Synthesis of 7,9-dideoxybaccatin IV analogs from sinenxan A

Article abstract of DOI:10.1016/j.tet.2005.03.137

Sinenxan A, a taxoid isolated from callus tissue cultures of Taxus yunnanensis was converted into 13-oxo-7,9-dideoxy-2-debenzoyl-2-acetyl-baccatin IV and 7,9-dideoxy-2-debenzoyl-4-deacetyl-baccatin IV, a key framework of 1,7,9-trideoxypaclitaxel. Several special steps in this transformation are worthy of note: (1) deoxygenation by treatment with hypophosphorous acid at C-14 position; (2) a highly regioselective O-deacetylation of taxanes at C-5 position; and (3) stereoselective reduction of the 13-carbonyl group by transannular assistance from the C-4-hydroxyl.

Full text of DOI:10.1016/j.tet.2005.03.137

Tetrahedron 61 (2005) 5519–5527
Synthesis of 7,9-dideoxybaccatin IV analogs from sinenxan A
*
Meng Zhang, Dali Yin, Ji-Yu Guo and Xiao-Tian Liang
Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050,
People’s Republic of China
Received 30 November 2004; revised 23 March 2005; accepted 25 March 2005
Abstract—Sinenxan A, a taxoid isolated from callus tissue cultures of Taxus yunnanensis was converted into 13-oxo-7,9-dideoxy-2-
debenzoyl-2-acetyl-baccatin IV and 7,9-dideoxy-2-debenzoyl-4-deacetyl-baccatin IV, a key framework of 1,7,9-trideoxypaclitaxel. Several
special steps in this transformation are worthy of note: (1) deoxygenation by treatment with hypophosphorous acid at C-14 position; (2) a
highly regioselective O-deacetylation of taxanes at C-5 position; and (3) stereoselective reduction of the 13-carbonyl group by transannular
assistance from the C-4-hydroxyl.
q 2005 Published by Elsevier Ltd.
1. Introduction
The diterpenoid paclitaxel (taxol), isolated from the
Pacific yew (Taxus brevifolia Nutt.) in 1971,1 is currently
one of the most promising antitumor agents available in
clinical trials for the treatment of skin, head and neck
cancers and has been approved for the treatment of
advanced ovarian, breast and lung cancer by FDA. For a
long time, paclitaxel, due to its complex molecular
Sinenxan A that possesses the typical 6/8/6 taxoid ring
structure, significant biological activity and its unique
and lack of 1, 7, and 9 oxygen groups is readily available
as a biosynthetic taxane in good yield.4 The development
of a procedure using sinenxan A as the starting material
mechanism of action, has been the subject of extensive
chemical and biological studies.
for preparation of 1,7,9-trideoxypaclitaxel and ‘second-
generation’ taxoid anticancer agents will be of significance.
Recently, we reported the synthesis of 7,9-dideoxy-2-
Recently, the study of taxanes has been focused on the
treatment of multidrug-resistance (MDR) cancer cells,
which is mainly caused by the overexpression of P-
debenzoyl-4-deacetyl-baccatin IV, a secondary target of
glycoprotein (P-gp). The overexpression of P-gp results in
1,7,9-trideoxypaclitaxel via sinenxan A.5 Herein, we
decreased accumulation of the drug within the cancer
provide a complete account of our work in this area.
cells. Taxane-like multidrug-resistant reversal agents have
been discovered that could increase cellular accumulation
of vincristin (VCR) in MDR tumor cell, such as taxinine
and its derivatives.2 The ‘second-generation’ taxoid
2. Results and discussion
anticancer agents that would not be recognized by P-gp
2.1. Synthesis of 13-oxo-baccatin IV analogue (10)
have also been developed and have displayed a notable
activity against the MDR cancer cells, such as SB-RA
4001, IDN-5109, etc.3
Our synthesis (Scheme 1) was started with the functional
group manipulation on ring A. Initial attempts to introduce
oxygen group at C-13 by treatment with PCC or SeO2 was
failed. It was probably due to the steric hindrance of the
acetyl group at C-14. Thus, C-14 oxygen group was
designed to be removed above all. 14-Deacetyl-sinenxan
A was readily available according to the method of the
literature.6 Although, the yield of O-deacetyl of C-14 was
Keywords: Sinenxan A; Deoxygenation; Paclitaxel.
*
Corresponding author. Tel.: C86 10 63165248; fax: C86 10 63017757;
e-mail: yindali@imm.ac.cn
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.03.137

5520
M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
In an attempt to construct an oxetane moiety, treatment of 4
with OsO4/NMO, followed by Ac2O afforded 6 as the major
product. The configuration of 4-b-CH2OH was confirmed
by NOE differential spectra. The secondary hydroxyl group
at C-5 was mesylated to give 7. Because of intramolecular
acetyl transfer, 2-acetyl and 20-acetyl were removed at the
same time to provide compound 8 in quantitative yield. The
oxetane ring was formed according to Potier’s procedure9 to
give 9 in 36% yield. To protect 9 from opening of the
oxetane ring, the newly formed 9 was immediately
converted into 10 by treatment with Ac2O/DMAP
(Scheme 2).
Noticeably, compound 9 was very sensitive to acidic
medium so that a trace of acidic impurities in CDCl3,
which did not be processed by K2CO3 would convert the
oxetane ring to a furan ring (11) (Scheme 3). The protons at
C-20 position of 11 had a characteristic coupling constant
JZ10 Hz of furan ring, which was in agreement with the
literature.10 And 12, obtained from 11, was observed a
evident H-5 shift from 3.96 to 4.99 ppm, which indicated an
acetylation at 5-hydroxy.
Scheme 1. (a) K2CO3/MeOH, 40%; (b) NaH/CS2/THF, then MeI, 95%;
(c) Bu3SnH/AIBN/toluene, 82%; (d) PCC/NaOAc/Celite/benzene, 65%
based on 75% conversion.
only 40%, due to the poor selectivity, this could be
overcome by reacetylation of the other hydrolysates back
to sinenxan A by treatment with Ac2O/pyridine. The C-14
deoxy compound 2 was prepared from 1, via the S-methyl-
dithiocarbonate, using Barton’s deoxygenation procedure
(NaH/CS2, then with MeI, heat, 95%, followed by Bu3SnH-
AIBN, heat, 82%). Because of toxicity of tin compounds, an
alternative deoxygenation method was utilized to prepare 2
by treatment of 1 with hypophosphorous acid. Studies
indicated addition of an olefin was necessary to raise the
yield of 2 (Table 1). It could be explained that the additional
olefin would quench the excess phosphorus radical pro-
duced in the reaction, which may further, react with D4,20
double bond of taxane. After C-14 oxygen group was
removed, compound 3 was successfully obtained in
moderate yield by allylic oxidation (PCC in refluxing
benzene) at C-13. In this step, the reaction time had to be
controlled because the newly formed 3 in reaction mixture
would be diminished after a long time of heating.
Table 1. Deoxygenation of C-14 S-methyl-dithiocarbonate with hypophos-
phorous acid
Entry
Conditions
2 (%)
1
2
3
4
50% H3PO2, AIBN, Et3N, 1,4-dioxane
42
39
74
75
50% H3PO2, AIBN, i-Pr2EtN, 1,4-dioxane
50% H3PO2, AIBN, Et3N, cyclohexene, 1,4-dioxane
50% H3PO2, AIBN, Et3N, 1-dodecene, 1,4-dioxane
Various methods for preparation of 7-deoxypaclitaxel from
13-oxo taxane such as taxine B have been reported. A
similar synthetic route was designed following literature
methods.7 Thus, the next target was the construction of ring
D. O-Deacetyl of the three acetyl groups of 3 with K2CO3/
MeOH was in the order of C-10OC-2OC-5. Thus, initial
synthetic strategy of thorough hydrolysis and then selective
acetylation was used to deal with 3 to obtain compound 4,
but the yield was low. Fortuitously, we found that the 5-O-
acetate of 3 could be selectively cleaved by t-BuOK in THF
to give 4 in 93% yield. And this regioselective deacetylation
by t-BuOK could also be used to remove 5-O-acetyl group
of compound 2 in good yield. A possible mechanism
involving the formation of ketene has been proposed in our
previous study.8
Scheme 2. (a) OsO4/NMO, then NaHSO3; (b) Ac2O/CH2Cl2/pyridine, two
steps 85%; (c) MsCl/pyridine, 86%; (d) K2CO3/MeOH, quantitative;
(e) DBU/toluene, 36%; (f) Ac2O/DMAP/pyridine, 63%.

