Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity

Article abstract of DOI:10.1002/cjoc.201600381

7-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl group simply using Ag₂O as catalyst and DMF as solvent. The catalyst could be quantitatively recovered by filtration without loss of catalytic activity. This condition is also applicable to the direct epimerization of taxane derivatives (e.g., docetaxel and paclitaxel) to 7-epi-taxane derivatives (e.g., 7-epi-docetaxel and 7-epi-paclitaxel). Furthermore, 33 ester derivatives of 7-epi-taxane with different amino acid moieties at the position of C-13 were successfully synthesized via esterification without protecting C-7-OH. Bioassay results revealed that compounds 13 and 18 have good selectivity against prostatic cancer cell line DU145, with IC₅₀value as low as 15.9 nmol/L for 18.

Full text of DOI:10.1002/cjoc.201600381

FULL PAPER
DOI: 10.1002/cjoc.201600381
Facile Synthesis of 7-epi-Taxane and Its Derivatives and
Preliminary Evaluation of Anticancer Activity
†,a,b
†,b,c
a,b
b
b
b
,b
Zhao Li,
Jia Feng,
Kun Zou, Zhuo Yang, Yong Zhang, Zhijian Xu, Bo Li,*
,d,e
a
,b
a,b
Jiye Shi,* Yiming Li, Weiliang Zhu,* and Kaixian Chen
a
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Centre, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203, China
b
c
Nano Science and Technology Institute, University of Science and Technology of China, Suzhou,
Jiangsu 215123, China
UCB Biopharma SPRL, Chemin du Foriest, Braine-l'Alleud, Belgium
d
e
Kellogg College, University of Oxford, 60-62 Banbury Road, Oxford, OX2 6PN, United Kingdom
7
-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl
group simply using Ag O as catalyst and DMF as solvent. The catalyst could be quantitatively recovered by filtra-
2
tion without loss of catalytic activity. This condition is also applicable to the direct epimerization of taxane deriva-
tives (e.g., docetaxel and paclitaxel) to 7-epi-taxane derivatives (e.g., 7-epi-docetaxel and 7-epi-paclitaxel). Fur-
thermore, 33 ester derivatives of 7-epi-taxane with different amino acid moieties at the position of C-13 were suc-
cessfully synthesized via esterification without protecting C-7-OH. Bioassay results revealed that compounds 13
and 18 have good selectivity against prostatic cancer cell line DU145, with IC50 value as low as 15.9 nmol/L for 18.
Keywords taxane, 7-epi-taxane, silver oxide, amino acid, C-13 derivative of taxane, anticancer activity
Introduction
Therefore, 7-epi-taxane might have potential application
in developing metabolically more stable drugs than
taxane and its derivatives.
[
1,2]
Taxane belongs to the family of diterpenoids
with
®
famous derivatives such as Paclitaxel (Taxol , Figure
Most of the reported reactions for taxane epimeriza-
[
3]
®
[4]
1
)
and Docetaxel (Taxotere , Figure 1). They are
tion were under basic or base-catalyzed conditions.
important anticancer agents widely used in clinical, es-
pecially, for the treatment of ovarian, breast and lung
[13]
Chaudhary et al.
reported that paclitaxel could un-
dergo epimerization to produce 7-epi-paclitaxel after
[5]
cancers. Meanwhile, great effort has been continu-
ously made to modify the molecular structure of the
natural product to further extend its application and
overcome its clinical defects, e.g., poor water solubility,
multi-drug resistance (MDR), and serious dose-limiting
being treated with sodium hydride in tetrahydrofuran.
[
14]
Py et al.
obtained 7-epi-10-deacetylpaclitaxel from
1
0-deacetyl-paclitaxel by using DBU in toluene. Alt-
hough these reported methods are used widely, other
active moieties of taxane derivatives might be influ-
enced by the bases used, e.g., sodium hydride and DBU.
Thus, new method for easily synthesizing 7-epi-pacli-
taxel and its derivatives is of importance.
[6]
toxicity.
Cytochrome P450 is one of the main metabolic en-
[
7]
zyme of paclitaxel. The 7β-hydroxyl group of
paclitaxel is the primary group recognized by cyto-
chrome P450, leading to the spontaneous conversion of
®
Cabazitaxel (Jevtana , Figure 1) is the dimethyloxyl
[15]
derivative of docetaxel.
When we synthesized the
7
β-hydroxyl group to 7α-hydroxy (Figure 1) with better
derivatives of Cabazitaxel, we accidently obtained the
chemical stability under natural or physiological condi-
tions. The conversion may be attributed to the stable
intramolecular hydrogen bond between 7α-OH and
7-epi-paclitaxel with neutral Ag O as catalyst, and the
2
absolute structure of the product was confirmed accord-
[13]
ing to Kingston’s report. This unexpected result en-
couraged us to systematically study the new method for
facile synthesis of 7-epi-taxanes, which could promote
the drug development based on 7-epi-taxane derivatives.
[
8-10]
4
-OAc in 7-epi-paclitaxel.
Therefore, 7-epi-pac-
litaxel is more metabolically stable against the enzyme
[11,12]
to inhibit the formation of 6α-hydroxy-paclitaxel.
*
E-mail: wlzhu@simm.ac.cn; Tel.: 0086-021-50805020
Received June 22, 2016; accepted August 8, 2016; published online XXXX, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600381 or from the author.
These authors contributed equally to this work.
†
Chin. J. Chem. 2016, XX, 1—12
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Li et al.
FULL PAPER
Recently, the modification of paclitaxel mainly fo-
doublet of doublets, td＝triplet of doublets, ddd＝
doublet of doublet of doublets, m＝multiplet, brs＝
broad singlet. Coupling constants (J) were measured in
hertz (Hz). The ESI-MS was recorded on Finnigan
LCQ/DECA, and the HRMS on Micromass Ultra
Q-TOF (ESI). All HPLC data were gathered on an Ag-
ilent 1200 infinity, DAD. Reactions were analysed by
thin layer chromatography (TLC) on silica gel F254 and
the visualization was accomplished with UV light (254
nm). Colum chromatography was performed using silica
gel (300－400 mesh).
cused on the C-13 side chain of α-hydroxy-β-amino acid
[16,17]
of paclitaxel.
Numerous structure-activity studies
elucidated that the C-13 side chain of paclitaxel plays an
important role to affect the polymerization of tubulin
[
18,19]
and the cytotoxicity.
Amino acids not only are the
unit of the protein skeleton but also have some functions.
Thus, they have been frequently used for lead optimiza-
[20]
tion.
R2
R1
O
R3
7
4
6
General procedures for the preparation of 7-epi-pac-
NH
O
H
1
3
litaxel (2), 7-epi-docetaxel (5) and 7-epi-baccatin III
H
O
O
O
(6)
OHO
O
OH
O
To a solution of paclitaxel (1, 2.0 g, 2.34 mmol) in
DMF (150 mL) was added silver oxide (0.54 g, 2.34
mmol) at room temperature. It was then heated to
100 ℃ for 3 h. The reaction mixture was quenched
with excess water and extracted three times with ethyl
acetate. The organic layer was washed with excess wa-
R1
R1
R1
R1
R1
=
=
=
=
=
-OH, R = COOCH , R = COC H , Paclitaxel (1)
2
3
3
6 5
2
3
-OH, R = COOCH , R = COC H , 7-epi-Paclitaxel (2)
3
6 5
2
3
-OH, R = OH, R = COO(CH ) , Docetaxel (3)
3
3
2
3
-OCH , R = OCH , R = COO(CH ) , Cabazitaxel (4)
3
3
3 3
2 4
ter and brine, dried with Na SO , and evaporated under
2
3
-OH, R = OH, R = COO(CH ) , 7-epi-Docetaxel (5)
3
3
vacuum to dryness. The crude residue was separated on
silica gel (DCM/Methanol, 120∶1) to give 2. The
preparation of 5 and 6 was performed as above proce-
dure.
Figure 1 Examples of taxanes.
Herein, we report an efficient approach to converting
taxane to 7-epi-taxane with Ag O as recoverable and
recyclable catalyst (Scheme 1). Furthermore, we syn-
thesized a series of 7-epi-taxane derivatives with differ-
ent amino acid moieties on the position of C-13
2
7
-epi-Paclitaxel (2) White solid, 1.60 g, yield 80%.
H NMR (400 MHz, CDCl ) δ: 8.20 (d, J＝7.28 Hz,
H), 7.74 (d, J＝7.33 Hz, 2H), 7.64 (t, J＝7.32 Hz, 1H),
1
3
2
7
1
.59－7.34 (m, 10H), 7.02 (d, J＝9.16 Hz, 1H), 6.81 (s,
H), 6.26 (t, J＝8.60 Hz, 1H), 5.83 (dd, J＝2.40, 9.00
(
Scheme 2) and found that some compounds have anti-
cancer activity. Especially, compound 18 exhibited good
selectivity against human prostatic cancer cell line
DU145 with an IC50 value of 15.9 nmol/L.
Hz, 1H), 5.78 (d, J＝7.53 Hz, 1H), 4.93 (dd, J＝3.44,
.10 Hz, 1H), 4.83 (dd, J＝2.69, 4.92 Hz, 1H), 4.71 (d,
9
J＝11.67 Hz, 1H), 4.41 (s, 2H), 3.94 (d, J＝7.44 Hz,
1H), 3.72 (ddd, J＝2.00, 4.86, 11.63 Hz, 1H), 3.56 (d,
J＝5.08 Hz, 1H), 2.53 (s, 3H), 2.47－2.25 (m, 4H), 2.22
Scheme 1 Synthesis of 7-epi-taxane
(
s, 3H), 1.90 (s, 1H), 1.81 (s, 3H), 1.69 (s, 3H), 1.22 (s,
13
3
2
1
1
7
5
2
H), 1.17 (s, 3H); C NMR (125 MHz, CDCl ) δ:
3
06.77, 172.25, 171.85, 168.99, 166.68, 139.30, 137.55,
33.27, 133.18, 132.88, 131.51, 129.82, 128.85, 128.58,
28.36, 128.22, 127.84, 126.64, 126.45, 82.31, 81.61,
8.71, 77.63, 77.20, 75.29, 74.86, 72.74, 71.71, 57.11,
4.49, 42.19, 39.88, 35.71, 34.86, 25.56, 22.13, 20.88,
0.45, 15.78, 14.33; ＋ HRMS (ESI): calcd for
Experimental
C
47
H
7
51
O
14NNa [M＋Na] 876.3202, found 876.3187.
-epi-Docetaxel (5) White solid, 1.48 g, yield 80%.
H NMR (400 MHz, CDCl ) δ: 8.15 (d, J＝7.56 Hz,
General experimental procedures
1
3
All starting materials and solvents were purchased
from commercial suppliers and used without further
purification unless otherwise stated. Anhydrous toluene
was dried by calcium hydride using standard procedures.
