc (3 ꢀ 10 mL). The organic phase was washed with
brine (10 mL), dried over Na2SO4, concentrated, and purified by flash chrom-
atography (EtOAc–petroleum ether, 1:2) to furnish the alcohol 17 as a yellow
1
oil (15 mg, 71.4%). H NMR (500 MHz) d 8.05 (d, J ¼ 7.5 Hz, 2H), 7.60
(t, J ¼ 7.5 Hz, 1H), 7.48 (t, J ¼ 7.5 Hz, 2H), 5.88 (d, J ¼ 3 Hz, 1H), 4.76
(dd, J ¼ 3 Hz, 7.5 Hz, 1H), 4.42 (d, J ¼ 10 Hz, 1H), 4.35 (d, J ¼ 8 Hz,
1H), 4.27 (d, J ¼ 8 Hz, 1H), 2.85 (d, J ¼ 16 Hz, 1H), 2.80 (d, J ¼ 5 Hz,
1H), 2.78–2.73 (m, 1H), 2.44 (d, J ¼ 15.5 Hz, 1H), 2.40 (dd, J ¼ 2.5 Hz,
19 Hz, 1H), 2.18 (d, J ¼ 9 Hz, 1H), 2.01–1.99 (m, 1H), 1.96 (d, J ¼ 6 Hz,
1H), 1.90 (s, 3H), 1.62–1.60 (m, 2H), 1.45 (s, 3H), 1.38 (s, 3H), 1.00
(s, 3H); 13C NMR (100 MHz) d 200.3, 166.4, 142.8, 136.2, 133.7, 128.8,
128.1, 76.4, 72.8, 68.2, 67.8, 64.2, 56.4, 47.5, 44.3, 39.8, 35.2, 34.1, 32.1,
29.8, 27.6, 27.2, 22.9, 21.3, 14.7. HRESIMS calcd. for C27H35O6 (M þ H)þ
455.2428; found 455.2438.
4-Deacety-1,7,9-trideoxy-10-oxopaclitaxel (1)
Alcohol 17 (9 mg, 0.02 mmol), DCC (21 mg, 0.1 mmol), DMAP (5 mg,
0.04 mmol), and 17a (36 mg, 0.1 mmol) in toluene (5 mL) were stirred at rt
for 10 h. MeOH (2 mL) was then added to quench the reaction; the
resulting mixture was concentrated and extracted with EtOAc (3 ꢀ 20 mL).
The organic phase was washed with brine (10 mL); the obtained crude
product was mixed with EtOH (2 mL) and 0.5% aqueous HCl (0.2 mL) at rt

3790
H. Du et al.
for 12 h. Then the mixture was neutralized with saturated aqueous NaHCO3
and extracted with EtOAc (3 ꢀ 10 mL). The organic phase was washed
with brine (10 mL) and purified by TLC (EtOAc–petroleum ether, 1:1) to
give 12 (9 mg, 62.9%). Mp 201–2028C; [a]2D0 214º (c 0.4, CHCl3);
1H NMR (500 MHz) d 8.14 (d, J ¼ 7.5 Hz, 2H), 7.70 (d, J ¼ 7.5 Hz, 2H),
7.53 (d, J ¼ 7.0 Hz, 2H), 7.44 (t, J ¼ 7.0 Hz, 2H), 7.34 (t, J ¼ 7.5 Hz, 4H),
7.28–7.25 (m, 3H), 7.04 (d, J ¼ 10 Hz, 1H), 6.10 (d, J ¼ 10 Hz, 1H), 5.90
(dd, J ¼ 3 Hz, 6 Hz, 1H), 5.75–5.72 (m, 1H), 4.85 (dd, J ¼ 3 Hz, 7 Hz,
1H), 4.63 (d, J ¼ 1.5 Hz, 1H), 4.23 (d, J ¼ 8 Hz, 1H), 4.06 (d, J ¼ 8 Hz,
1H), 2.77 (d, J ¼ 15 Hz, 1H), 2.64 (d, J ¼ 6 Hz, 1H), 2.60–2.54 (m, 2H),
2.46 (d, J ¼ 15 Hz, 1H), 2.00–1.94 (m, 2H), 1.88–1.81 (m, 1H), 1.73
(s, 3H), 1.61–1.55 (m, 1H), 1.42 (s, 3H), 1.40–1.38 (m, 1H), 1.34 (s, 3H),
1.00 (s, 3H); 13C NMR (125 MHz) d 204.6, 172.3, 167.1, 165.6, 145.3,
139.6, 134.3, 133.9, 133.3, 131.8, 130.1, 129.6, 128.9, 128.6, 128.1, 127.1,
127.0, 88.5, 80.8, 75.2, 73.5, 73.0, 70.6, 60.4, 59.1, 54.1, 46.4, 38.4, 36.9,
36.1, 30.8, 27.5, 26.9, 26.2, 23.2, 15.9. HRESIMS calcd. for C43H48NO9
(M þ H)þ 722.3323; found 722.3330.
ACKNOWLEDGMENTS
This authors gratefully acknowledge financial supported of this work by
National Natural Science Foundation of China (Project No. 30572243) and
Beijing Natural Science Foundation (Project No. 7062048). We thank
Jungui Dai for kindly providing Sinenxan A (SIA).
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