M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
5521
Excitingly, 13-a-alcohol 15 was generated as the major
product in 84% yield. From a molecular model of 6,
compound 6 has a ABC ring skeleton, which is quite more
flexible than the rigid ABCD ring skeleton of 13-oxo-
baccatin III and the distance between C-13-O and C-4-O
is so close that a slight torsion of B ring will make the
4-hydroxy group and the 13-oxo group to form a hydrogen
bond. Thus, we hypothesized a possible mechanism of the
C-13 oxo reduction (Scheme 5). The reason of 13-a-alcohol
15 as the major product could be explained that, on one hand
the formation of a hydrogen bond changed the conformation
of the A-ring making the C-13 carbonyl vulnerable to the
borohydride reagent from top, and on the other hand it also
hindered borohydride reagent from conjugating to C-13-O
and C-4-O and attacking 13-carbonyl from below. An
indirect proof happened to be the same view. When 7 was
treated with NaBH4/CeCl3$7H2O under the same con-
ditions, the C-13-hydroxyl product was not obtained
because the C-4-hydroxyl group formed a hydrogen bond
with the 5-mesyl rather than with C-13-oxo group. Thus,
without the assistance of the 4-hydroxyl group, the C-13
ketone could not be reduced (Scheme 5).
Scheme 3. (a) CDCl3, quantitative; (b) Ac2O/pyridine, 90%.
Although, we have had 13-oxo-baccatin IV analogue (10),
all attempts to reduce 13-oxo of 10 to 13-a-hydroxy,
including using NaBH4, K-selectride as reductants, were
unsuccessful.
2.2. Reduction of 13-ketone
Since the oxetane ring is unstable under certain reaction
conditions, we considered to study the reduction of 13-
ketone prior to ring closure. NaBH4, as a mild reductant,
which hardly attacks other functional groups on the taxane
skeleton, was employed to investigate reduction of 13-
ketone. Compound 3 and 4 were used to study the reduction
of 13-ketone. Like 10, reduction of 3 using NaBH4 was also
failed to yield any expected alcohol product. When 4 was
treated with an excess NaBH4, both 13-a-OH (25%) and 13-
b-OH (64%) products were obtained (Scheme 4). A
transannular delivery of borohydride reagent11 may explain
the formation of 13-b-OH product. The exposed 5-OH of 4
was bonded to borohydride and this borohydride was
conjugated to the C-13 ketone, and then attacked 13-ketone
below the face to give 13-b-OH product. It was interesting
that the 13-a-OH product 14 was also formed. It was very
difficult to give an exact explanation, because the confor-
mation of 3 is hardly different from that of 4 from their
molecular models. Maybe the borohydride bonding to the
C-13 ketone and the C-5 hydroxy caused a little tortion of
the carbonyl group of 4 toward inside of the ‘cup’ and then
excess borohydride reagent attacked the 13-ketone from the
top face.
Scheme 5. Reduction of 13-ketone by transannular assistance from the C-4-
hydroxyl. (a) NaBH4/CeCl3$7H2O.
Compound 6 with free 4-OH and 5-OH was also chosen to
study the reduction of 13-ketone under the same conditions.
2.3. Synthesis of 7,9-dideoxy-2-debenzoyl-4-deacetyl-
baccatin IV
Having successfully performed the selective reduction of
C-13 carbonyl group, we changed our synthetic strategy
(Scheme 6). An acetyl group was chosen for protection of
13-hydroxy since, the acetyl group at C-13 could be
selectively removed with Red-Al.12 16, prepared from 15
by treatment with Ac2O in pyridine, was converted into 17
in moderate yield. Because of the steric hindrance extended
from the group at C-13 position, the mesylation of C-5-
hydroxy was a hard procedure. The reaction conditions
needed to be controlled carefully. A higher temperature and
a stronger base such as Et3N resulted in the formation of
some byproducts.13 The acetyl groups at C-20 and C-2
position were selectively removed to give intermediate 18
followed by treatment with DBU in toluene to produce 19 in
93% yield. 1H NMR spectrum showed that 2J of H-20
changed from 11 Hz for 15 to 8 Hz for 19, which indicated
the formation of the oxetane ring. Compound 19 has all the
desired configuration of the chiral centers of 1,7,9-
trideoxypalitaxel, without the amino acid side-chain.
Scheme 4. Reduction of 13-ketone by transannular assistance from the C-5-
hydroxyl. (a) NaBH4/CeCl3$7H2O.

5522
M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
solution was refluxed for 12 h under N2. The reaction
mixture was then cooled to room temperature and treated
with methyl iodide (1 mL, 17.32 mmol). After stirred at
40 8C for an additional 2 h, the reaction mixture was filtered
through a short silica column. The filtrate was poured into
aqueous saturated NH4Cl (25 mL) and extracted with
EtOAc (25 mL!3). The organic layers were combined,
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The crude residue was subjected to chromatography
to give corresponding xanthate 1 (1.82 g, 95%) as a light
yellow solid.
Compound 1. Mp: 44–46 8C; 1H NMR (300 MHz CDCl3, d
ppm) 6.07 (dd, 1H, JZ5.7, 12 Hz, H-10), 5.80 (dd, 1H, JZ
4.5, 9.0 Hz, H-14), 5.39 (dd, 1H, JZ2.1, 6.6 Hz, H-2), 5.29
(t, 1H, JZ2.7 Hz, H-5), 5.27 (s, 1H, H-20), 4.84 (s, 1H,
H-20), 3.02 (dd, 1H, JZ9.0, 18.9 Hz, H-13), 2.90 (d, 1H,
JZ6.3 Hz, H-3), 2.52 (s, 3H, OS2CMe14), 2.49 (dd, 1H, JZ
3.9, 18.9 Hz, H-13), 2.39 (dd, 1H, JZ12.0, 14.7 Hz, H-13),
2.18 (s, 3H, OAc-CH3), 2.10 (s, 3H, CH3-18), 2.07 (s, 3H,
OAc-CH3), 2.01 (s, 3H, OAc-CH3), 2.10–1.91 (m, 2H, H-6,
H-1), 1.76–1.82 (m, 2H, H-6, H-7), 1.69 (s, 3H, CH3-16),
1.63 (dd, 1H, JZ5.4, 15.0 Hz, H-9), 1.21–1.24 (m, 1H,
H-7), 1.16 (s, 3H, CH3-17), 0.84 (s, 3H, CH-193).
Scheme 6. (a) Ac2O/pyridine, 87%; (b) MsCl/pyridine, 90% based on 59%
conversion; (c) K2CO3/MeOH, 97%; (d) DBU/toluene, 93%.
Currently, the synthesis of 1,7,9-trideoxypaclitaxel and its
analogs are underway in our group.
3. Conclusion
In conclusion, starting from sinenxan A, we have developed
a facile and practical synthetic strategy to fabricate the key
framework, 7,9-dideoxy-2-debenzoyl-4-deacetyl-baccatin
IV (19). The strategy was capitalized on regioselective
removal of C-5-acetyl and stereoselective reduction of
the 13-carbonyl group by transannular assistance from the
C-4-hydroxy. Compound 19 was obtained in 12 steps and
3.5% overall yield from sinenxan A.
4.1.2. 2a,5a,10b-Triacetoxy-4(20), 11-taxadiene (2).
4.1.2.1. Barton’s deoxygenation procedure. Under
argon, to a solution of thiocarbarmate 1 (250 mg,
0.45 mmol) in degassed toluene (35 mL) stirred at 80 8C
was added tributyltin hydride (Bu3SnH, 1.22 mL,
4.53 mmol) and azobis(isobutyronitrile) (AIBN, 8 mg,
0.05 mmol). After the reaction mixture was stirred at this
temperature for 7 h, the solvent was removed under reduced
pressure. The crude residue was purified through flash
chromatography (silica, 10–15% EtOAc in petroleum ether)
to produce the deoxygenated compound 3 (165 mg, 82%).