2H), 7.64 (t, J＝7.34 Hz, 1H), 7.53 (t, J＝7.69 Hz, 2H),
7.45－7.32 (m, 5H), 6.28 (t, J＝8.56 Hz, 1H), 5.75 (d,
J＝7.43 Hz, 1H), 5.47 (d, J＝7.19 Hz, 2H), 5.30 (d, J＝
8.43 Hz, 1H), 4.93 (dd, J＝3.78, 8.86 Hz, 1H), 4.74 (d,
J＝11.78 Hz, 1H), 4.64 (s, 1H), 4.46－4.36 (m, 2H),
4.16 (s, 1H), 3.94 (d, J＝7.16 Hz, 1H), 3.69 (dd, J＝
2.89, 11.91 Hz, 1H), 3.39 (d, J＝4.56 Hz, 1H), 2.51 (s,
3H), 2.41－2.21 (m, 4H), 1.81 (s, 3H), 1.77 (s, 1H),
Reactions requiring anhydrous conditions were per-
1
formed under N
2
atm. The H spectra were recorded on
a Bruker Avance-500 or 400 NMR spectrometer operat-
1
ing at 400 MHz for H, and 125 MHz or 100 MHz for
1
3
13
C, using TMS as internal standard and CDCl
3
as the
1.73 (s, 3H), 1.34 (s, 9H), 1.25 (s, 3H), 1.11 (s, 3H); C
solvent. Peak multiplicities are expressed as follows: s
NMR (125 MHz, CDCl ) δ: 215.03, 172.69, 172.28,
3
＝
singlet, d＝doublet, t＝triplet, q＝quadruplet, dd＝
167.13, 155.35, 138.41, 138.14, 135.53, 133.69, 130.20,
2
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—12

Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity
Scheme 2 Synthesis of C-13 derivatives of 7-epi-baccatin III
O
O
O
O
O
OH
O
O
OH
O
O
OH
O
7
7
7
R2
OH
O
O
H
O
H
O
Formic acid
Acetonitirle
H
O
R3
13
O
1
3
13
H
R2
H
H
HO
DPC/DMAP/Toluene
O
O
O
OHO
O
O
HO
O
OHO
O
O
H N
2
H
O
O
O
3
7 - 39
6
7 - 36
H
H
HN
O
O
H
H
S
R2
=
R2
R2
N
S
2
=
=
R =
S
N
NH
N
O
N
H
HN
H
NH
Boc
Boc
Boc
Boc
7
, 43%
10, 18%
9
, 56%
8
, 71%
H H
Boc
H
N
R2
=
R2
2
2
Boc
=
R =
R =
N
H
HN
Boc
HN
1
1, 56%
Boc
1
3, 84%
1
2, 70%
14, 70%
H
H
H
2
2
R =
R =
R2
O
R2
NH
N
=
=
S
Boc
HN
HN
Boc
HN
Boc
16, 34%
Boc
Boc
1
7, 61%
1
5, 31%
1
8, 66%
H
Cl
H
O
H
2
H
O
2
R =
R2
R2
=
R =
=
Cl
HN
O
HN
Boc
0, 36%
O
Boc
HN
O
Boc
HN
Boc
1, 28%
1
9, 76%
2
2
22, 55%
H
H
HN
H
H
N
H
2
2
R =
2
R =
R =
O
2
O
R =
HN
HN
HN
O
Boc
Boc
Boc
Boc
2
3, 21%
24, 38%
25, 81%
2
6, 44%
Boc
HN
O
F
O
H
2
N
R2
=
2
2
F
R =
R =
R =
O
O
O
Cl
HN
O
Boc
30, 18%
NH
2
7, 65%
28
, 14%
2
9, 38%
Cl
H
N
N
2
R2
=
2
2
R =
O
R =
R =
O
O
Cl
3
2, 83%
NO2
3
3, 95%
3
1, 96%
34, 71%
O
3
S
R3
R3
=
2
2
R =
=
S
R =
R =
S
O
38, 66%
NO2
39
, 59%
3
5, 84%
37, 68%
3
6, 32%
＋
1
8
5
2
29.28, 128.88, 128.78, 128.05, 126.60, 82.64, 82.07,
0.20, 79.24, 77.90, 77.76, 75.85, 75.40, 73.72, 72.33,
7.29, 42.57, 40.28, 36.15, 35.36, 28.17, 25.95, 22.56,
0.58, 16.68, 14.50; HRMS (ESI) calcd for
43 53 14
C H O NNa: [M＋Na] 830.3358, found 830.3361.
7-epi-Baccatin III (6) White solid, 1.07 g, yield
78%. H NMR (400 MHz, CDCl
1
3
) δ: 8.13 (d, J＝7.17
Hz, 2H), 7.64 (t, J＝7.42 Hz, 1H), 7.51 (t, J＝7.65 Hz,
Chin. J. Chem. 2016, XX, 1—12
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Li et al.
FULL PAPER
2
H), 6.83 (s, 1H), 5.72 (d, J＝7.36 Hz, 1H), 4.96 (dd,
J＝3.04, 9.09 Hz, 1H), 4.87 (d, J＝11.67 Hz, 1H), 4.85
4.78 (m, 1H), 4.45－4.33 (m, 2H), 4.03 (d, J＝7.47
Hz, 1H), 3.69 (dd, J＝3.14, 11.53 Hz, 1H), 2.37 (s, 4H),
1H), 3.46－3.36 (m, 1H), 3.29－3.18 (m, 1H), 2.40－
2.26 (m, 5H), 2.26－2.19 (m, 5H), 1.79 (s, 1H), 1.66 (s,
1
3
－
6H), 1.44 (s, 9H), 1.19 (s, 3H), 1.15 (s, 3H); C NMR
(100 MHz, CDCl ) δ: 206.88, 172.05, 171.70, 168.97,
3
2
1
.36－2.24 (m, 4H), 2.21 (s, 3H), 2.00 (s, 3H), 1.80 (s,
166.57, 154.75, 139.70, 135.78, 133.33, 132.55, 129.65,
128.86, 128.29, 126.96, 122.15, 122.10, 119.49, 118.11,
110.94, 109.36, 82.26, 81.43, 79.76, 78.77, 77.70, 77.15,
75.19, 74.74, 70.33, 57.12, 54.00, 42.07, 39.89, 35.83,
34.86, 27.92, 27.84, 25.49, 21.82, 20.60, 20.47, 15.73,
1
3
H), 1.65 (s, 3H), 1.13 (s, 3H), 1.07 (s, 3H); C NMR
) δ: 207.16, 171.96, 169.00, 166.72,
(
125 MHz, CDCl
3
1
8
4
1
43.21, 133.28, 131.78, 129.64, 129.00, 128.23, 82.21,
1.36, 78.66, 78.35, 77.20, 75.13, 74.74, 67.37, 57.24,
1.70, 40.27, 38.08, 34.95, 26.03, 22.10, 20.52, 19.86,
56 2
14.50; HRMS (ESI) calcd for C47H N O14Na: [M＋
＋
5.77, 15.23; HRMS (ESI) calcd for C31
H
38
O11Na: [M
Na] 895.3629, found 895.3655.
＋
＋
Na] 609.2306, found 609/2309.
7-epi-13-O-(S-(Acetylaminomethyl)-N-Boc-L-
cysteine)-baccatin III ester (9) S-(Acetylamino-
methyl)-N-Boc-L-cysteine (49.7 mg, 0.17 mmol) was
General procedures for the preparation of
7
-epi-13-O-acyl-baccatin III (7－39)
used as carboxylic acid to give a white solid, 32.6 mg,
1
To a solution of 7-epi-baccatin III (6, 40.0 mg, 0.068
yield 56%. H NMR (400 MHz, CDCl ) δ: 8.12 (d, J＝
3
mmol) in dry toluene (3 mL) was added carboxylic acid
0.17 mmol), di-2-pyridyl-carbonate (DPC, 53.4 mg,
7
.62 Hz, 2H), 7.65 (t, J＝7.40 Hz, 1H), 7.53 (t, J＝7.68
(
Hz, 2H), 6.84 (s, 1H), 6.49 (s, 1H), 6.20 (t, J＝9.60 Hz,
0
8
.20 mmol), and 4-(dimethylamino)-pyridine (DMAP,
.3 mg, 0.068 mol) under N at room temperature. Then,
1
4
1
1
3
1
3
1
1
H), 5.77 (d, J＝7.35 Hz, 1H), 5.54 (d, J＝8.20 Hz, 1H),
.96 (dd, J＝3.33, 9.01 Hz, 1H), 4.76 (d, J＝11.70 Hz,
H), 4.62－4.53 (m, 1H), 4.49 (dd, J＝6.48, 13.97 Hz,
H), 4.42 (d, J＝8.69 Hz, 1H), 4.38－4.29 (m, 2H),
.94 (d, J＝7.37 Hz, 1H), 3.72 (dd, J＝3.63, 11.39 Hz,
H), 3.16－3.08 (m, 1H), 3.07－2.96 (m, 1H), 2.49 (s,
H), 2.43－2.24 (m, 4H), 2.22 (s, 3H), 2.02 (s, 3H),
2
the reaction mixture was heated to 78 ℃ for 10 h un-
der nitrogen. After completion of the reaction, the mix-
ture was quenched with water at room temperature and
extracted three times with ethyl acetate. The organic
layer was washed with water and brine, dried with
Na
crude residue was separated on silica gel to give 7－39.
-epi-13-O-(N-Boc-L-methionine)-baccatin III es-
ter (7) N-Boc-L-methionine (42.5 mg, 0.17 mmol)
was used as carboxylic acid to give a white solid, 24.0
mg, yield 43%. H NMR (400 MHz, CDCl
J＝7.77 Hz, 2H), 7.64 (t, J＝7.25 Hz, 1H), 7.52 (t, J＝
2 4
SO , and evaporated under vacuum to dryness. The
.94 (s, 1H), 1.90 (s, 3H), 1.67 (s, 3H), 1.50 (s, 9H),
13
.23 (s, 3H), 1.17 (s, 3H); C NMR (125 MHz, CDCl )
3
7
δ: 206.79, 171.48, 170.71, 169.83, 168.85, 166.58,
39.62, 133.31, 132.71, 129.59, 128.76, 128.26, 82.18,
81.49, 80.45, 78.77, 77.63, 77.05, 75.23, 74.85, 71.14,
1
1
3
) δ: 8.09 (d,
5
2
7.06, 53.70, 42.18, 41.75, 39.90, 35.55, 34.78, 33.60,
7.83, 25.47, 22.69, 21.87, 20.79, 20.38, 15.73, 14.32＋;
7
5
.54 Hz, 2H), 6.82 (s, 1H), 6.21 (t, J＝8.82 Hz, 1H),
.76 (d, J＝7.41 Hz,1H), 5.19 (d, J＝8.42 Hz, 1H), 4.92
HRMS (ESI) calcd for C H O N NaS: [M＋Na]
4
2
56 15
2
8
83.3294, found 883.3279.
-epi-13-O-(N-Boc-L-histidine(tosyl))-baccatin III
(
dd, J＝3.53, 9.14 Hz, 1H), 4.72 (s, 1H), 4.53 (td, J＝
7
3
7
2
3
1
.62, 8.60 Hz, 1H), 4.44－4.31 (m, 2H), 3.97 (d, J＝
.35 Hz, 1H), 3.71 (dd, J＝3.80, 11.42 Hz, 1H), 2.70－
.55 (m, 2H), 2.51 (s, 3H), 2.42－2.23 (m, 5H), 2.21 (s,
H), 2.16 (s, 3H), 2.01－1.88 (m, 4H), 1.87 (s, 1H),
.67 (s, 3H), 1.47 (s, 9H), 1.19 (s, 3H), 1.16 (s, 3H); C
) δ: 207.12, 172.36, 172.15,
69.31, 167.07, 155.49, 139.67, 133.81, 133.60, 130.05,
29.23, 128.76, 82.71, 82.05, 80.39, 79.11, 78.10, 77.64,
5.59, 75.16, 70.93, 57.67, 52.75, 42.54, 40.39, 36.25,
5.38, 32.10, 30.05, 29.69, 28.31, 26.00, 22.74, 20.88,
6.11, 15.62, 15.55; ＋HRMS (ESI) calcd for
ester (10) N-Boc-L-histidine(tosyl) (69.6 mg, 0.17
mmol) was used as carboxylic acid to give a white solid,
1
1
8
2.1 mg, yield 18%. H NMR (400 MHz, CDCl ) δ:
3
13
.10 (d, J＝7.79 Hz, 2H), 7.94 (s, 1H), 7.81 (d, J＝8.08
Hz, 2H), 7.65 (t, J＝7.25 Hz, 1H), 7.53 (t, J＝7.69 Hz,
NMR (125 MHz, CDCl
3
2
6
H), 7.38 (d, J＝8.09 Hz, 2H), 7.12 (s, 1H), 6.79 (s, 1H),
.15 (t, J＝8.65 Hz, 1H), 5.76 (d, J＝7.41 Hz, 1H), 5.67
1
1
7
3
1
(
d, J＝8.37 Hz, 1H), 4.93 (dd, J＝3.38, 8.46 Hz, 1H),
.70－4.58 (m, 2H), 4.38 (q, J＝8.84 Hz, 2H), 3.95 (d,
J＝7.41 Hz, 1H), 3.70 (dd, J＝3.30, 11.74 Hz, 1H), 3.17
dd, J＝4.62, 14.75 Hz, 1H), 3.03 (dd, J＝6.62, 15.03
Hz, 1H), 2.50 (s, 3H), 2.46 (s, 3H), 2.37－2.24 (m, 4H),
.22 (s, 3H), 1.79 (s, 1H), 1.78 (s, 3H), 1.67 (s, 3H),
4
(
C
41
H
55
O14NNaS: [M＋Na] 840.3235, found 840.3225.
