Syntheses and structure-activity relationships of novel 3′-difluoromethyl and 3′-trifluoromethyl-taxoids

Article abstract of DOI:10.1016/j.jfluchem.2008.05.013

A series of novel 3′-difluoromethyl-taxoids and 3′-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR),

Full text of DOI:10.1016/j.jfluchem.2008.05.013

Journal of Fluorine Chemistry 129 (2008) 817–828
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Syntheses and structure–activity relationships of novel 30-difluoromethyl
and 30-trifluoromethyl-taxoids
Larissa V. Kuznetsova a,1, Antonella Pepe a,1, Ioana M. Ungureanu a, Paula Pera c,
Ralph J. Bernacki c, Iwao Ojima a,b,
*
a Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, United States
b Institute of Chemical Biology & Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, United States
c Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, Elm and Carlton Streets, Buffalo, NY 14263, United States
A R T I C L E I N F O
A B S T R A C T
A series of novel 30-difluoromethyl-taxoids and 30-trifluoromethyl-taxoids with modifications at the C2
and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast
carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon
adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to
more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-
WT, H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than
paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure–activity relation-
ship study shows the importance of the C10 modification for increasing the activity against multidrug-
resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 30-
difluoromethyl-taxoid series are very clear (i.e., F < MeO < Cl < N3), while those in the 30-trifluor-
omethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are
observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux
pumps.
Article history:
Received 29 March 2008
Received in revised form 19 May 2008
Accepted 19 May 2008
Available online 28 May 2008
Keywords:
Anticancer agent
Taxoid
Fluoro-taxoid
b-Lactam synthon method
Difluoromethyl
Trifluoromethyl
Baccatin
Structure–activity relationship
ß 2008 Elsevier B.V. All rights reserved.
1. Introduction
these drugs encounters many undesirable side effects as well as
multidrug-resistance (MDR) caused by overexpression of ABC efflux
The importance of fluorine in medicinal chemistry has been
demonstrated by a large number of fluorinated compounds
approved by the FDA for medical use [1,2]. It appears that fluorine
has become the second ‘‘favorite heteroatom’’, after nitrogen in
drug design [3]. Higher metabolic stability, often increased binding
to target molecules, increased lipophilicity and membrane
permeability, are some of the properties associated with the
replacement of a C–H or C–O bond with a C–F bond in medicinally
active compounds [4].
Paclitaxel(Taxol1) and its semi-synthetic analoguedocetaxelare
two of the most important chemotherapeutic drugs, currently used
for the treatment of advanced ovarian cancer, metastatic breast
cancer, melanoma, non-small celllungcancerand Karposi’s sarcoma
[5,6]. More recently, these drugs have been used for the treatment of
neck, prostate and cervical cancers [5,6]. Although paclitaxel and
docetaxel possess potent antitumor activity, chemotherapy with
pumps, e.g., P-glycoprotein [5,7,8]. Therefore, it is important to
develop new taxoid anticancer drugs as well as efficacious drug
delivery systems with fewer side effects, superior pharmacological
properties, and improved activity against various classes of tumors,
especially against drug-resistant cancers.
Because of the aforementioned advantages of introducing
fluorine into medicinally active molecules, we have been
investigating the effects of strategic incorporation of fluorine(s)
into paclitaxel and docetaxel molecules on the cytotoxicity and the
blockage of known metabolic pathways through design, synthesis
and structure–activity relationship (SAR) studies of novel ‘‘fluoro-
taxoids’’ [9–12]. Along this line, we reported the synthesis and
biological evaluation of a series of 30-difluoromethyl- and 30-
trifluoromethyl-taxoids [11–14], which exhibited substantially
better in vitro potency than paclitaxel and docetaxel against
several human cancer cell lines, i.e., ovarian (A121), colon (HT-29),
non-small cell lung (A549), breast (MCF-7, LCC6-WT) and drug-
resistant breast (MCF7-R, LCC6-MDR) cancer cell lines. We
describe here the synthesis and biological activity of a series of
novel C2- and C10-modified 30-difluoromethyl- and trifluoro-
methyl-taxoids (‘‘second-generation fluoro-taxoids’’).
* Corresponding author. Tel.: +1 631 632 1339; fax: +1 631 632 7942.
E-mail address: iojima@notes.cc.sunysb.edu (I. Ojima).
1
L.V. Kuznetsova and A. Pepe equally contributed to this work.
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.05.013