4. Experimental
4.1. General
Melting points were obtained on a Yamaco micrometer and
all of the temperatures were uncorrected. NMR spectra were
recorded on a Bruker AM 300 and Varian INOVA 500
4.1.2.2. Deoxygenation by treatment with hypophos-
phorous acid. Method A: in the absence of olefin. Under
argon, to a solution of 1 (40 mg, 0.075 mmol) in degassed
dioxane (3 mL) was added Et3N (54 mL, 0.39 mmol), 50%
aqueous H3PO2 (38 mL, 0.37 mmol). The reaction solution
was refluxed and treated with AIBN (16 mg in 0.8 mL of
dioxane, 0.1 mmol) added in eight portions. After being
stirred for 4 h, the reaction mixture was diluted with EtOAc
(20 mL), and then washed with H2O (5 mL), aqueous
NaHCO3 (5 mL), and brine (5 mL), dried over Na2SO4,
concentrated in vacuo. The crude residue was purified by
flash chromatography (silica, 10% acetone in petroleum
ether) to give compound 3 (14 mg, 42%).
1
spectrometers (300 and 500 MHz for H and 125 MHz for
13C in CDCl3 unless otherwise noted, TMS as an internal
standard). Mass spectra and accurate mass data were
obtained on an Autospec-Ultima ETOF spectrometer.
Optical rotation was recorded on a Perkin–Elmer 241
polarimeter. TLC analysis was performed on silica gel
(GF254) plates and column chromatography over silica gel
(200–300 mesh), which were both obtained from Qingdao
Ocean Chemicals. Tetrahydrofuran, toluene and benzene
were distilled from sodium benzophenone ketyl immedi-
ately prior to use. Dichloromethane was dried with
anhydrous potassium carbonate. Pyridine and triethylamine
were dried with potassium hydroxide. Commercially
available reagents were used as received except as
indicated. Sinenxan A was provided by Biosynthetic
Laboratory of Institute of Materia Medica.
Method B: in the presence of olefin. Under argon, to a
solution of 1 (23 mg, 0.043 mmol) in degassed dioxane
(2.5 mL) was added Et3N (35 mL, 0.25 mmol), 50% aqueous
H3PO2 (24 mL, 0.23 mmol), cyclohexene (20 mL) and AIBN
(2 mg in 0.1 mL of dioxane, 0.012 mmol).The reaction
mixture was stirred at reflux for 0.5 h. After dilution with
EtOAc (15 mL), the organic layer was washed with H2O
(5 mL), aqueous NaHCO3 (5 mL), and brine (5 mL), dried
over Na2SO4, concentrated in vacuo. The crude residue was
purified by flash chromatography (silica, 10% acetone in
petroleum ether) to give compound 3 (14 mg, 74%).
4.1.1. 4b-S-Methyl-dithiocarboxy-2a,5a,10b-triacetoxy-
4(20), 11-taxadiene (1). To a solution of 14-deacetylsinen-
xan A (1.6 g, 3.46 mmol) in 45 mL of THF was added NaH
(0.83 g, 20.78 mmol, 60% suspension in mineral oil) and
CS2 (4.1 mL, 69.30 mmol). The resulting red-orange

M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
5523
Compound 2. [a]2D0 C548 (c 0.8, CHCl3). Mp: 128–131 8C;
HR-FAB-MS (GlyCNaCl): found 469.2562, calcd
chromatography (25% EtOAc in petroleum ether) to yield
compound 4 (68 mg, 93%).
1
469.2567, C26H38O6CNaC; H NMR (500 MHz, CDCl3,
d ppm) 6.06 (dd, 1H, JZ5.3, 12.3 Hz, H-10), 5.38 (dd, 1H,
JZ2.0, 6.3 Hz, H-2), 5.27 (t, 1H, JZ3.0 Hz, H-5), 5.25 (s,
1H, H-20), 4.89 (s, 1H, H-20), 3.08 (d, 1H, JZ6.0 Hz, H-3),
2.44–2.40 (m, 1H, H-13), 2.37 (dd, 1H, JZ12.0, 14.5 Hz,
H-9), 2.12 (s, 3H, OAc-CH3), 2.06 (s, 3H, CH3-18), 2.04 (s,
3H, OAc-CH3), 2.03 (s, 3H, OAc-CH3), 2.09–1.87 (m, 3H,
H-7, 13-H, H-14), 1.82–1.78 (m, 3H, 1-H, 2!H-6), 1.70–
1.64 (m, 1H, H-14), 1.59 (s, 3H, CH3-16), 1.61–1.54 (m, 1H,
H-9), 1.25–1.20 (m, 1H, H-7), 1.05 (s, 3H, CH3-17), 0.85 (s,
3H, CH3-19); 13C NMR (125 MHz, CDCl3, d ppm) 170.2
(OAc-C]O), 169.6 (OAc-C]O), 169.6 (OAc-C]O),
144.4 (C-4), 137.0 (C-12), 133.9 (C-11), 116.4 (C-20),
78.7 (C-5), 72.3 (C-2), 70.5 (C-10), 52.0 (C-1), 43.8 (C-9),
41.2 (C-3), 39.7 (C-8), 37.1 (C-15), 33.7 (C-7), 31.7 (C-17),
30.1 (C-13), 29.0 (C-6), 25.3 (C-16), 22.5 (19-CH3), 22.0
(OAc-CH3), 21.7 (OAc-CH3), 21.7 (OAc-CH3), 21.2
(18-CH3), 18.3 (C-14).
Compound 4. Mp: 153 8C; ESIMS m/z 419 (MC1), 441
(MCNa), 457 (MCK); 1H NMR (500 MHz, CDCl3, d ppm)
6.11 (dd, 1H, JZ12.0, 5.5 Hz, H-10), 5.47 (dd, 1H, JZ2.0,
6.5 Hz, H-2), 5.09 (s, 1H, H-20), 4.75 (s, 1H, H-20), 4.16
(br s, 1H, H-5), 3.52 (d, 1H, JZ6.0 Hz, H-3), 2.77 (dd, 1H,
JZ7.0, 19.5 Hz, H-14), 2.44 (dd, 1H, JZ12.3, 14.7 Hz,
H-9), 2.37 (d, 1H, JZ20.0 Hz, H-14), 2.17 (s, 3H, OAc-
CH3-10), 2.12 (dd, 1H, JZ1.7, 6.7 Hz, H-1), 2.09 (s, 3H,
OAc-CH3-2), 2.07 (s, 3H, CH3-18), 2.12–2.06 (m, 1H, H-7),
1.76–1.70 (m, 3H, 2!H-6, H-9), 1.69 (s, 3H, CH3-16),
1.19–1.15 (m, 1H, H-7), 1.13 (s, 3H, CH3-17), 0.87 (s, 3H,
CH3-19); 13C NMR (125 MHz, CDCl3, d ppm) 199.9
(13-C]O), 170.0 (OAc-C]O), 169.7 (OAc-C]O), 152.8
(C-11), 147.75 (C-4), 136.8 (C-12), 113.1 (C-20), 76.1 (C-5),
71.1 (C-10), 70.9 (C-2), 49.1 (C-1), 42.9 (C-9), 39.8 (C-3),
39.1 (C-8), 38.0 (C-15), 37.3 (C-17), 36.10 (C-14), 32.9 (C-7,
31.0 (C-6), 24.8 (C-16), 22.5 (C-19), 21.5 (OAc-CH3), 21.3
(OAc-CH3), 13.9 (C-18).
4.1.3. 2a,5a,10b-Triacetoxy-4(20), 11-taxadien-13-one
(3). Under nitrogen, a solution of 2 (1.26 g, 2.83 mmol) in
benzene (50 mL) was treated with anhydrous NaOAc
(6.95 g, 84.75 mmol), anhydrous Celite (18.2 g) and
pyridium chlorochromate (18.2 g, 84.75 mmol), and stirred
at reflux for 7 h. The reaction mixture was filtered through
silica gel, eluted with Et2O (500 mL), concentrated, and the
residue was purified by flash chromatography (silica, 12%
acetone in petroleum ether) to give 3 (650 mg) and recover 2
(300 mg), 65% yield based on 75% conversion.
4.1.4.2. 5a-Hydroxy-2a,10b-diacetoxy-4(20), 11-taxa-
diene (5). Under nitrogen, to a solution of 2 (43 mg,
0.096 mmol) in dry THF (3 mL) was added t-BuOK (44 mg,
0.39 mmol) at K78 8C. The reaction mixture was stirred at
K20 8C for 40 min. The resulting mixture was diluted with
EtOAc (20 mL) and poured into saturated aqueous NaHCO3
(5 mL). The organic layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by flash chromatography (10% acetone in petroleum ether)
to yield compound 5 (38 mg, 98%).