7
-epi-13-O-(N-Boc-L-tryptophan)-baccatin III
2
ester (8) N-Boc-L-tryptophan (51.9 mg, 0.17 mmol)
was used as carboxylic acid to give a white solid, 42.5
mg, yield 71%. H NMR (400 MHz, CDCl
13
1.44 (s, 9H), 1.18 (s, 3H), 1.16 (s, 3H); C NMR (125
MHz, CDCl ) δ: 207.20, 172.19, 171.38, 169.33, 167.05,
1
3
) δ: 8.24 (s,
3
1
7
H), 8.10 (d, J＝7.92 Hz, 2H), 7.65 (d, J＝7.66 Hz, 2H),
.53 (t, J＝7.66 Hz, 2H), 7.38 (d, J＝8.14 Hz, 1H), 7.21
155.32, 146.52, 140.07, 139.48, 136.55, 134.67, 133.82,
133.18, 130.53, 130.04, 129.23, 128.78, 127.35, 115.07,
82.71, 82.07, 80.23, 79.06, 78.14, 77.66, 75.56, 75.12,
70.87, 57.64, 52.86, 42.48, 40.37, 36.30, 35.40, 30.21,
(
dt, J＝7.24, 21.21 Hz, 2H), 7.09 (d, J＝2.00 Hz, 1H),
.78 (s, 1H), 6.11 (t, J＝8.70 Hz, 1H), 5.74 (d, J＝7.53
Hz, 1H), 5.11 (d, J＝8.01 Hz, 1H), 4.91 (dd, J＝3.42,
6
28.28, 25.98, 22.63, 21.74, 20.91, 16.12, 15.37; HRMS
＋
8
3
.96 Hz, 1H), 4.77－4.64 (m, 2H), 4.42－4.31 (m, 2H),
.90 (d, J＝7.65 Hz, 1H), 3.69 (dd, J＝3.97, 11.45 Hz,
(ESI) calcd for C H O N S [M＋H] 978.3689,
found 978.3682.
49
60 16
3
4
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—12

Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity
7
-epi-13-O-(N-Boc-3-carboxyazetidine-1-carbo-
22.58, 20.89, 20.84, 16.18, 15.12; HRMS (ESI) calcd
＋
xylic acid)-baccatin III ester (11) N-Boc-3-carboxya-
for C38
H
49
O14NNa: [M ＋ Na]
766.3045, found
zetidine-1-carboxylic acid (34.3 mg, 0.17 mmol) was
766.3027.
used as carboxylic acid to give a white solid, 29.5 mg,
7-epi-13-O-(N-Boc-L-isoleucine)-baccatin III ester
(14) N-Boc-L-isoleucine (39.4 mg, 0.17 mmol) was
1
yield 56%. H NMR (400 MHz, CDCl
3
) δ: 8.08 (d, J＝
7
.56 Hz, 2H), 7.65 (t, J＝7.42 Hz, 1H), 7.52 (t, J＝7.61
used as carboxylic acid to give a white solid, 38.2 mg,
1
Hz, 2H), 6.82 (s, 1H), 6.23 (t, J＝8.61 Hz, 1H), 5.76 (d,
J＝7.28 Hz, 1H), 4.94 (dd, J＝3.24, 9.09 Hz, 1H), 4.62
yield 70%. H NMR (400 MHz, CDCl
3
) δ: 8.11 (d, J＝
7.43 Hz, 2H), 7.65 (t, J＝7.47 Hz, 1H), 7.53 (t, J＝7.58
Hz, 2H), 6.85 (s, 1H), 6.21 (t, J＝8.62 Hz, 1H), 5.77 (d,
J＝7.15 Hz, 1H), 5.06 (d, J＝9.29 Hz, 1H), 4.94 (dd,
J＝3.21, 8.65 Hz, 1H), 4.72 (d, J＝11.49 Hz, 1H), 4.45
－4.31 (m, 3H), 3.99 (d, J＝7.31 Hz, 1H), 3.72 (dd, J＝
4.49, 11.14 Hz, 1H), 2.47 (s, 3H), 2.44－2.24 (m, 5H),
2.21 (s, 3H), 2.07－2.00 (m, 1H), 1.90 (s, 3H), 1.68 (s,
3H), 1.48 (s, 9H), 1.27 (s, 2H), 1.21 (s, 3H), 1.17 (s, 3H),
(
(
d, J＝11.64 Hz, 1H), 4.44－4.32 (m, 2H), 4.25－4.11
m, 4H), 3.94 (d, J＝7.23 Hz, 1H), 3.71 (dd, J＝4.09,
11.44 Hz, 1H), 3.49－3.37 (m, 1H), 2.36 (s, 4H), 2.31－
2
1
.23 (m, 3H), 2.22 (s, 3H), 1.86 (s, 4H), 1.66 (s, 3H),
13
.47 (s, 9H), 1.22 (s, 3H), 1.17 (s, 3H); C NMR (125
) δ: 207.11, 171.90, 171.46, 169.35, 167.04,
55.97, 139.95, 133.86, 133.44, 129.99, 129.22, 128.76,
MHz, CDCl
3
1
8
7
2
13
2.63, 82.27, 80.29, 79.08, 78.12, 77.57, 75.55, 75.18,
0.55, 57.59, 42.58, 40.38, 36.00, 35.34, 32.10, 28.35,
1.08 (d, J＝6.70 Hz, 3H), 0.94 (t, J＝7.27 Hz, 3H); C
NMR (125 MHz, CDCl ) δ: 206.76, 171.68, 171.66,
3
5.98, 22.31, 20.98, 20.90, 16.16, 15.06; HRMS (ESI)
168.92, 166.64, 155.44, 139.47, 133.36, 132.96, 129.60,
128.78, 128.32, 82.28, 81.67, 79.68, 78.71, 77.71, 77.18,
75.20, 74.72, 70.16, 58.21, 57.22, 42.10, 39.95, 36.98,
35.94, 34.95, 27.87, 25.48, 23.41, 22.16, 20.50, 20.44,
＋
calcd for C40
92.3192.
-epi-13-O-(N-Boc-L-phenylalanine)-baccatin III
51
H O14NNa: [M＋Na] 792.3202, found
7
7
ester (12) N-Boc-L-phenylalanine (45.2 mg, 0.17
15.72, 15.65, 15.00, 11.00; HRMS (ESI) calcd for
＋
mmol) was used as carboxylic acid to give a white solid,
C
42
H
57
O
14NNa: [M＋Na] 822.3671, found 822.3654.
1
3
8
9.6 mg, yield 70%. H NMR (400 MHz, CDCl
.10 (d, J＝7.74 Hz, 2H), 7.65 (t, J＝7.30 Hz, 1H), 7.52
3
) δ:
7-epi-13-O-(N,N-Bis-Boc-L-lysine)-baccatin III
ester (15) N,N-Bis-Boc-L-lysine (59.1 mg, 0.17 mmol)
(
7
t, J＝7.58 Hz, 2H), 7.34 (dt, J＝6.79, 12.94 Hz, 3H),
.22 (d, J＝7.42 Hz, 2H), 6.79 (s, 1H), 6.14 (t, J＝8.44
Hz, 1H), 5.75 (d, J＝7.51 Hz, 1H), 5.00 (d, J＝8.38 Hz,
H), 4.93 (dd, J＝2.82, 8.61 Hz, 1H), 4.70 (d, J＝11.65
Hz, 1H), 4.61 (q, J＝7.47 Hz, 1H), 4.37 (q, J＝8.65 Hz,
H), 3.92 (d, J＝7.16 Hz, 1H), 3.70 (dd, J＝4.28, 11.03
Hz, 1H), 3.21 (dd, J＝6.26, 13.79 Hz, 1H), 3.13－3.00
m, 1H), 2.39 (s, 3H), 2.37－2.23 (m, 4H), 2.21 (s, 3H),
was used as carboxylic acid to give a white solid, 19.8
1
mg, yield 31%. H NMR (400 MHz, CDCl
3
) δ: 8.10 (d,
J＝7.48 Hz, 2H), 7.65 (t, J＝7.49 Hz, 1H), 7.52 (t, J＝
7.56 Hz, 2H), 6.82 (s, 1H), 6.20 (d, J＝9.25 Hz, 1H),
5.76 (d, J＝7.51 Hz, 1H), 5.24 (d, J＝7.93 Hz, 1H),
4.93 (dd, J＝3.32, 8.68 Hz, 1H), 4.77－4.62 (m, 2H),
4.46－4.26 (m, 3H), 3.97 (d, J＝7.41 Hz, 1H), 3.71 (dd,
J＝4.39, 11.39 Hz, 1H), 3.24－3.05 (m, 2H), 2.45 (s,
3H), 2.42－2.25 (m, 4H), 2.21 (s, 3H), 2.05－1.93 (m,
1H), 1.87 (s, 3H), 1.86－1.71 (m, 4H), 1.67 (s, 3H),
1.56 (dd, J＝7.24, 14.70 Hz, 2H), 1.47 (s, 9H), 1.46 (s,
1
2
(
1
1
.86 (s, 1H), 1.69 (s, 3H), 1.66 (s, 3H), 1.43 (s, 9H),
13
3
.20 (s, 3H), 1.15 (s, 3H); C NMR (125 MHz, CDCl )
δ: 207.25, 172.08, 169.37, 167.03, 155.05, 140.00,
1
3
1
1
7
4
2
35.42, 133.78, 133.12, 130.07, 129.36, 129.28, 129.16,
28.90, 128.73, 127.40, 82.73, 81.97, 80.30, 79.21,
8.12, 77.60, 75.61, 75.20, 70.93, 57.57, 54.65, 42.53,
0.37, 38.39, 36.29, 35.33, 28.31, 28.26, 25.97, 22.48,
9H), 1.19 (s, 3H), 1.16 (s, 3H); C NMR (125 MHz,
CDCl ) δ: 206.64, 171.97, 171.56, 168.84, 166.54,
3
155.64, 155.09, 139.33, 133.30, 133.01, 129.54, 128.74,
128.25, 82.20, 81.62, 79.68, 78.54, 77.62, 77.14, 75.06,
74.65, 70.18, 57.14, 42.01, 39.87, 39.40, 35.76, 34.90,
31.45, 29.20, 27.94, 27.84, 27.51, 25.49, 22.16, 22.05,
20.37, 15.62, 14.93; ＋HRMS (ESI): calcd for
1.02, 20.92, 16.16, 15.10; HRMS (ESI) calcd for
＋
C
45
H
55
O14NNa: [M＋Na] 856.3515, found 856.3503.
7
-epi-13-O-(N-Boc-glycine)-baccatin III ester (13)
N-Boc-glycine (29.8 mg, 0.17 mmol) was used as car-
C
47
H
66
O
16
2
N Na: [M＋Na] 937.4305, found 937.4293.
boxylic acid to give a white solid, 42.8 mg, yield 84%.
7-epi-13-O-((S)-N-Boc-3-proline)-baccatin III
ester (16) (S)-N-Boc-3-proline (36.6 mg, 0.17 mmol)
1
H NMR (400 MHz, CDCl
3
) δ: 8.07 (d, J＝7.66 Hz,
2
6
H), 7.63 (t, J＝7.35 Hz, 1H), 7.51 (t, J＝7.62 Hz, 2H),
.81 (s, 1H), 6.20 (t, J＝8.56 Hz, 1H), 5.74 (d, J＝7.36
was used as carboxylic acid to give a white solid, 18.0
1
mg, yield 34%. H NMR (400 MHz, CDCl
3
) δ: 8.09 (d,
Hz, 1H), 5.22 (t, J＝3.87 Hz, 1H), 4.91 (dd, J＝3.33,
J＝7.81 Hz, 2H), 7.64 (t, J＝7.43 Hz, 1H), 7.51 (t, J＝
7.77 Hz, 2H), 6.82 (s, 1H), 6.19 (t, J＝8.86 Hz, 1H),
5.76 (d, J＝7.45 Hz, 1H), 4.95 (dd, J＝3.23, 8.85 Hz,
1H), 4.64 (d, J＝10.42 Hz, 1H), 4.46－4.32 (m, 2H),
3.96 (d, J＝7.31 Hz, 1H), 3.85－3.61 (m, 3H), 3.61－
3.50 (m, 1H), 3.48－3.36 (m, 1H), 3.17－3.04 (m, 1H),
2.41 (s, 3H), 2.39－2.23 (m, 5H), 2.21 (s, 3H), 1.91－
1.80 (m, 5H), 1.66 (s, 3H), 1.48 (s, 9H), 1.21 (s, 3H),
9
2
3
2
1
.15 Hz, 1H), 4.70 (d, J＝11.53 Hz, 1H), 4.43－4.29 (m,
H), 4.06 (dd, J＝6.57, 18.54 Hz, 1H), 3.93 (s, 2H),
.74－3.61 (m, 1H), 2.42 (s, 3H), 2.40－2.23 (m, 4H),
.20 (s, 3H), 1.97 (s, 1H), 1.85 (s, 3H), 1.65 (s, 3H),
13
.47 (s, 9H), 1.17 (s, 3H), 1.14 (s, 3H); C NMR (125
) δ: 207.18, 171.77, 169.94, 169.38, 167.00,
55.74, 139.97, 133.83, 133.45, 130.00, 129.24, 128.76,
MHz, CDCl
3
1
8
7
1
3
2.63, 82.11, 80.42, 79.01, 78.18, 77.56, 75.59, 75.20,
0.67, 57.59, 42.50, 40.43, 36.05, 35.30, 28.31, 25.98,
3
1.16 (s, 3H); C NMR (125 MHz, CDCl ) δ: 207.15,
172.49, 171.44, 169.35, 167.02, 154.11, 140.26, 140.16,
Chin. J. Chem. 2016, XX, 1—12
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Li et al.
FULL PAPER
1
7
4
3
1
8
33.82, 133.36, 130.01, 129.27, 128.73, 82.68, 82.27,
9.94, 79.12, 78.14, 77.60, 75.54, 75.22, 70.21, 57.59,
8.50, 48.30, 45.16, 44.78, 43.44, 42.58, 40.37, 36.06,
5.34, 29.71, 28.47, 25.98, 22.43, 21.02, 20.90, 16.14＋,
4.86－4.76 (m, 1H), 4.70 (d, J＝11.65 Hz, 1H), 4.46－
4.33 (m, 3H), 3.97 (d, J＝7.35 Hz, 1H), 3.71 (dd, J＝
3.86, 11.40 Hz, 1H), 2.49 (s, 3H), 2.47－2.23 (m, 8H),
2.21 (s, 3H), 2.01－1.94 (m, 1H), 1.90 (s, 3H), 1.82－
1.69 (m, 4H), 1.67 (s, 3H), 1.61－1.51 (m, 1H), 1.46 (s,
5.06; HRMS (ESI) calcd for C41
53
H O14NNa [M＋Na]
13
06.3358, found 806.3350.
7
9H), 1.43－1.25 (m, 5H), 1.20 (s, 3H), 1.16 (s, 3H); C
NMR (125 MHz, CDCl ) δ: 207.20, 172.19, 171.86,
-epi-13-O-(N-Boc-O-benzyl-L-serine)-baccatin
III ester (17) N-Boc-O-benzyl-L-serine (50.2 mg,
.17 mmol) was used as carboxylic acid to give a white
3
169.38, 167.03, 155.48, 139.80, 133.80, 133.43, 130.05,
129.23, 128.76, 82.73, 81.98, 80.30, 79.09, 78.13, 77.63,
75.59, 75.19, 73.26, 70.97, 57.63, 53.17, 42.54, 40.35,
36.24, 35.36, 31.60, 31.57, 30.52, 28.30, 27.40, 25.96,
0
1
solid, 35.7 mg, yield 61%. H NMR (400 MHz, CDCl
δ: 8.09 (d, J＝7.71 Hz, 2H), 7.65 (t, J＝7.35 Hz, 1H),
3
)
7
1
7
3
.53 (t, J＝7.56 Hz, 2H), 7.40－7.30 (m, 4H), 7.29 (s,
H), 6.82 (s, 1H), 6.24 (t, J＝8.51 Hz, 1H), 5.77 (d, J＝
.35 Hz, 1H), 5.52 (d, J＝9.06 Hz, 1H), 4.94 (dd, J＝
.54, 8.82 Hz, 1H), 4.66 (d, J＝11.54 Hz, 1H), 4.58 (d,
25.32, 23.75, 22.56, 20.96, 20.90, 16.14, 15.39; HRMS
＋
(ESI) calcd for C47
found 920.4015.
63
H O16NNa: [M＋Na] 920.4039,
7-epi-13-O-(N-Boc-O-(t-butyl)-L-tyrosine)-bacca-
tin III ester (20) N-Boc-O-(t-butyl)-L-tyrosine (57.5
mg, 0.17 mmol) was used as carboxylic acid to give a
J＝11.89 Hz, 1H), 4.56－4.46 (m, 2H), 4.45－4.35 (m,
H), 4.01 (dd, J＝3.00, 9.31 Hz, 1H), 3.97 (d, J＝7.33
Hz, 1H), 3.80 (dd, J＝3.25, 9.27 Hz, 1H), 3.72 (dd, J＝
2
1
white solid, 22.2 mg, yield 36%. H NMR (400 MHz,
3
2
1
.89, 11.38 Hz, 1H), 2.40 (s, 3H), 2.39－2.24 (m, 4H),
3
CDCl ) δ: 8.11 (d, J＝7.76 Hz, 2H), 7.65 (t, J＝7.45 Hz,
.22 (s, 3H), 1.76 (s, 1H), 1.68 (s, 6H), 1.48 (s, 9H),
1H), 7.54 (t, J＝7.59 Hz, 2H), 7.11 (d, J＝8.20 Hz, 2H),
6.98 (d, J＝8.07 Hz, 2H), 6.81 (s, 1H), 6.13 (t, J＝8.25
Hz, 1H), 5.76 (d, J＝7.45 Hz, 1H), 5.01－4.89 (m, 2H),
4.69 (d, J＝11.29 Hz, 1H), 4.59 (q, J＝7.61 Hz, 1H),
4.38 (q, J＝8.67 Hz, 2H), 3.95 (d, J＝7.16 Hz, 1H),
3.71 (dd, J＝3.89, 11.45 Hz, 1H), 3.20 (dd, J＝6.30,
14.25 Hz, 1H), 2.99 (dd, J＝7.69, 13.76 Hz, 1H), 2.41
(s, 3H), 2.39－2.26 (m, 4H), 2.22 (s, 3H), 1.67 (s, 7H),
13
3
.20 (s, 3H), 1.16 (s, 3H); C NMR (100 MHz, CDCl )
δ: 207.15, 171.87, 170.00, 169.38, 167.06, 155.53,
1
1
7
5
2
40.16, 136.91, 133.83, 133.33, 130.03, 129.22, 128.78,
28.54, 128.06, 127.74, 82.70, 82.20, 80.42, 79.02,
8.15, 77.68, 75.52, 75.13, 73.44, 70.76, 69.74, 57.62,
4.16, 42.46, 40.37, 36.33, 35.42, 28.33, 26.04, 22.65,
0.90, 16.13, 15.05; ＋ HRMS (ESI) calcd for
13
C
46
H
57
O
15NNa: [M＋Na] 886.3620, found 886.3608.
-epi-13-O-(S-Benzyl-N-Boc-L-cysteine)-baccatin
III ester (18) S-Benzyl-N-Boc-L-cysteine (53.0 mg,
.17 mmol) was used as carboxylic acid to give a white
1.43 (s, 9H), 1.36 (s, 9H), 1.21 (s, 3H), 1.16 (s, 3H); C
7
3
NMR (100 MHz, CDCl ) δ: 207.22, 172.15, 172.08,
169.30, 167.06, 155.05, 154.70, 139.92, 133.75, 133.23,
130.06, 129.61, 129.25, 128.78, 124.41, 82.72, 82.01,
80.24, 79.23, 78.64, 78.10, 77.62, 75.60, 75.17, 70.98,
57.59, 54.60, 42.53, 40.38, 37.75, 36.31, 35.36, 28.80,
0
1
solid, 39.5 mg, yield 66%. H NMR (400 MHz, CDCl
δ: 8.09 (d, J＝7.05 Hz, 2H), 7.64 (tt, J＝1.29, 6.99 Hz,
H), 7.51 (t, J＝7.71 Hz, 2H), 7.41－7.30 (m, 5H), 6.82
s, 1H), 6.20－6.11 (m, 1H), 5.75 (d, J＝7.36 Hz, 1H),
3
)
1
(
5
1
4
2
28.27, 25.98, 22.51, 20.99, 20.89, 16.15, 15.33; HRMS
＋
(ESI) calcd for C49
found 928.4082.
63
H O15NNa: [M＋Na] 928.4090,
.31 (d, J＝6.56 Hz, 1H), 4.94 (dd, J＝3.42, 9.01 Hz,
H), 4.68 (d, J＝11.64 Hz, 1H), 4.59－4.51 (m, 1H),
.41－4.35 (m, 2H), 3.96 (d, J＝7.42 Hz, 1H), 3.79 (s,
H), 3.72 (ddd, J＝1.65, 4.58, 11.63 Hz, 1H), 2.97 (dd,
7-epi-13-O-(N-Boc-L-3,4-dichlorophe)-baccatin
III ester (21) N-Boc-L-3,4-dichlorophe (57.0 mg,
0.17 mmol) was used as carboxylic acid to give a white
1
J＝4.76, 13.33 Hz, 1H), 2.85 (dd, J＝6.53, 13.33 Hz,
solid, 17.3 mg, yield 28%. H NMR (400 MHz, CDCl
3
)
1
1
1
H), 2.42 (s, 3H), 2.37－2.27 (m, 4H), 2.22 (s, 3H),
δ: 8.10 (d, J＝7.68 Hz, 2H), 7.66 (t, J＝7.45 Hz, 1H),
7.53 (t, J＝7.71 Hz, 2H), 7.43 (d, J＝8.23 Hz, 1H), 7.34
(d, J＝1.70 Hz, 1H), 7.08 (dd, J＝1.72, 8.18 Hz, 1H),
6.82 (s, 1H), 6.18 (t, J＝8.86 Hz, 1H), 5.77 (d, J＝7.43
Hz, 1H), 5.04 (d, J＝8.40 Hz, 1H), 4.95 (dd, J＝3.26,
8.97 Hz, 1H), 4.66 (d, J＝11.61 Hz, 1H), 4.63－4.56 (m,
1H), 4.45－4.33 (m, 2H), 3.97 (d, J＝7.33 Hz, 1H),
3.72 (dd, J＝3.61, 11.34 Hz, 1H), 3.27 (dd, J＝5.35,
13.97 Hz, 1H), 2.94 (dd, J＝8.06, 14.30 Hz, 1H), 2.43
(s, 3H), 2.40－2.25 (m, 4H), 2.23 (s, 3H), 1.84 (s, 3H),
1.79 (s, 1H), 1.68 (s, 3H), 1.43 (s, 9H), 1.22 (s, 3H),
.85 (s, 3H), 1.72 (s, 1H), 1.67 (s, 3H), 1.49 (s, 9H),
13
3
.19 (s, 3H), 1.16 (s, 3H); C NMR (125 MHz, CDCl )
δ: 207.18, 171.97, 170.68, 169.38, 167.04, 155.15,
1
1
7
4
2
39.83, 137.21, 133.82, 133.38, 130.04, 129.21, 128.89,
28.79, 128.76, 127.51, 82.73, 82.10, 80.53, 79.11,
8.11, 77.64, 75.57, 75.14, 71.20, 57.63, 53.34, 42.49,
0.37, 36.99, 36.28, 35.39, 33.43, 28.33, 26.00, 22.61,
0.91, 16.15, 15.45; ＋HRMS (ESI) calcd for
C
46
H
57
O
14NNaS: [M＋Na] 902.3392, found 902.3379.