Ketone 3. [a]2D0 C698 (c 0.6, CHCl3). Mp: 72–74 8C;
HR-FAB-MS (GlyCNaCl): found 483.2346, calcd 483.2359,
C26H36O7CNaC; 1H NMR (500 MHz, CDCl3, d ppm) 6.06
(dd, 1H, JZ12.0, 5.5 Hz, H-10), 5.46 (dd, 1H, JZ2.0,
6.5 Hz, H-2), 5.27 (s, 1H, H-20), 5.23 (t, 1H, JZ3.0 Hz,
H-5), 4.82 (s, 1H, H-20), 3.19 (d, 1H, JZ6.0 Hz, H-3), 2.87
(dd, 1H, JZ6.7, 19.7 Hz, H-14), 2.48 (dd, 1H, JZ12.0,
15 Hz, H-9), 2.33 (d, 1H, JZ19.5 Hz, H-14), 2.20 (s, 3H,
OAc-CH3-10), 2.14 (dd, 1H, JZ2, 6.7 Hz, H-1), 2.10 (s, 3H,
OAc-CH3-2), 2.06 (s, 3H, OAc-CH3-5), 1.99 (s, 3H, CH3-18),
2.14–1.85 (m, 1H, H-7), 1.82–1.74 (m, 3H, 2!H-6, H-9),
1.69 (s, 3H, CH3-16), 1.25–1.20 (m, 1H, H-7), 1.13 (s, 3H,
CH3-17), 0.90 (s, 3H, CH3-19); 13C NMR (125 MHz,
CDCl3, d ppm) 199.4 (13-C]O), 170.3 (OAc-C]O), 170.0
(OAc-C]O), 169.8 (OAc-C]O), 153.6 (C-11), 142.5 (C-4),
136.0 (C-12), 116.4 (C-20), 77.8 (C-5), 71.0 (C-10), 70.4
(C-2), 49.0 (C-1), 42.8 (C-9), 40.9 (C-3), 39.6 (C-8), 37.3
(C-15), 36.0 (C-17), 33.7 (C-14), 29.7 (C-7), 29.0 (C-6),
24.7 (C-16), 22.7 (C-19), 21.5 (OAc-CH3), 21.4 (OAc-
CH3), 21.3 (OAc-CH3), 13.8 (C-18).
Compound 5. Mp: 53–55 8C; 1H NMR (500 MHz, CDCl3, d
ppm) 6.11 (dd, 1H, JZ12.0, 5.5 Hz, H-10), 5.38 (d, 1H, JZ
6.0 Hz, H-2), 5.10 (s, 1H, H-20), 4.80 (s, 1H, H-20), 4.20 (br
s, 1H, H-5), 3.35 (d, 1H, JZ6.0 Hz, H-3), 2.40–2.36 (m, 1H,
H-13), 2.33 (dd, 1H, JZ12.0, 15.0 Hz, H-9), 2.19–2.04 (m,
2H, H-7, H-13), 2.06–2.04 (3s, 9H, 2!OAc-CH3, CH3-18),
1.96–1.84 (m, 1H, H-14), 1.78–1.65 (m, 4H, H-1, 2!H-6,
H-14), 1.60 (s, 3H, CH3-16), 1.59 (dd, 1H, JZ5.5, 15.0 Hz,
H-9), 1.20–1.13 (m, 1H, H-7), 1.06 (s, 3H, CH3-17), 0.83 (s,
3H, CH3-19).
4.1.5. 4a,5a-Dihydroxy-2a,10b,20-triacetoxy-11-taxen-
13-one (6). To a solution of 5 (12 mg, 0.029 mmol) in a
mixture of THF (3 mL) acetone (4.5 mL) and water
(1.2 mL) under nitrogen was added 4-methylmorpholine
N-oxide (NMO, 17 mg, 0.14 mmol) and 4% aqueous OsO4
(18 mL, 0.0029 mmol). After the mixture was vigorously
stirred at room temperature for 4 h, 0.5 mL of saturated
aqueous NaHSO3 was added and stirring was continued for
additional 4 h. The reaction mixture was concentrated in
vacuo, poured into saturated aqueous NaHCO3 (5 mL) and
extracted with EtOAc (15 mL!3). The combined organic
phase was washed with brine (5 mL), dried over Na2SO4
and concentrated in vacuo to give crude product (14 mg).
4.1.4. Regioselective deacetylation by treatment with
t-BuOK.
4.1.4.1. 5a-Hydroxy-2a,10b-diacetoxy-4(20), 11-taxa-
dien-13-one (4). Under nitrogen, to a solution of 4 (80 mg,
0.17 mmol) in dry THF (3 mL) was added t-BuOK (78 mg,
0.70 mmol) at K78 8C. The reaction mixture was stirred at
K20 8C for 1 h, then diluted with EtOAc (20 mL) and
poured into saturated aqueous NaHCO3 (5 mL). The organic
layer was washed with brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash
To a stirred solution of this crude triol compound in a mixed
solvent of CH2Cl2 (3 mL) and pyridine (2 mL) was added
Ac2O (0.032 mL, 0.34 mmol). After the mixture was stirred
at room temperature for 4 h, methanol (0.05 mL) was added
to quench the reaction. The resulting mixture was

5524
M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
neutralized with 1 mol/L aqueous HCl and diluted with
EtOAc (20 mL). The organic layer was separated, washed
with 1 mol/L aqueous HCl (5 mL), saturated aqueous
NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4,
concentrated and purified by TLC (60% EtOAc in
petroleum ether) to give desired diol 6 (12 mg, 85%) as a
white powder.
resulting mixture was concentrated and extracted with
EtOAc (10 mL). The organic layer was washed with
saturated aqueous NaHCO3, brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash
chromatography to give compound 8 (59 mg, 99%).
Triol 8. FABMS m/z 489 (MC1), 511 (MCNa), 527 (MC
1
K); H NMR (500 MHz, CDCl3, d ppm) 6.00 (dd, 1H, JZ
Diol 6. [a]2D0 C908 (c 1.0, CHCl3). Mp: 198–200 8C;
HR-FABMS (GlyCNaCl): found 517.2400, calcd 517.2414,
C26H38O9CNaC; 1H NMR (500 MHz, CDCl3, d ppm) 6.04
(dd, 1H, JZ12.0, 5.0 Hz, H-10), 5.49 (dd, 1H, JZ2.0,
5.0 Hz, H-2), 4.49 (d, 1H, JZ11.5 Hz, H-20), 4.04 (d, 1H,
JZ12.0 Hz, H-20), 3.80 (t, JZ2.7 Hz, 1H, H-5), 3.14 (d,
1H, JZ19.7 Hz, H-14), 2.99 (d, 1H, JZ5.0 Hz, H-3), 2.72
(dd, 1H, JZ6.7, 19.7 Hz, H-14), 2.40 (dd, 1H, JZ12.5,
15 Hz, H-9), 2.24 (s, 3H, OAc-CH3-20), 2.19–2.16 (m, 1H,
H-1), 2.12 (s, 3H, OAc-CH3-10), 2.08 (s, 3H, OAc-CH3-2),
2.07 (s, 3H, CH3-18), 2.04–1.98 (m, 1H, H-7), 1.81–1.72
(m, 2H, 2!H-6), 1.68 (s, 3H, CH3-16), 1.54 (dd, 1H, JZ
5.5, 15 Hz, H-9), 1.13 (s, 3H, CH3-17), 1.11–1.07 (m, 1H,
H-7), 0.89 (s, 3H, CH3-19); 13C NMR (125 MHz, CDCl3, d
ppm) 200.4 (C]O-13), 171.3 (OAc-C]O), 169.9 (OAc-
C]O), 169.8 (OAc-C]O), 152.2 (C-11), 137.2 (C-12),
77.1 (C-5), 72.6 (C-4), 70.9 (C-10), 69.4 (C-2), 65.5 (C-20),
48.4 (C-1), 44.2 (C-9), 41.4 (C-3), 38.2 (C-8), 37.5 (C-15),
37.3 (C-17), 35.8 (C-14), 31.0 (C-7), 24.6 (C-6), 24.5 (C-16),
24.2 (C-19), 21.6 (OAc-CH3), 21.2 (OAc-CH3), 20.8 (OAc-
CH3), 13.3 (C-18).
12.0, 5.5 Hz, H-10), 4.89 (br s, 1H, H-5), 4.28 (d, 1H, JZ
11.0 Hz, H-20), 4.14 (dd, 1H, JZ2.0, 5.0 Hz, H-2), 3.67 (d,
1H, JZ11.0 Hz, H-20), 3.06 (s, 3H, CH3SO2), 2.92 (d, 1H,
JZ19.5 Hz, H-14), 2.78 (dd, 1H, JZ6.7, 19.7 Hz, H-14),
2.59 (d, 1H, JZ5.0 Hz, H-3), 2.35 (dd, 1H, JZ12.5, 15 Hz,
H-9), 2.26 (dd, 1H, JZ2.0, 6.5 Hz, H-1), 2.17 (s, 1H, OH),
2.16 (s, 3H, OAc-CH3-10), 2.08 (s, 3H, CH3-18), 1.98–1.85
(m, 3H, H-7, 2!H-6), 1.61 (s, 3H, CH3-16), 1.55 (dd, 1H,
JZ5.5, 14.5 Hz, H-9), 1.27–1.24 (m, 1H, H-7), 1.18 (s, 3H,
CH3-17), 0.955 (s, 3H, CH3-19); 13C NMR (125 MHz,
CDCl3, d ppm) 200.45 (C]O-13), 169.76 (OAc-C]O),
153.75 (C-11), 136.39 (C-12), 79.84 (C-5), 76.98 (C-4),
70.89 (C-10), 70.74 (C-2), 64.99 (C-20), 51.69 (C-1), 44.07
(C-9), 42.42 (C-3), 38.73 (CH3SO2), 38.04 (C-8), 37.83
(C-17), 37.28 (C-15), 35.22 (C-14), 31.98 (C-7), 25.68
(C-6), 24.81 (C-16), 24.26 (C-19), 21.19 (OAc-CH3), 13.28
(C-18).
4.1.8. 5b,20-Epoxy-2a,4a-dihydroxy-10b-acetoxy-11-
taxen-13-one (9). Under argon, to a stirred solution of 8
(14 mg, 0.029 mmol) in dry toluene (2 mL) was added DBU
(6.5 mL, 0.043 mmol). The reaction solution was heated to
reflux for 2 h, and then cooled to room temperature. The
resulting solution was column chromatographed (50–70%
EtOAc in petroleum ether) to yield oxetane 9 (4 mg, 36%).
4.1.6. 5a-Methanesulfonyloxy-4a-hydroxy-2a,10b,20-
triacetoxy-11-taxen-13-one (7). To a solution of 6
(10 mg, 0.02 mmol) in pyridine (2 mL) was added metha-
nesulfonyl chloride (8 mL, 0.1 mmol). The reaction mixture
was stirred at room temperature for 2.5 h, and then warmed
to 30–40 8C for additional 4 h. The reaction was quenched
with ice-water (0.2 mL). The mixture was diluted with
EtOAc (20 mL) and adjusted to pH 6–7 with 1 mol/L
aqueous HCl. The organic layer was separated, washed with
1 mol/L aqueous HCl (5 mL), saturated aqueous NaHCO3
(5 mL) and brine (5 mL), dried over Na2SO4, concentrated
and purified by TLC (30% acetone in petroleum ether) to
give compound 7 (10 mg, 86%).
1
Oxetane 9. H NMR (500 MHz, CDCl3, d ppm) 5.95 (dd,
1H, JZ12.0, 5.5 Hz, H-10), 4.73 (d, 1H, JZ8.5 Hz, H-20),
4.67 (dd, 1H, JZ3.0, 9.0 Hz, H-5), 4.35 (d, 1H, JZ8.0 Hz,
H-20), 4.22–4.18 (m, 1H, JZ3.0, 5.5, 9 Hz, H-2), 3.216 (s,
1H, OH), 2.56 (d, 1H, JZ9.5 Hz, OH-2), 2.74 (d, 2H, JZ
3.5 Hz, H-14), 2.44 (dd, 1H, JZ12.0, 14.7 Hz, H-9), 2.22
(dd, 1H, JZ3.5, 6.5 Hz, H-1), 2.14–2.09 (m, 1H, H-6),
2.081 (s, 3H, OAc-CH3-10), 2.01 (sCm, 4H, H-6, CH3-18),
1.97 (d, 1H, JZ5.5 Hz, H-3), 1.65 (s, 3H, CH3-16), 1.64–
1.57 (m, 3H, H-9, 2!H-7), 1.38 (s, 3H, CH3-19), 1.17 (s,
3H, CH3-17).
1
Mesylate 7. H NMR (300 MHz, CDCl3, d ppm) 6.04 (dd,
1H, JZ12.0, 5.1 Hz, H-10), 5.30 (dd, 1H, JZ2.1, 4.8 Hz,
H-2), 4.97 (br s, 1H, H-5), 4.71 (d, 1H, JZ12.3 Hz, H-20),
3.96 (d, 1H, JZ12.6 Hz, H-20), 3.06 (d, 1H, JZ19.5 Hz,
H-14), 3.01 (s, 3H, CH3SO2), 2.86 (d, 1H, JZ4.5 Hz,
H-3), 2.75 (dd, 1H, JZ6.9, 19.5 Hz, H-14), 2.43 (dd, 1H,
JZ12.0, 15.3 Hz, H-9), 2.24 (s, 3H, OAc-CH3-20), 2.18 (s,
3H, OAc-CH3-10), 2.12 (s, 3H, OAc-CH3-2), 2.08 (s, 3H,
CH3-18), 2.19–2.05 (m, 2H, H-1,H-7), 1.97–1.95 (m, 2H,
2!H-6), 1.68 (s, 3H, CH3-16), 1.59 (dd, 1H, JZ5.7,
15.0 Hz, H-9), 1.27–1.25 (m, 1H, H-7), 1.149 (s, 3H, CH3-
17), 0.93 (s, 3H, CH3-19).
4.1.9. 5b,20-Epoxy-2a,4a,10b-triacetoxy-11-taxen-13-
one (10). To a solution of 9 (50 mg, 0.12 mmol) in pyridine
(1 mL) was added Ac2O (0.2 mL, 2.12 mmol) and DMAP
(120 mg, 0.98 mmol). The reaction mixture was stirred at
room temperature for 12 h, and then diluted with EtOAc
(15 mL) and 1 mol/L aqueous HCl (15 mL). The organic
layer was separated, washed with aqueous CuSO4 (10 mL!
2), aqueous NaHCO3 (10 mL), brine (5 mL), concentrated,
and purified by TLC (25% EtOAc in petroleum ether) to
give 10 (38 mg, 63%) as a colorless foam.
4.1.7. 5a-Methanesulfonyloxy-2a,4a,20-triihydroxy-
10b-acetoxy-11-taxen-13-one (8). To a solution of 7
(70 mg, 0.12 mmol) in methanol (2 mL) was added 1 mol/
L aqueous K2CO3 (0.25 mL, 0.25 mmol). The reaction
mixture was stirred at room temperature for 0.5 h. The
reaction was quenched with 1 mol/L aqueous HCl, and the
Compound 10. [a]2D0 C988 (c 0.5, CHCl3); HR-FABMS
(GlyCNaCl): found 499.2302, calcd 499.2308, C26H36O8C
NaC; 1H NMR (500 MHz, CDCl3, d ppm) 5.98 (dd, 1H, JZ
12.0, 5.5 Hz, H-10), 5.48 (dd, 1H, JZ2.5, 6.0 Hz, H-2), 4.93
(d, 1H, JZ9.0 Hz, 1H, H-5), 4.50 (d, 1H, JZ8.0 Hz, H-20),
4.18 (d, 1H, JZ8.0 Hz, H-20), 2.87 (d, 1H, JZ6.5 Hz, H-3),

M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
5525
2.73 (dd, 1H, JZ7.0, 19.5 Hz, H-14), 2.51 (dd, 1H, JZ12.0,
15.0 Hz, H-9), 2.31 (d, 1H, JZ20.5 Hz, H-14), 2.24–2.17
(m, 1H, H-6), 2.10 (dd, 1H, JZ6.5, 2.5 Hz, H-1), 2.08 (s,
3H, OAc-CH3-10), 2.073 (s, 3H, OAc-CH3-4), 2.04 (s, 3H,
OAc-CH3-2), 2.02 (s, 3H, CH3-18), 1.98–1.89 (m, 1H, H-6),
1.69 (s, 3H, CH3-16), 1.67 (dd, 1H, JZ5.5, 15.0 Hz, H-9),
1.59–1.55 (m, 2H, 2!H-7), 1.37 (s, 3H, CH3-19), 1.13 (s,
3H, CH3-17); 13C NMR (125 MHz, CDCl3, d ppm) 199.0
(C]O-13), 169.9 (OAc-C]O), 169.7 (2!OAc-C]O),
153.6 (C-11), 137.1 (C-12), 84.9 (C-4), 82.4 (C-5), 76.3
(C-10), 70.9 (C-20), 70.9 (C-2), 47.2 (C-1), 44.0 (C-9), 41.2
(C-3), 38.0 (C-8), 37.6 (C-17), 36.9 (C-15), 35.3 (C-14),
35.1 (C-7), 27.4 (C-6), 24.5 (C-16), 21.8 (OAc-CH3), 21.6
(OAc-CH3), 21.5 (C-19), 21.2 (OAc-CH3), 13.5 (C-18).