-epi-13-O-(5-Cyclohexyl-N-Boc-glutamic)-
baccatin III ester (19) 5-Cyclohexyl-N-Boc-glutamic
56.2 mg, 0.17 mmol) was used as carboxylic acid to
7
1
3
3
1.18 (s, 3H); C NMR (100 MHz, CDCl ) δ: 207.03,
(
171.95, 171.53, 169.36, 167.09, 154.98, 139.43, 135.78,
133.85, 133.67, 132.76, 131.58, 131.19, 130.68, 130.05,
129.18, 128.77, 128.44, 82.70, 82.16, 80.64, 79.11,
78.06, 77.63, 77.23, 75.54, 75.10, 71.31, 57.66, 54.10,
42.57, 40.37, 37.57, 36.23, 35.39, 28.21, 26.04, 22.63,
20.90, 16.10, 15.39; HRMS (ESI): calcd for
1
give a white solid, 46.8 mg, yield 76%. H NMR (400
MHz, CDCl ) δ: 8.10 (d, J＝7.46 Hz, 2H), 7.64 (t, J＝
.39 Hz, 1H), 7.52 (t, J＝7.69 Hz, 2H), 6.83 (s, 1H),
.18 (t, J＝8.61 Hz, 1H), 5.75 (d, J＝7.41 Hz, 1H), 5.21
3
7
6
(
d, J＝8.72 Hz, 1H), 4.94 (dd, J＝3.02, 8.62 Hz, 1H),
6
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—12

Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity
＋
C
9
45
H
53
O14NCl
2
Na: [M ＋ Na]
924.2735, found
δ: 206.63, 171.41, 169.85, 168.84, 166.56, 155.66,
139.57, 137.09, 133.30, 132.73, 129.54, 128.74, 128.27,
127.95, 127.75, 127.27, 126.78, 82.21, 81.74, 79.80,
78.59, 77.63, 77.18, 75.04, 74.66, 73.74, 70.29, 69.66,
58.21, 57.10, 41.99, 39.85, 35.97, 34.92, 27.82, 25.50,
24.2709.
-epi-13-O-(N-Boc-3-cyclohexyloxycarbonyl-L-
aspartic acid)-baccatin III ester (22) N-Boc-3-cyclo-
hexyloxycarbonyl-L-aspartic acid (53.8 mg, 0.17 mmol)
7
was used as carboxylic acid to give a white solid, 33.0
22.12, 20.42, 20.38, 15.64, 14.72; HRMS (ESI) calcd
1
＋
mg, yield 55%. H NMR (400 MHz, CDCl
3
) δ: 8.10 (d,
for C47
H
59
O15NNa: [M ＋ Na]
900.3777, found
J＝7.48 Hz, 2H), 7.65 (t, J＝7.37 Hz, 1H), 7.53 (t, J＝
900.3750.
7
5
4
.56 Hz, 2H), 6.82 (s, 1H), 6.17 (t, J＝8.63 Hz, 1H),
.76 (d, J＝7.27 Hz, 1H), 5.56 (d, J＝8.85 Hz, 1H),
.94 (dd, J＝3.43, 8.76 Hz, 1H), 4.79 (td, J＝4.06, 9.06
7-epi-13-O-(N-Boc-L-alanine)-baccatin III ester
(25) N-Boc-L-alanine (32.2 mg, 0.17 mmol) was used
as carboxylic acid to give a white solid, 41.6 mg, yield
1
Hz, 1H), 4.70－4.58 (m, 2H), 4.44－4.34 (m, 2H), 3.97
d, J＝7.36 Hz, 1H), 3.71 (dd, J＝3.54, 11.45 Hz, 1H),
81%. H NMR (400 MHz, CDCl
3
) δ: 8.10 (d, J＝7.89
(
Hz, 2H), 7.65 (t, J＝7.43 Hz, 1H), 7.52 (t, J＝7.68 Hz,
2H), 6.82 (s, 1H), 6.20 (t, J＝8.83 Hz, 1H), 5.76 (d, J＝
7.47 Hz, 1H), 5.16 (d, J＝7.79 Hz, 1H), 4.94 (dd, J＝
3.37, 8.74 Hz, 1H), 4.68 (d, J＝11.56 Hz, 1H), 4.45－
4.31 (m, 3H), 3.98 (d, J＝7.44 Hz, 1H), 3.75－3.65 (m,
1H), 2.47 (s, 3H), 2.41－2.24 (m, 4H), 2.21 (s, 3H),
1.87 (s, 3H), 1.82 (s, 1H), 1.67 (s, 3H), 1.53 (d, J＝7.26
3
2
9
.06－2.90 (m, 2H), 2.45 (s, 3H), 2.41－2.24 (m, 4H),
.22 (s, 4H), 1.90－1.81 (m, 5H), 1.69 (s, 3H), 1.48 (s,
13
H), 1.45－1.24 (m, 8H), 1.20 (s, 3H), 1.16 (s, 3H); C
) δ: 207.11, 171.92, 170.50,
69.99, 169.38, 167.04, 155.39, 139.81, 133.82, 133.37,
NMR (100 MHz, CDCl
3
1
1
7
5
2
1
8
30.05, 129.21, 128.77, 82.73, 82.19, 80.54, 79.12,
8.09, 77.65, 77.23, 75.54, 75.11, 74.22, 71.23, 57.63,
0.20, 42.52, 40.35, 37.11, 36.43, 35.39, 31.52, 28.31,
5.97, 25.19, 23.72, 23.69, 22.53, 20.93, 20.90, 16.12＋,
13
Hz, 3H), 1.48 (s, 9H), 1.19 (s, 3H), 1.16 (s, 3H); C
NMR (125 MHz, CDCl ) δ: 206.63, 172.52, 171.52,
3
168.83, 166.55, 154.66, 139.41, 133.31, 133.02, 129.53,
128.74, 128.26, 82.19, 81.62, 79.71, 78.50, 77.63, 77.14,
75.05, 74.65, 70.07, 57.16, 48.88, 41.99, 39.90, 35.65,
34.89, 27.83, 25.53, 22.05, 20.38, 20.32, 18.27, 15.61,
5.17; HRMS (ESI) calcd for C46
62
H O16N: [M＋H]
84.4063, found 884.4082.
7
-epi-13-O-(N-Boc-L-2-phenylacetic acid)-bacca-
tin III ester (23) N-Boc-L-2-phenylacetic acid (42.8
14.86; HRMS (ESI) calcd for C39
51
H O14NNa: [M＋
＋
mg, 0.17 mmol) was used as carboxylic acid to give a
white solid, 11.7 mg, yield 21%. H NMR (400 MHz,
Na] 780.3202, found 780.3188.
1
6
2
7-epi-13-O-(N -Cbz-N -Boc-lysine)-baccatin III
6
2
CDCl
3
) δ: 8.12 (d, J＝7.76 Hz, 2H), 7.66 (t, J＝7.52 Hz,
H), 7.54 (t, J＝7.56 Hz, 2H), 7.41 (s, 5H), 6.70 (s, 1H),
.10 (t, J＝8.71 Hz, 1H), 5.74 (d, J＝7.50 Hz, 1H), 5.59
ester (26) N -Cbz-N -Boc-lysine (64.8 mg, 0.17 mmol)
1
6
was used as carboxylic acid to give a white solid, 28.6
1
mg, yield 44%. H NMR (400 MHz, CDCl
3
) δ: 8.10 (d,
(
d, J＝7.62 Hz, 1H), 5.30 (d, J＝7.20 Hz, 1H), 4.94 (dd,
J＝3.32, 8.86 Hz, 1H), 4.62 (d, J＝11.59 Hz, 1H), 4.45
4.31 (m, 2H), 3.88 (d, J＝7.37 Hz, 1H), 3.67 (dd, J＝
J＝7.59 Hz, 2H), 7.65 (t, J＝7.65 Hz, 1H), 7.53 (t, J＝
7.65 Hz, 2H), 7.41－7.30 (m, 5H), 6.83 (s, 1H), 6.19 (t,
J＝8.36 Hz, 1H), 5.76 (d, J＝7.07 Hz, 1H), 5.23 (d, J＝
8.65 Hz, 1H), 5.17－5.05 (m, 2H), 4.99－4.84 (m, 2H),
4.66 (d, J＝11.47 Hz, 1H), 4.47－4.26 (m, 3H), 3.97 (d,
J＝7.55 Hz, 1H), 3.71 (dd, J＝2.98, 11.01 Hz, 1H), 3.24
(dp, J＝6.58, 13.46 Hz, 2H), 2.44 (s, 3H), 2.39－2.24
(m, 4H), 2.21 (s, 3H), 2.09－1.93 (m, 1H), 1.87 (s, 3H),
1.81 (s, 1H), 1.74－1.70 (m, 1H), 1.67 (s, 3H), 1.65－
1.53 (m, 2H), 1.47 (s, 11H), 1.20 (s, 3H), 1.17 (s, 3H);
－
4
2
1
.00, 10.91 Hz, 1H), 2.53 (s, 3H), 2.41－2.24 (m, 4H),
.16 (s, 3H), 1.78 (s, 1H), 1.68 (s, 3H), 1.65 (s, 3H),
13
.47 (s, 9H), 1.17 (s, 3H), 1.13 (s, 3H); C NMR (125
) δ: 206.71, 171.36, 170.46, 168.79, 166.57,
54.33, 139.91, 135.33, 133.31, 132.50, 129.57, 128.75,
MHz, CDCl
3
1
1
7
3
28.26, 126.84, 82.18, 81.52, 79.95, 78.69, 77.51, 77.10,
5.07, 74.69, 70.65, 57.64, 57.08, 41.94, 39.87, 35.95,
4.85, 27.82, 25.49, 22.28, 20.47, 20.31, 15.61, 14.24＋;
1
3
3
C NMR (125 MHz, CDCl ) δ: 206.62, 171.95, 171.56,
HRMS (ESI): calcd for C44
42.3358, found 842.3353.
-epi-13-O-(N-Boc-benzyl-L-threonine)-baccatin
III ester (24) N-Boc-benzyl-L-threonine (52.7 mg,
.17 mmol) was used as carboxylic acid to give a white
H
53
O
14NNa: [M＋Na]
168.85, 166.54, 156.04, 136.03, 133.31, 133.05, 129.54,
128.74, 128.26, 128.03, 127.64, 82.18, 81.64, 79.75,
78.53, 77.62, 77.14, 75.05, 74.64, 70.22, 66.22, 57.15,
42.01, 39.98, 39.88, 35.73, 34.90, 31.54, 29.06, 27.83,
8
7
0
25.50, 22.16, 22.04, 20.38, 15.60, 14.95; HRMS (ESI)
1
＋
solid, 23.0 mg, yield 38%. H NMR (400 MHz, CDCl
3
)
64 16 2
calcd for C50H 0 N Na: [M＋Na] 971.4148, found
δ: 8.10 (d, J＝7.99 Hz, 2H), 7.65 (t, J＝7.37 Hz, 1H),
971.4125.
7
2
.52 (t, J＝7.70 Hz, 2H), 7.36－7.29 (m, 3H), 7.27 (s,
H), 6.79 (s, 1H), 6.22－6.14 (m, 1H), 5.77 (d, J＝7.33
7-epi-13-O-(N-Boc-L-cyclohexylglycine)-baccatin
III ester (27) N-Boc-L-cyclohexylglycine (43.8 mg,
Hz, 1H), 5.43 (d, J＝9.49 Hz, 1H), 4.95 (dd, J＝3.30,
0.17 mmol) was used as carboxylic acid to give a white
1
9
4
3
2
1
1
.00 Hz, 1H), 4.65 (t, J＝11.92 Hz, 2H), 4.43－4.33 (m,
H), 4.32－4.23 (m, 1H), 3.96 (d, J＝7.41 Hz, 1H),
.71 (dd, J＝3.34, 11.31 Hz, 1H), 2.43 (s, 3H), 2.40－
.25 (m, 4H), 2.22 (s, 3H), 1.78 (s, 3H), 1.74 (s, 1H),
.68 (s, 3H), 1.49 (s, 9H), 1.39 (d, J＝6.20 Hz, 3H),
solid, 36.8 mg, yield 65%. H NMR (400 MHz, CDCl
3
)
δ: 8.10 (d, J＝7.77 Hz, 2H), 7.65 (t, J＝7.31 Hz, 1H),
7.53 (t, J＝7.71 Hz, 2H), 6.85 (s, 1H), 6.19 (t, J＝8.91
Hz, 1H), 5.77 (d, J＝7.30 Hz, 1H), 5.10 (d, J＝9.18 Hz,
1H), 4.95 (dd, J＝3.42, 8.81 Hz, 1H), 4.75 (d, J＝11.59
Hz, 1H), 4.39 (q, J＝8.66 Hz, 2H), 4.31 (dd, J＝3.83,
13
3
.21 (s, 3H), 1.16 (s, 3H); C NMR (125 MHz, CDCl )
Chin. J. Chem. 2016, XX, 1—12
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Li et al.