0.048 mmol) in a mixture of methanol (1 mL) and THF
(0.5 mL) was added CeCl3$7H2O (71 mg, 0.19 mmol) and
NaBH4 (180 mg, 4.86 mmol). The reaction mixture was
stirred at room temperature for 6 h. The reaction was
quenched with saturated aqueous NH4Cl (2 mL). After
dilution with EtOAc (15 mL), the organic layer was
separated, washed with 1 mol/L aqueous HCl, aqueous
NaHCO3 and brine, dried over Na2SO4, concentrated in
vacuo, and purified by flash chromatography (25–35%
EtOAc in petroleum ether) to give 13-b-hydroxy compound
13 (13 mg, 64%) and 13-a-hydroxy compound 14 (5 mg,
25%).
13-b-Hydroxy compound 13. [a]2D0 C368 (c 0.3, CHCl3);
FABMS m/z 443 (MCNa); H NMR (500 MHz, CDCl3, d
1
ppm) 6.06 (dd, 1H, JZ6.0, 12.3 Hz, H-10), 5.41 (dd, 1H,
JZ2.0, 6.5 Hz, H-2), 5.11 (s, 1H, H-20), 4.69 (t, 1H, JZ
1.5 Hz, H-20), 4.30 (dd, 1H, JZ4.0, 9.5 Hz, H-13), 4.20 (t,
1H, JZ2.7 Hz, H-5), 3.17 (d, 1H, JZ7.0 Hz, H-3), 2.40 (dd,
1H, JZ12.0, 14.7 Hz, H-9), 2.19 (dd, 1H, JZ9.5, 15.5 Hz,
H-14), 2.12 (s, 3H, 18-CH3), 2.09–2.03 (m, 1H, H-14),
2.05–2.04 (2s, 6H, 2!OAc-CH3), 1.98 (dd, 1H, JZ2.0,
7.5 Hz, H-1), 1.76–1.71 (m, 2H, H-6, H-7), 1.61–1.57 (mC
s, 5H, H-6, H-9, 16-CH3), 1.28 (s, 3H, 17-CH3), 1.15–1.12
(m, 1H, H-7), 0.85 (s, 3H, 19-CH3); 13C NMR (125 MHz,
CDCl3, d ppm) 170.2 (OAc-C]O), 169.7 (OAc-C]O),
147.9 (C-4), 139.1 (C-12), 137.3 (C-11), 113.1 (C-20), 76.2
(C-5), 71.2 (C-10), 70.9 (C-2), 70.5 (C-2), 56.8 (C-1), 43.1
(C-9), 40.3 (C-3), 40.1 (C-8), 36.7 (C-15), 36.5 (C-17), 33.1
(C-14), 31.3 (C-7), 29.9 (C-6), 25.4 (C-16), 22.4 (C-19),
21.5 (OAc-CH3), 21.4 (OAc-CH3), 18.8 (C-18).
4.1.10. 2a,20-Epoxy-4a,5b-dihydroxy-10b-acetoxy-11-
taxen-13-one (11) and 2a,20-epoxy-4a-hydroxy-5b,10b-
diacetoxy-11-taxen-13-one (12). Compound 9 (2 mg) was
dissolved in CDCl3 (1 mL), which was not processed by
K2CO3 and maintained at room temperature for 2 min. The
solvent was removed in vacuo to give 11 (2 mg).
To a solution of 11 (2 mg, 0.0051 mmol) in pyridine
(0.5 mL) was added Ac2O (0.018 mL, 0.19 mmol). The
reaction mixture was stirred at room temperature for 6 h,
and then quenched with 1 mol/L aqueous HCl. After the
dilution of EtOAc (6 mL), the organic layer was separated,
washed with aqueous CuSO4 (5 mL), aqueous NaHCO3
(5 mL) and brine (5 mL), concentrated in vacuo, and
purified by TLC (45% acetone in petroleum ether) to give
12 (2 mg, 90%).
13-a-Hydroxy compound 14. FABMS m/z 443 (MCNa); 1H
NMR (500 MHz, CDCl3, d ppm) 6.09 (dd, 1H, JZ5.5,
12 Hz, H-10), 5.61 (dd, 1H, JZ1.5, 6.0 Hz, H-2), 5.15 (s,
1H, H-20), 4.83 (t, 1H, JZ1.5 Hz, H-20), 4.35 (dd, 1H, JZ
3.3, 10.2 Hz, H-13), 4.28 (br s, 1H, H-5), 3.40 (d, 1H, JZ
5.5 Hz, H-3), 2.70 (dt, 1H, JZ10.0, 15.5 Hz, H-14), 2.32
(dd, 1H, JZ12.0, 14.5 Hz, H-9), 2.20 (s, 3H, 18-CH3),
2.18–2.12 (m, 1H, H-7), 2.05 (br s, 6H, 2!OAc-CH3),
1.81–1.71 (m, 3H, 2!H-6, H-1), 1.63 (dt, 1H, JZ3.0,
15.5 Hz, H-14), 1.59 (s, 3H, 16-CH3), 1.47–1.41 (m, 1H,
H-9), 1.19–1.16 (m, 1H, H-7), 0.93 (s, 3H, 17-CH3), 0.84 (s,
3H, 19-CH3).
Compound 11. 1H NMR (500 MHz, CDCl3, d ppm) 6.09 (t,
1H, JZ4.0 Hz, H-10), 4.37 (br d, 1H, JZ4.5 Hz, H-2), 3.90
(dd, 1H, JZ6.0, 11.5 Hz, H-5), 3.69 (d, 1H, JZ10.0 Hz, H-
20), 3.51 (d, 1H, JZ10.0 Hz, H-20), 2.77 (dd, 1H, JZ7.5,
19.5 Hz, H-14), 2.60 (d, 1H, JZ19.5 Hz, H-14), 2.36 (dd,
1H, JZ2.0, 7.0 Hz, H-1), 2.11 (s, 3H, OAc-CH3-10), 2.1–
2.06 (m, 1H, H-6), 1.90 (s, 3H, CH3-18), 1.86 (d, JZ5.5 Hz,
1H, H-3), 1.78–1.70 (m, 3H, OH, H-9, H-6), 1.57 (s, 3H,
CH3-16), 1.54–1.36 (m, 3H, H-9, 2!H-7), 1.24 (s, 3H,
CH3-19), 1.19 (s, 3H, CH3-17); 13C NMR (125 MHz,
CDCl3, d ppm) 199.3 (C]O-13), 170.3 (OAc-C]O), 156.2
(C-12), 132.8 (C-11), 84.2, 82.1, 76.2, 73.0, 72.7 (5!C–O),
53.1 (C-1), 47.9 (C-9), 46.8 (C-3), 41.7 (C-17), 39.3 (C-8),
37.0 (C-15), 36.5 (C-14), 35.3 (C-7), 27.9 (C-6), 25.3 (C-16),
24.2 (C-19), 21.4 (OAc-CH3), 14.3 (C-18).
4.1.12. 13a,4a,5a-Trihydroxy-2a,10b,20-triacetoxy-11-
taxene (15). To a solution of 6 (38 mg, 0.077 mmol) in a
mixture of methanol (1.6 mL) and THF (0.8 mL) was added
CeCl3$7H2O (71 mg, 0.19 mmol) and NaBH4 (15 mg,
0.41 mmol). The reaction mixture was stirred at room
temperature for 1 h, and then quenched with saturated
aqueous NH4Cl (2 mL). After dilution with EtOAc (25 mL),
the organic layer was separated, washed with 1 mol/L
aqueous HCl, aqueous NaHCO3 and brine, dried over
Na2SO4, concentrated in vacuo, and purified by flash
chromatography (30–50% EtOAc in petroleum ether) to
give desired 13-a-hydroxy compound 15 (32 mg, 84%).
Compound 12. FABMS m/z 435 (MC1), 457 (MCNa); 1H
NMR (500 MHz, CDCl3, d ppm) 6.09 (t, 1H, JZ5.0 Hz,
H-10), 4.94 (dd, 1H, JZ7.0, 11.0 Hz, H-5), 4.34 (dd, 1H,
JZ2.0, 6.0 Hz, H-2), 3.49 (d, 1H, JZ10.0 Hz, H-20), 3.45
(d,1H, JZ10.0 Hz, H-20), 2.87 (d, 1H, JZ20.0 Hz, H-14),
2.71 (dd, 1H, JZ7.5, 20.0 Hz, H-14), 2.35 (dd, 1H, JZ2.5,
7.0 Hz, H-1), 2.10 (s, 3H, OAc-CH3-10), 2.07 (s, 3H, OAc-
CH3-5), 1.99 (d, JZ6.0 Hz, 1H, H-3), 1.93 (s, 3H, CH3-18),
1.91–1.81 (m, 3H, H-9, 2!H-6), 1.57 (s, 3H, CH3-16),
1.54–1.46 (m, 3H, H-9, 2!H-7), 1.21 (s, 3H, CH3-19), 1.18
(s, 3H, CH3-17).
Compound 15. [a]2D0 C618 (c 0.8, CHCl3); HR-FABMS
(GlyCNaCl): found 519.2558, calcd 519.2570,
C26H40O9CNaC; 1H NMR (300 MHz, CDCl3, d ppm)
6.02 (dd, 1H, JZ10.7, 6.0 Hz, H-10), 5.41 (dd, 1H, JZ1.8,
4.8 Hz, H-2), 4.40 (d, 1H, JZ11.7 Hz, H-20), 4.34 (br d,
4.1.11. 5a,13b-Dihydroxy-2a,10b-diacetoxy-4(20), 11-
taxadiene (13) and 5a,13a-dihydroxy-2a,10b-diace-
toxy-4(20), 11-taxadiene (14). To a solution of 4 (20 mg,

5526
M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
1H, JZ8.7 Hz, H-13), 4.02 (d, 1H, JZ11.7 Hz, H-20), 3.95
(br s, 1H, H-5), 3.10 (d, 1H, JZ5.1 Hz, H-3), 2.60 (dt, 1H,
JZ7.8, 15.0 Hz, H-14), 2.27 (dd, 1H, JZ12.6, 15.6 Hz,
H-9), 2.19–2.04 (5sCm, 14H, 4!OAc-CH3, CH3-18, H-14,
H-7), 1.82–1.76 (m, 2H, 2!H-6), 1.67 (dd, 1H, JZ2.0,
8.0 Hz, H-1), 1.58 (s, 3H, CH3-16), 1.43 (dd, 1H, JZ5.5,
15 Hz, H-9), 1.10–1.04 (m, 1H, H-7), 0.92 (s, 3H, CH3-17),
0.86 (s, 3H, CH3-19).
4.1.15. 5a-Methanesulfonyloxy-2a,4a,20-trihydroxy-
10b,13a-diacetoxy-11-taxene (18). To a solution of 17
(115 mg, 0.19 mmol) in a mixed solvent of methanol (4 mL)
and THF (3 mL) was added 1 mol/L aqueous K2CO3
(0.3 mL, 0.3 mmol). The reaction mixture was stirred at
0 8C for 0.5 h. The reaction was quenched with 1 mol/L
aqueous HCl. The resulting solution was concentrated and
diluted with 40 mL of EtOAc. The organic phase was
washed with aqueous NaHCO3 and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by flash chromatography (60% EtOAc in petroleum ether)
to yield triol 18 (96 mg, 97%).
4.1.13. 4a,5a-Dihydroxy-2a,10b,13a,20-tetraacetoxy-
11-taxene (16). To a solution of 15 (240 mg, 0.48 mmol)
in pyridine (15 mL) was added Ac2O (0.8 mL, 8.49 mmol)
and DMAP (100 mg, 0.82 mmol). The reaction mixture was
stirred at room temperature for 1 h, and then quenched with
methanol (1 mL). The resulting mixture was diluted with
EtOAc (100 mL), poured into 1 mol/L aqueous HCl (50 mL)
and extracted with EtOAc (50 mL!2). The combined
organic phase was washed with aqueous NaHCO3 and brine,
dried over Na2SO4, concentrated in vacuo, purified by flash
chromatography (50% EtOAc in petroleum ether) to yield
corresponding compound 16 (225 mg, 87%).
Triol 18. 1H NMR (500 MHz, CDCl3, d ppm) 6.02 (dd, 1H,
JZ12.0, 5.5 Hz, H-10), 5.84 (dd, 1H, JZ6.5, 9.0 Hz, H-13),
4.77 (s, 1H, H-5), 4.26 (d, 1H, JZ11.5 Hz, H-20), 4.08 (br
d, 1H, JZ6.0 Hz, H-2), 4.03 (s, 1H, OH), 3.62 (dd, 1H, JZ
8.0, 11.0 Hz, H-20), 3.45 (d, 1H, JZ8.0 Hz, OH), 3.10 (s,
3H, CH3SO2), 2.74 (d, 1H, JZ6.0 Hz, OH-2), 2.65 (d, 1H,
JZ5.0 Hz, H-3), 2.58 (dt, 1H, JZ9.5, 15.5 Hz, H-14), 2.28
(dd, 1H, JZ12.5, 14.5 Hz, H-9), 2.20 (s, 3H, CH3-18),
2.03–1.92 (2sCm, 11H, 2!OAc-CH3, H-7, H-1, H-14, 2!
H-6), 1.57 (s, 3H, CH3-16), 1.43 (dd, 1H, JZ5.5, 15.0 Hz,
H-9), 1.25–1.22 (m, 1H, H-7), 1.10 (s, 3H, CH3-17), 0.93 (s,
3H, CH3-19); 13C NMR (125 MHz, CDCl3, d ppm) 171.1
(OAc-C]O), 167.0 (OAc-C]O), 136.0 (C-12), 135.2
(C-11), 81.2 (C-5), 77.5 (C-4), 72.3 (C-2), 67.0 (C-10), 69.8
(C-13), 65.6 (C-20), 51.2 (C-1), 44.9 (C-9), 43.6 (C-3), 38.2
(C-8), 37.7 (C-15), 37.1 (CH3SO2), 32.3 (C-14), 31.9 (C-17),
27.1 (C-7), 26.1 (C-6), 25.4 (C-16), 24.2 (C-19), 21.4 (OAc-
CH3), 21.2 (OAc-CH3), 14.9 (C-18).
Compound 16. Mp: 81–83 8C; [a]2D0 C698 (c 0.4, CHCl3);
FABMS m/z 561 (MCNa); H NMR (500 MHz, CDCl3, d
1
ppm) 6.04 (dd, 1H, JZ12.0, 5.5 Hz, H-10), 5.59 (dd, 1H,
JZ7.0, 8.5 Hz, H-13), 5.41 (dd, 1H, JZ2.0, 5.0 Hz, H-2),
4.45 (d, 1H, JZ12.0 Hz, H-20), 4.06 (d, 1H, JZ12.0 Hz,
H-20), 3.89 (t, 1H, JZ2.7 Hz, H-5), 3.19 (s, 1H, OH), 3.06
(d, 1H, JZ5.0 Hz, H-3), 2.95 (d, 1H, JZ2.0 Hz, OH), 2.63–
2.58 (m, 1H, H-14), 2.30 (dd, 1H, JZ12.5, 14.5 Hz, H-9),
2.17–2.04 (5s, 4!OAc-CH3, CH3-18), 2.16 (dd, 1H, JZ
3.0, 15.5 Hz, H-14), 2.12–2.01 (m, 1H, H-7), 1.84–1.75 (m,
2H, 2!H-6), 1.72 (dd, 1H, JZ2.0, 8.0 Hz, H-1), 1.62 (s,
3H, CH3-16), 1.45 (dd, 1H, JZ5.5, 15 Hz, H-9), 1.09–1.07
(m, 1H, H-7), 0.99 (s, 3H, CH3-17), 0.86 (s, 3H, CH3-19).
4.1.16. 7,9-Dideoxy-2-debenzoyl-4-deacetyl-baccatin IV
(19). Under argon, to a solution of 18 (85 mg, 0.16 mmol)
in dry toluene (5 mL) was added DBU (30 mL, 0.2 mmol).