FULL PAPER
9
3
2
1
1
.06 Hz, 1H), 3.99 (d, J＝7.35 Hz, 1H), 3.72 (dd, J＝
.77, 11.99 Hz, 1H), 2.46 (s, 3H), 2.42－2.25 (m, 4H),
.21 (s, 3H), 2.01－1.89 (m, 4H), 1.88－1.72 (m, 4H),
.68 (s, 3H), 1.54 (d, J＝12.71 Hz, 1H), 1.48 (s, 9H),
.41－1.22 (m, 4H), 1.20 (s, 3H), 1.19－1.07 (m, 5H);
57.27, 42.23, 40.11, 35.43, 34.87, 25.77, 25.64, 22.26,
21.72, 20.45, 15.69, 14.90, 13.69; HRMS (ESI) calcd
＋
for C46
H
48
O
15
N
2
Na: [M ＋ Na]
891.2947, found
891.2925.
7-epi-13-O-(2-(4-(4-Chlorobenzoyl)-phenoxyl)-2-
methylpropionic acid)-baccatin III ester (30) 2-(4-
(4-Chlorobenzoyl)-phenoxyl)-2-methylpropionic acid
(54.3 mg, 0.17 mmol) was used as carboxylic acid to
1
3
3
C NMR (125 MHz, CDCl ) δ: 206.70, 171.58, 168.87,
1
1
7
3
2
66.58, 155.33, 139.47, 133.30, 132.93, 129.55, 128.73,
28.27, 82.23, 81.60, 79.59, 78.63, 77.66, 77.13, 75.15,
4.68, 70.05, 57.96, 57.16, 42.03, 40.23, 39.92, 35.88,
4.88, 29.78, 27.83, 26.81, 25.61, 25.42, 25.28, 25.19,
1
give a white solid, 11.0 mg, yield 18%. H NMR (400
3
MHz, CDCl ) δ: 7.82 (d, J＝7.96 Hz, 2H), 7.76 (d, J＝
2.12, 20.42, 20.37, 15.66, 14.90; HRMS (ESI) calcd
7.89 Hz, 2H), 7.53－7.42 (m, 3H), 7.33－7.28 (m, 4H),
6.86 (d, J＝7.62 Hz, 2H), 6.82 (s, 1H), 6.30 (t, J＝8.84
Hz, 1H), 5.68 (d, J＝7.70 Hz, 1H), 4.91 (d, J＝7.36 Hz,
1H), 4.75 (d, J＝11.12 Hz, 1H), 4.30 (q, J＝8.72 Hz,
2H), 3.87 (d, J＝7.56 Hz, 1H), 3.70 (d, J＝7.03 Hz, 1H),
2.45 (s, 3H), 2.41－2.24 (m, 3H), 2.22 (s, 3H), 2.09－
2.03 (m, 1H), 1.85 (d, J＝4.78 Hz, 6H), 1.79－1.72 (m,
＋
for C44
8
H
59
O14NNa: [M ＋ Na]
848.3828, found
48.3803.
3
7
-epi-13-O-((S)-N -Boc-3-((S)-5,6-difluoro-2,3-
dihydro-1H-inden-1-yl)propanoic acid)-baccatin III
ester (28) (S)-N -Boc-3-((S)-5,6-difluoro-2,3-dihydro-
1
was used as carboxylic acid to give a white solid, 8.9
mg, yield 14%. H NMR (400 MHz, CDCl
3
H-inden-1-yl)propanoic acid (58.0 mg, 0.17 mmol)
1
3
4H), 1.65 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H); C NMR
(125 MHz, CDCl ) δ: 206.73, 193.44, 173.37, 171.81,
1
3
) δ: 8.13 (dd,
3
J＝1.23, 8.30 Hz, 2H), 7.70－7.63 (m, 1H), 7.55 (t, J＝
168.83, 166.53, 158.36, 139.72, 137.94, 135.38, 133.42,
132.73, 131.64, 130.53, 130.31, 129.21, 128.50, 128.14,
127.99, 115.93, 82.25, 81.41, 79.12, 79.00, 77.52, 76.98,
75.29, 74.88, 70.59, 57.03, 42.20, 39.91, 35.14, 34.79,
27.15, 25.48, 22.46, 21.61, 20.83, 20.43, 15.72, 14.28＋;
7
6
.69 Hz, 2H), 7.03 (ddd, J＝7.47, 10.25, 22.25 Hz, 2H),
.84 (s, 1H), 6.26 (td, J＝1.18, 8.92 Hz, 1H), 5.79 (d,
J＝7.36 Hz, 1H), 5.02－4.92 (m, 2H), 4.70 (d, J＝11.53
Hz, 1H), 4.48－4.34 (m, 2H), 4.24－4.13 (m, 1H), 3.98
(
d, J＝7.24 Hz, 1H), 3.72 (ddd, J＝1.68, 4.70, 11.29 Hz,
HRMS (ESI) calcd for C48
51
H O14ClNa: [M＋Na]
1
1
2
1
1
H), 3.49 (s, 1H), 3.08－2.95 (m, 1H), 2.90－2.77 (m,
H), 2.69 (d, J＝5.09 Hz, 2H), 2.42－2.32 (m, 6H),
.32－2.20 (m, 5H), 2.08－1.95 (m, 1H), 1.89 (d, J＝
.24 Hz, 3H), 1.79 (s, 1H), 1.68 (s, 3H), 1.44 (s, 9H),
909.2860, found 909.2846.
7-epi-13-O-(N-Cbz-L-alanine)-baccatin III ester
(31) N-Cbz-L-alanine (47.5 mg, 0.17 mmol) was used
as carboxylic acid to give a white solid, 64.9 mg, yield
13
1
.23 (s, 3H), 1.18 (s, 3H); C NMR (100 MHz, CDCl
3
)
96%. H NMR (400 MHz, CDCl
3
) δ: 8.09 (d, J＝7.72
δ: 207.20, 171.71, 169.35, 167.18, 140.16, 133.91,
Hz, 2H), 7.64 (t, J＝7.30 Hz, 1H), 7.52 (t, J＝7.62 Hz,
2H), 7.37 (d, J＝3.97 Hz, 6H), 6.82 (s, 1H), 6.19 (t, J＝
8.34 Hz, 1H), 5.76 (d, J＝7.33 Hz, 1H), 5.52 (d, J＝
8.59 Hz, 1H), 5.22－5.06 (m, 3H), 4.93 (dd, J＝3.10,
8.75 Hz, 1H), 4.67 (d, J＝11.41 Hz, 1H), 4.51－4.31 (m,
3H), 3.97 (d, J＝7.90 Hz, 1H), 3.70 (dd, J＝4.24, 11.46
Hz, 1H), 2.45 (s, 2H), 2.39－2.24 (m, 4H), 2.21 (s, 3H),
1.97 (s, 1H), 1.87 (s, 3H), 1.66 (s, 3H), 1.55 (d, J＝7.22
1
7
3
1
33.36, 130.05, 129.16, 128.81, 82.62, 82.19, 79.18,
8.21, 77.60, 75.61, 75.20, 69.87, 57.62, 42.58, 40.46,
6.02, 35.34, 30.62, 28.30, 25.96, 22.40, 20.96, 20.90,
57 2
6.20, 15.17; HRMS (ESI) calcd for C48H O14NF Na:
＋
[
M＋Na] 932.3639, found 932.3622.
-epi-13-O-(2-(4-((2-(Methylcarbamoyl)pyridin-4-
yl)oxy)phenyl)-2-oxoacetic acid)-baccatin III ester
29) 2-(4-((2-(Methylcarbamoyl)pyridin-4-yl)oxy)-
7
1
3
(
Hz, 2H), 1.18 (s, 3H), 1.15 (s, 3H); C NMR (125 MHz,
CDCl ) δ: 207.10, 172.72, 171.96, 169.35, 167.05,
phenyl)-2-oxoacetic acid (51.0 mg, 0.17 mmol) was
3
used as carboxylic acid to give a white solid, 22.0 mg,
155.70, 139.73, 136.05, 133.84, 133.65, 130.06, 129.22,
128.78, 128.60, 128.53, 128.32, 128.09, 82.70, 82.17,
78.99, 78.12, 77.65, 75.55, 75.13, 70.85, 67.13, 57.68,
49.86, 42.51, 40.40, 36.20, 35.40, 26.04, 22.57, 20.89,
1
yield 38%. H NMR (400 MHz, CDCl
3
) δ: 8.53 (d, J＝
5
1
.87 Hz, 1H), 8.17 (d, J＝8.89 Hz, 2H), 8.12 (dd, J＝
.10, 8.21 Hz, 2H), 8.04 (d, J＝5.38 Hz, 1H), 7.83 (d,
J＝2.27 Hz, 1H), 7.68－7.62 (m, 1H), 7.53 (t, J＝7.71
Hz, 2H), 7.26 (d, J＝8.89 Hz, 2H), 7.13 (dd, J＝2.53,
20.83, 18.77, 16.11, 15.37; HRMS (ESI) calcd for
＋
C
42
H
49
O14NNa: [M＋Na] 814.3045, found 814.3038.
5
5
1
4
1
2
3
1
1
1
1
8
.51 Hz, 1H), 6.88 (s, 1H), 6.43 (t, J＝8.61 Hz, 1H),
.79 (d, J＝7.32 Hz, 1H), 4.95 (dd, J＝3.18, 8.98 Hz,
H), 4.78 (d, J＝11.55 Hz, 1H), 4.46－4.31 (m, 2H),
.01 (d, J＝7.43 Hz, 1H), 3.72 (dd, J＝3.09, 11.62 Hz,
H), 3.50 (d, J＝6.91 Hz, 1H), 3.05 (d, J＝5.13 Hz, 3H),
.45 (t, J＝9.14 Hz, 2H), 2.34－2.30 (m, 4H), 2.24 (s,
H), 2.00 (d, J＝1.27 Hz, 3H), 1.83 (s, 1H), 1.68 (s, 3H),
7-epi-13-O-((4-Chlorophenoxy)-acetic acid)-
baccatin III ester (32) (4-Chlorophenoxy)-acetic acid
(31.8 mg, 0.17 mmol) was used as carboxylic acid to
1
give a white solid, 53.1 mg, yield 83%. H NMR (400
3
MHz, CDCl ) δ: 8.08 (d, J＝7.60 Hz, 2H), 7.65 (t, J＝
7.37 Hz, 1H), 7.51 (t, J＝7.72 Hz, 2H), 7.30 (d, J＝9.10
Hz, 2H), 6.89 (d, J＝8.90 Hz, 2H), 6.81 (s, 1H), 6.21 (t,
J＝8.62 Hz, 1H), 5.75 (d, J＝7.42 Hz, 1H), 4.95 (dd,
J＝3.29, 9.04 Hz, 1H), 4.73 (s, 2H), 4.69 (d, J＝11.55
Hz, 1H), 4.44－4.31 (m, 2H), 3.94 (d, J＝7.34 Hz, 1H),
3.72 (dd, J＝1.40, 4.62 Hz, 1H), 2.43 (s, 3H), 2.40－
2.21 (m, 5H), 2.20 (s, 3H), 1.76 (s, 3H), 1.66 (s, 3H),
1
3
3
.21 (s, 6H); C NMR (125 MHz, CDCl ) δ: 206.68,
83.33, 171.88, 168.84, 166.72, 163.82, 163.64, 162.33,
59.74, 152.34, 149.80, 138.71, 133.63, 133.44, 132.39,
29.62, 128.71, 128.55, 128.34, 119.88, 115.26, 111.09,
2.23, 81.40, 78.74, 77.71, 77.10, 75.19, 74.75, 71.37,
8
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—12

Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity
13
1
.18 (s, 3H), 1.15 (s, 3H); C NMR (125 MHz, CDCl
3
)
1H), 2.46 (s, 3H), 2.43－2.24 (m, 5H), 2.22 (s, 3H),
δ: 207.09, 171.73, 169.34, 168.15, 167.01, 156.05,
1.93 (s, 3H), 1.67 (s, 4H), 1.19 (s, 3H), 1.16 (s, 3H),
1.14－0.95 (m, 4H); C NMR (100 MHz, CDCl ) δ:
3
206.87, 173.95, 171.27, 168.96, 166.57, 140.43, 133.32,
132.49, 129.59, 128.88, 128.27, 82.21, 81.71, 78.68,
77.85, 77.19, 76.80, 75.10, 74.76, 69.40, 57.15, 42.01,
39.99, 35.89, 34.93, 25.55, 22.05, 20.47, 20.40, 15.73,
1
3
1
1
7
2
39.71, 133.85, 133.58, 130.00, 129.72, 129.25, 128.74,
27.26, 115.85, 82.63, 82.14, 79.16, 78.10, 77.55, 75.59,
5.21, 71.07, 65.69, 57.59, 42.55, 40.47, 36.15, 35.32,
5.98, 22.21, 20.90, 20.87, 16.15, 15.05; HRMS (ESI)
＋
calcd for C39
77.2268.