The reaction solution was stirred at reflux for 1 h, and
then cooled to room temperature. The resulting solution
was column chromatographed (50–70% EtOAc in petro-
leum ether) to yield baccatin IV analogue 19 (65 mg,
93%).
4.1.14. 5a-Methanesulfonyloxy-4a-hydroxy-2a,10b,13a,
20-tetraacetoxy-11-taxene (17). To a solution of 16
(120 mg, 0.22 mmol) in pyridine (8 mL) was added drop-
wise methanesulfonyl chloride (0.35 mL, 4.51 mmol). The
reaction solution was stirred at 30 8C for 60 h, and then
diluted with EtOAc (40 mL), poured into 1 mol/L aqueous
HCl (20 mL) and extracted with EtOAc (20 mL!2). The
combined organic phase was washed with aqueous CuSO4,
aqueous NaHCO3 and brine, dried over Na2SO4, concen-
trated in vacuo, and purified by flash chromatography (20%
acetone in petroleum ether) to yield 73 mg (90% based on
59% conversion) of corresponding mesylate 17 and 49 mg
of recovered alcohol 16 (41%).
Compound 19. Mp: 71–73 8C; [a]2D0 C46 (c 0.6, CHCl3);
HR-FABMS (GlyCNaCl): found 459.2349, calcd
1
459.2359, C24H36O7CNaC; H NMR (500 MHz, CDCl3,
d ppm) 5.91 (dd, 1H, JZ12.0, 5.5 Hz, H-10), 5.64 (d, 1H,
JZ9.5 Hz, H-13), 4.70 (d, 2H, JZ8.5 Hz, H-2, H-20), 4.39
(d, 1H, JZ8.0 Hz, H-20), 4.10–4.06 (m, 1H, H-5), 2.76 (s,
1H, OH), 2.68–2.60 (m, 2H, H-3, H-14), 2.32 (dd, 1H, JZ
12.5, 15.0 Hz, H-9), 2.17–2.15 (m, 2H, 2!H-6), 2.12 (s,
3H, OAc-CH3), 2.05 (s, 3H, OAc-CH3), 2.04–1.96 (m, 1H,
H-7), 1.89 (s, 3H, CH3-18), 1.85 (dd, 1H, JZ2.5, 8.0 Hz,
H-1), 1.77 (dd, 1H, JZ3.0, 15.6 Hz, H-14), 1.67–1.60 (m,
1H, H-7), 1.57 (s, 3H, CH3-16), 1.52 (dd, 1H, JZ5.5,
15.0 Hz, H-9), 1.33 (s, 3H, CH3-19), 1.01 (s, 3H, CH3-17);
13C NMR (125 MHz, CDCl3, d ppm) 170.0 (OAc-C]O),
169.7 (OAc-C]O), 138.6 (C-12), 133.9 (C-11), 87.5 (C-5),
80.33 (C-4), 77.5 (C-10), 70.5 (C-20), 70.3 (C-13), 69.8
(C-2), 49.4 (C-1), 47.6 (C-9), 44.3 (C-3), 37.2 (C-8), 36.6
(C-15), 35.7 (C-14), 33.8 (C-17), 27.5 (C-7), 27.0 (C-6),
25.1 (C-16), 22.0 (C-19), 21.4 (OAc-CH3), 21.1 (OAc-
CH3), 15.7 (C-18).
Mesylate 17. Mp: 130–133 8C; [a]2D0 C648 (c 0.3, CHCl3);
HR-FABMS (GlyCNaCl): found 639.2440, calcd
639.2451, C29H44O12SCNaC; 1H NMR (500 MHz,
CDCl3, d ppm) 5.99 (dd, 1H, JZ12.0, 5.5 Hz, H-10), 5.78
(dd, 1H, JZ7.0, 8.5 Hz, H-13), 5.40 (d, 1H, JZ5.0 Hz,
H-2), 4.75 (s, 1H, H-5), 4.51 (d, 1H, JZ12.5 Hz, H-20),
3.92 (d, 1H, JZ12.5 Hz, H-20), 3.01 (s, 3H, CH3SO2), 2.87
(d, 1H, JZ5.0 Hz, H-3), 2.42 (dt, 1H, JZ9.7, 14.7 Hz,
H-14), 2.30 (dd, 1H, JZ12.5, 15.0 Hz, H-9), 2.16–1.92
(5sCm, 19H, 4!OAc-CH3, CH3-18, H-7, H-14, 2!H-6),
1.73 (d, 1H, JZ9.0 Hz, H-1), 1.59 (s, 3H, CH3-16), 1.42
(dd, 1H, JZ5.5, 15.0 Hz, H-9), 1.29–1.23 (m, 1H, H-7),
1.03 (s, 3H, CH3-17), 0.84 (s, 3H, CH3-19).

M. Zhang et al. / Tetrahedron 61 (2005) 5519–5527
5527
5. Zhang, M.; Yin, D. L.; Guo, J. Y.; Liang, X. T. Tetrahedron
Lett. 2002, 43, 9425.
Acknowledgements
This research work was financially supported by NNSFC
grant No. 3977082 and No. 30100230.
6. Huang, G. Y.; Guo, J. Y.; Liang, X. T. Acta Pharm. Sinica
1998, 33, 576–586.
7. (a) Kingston, D. G. I. Pharmacol. Ther. 1991, 52, 1–34.
(b) Kingston, D. G. I. Trends Biotechnol. 1994, 12, 222–227.
(c) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 15–44. (d) Samaranayake, G.; Magri,
N. F.; Jitrangsri, C.; Kingston, D. G. I. J. Org. Chem. 1991, 56,
5114–5119. (e) Datta, A.; Jayasinghe, L. R.; Georg, G. I.
J. Med. Chem. 1994, 37, 4258–4260.
References and notes
1. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail,
A. T. J. Am. Chem. Soc. 1971, 93, 2325–2327.
8. Zhang, M.; Yin, D. L.; Guo, J. Y.; Liang, X. T. Chin. Chem.
Lett. 2002, 13, 501–504.
2. (a) Ando, M.; Sakai, S.; Zhang, Y.; et al J. Nat. Prod. 1997, 60,
499. (b) Hosoyama, H.; Shigemori, H.; Tomida, A.; et al
Bioorg. Med. Chem. Lett. 1999, 9, 389–394. (c) Sako, M.;
Suzuki, H.; Yamamoto, N.; Hirota, K. Bioorg. Med. Chem.
Lett. 1999, 9, 3403–3406.
9. Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron
1991, 47, 9823.
10. (a) Farina, V.; Huang, S. Tetrahedron Lett. 1992, 33, 3979.
3. (a) Ojima, I.; Slater, J. C.; Kuduk, S. D.; Takeuchi, C. S.; Gimi,
R. H.; Sun, C.-M.; Park, Y. H.; Pera, P.; Veith, J. M.; Bernacki,
R. J. J. Med. Chem. 1997, 40, 267–278. (b) Nicoletti, M. I.;
Colombo, T.; Rossi, C.; Monardo, C.; Stura, S.; Zucchetti, M.;
Riva, A.; Morazzoni, P.; Donati, M. B.; Bombardelli, E.;
D’Incalzi, M.; Giavazzi, R. Cancer Res. 2000, 60, 842–846.
(c) Ojima, I.; Bounaud, P.; Bernacki, R. J. Mod. Drug
Discovery 1999, 45–52.
´
´
(b) Wahl, A.; Gueritte-Voegelein, F.; Guenard, D.; Le Gott,
M.-T.; Potier, P. Tetrahedron 1992, 48, 6965.
11. Hoemann, M. Z.; Velde, D. V.; Aube, J.; Georg, G. I. J. Org.
Chem. 1995, 60, 2918–2921.
12. Kingston, D. G. I.; Choridia, M. D.; Jagtap, P. G.; Liang, J.;
Shen, Y.-C.; Long, B. H.; Fairchild, C. R.; Johnston, K. A.
J. Org. Chem. 1999, 64, 1814–1822.
13. Zhang, M.; Yin, D. L.; Guo, J. Y.; Liang, X. T. Chin. Chem.
Lett. 2004, 15, 1033–1035.
4. Cheng, K. D.; Chen, W. M.; Zhu, W. H.; PCT. Int. Appl. WO
9,406,740 (CI C07035/37), 1994; JP Appl. 92/249, 047, 1992.