-epi-13-O-(2-(4-Methoxyphenyl)-acetic acid)-
43
H O13ClNa: [M＋Na] 777.2284, found
7
14.81, 12.38, 8.77, 8.61; HRMS (ESI) calcd for
＋
7
C
35
H
42
O
12Na: [M＋Na] 677.2568, found 677.2550.
baccatin III ester (33) 2-(4-Methoxyphenyl)-acetic
7-epi-13-O-(6-((2,4-Dinitrophenyl)thio)hexanoic
acid (59.6 mg, 0.17 mmol) was used as carboxylic acid
to give a white solid, 59.6 mg, yield 95%. H NMR (400
acid)baccatin III ester (36) 6-((2,4-Dinitrophenyl)-
thio)hexanoic acid (32 mg, 0.17 mmol) was used as
1
MHz, CDCl
3
) δ: 8.09 (d, J＝7.77 Hz, 2H), 7.65 (t,
carboxylic acid to give a white solid, 24.0 mg, yield
1
J＝7.43 Hz, 1H), 7.52 (t, J＝7.68 Hz, 2H), 7.24 (d, J＝
32%. H NMR (400 MHz, CDCl
3
) δ: 9.11 (d, J＝2.35
8
6
.50 Hz, 2H), 6.91 (d, J＝8.50 Hz, 2H), 6.81 (s, 1H),
.15 (t, J＝8.64 Hz, 1H), 5.76 (d, J＝7.38 Hz, 1H), 4.96
Hz, 1H), 8.40 (dd, J＝2.53, 8.92 Hz, 1H), 8.10 (d, J＝
7.82 Hz, 2H), 7.64 (t, J＝7.10 Hz, 1H), 7.60－7.47 (m,
3H), 6.83 (s, 1H), 6.19 (t, J＝8.96 Hz, 1H), 5.76 (d, J＝
7.30 Hz, 1H), 4.96 (dd, J＝3.40, 8.87 Hz, 1H), 4.64 (d,
J＝11.29 Hz, 1H), 4.47－4.31 (m, 2H), 3.97 (d, J＝7.43
Hz, 1H), 3.71 (dd, J＝3.49, 11.56 Hz, 1H), 3.10 (t, J＝
7.19 Hz, 2H), 2.51 (dq, J＝7.23, 13.67 Hz, 2H), 2.43 (s,
3H), 2.39－2.25 (m, 4H), 2.22 (s, 3H), 1.94－1.85 (m,
5H), 1.85－1.77 (m, 2H), 1.75 (s, 1H), 1.69－1.67 (m,
(
dd, J＝3.03, 8.99 Hz, 1H), 4.69 (d, J＝11.57 Hz, 1H),
4
3
2
1
.39 (q, J＝8.68 Hz, 2H), 3.96 (d, J＝7.33 Hz, 1H),
.83 (s, 3H), 3.75－3.65 (m, 3H), 2.41 (s, 3H), 2.39－
.25 (m, 4H), 2.20 (s, 3H), 1.83 (s, 1H), 1.79 (s, 3H),
13
.66 (s, 3H), 1.18 (s, 3H), 1.15 (s, 3H); C NMR (125
) δ: 207.26, 171.65, 171.28, 169.35, 167.00,
59.00, 140.69, 133.79, 133.00, 130.17, 130.02, 129.34,
MHz, CDCl
3
1
1
7
4
1
7
1
3
28.72, 125.10, 114.21, 82.66, 82.20, 79.21, 78.20,
7.60, 75.61, 75.28, 70.06, 57.57, 55.31, 42.50, 40.54,
0.43, 36.23, 35.36, 25.93, 22.48, 20.95, 20.87, 16.19＋,
2H), 1.64 (s, 3H), 1.21 (s, 3H), 1.17 (s, 3H); C NMR
(125 MHz, CDCl ) δ: 206.70, 172.03, 171.17, 168.91,
3
166.59, 146.54, 144.43, 143.36, 139.99, 133.36, 132.78,
129.57, 128.83, 128.27, 126.67, 126.32, 121.37, 82.17,
81.82, 78.71, 77.76, 77.15, 75.13, 74.76, 69.12, 57.16,
42.07, 40.01, 35.61, 34.92, 33.63, 31.95, 27.91, 26.71,
5.18; HRMS (ESI) calcd for C40
46
H O13Na: [M＋Na]
57.2831, found 757.2821.
7
-epi-13-O-(4-Chloro-2-pyridinecarboxylic acid)-
baccatin III ester (34) 4-Chloro-2-pyridinecarboxy-
25.52, 23.87, 22.10, 20.45, 20.42, 15.72, 14.79; HRMS
＋
lic acid (33.6 mg, 0.17 mmol) was used as carboxylic
acid to give a white solid, 43.6 mg, yield 71%. H NMR
(ESI) calcd for C43
found 905.2785.
50 16 2
H O N NaS: [M＋Na] 905.2773,
1
(
400 MHz, CDCl
J＝1.45 Hz, 1H), 8.08 (d, J＝7.80 Hz, 2H), 7.61 (t, J＝
.31 Hz, 1H), 7.57 (dd, J＝1.74, 5.17 Hz, 1H), 7.48 (t,
J＝7.68 Hz, 2H), 6.88 (s, 1H), 6.39 (t, J＝8.77 Hz, 1H),
3
) δ: 8.68 (d, J＝5.19 Hz, 1H), 8.19 (d,
General procedures of hydrolyzation for preparation
of 37, 38 and 39
7
To a solution of 7-epi-13-O-(N-Boc-L-methionine)-
baccatin III ester (7, 55.5 mg, 0.068 mmol) in acetoni-
trile (1 mL) was added excess formic acid (1 mL) at
0 ℃, brought to room temperature and stirred for 3 h.
The reaction mixture was quenched with excess satu-
5
1
4
1
2
1
.79 (d, J＝7.43 Hz, 1H), 4.96 (dd, J＝3.24, 8.97 Hz,
H), 4.78 (d, J＝11.57 Hz, 1H), 4.43－4.33 (m, 2H),
.02 (d, J＝7.41 Hz, 1H), 3.73 (dd, J＝3.66, 11.47 Hz,
H), 2.52－2.41 (m, 2H), 2.41 (s, 3H), 2.39－2.25 (m,
H), 2.22 (s, 3H), 2.01 (s, 3H), 1.97 (s, 1H), 1.68 (s, 3H),
rated NaHCO
dichloromethane. The organic layer was washed with
excess water and brine, dried with Na SO , and evapo-
3
solution and extracted three times with
13
3
.27 (s, 3H), 1.19 (s, 3H); C NMR (125 MHz, CDCl )
δ: 206.83, 171.94, 168.91, 166.58, 163.66, 150.16,
2
4
1
1
7
3
48.66, 145.01, 139.83, 133.30, 132.92, 129.57, 128.84,
28.25, 127.03, 125.60, 82.29, 81.51, 78.88, 77.71,
7.17, 75.21, 74.88, 71.29, 57.18, 42.20, 39.98, 35.96,
rated under vacuum to dryness. The crude residue was
separated on silica gel (DCM/Methanol, 80∶1) to give
37. The preparation of 38 and 39 was performed as
above procedure.
4.92, 25.67, 21.72, 20.68, 20.46, 15.72, 14.84; HRMS
＋
(
ESI) calcd for C37
H
40
O12NClNa: [M＋Na] 748.2131,
7-epi-13-O-(L-Methionine)-baccatin III ester (37)
White solid, 33.0 mg, yield 68%. H NMR (400 MHz,
1
found 748.2125.
7
-epi-13-O-(Cyclopropanecarboxylic acid)-bacca-
CDCl ) δ: 8.08 (d, J＝7.84 Hz, 2H), 7.64 (t, J＝7.44 Hz,
3
tin III ester (35) Cyclopropanecarboxylic acid (17.0
μL, 0.17 mmol) was used as carboxylic acid to give a
white solid, 46.7 mg, yield 84%. H NMR (400 MHz,
1H), 7.56－7.46 (m, 2H), 6.82 (s, 1H), 6.18 (t, J＝8.88
Hz, 1H), 5.75 (d, J＝7.39 Hz, 1H), 4.94 (dd, J＝3.19,
8.86 Hz, 1H), 4.67 (s, 1H), 4.38 (q, J＝8.64 Hz, 2H),
3.96 (d, J＝7.32 Hz, 1H), 3.85－3.61 (m, 2H), 2.73
(hept, J＝6.48 Hz, 2H), 2.45 (s, 3H), 2.38－2.23 (m,
4H), 2.20 (s, 3H), 2.17 (s, 3H), 2.06－1.92 (m, 2H),
1.91 (s, 1H), 1.88 (s, 3H), 1.87－1.77 (m, 2H), 1.66 (s,
1
CDCl
3
) δ: 8.10 (s, 2H), 7.65 (t, J＝7.51 Hz, 1H), 7.52 (t,
J＝7.72 Hz, 2H), 6.85 (s, 1H), 6.09 (t, J＝8.67 Hz, 1H),
5
1
3
.77 (d, J＝7.37 Hz, 1H), 4.97 (dd, J＝3.34, 9.10 Hz,
H), 4.70 (d, J＝11.60 Hz, 1H), 4.46－4.34 (m, 2H),
.99 (d, J＝7.35 Hz, 1H), 3.72 (dd, J＝4.38, 11.15 Hz,
1
3
3H), 1.20 (s, 3H), 1.15 (s, 3H); C NMR (125 MHz,
Chin. J. Chem. 2016, XX, 1—12
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
9

Li et al.
FULL PAPER
CDCl
3
) δ: 207.15, 171.80, 169.35, 166.97, 140.01,
per well. The plates were shaken for 10 min to induce
cell lysis and incubated at room temperature for 2 min
to stabilize luminescent signal. The luminescence was
read on Envision with an integration time of 0.5 s.
1
7
4
1
33.81, 133.40, 130.01, 129.28, 128.74, 82.68, 82.12,
9.09, 78.11, 77.62, 75.55, 75.18, 70.40, 57.62, 42.54,
0.35, 36.31, 35.36, 30.39, 25.98, 22.65, 20.93, 20.88,
6.11, 15.54, 15.49; H＋ RMS (ESI): calcd for
C
36
H
47
O
12NNaS: [M＋Na] 740.2711, found 740.2722.
Results and Discussion
7
-epi-13-O-(3-Cyclohexyloxycarbonyl-L-aspartic
Chemistry
acid)-baccatin III ester (38) 7-epi-13-O-(N-Boc-3-
cyclohexyloxycarbonyl-L-aspartic acid)-baccatin III
ester (22, 150 mg, 0.17 mmol) was used as substrate to
Initially, 8 different transition-metal compounds and
2 alkaline earth metal oxides (MgO and CaO) were
tested for preparing the 7-epi-paclitaxel from paclitaxel
in acetonitrile under 80 ℃ (Table 1). Among these,
1
give a white solid, 88 mg, yield 66%. H NMR (500
MHz, CDCl
3
) δ: 8.07 (d, J＝7.31 Hz, 2H), 7.63 (t, J＝
.41 Hz, 1H), 7.50 (t, J＝7.72 Hz, 2H), 6.80 (s, 1H),
.16 (t, J＝8.45 Hz, 1H), 5.74 (d, J＝7.41 Hz, 1H), 4.92
7
6
Ag O gave the best yield of 64% without obvious side
2
products and the recovery ratio of the paclitaxel was
23% (Table 1, Entry 10). Besides, Ag CO also gave a
(
dd, J＝3.26, 9.01 Hz, 1H), 4.81 (tt, J＝3.77, 9.04 Hz,
2
3
1
2
H), 4.60 (d, J＝11.56 Hz, 1H), 4.36 (q, J＝8.71 Hz,
H), 3.96 (d, J＝7.35 Hz, 1H), 3.88 (s, 1H), 3.69 (dd,
good result (yield 57%, Table 1, Entry 1). However,
CaO, Fe(NO ) •9H O and Cu(NO ) •3H O made the
reactions too miscellaneous to recycle the reactant (Ta-
3
2
2
3 2
2
J＝3.49, 11.07 Hz, 1H), 2.93 (d, J＝16.24 Hz, 1H), 2.71
(
(
dd, J＝7.87, 15.86 Hz, 1H), 2.40 (s, 3H), 2.37－2.21
m, 5H), 2.20 (s, 3H), 1.84 (s, 3H), 1.78－1.68 (m, 3H),
ble 1, Entries 5 and 7, 8). When Cu O and MgO were
2
1
1
.65 (s, 3H), 1.60－1.51 (m, 1H), 1.50－1.25 (m, 8H),
Table 1 Optimization of reaction reagents of paclitaxel epimer-
ization
13
a
.18 (s, 3H), 1.14 (s, 3H); C NMR (125 MHz, CDCl
3
)
δ: 207.09, 171.76, 170.24, 169.33, 166.97, 139.96,
Recovery
b
1
7
4
2
33.80, 133.40, 130.00, 129.27, 128.73, 82.71, 82.23,
9.04, 78.11, 77.64, 75.49, 75.13, 73.90, 70.68, 57.64,
2.50, 40.35, 36.29, 35.40, 31.62, 31.59, 26.01, 25.25,
Entry Reagent
Solvent
T/℃ Yield /%
b,c
ratio
32
1
2
3
4
5
6
7
8
9
1
Ag CO
2
3
Acetonitrile 80 57
Acetonitrile 80 trace
Acetonitrile 80 trace
Acetonitrile 80 10
Acetonitrile 80 24
Acetonitrile 80 7
Acetonitrile 80 trace
3.75, 22.47, 20.89, 20.85, 16.08, 15.33; HRMS (ESI)
AgNO
3
＞99
＞99
86
＋
calcd for C41
06.3375.
-epi-13-O-(S-Benzyl-L-cysteine)-baccatin III
53
H O14NNa: [M＋Na] 806.3358, found
Fe O
2
3
8
7
Cu
CaO
MgO
Fe(NO
2
O
ester (39) 7-epi-13-O-(S-Benzyl-N-Boc-L-cysteine)-
baccatin III ester (18, 150 mg, 0.17 mmol) was used as
4
1
92
substrate to give a white solid, 94 mg, yield 59%. H
NMR (400 MHz, CDCl
3
) δ: 8.07 (d, J＝7.72 Hz, 2H),
3
)
2
•9H
2
O
trace
trace
＞99
23
7
－
.63 (t, J＝7.30 Hz, 1H), 7.50 (t, J＝7.63 Hz, 2H), 7.40
7.29 (m, 5H), 6.82 (s, 1H), 6.11 (t, J＝8.63 Hz, 1H),
Cu(NO ) •3H O Acetonitrile 80 trace
3
2
2
Cu (OH) CO
Acetonitrile 80 trace
Acetonitrile 80 64
2
2
3
5
1
3
.75 (d, J＝7.37 Hz, 1H), 4.93 (dd, J＝3.23, 8.99 Hz,
H), 4.66 (d, J＝9.91 Hz, 1H), 4.37 (q, J＝8.70 Hz, 2H),
.95 (d, J＝7.28 Hz, 1H), 3.80 (s, 2H), 3.72 (d, J＝3.47
0
Ag O
2
11
Ag O
Ethanol
THF
40 trace
40 trace
40 trace
40 trace
40 trace
40 28
＞99
＞99
＞99
＞99
＞99
53
2
Hz, 1H), 3.63 (s, 1H), 2.94 (d, J＝13.59 Hz, 1H), 2.68
dd, J＝8.17, 13.08 Hz, 1H), 2.43－2.29 (m, 6H), 2.29
2.15 (m, 5H), 1.97 (s, 2H), 1.83 (s, 3H), 1.66 (s, 3H),
1
2
3
Ag O
2
(
1
Ag O
Acetone
MTBE
CS2
2
－
13
1
.17 (s, 3H), 1.15 (s, 3H); C NMR (125 MHz, CDCl
3
)
14
Ag O
2
δ: 207.14, 171.66, 169.35, 166.95, 139.92, 137.53,
1
5
6
Ag O
2
1
1
7
2
33.80, 133.39, 130.00, 129.26, 128.87, 128.78, 128.74,
27.47, 82.69, 82.20, 79.06, 78.12, 77.62, 75.55, 75.14,
0.78, 57.64, 42.50, 40.36, 36.96, 36.33, 35.40, 26.01,
1
Ag O
EtOAc
Acetic acid
Dioxane
Dichloro-
ethane
2
17
Ag
O
80 2
68
2
2.50, 20.89, 16.13, 15.47; HRMS (ESI) calcd for
18
Ag O
80 7
93
2
＋
C
41
H
49
O
12NNaS: [M＋Na] 802.2868, found 802.2849.
Bioassay
Six types of human tumour cells (90 μL/well, 44000
19
Ag
2
O
80 28
67
2
0
1
2
Ag O
Toluene
DMF
80 35
80 70
80 59
65
29
40
2
cells/mL) were dispensed onto 96 well plates. The assay
plates were incubated for 24 h at 37 ℃, 5% CO under
2
Ag O
2
2
2
Ag O
DMSO
humidified conditions. After 24 h, the cells were treated
with various concentrations of test compounds and in-
2
a
Conditions: paclitaxel (40 mg), transition-metal (3 equiv.), sol-
vent (3 mL), 3 h. Detected by HPLC. Recovery ratio between
the recovered material and the material input.
b
c
cubated at 37 ℃, 5% CO
2
under humidified conditions.
Then CTG solutions (30 μL, Cell Titer-Glo) were added
10
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—12

Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity
used, object product was only obtained in 10% and 7%
yields, respectively (Table 1, Entries 4 and 6). Other
conditions did not give any obvious product. Accord-
O
R2
O
OH
O
O
O
OH
O
R1
NH
O
2
ingly, Ag O was chosen to be the optimal catalyst.
H
O
H
O
H
Then, different solvents were screened at 40 ℃ or
0 ℃ (Table 1). The results showed that DMF and
O
H
OHO
HO
O
OHO
8
OH
O
O
DMSO gave good yields, viz., 70% and 59%, respec-
tively (Table 1, Entries 21, 22). Hence, Ag O and DMF
O
2
were used as catalyst and solvent, respectively, for the
further exploration. According to the reports by Tian
R1 = COC H , R = COOCH3,
2
6
5
[
9,21]
7-epi-Paclitaxel (2) 80%
7-epi-Baccatin III (6) 78%
and McLaughlin,
the possible mechanism of epi-
1
2
R = COO(CH ) , R = OH,
merization under alkaline condition is a retro-aldol/aldol
process. As our reaction condition is different, more
study is needed to reveal whether the mechanism of the
3 3
7
-epi-Docetaxel (5) 80%
Figure 2 Substrate and large scale testing (Isolated yield. Con-
epimerization under the neutral Ag
aldol/aldol process.
2
O is also a retro-
ditions: taxane (2.34 mmol), Ag O (1 equiv., 0.54 g), DMF (150
ml), 100 ℃, 3 h).
2
Reaction time and reagent dosage were then investi-
gated (Table 2). The results revealed that temperature
did have significant effect on the yield with 0.1 to 2
in hand, we prepared 7-epi-baccatin III and esterified its
hydroxyl group at C-13 with carboxylic acid to synthe-
size C-13 derivatives by using condition of di-2-pyridyl
carbonate (DPC), DMAP and toluene reported by Den-
is in yields of 18%－96% (Scheme 2, compounds 7
－36). Notably, we did not protect C-7-hyroxy before
esterification reaction, which might be attributed to the
stability of 7-epi-taxane as mentioned before. We further
hydrolysed the t-butyloxycarbonyl of compounds 7, 22
and 18 to obtain compounds 37, 38 and 39 in yields of
equiv. of Ag
Ag O is recoverable and recyclable, and found that less
amount of solvent DMF could generate similar yields
Table 2, Entries 9, 10). Accordingly, we confirmed the
optimal reaction conditions: 0.1 equiv. of Ag O as the
catalyst under 100 ℃ for 3 h in DMF (Table 2, Entry
).
2
O as catalyst. Furthermore, we verified that
2
[
22]
(
2
9
Table 2 Optimization of reaction temperature, time and dosage
5
9%－68% (Scheme 2).
a
of Ag O of paclitaxel epimerization
2
b
In vitro cytotoxicity assay
Entry T/℃
Time/h
Ag
1
2
O (equiv.)
Yield /%
13
Some of these compounds were evaluated with CTG
assay method against 6 human tumour cell lines at 10
μmol/L concentration, including A549 (human non-
small-cell lung carcinoma), MCF-7 (human breast ade-
nocarcinoma), HCT116 (human colon carcinoma),
HepG2 (human hepatoblastoma carcinoma), SKOV3
(human ovary adenocarcinoma), and DU145 (human
prostate carcinoma). Paclitaxel was used as a control
1
2
3
4
5
6
7
8
9
25
3
3
3
6
12
3
3
6
3
3
60
1
26
100
100
100
100
100
100
100
100
1
81
1
73
1
67
0.1
2
61
61
(Table 3).
0.1
0.1
0.5
74
The bioassay data showed that compound 10 had
similar inhibition rate to that of paclitaxel on all of the 6
c
82
c
1
0
79
cancer cell lines at 10 mol/L. Remarkably, compounds
a
Conditions: paclitaxel (40 mg), Ag
2
O (equiv.), DMF (3 mL), T
℃). Detected by HPLC. Conditions: paclitaxel (200 mg) in
DMF (1.5 mL).
1
3 and 18 exhibited good inhibition rate (70.14% and
b
c
(
7
5.25%) against DU145 but poor inhibition rate on the
other 5 cell lines at 10 μmol/L. This indicated that 13
and 18 might have good selectivity against DU145. Ac-
cordingly, the IC50 value of 18 was determined against
DU145 (Table 4), which is 15.9 nmol/L. Although the
To test the transferability of the method, baccatin III
and docetaxel were used as reactants (Figure 2). The
result with yields around 80% was pretty satisfying.
Accordingly, this approach is also applicable for taxane
derivatives. To further prove if the reaction was suitable
for gram scale, 2.34 mmol paclitaxel was used to react
in 150 mL of DMF, and the 7-epi-paclitaxel (2) was ob-
tained with isolated yield of 80%. More meaningfully,
activity is a little weaker than that of paclitaxel (IC50
＝
2
.3 nmol/L), 18 has good selectivity with inhibition rate
less than 33% at 10 mol/L against other 5 cell lines.
Conclusions
we found that Ag
2
O could be recycled without the loss
In conclusion, we have successfully found an effi-
of activity via filtration with recovery ratio of 99%. This
would greatly reduce the cost of the reaction.
cient approach to converting taxane into 7-epi-taxane by
using Ag
2
O as a recoverable catalyst. This approach has
With the optimal reaction condition of epimerization
the following advantages: mild condition, good group
Chin. J. Chem. 2016, XX, 1—12
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
11

Li et al.
FULL PAPER
Table 3 Cytotoxicity of 7-epi-taxane derivatives (10 μmol/L)
epimerization method should be useful in preparing the
new derivatives of 7-epi-taxane for other potential ap-
plications.
Inhibition/%
Compound
A549 MCF-7 HCT116 HepG2 SKOV3 DU145
2
7
9
1
53.59 17.77 36.11
59.38 41.27 65.39
51.04 17.91 36.07
76.84 53.32 87.71
18.23 29.05 25.47
18.77 3.28
3.03
53.19
8.14
86.37
0
Acknowledgement
a
79.06
0
The bioassay was performed at Shanghai Chem-
Partner Co., Ltd.
25.35 10.03
79.52 64.48
0
11
0
0
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12
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—12