818
L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
Scheme 1.
2. Results and discussion
(3-substituted benzoyl)-triTES-DAB (8a–d) in good to excellent
yields [20]. Then, the deprotection of the TES groups at the C7, C10
and C13 positions of 8a–d with HF/pyridine gave the desired C2-
modified baccatins 9a–d in high yields (Scheme 2) [20].
2.1. Synthesis of second-generation 30-difluoromethyl- and 30-
trifluoromethyl-taxoids
C2-Modified baccatins, 9a, 9c and 9d, were reacted with acetic
or propanoic anhydrides in the presence of cerium chloride [23],
which gave the corresponding 10-acyl baccatins, 10-1(a,c,d) and
10-2(a,c,d), exclusively in good to excellent yields. Protection the
C7-hydroxyl group with TESCl/imidazole afforded the coupling-
ready 7-TES-2,10-modified-baccatins, 5-1(a,c,d) and 5-2(a,c,d), in
high yields (Scheme 3).
Since the C10-acylation method mentioned above only worked
when acid anhydrides were used, we needed to use another
acylation method for employing acid chlorides and a silyl chloride.
Thus, the C7-hydroxyl group of 9a–d was protected with TESCl/
imidazole first to afford baccatins 11a–d in high yields. Acylation of
the C10 hydroxyl group of 11a–d with N,N-dimethylcarbamoyl
chloride, methyl chloroformate and TES-Cl gave the coupling-
ready 7-TES-2,10-modified-baccatins, 5-1b, 5-2b, 5-3(a–d), 5-4(a–
d) and 5-5(a–d), in high to excellent yields (Scheme 4).
A series of novel second-generation 30-difluoromethyl-taxoids
1 and 30-trifluoromethyl-taxoids 2 were synthesized from 4-Rf-
b-
lactams 3/4 and modified baccatins 5 using the highly efficient
Ojima-Holton coupling protocol based on the
method (Scheme 1) [14–19].
b-lactam synthon
The C2,10-modified baccatins 5 were synthesized starting from
commercially available natural product, 10-deacetylbaccatin III
(10-DAB), following the procedures previously reported by us with
some modifications [20]. First, hydroxyl groups at the C7, C10, and
C13 positions were protected with chlorotriethylsilane (TESCl)
using imidazole as the base, yielding 7,10,13-triTES-10-deacetyl-
baccatin (6) [21]. Next, the benzoyl group at the C2 position of 6
was reductively removed with Red-Al in THF at ꢀ10 8C to give 2-
debenzoyl-7,10,13-triTES-DAB (7) in 97% yield [22]. Esterification
of 7 with different meta-substituted benzoic acids (substituents:
MeO, F, Cl and N3) using DIC/DMAP afforded the corresponding 2-
Next, (3R,4R)-1-t-Boc-3-TIPSO-4-difluoromethylazetidine (3)
and (3R,4R)-1-t-Boc-3-TIPSO-4-trifluoromethylazetidine (4), the
coupling partners of these 7-TES-2,10-modified-baccatins 5, were
Scheme 2.
Scheme 3.

L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
819
LCC6-MDR) as well as non-small cell lung carcinoma (H460) and
colon adenocarcinoma (HT-29) cell lines. Results are summarized
in Tables 1 and 2. The IC50 values were determined through 72 h
exposure of the fluoro-taxoids to the cancer cells by means of the
methods developed by Skehan et al. [24].
As Tables 1 and 2 show, 30-difluoromethyl-taxoids 1 and 30-
trifluoromethyl-taxoids 2 possess substantially higher potency
than those of paclitaxel and docetaxel with IC50 in the sub-
nanomolar range against drug-sensitive cancer cell lines, i.e.,
MCF7-S, LCC6-WT, H460, and HT-29 (except for 1d against LCC6-
WT, 1p against MCF7-S, and 2m–p against LCC6-WT). Even more
impressive are the cytotoxicity of fluoro-taxoids 1 and 2 against
multidrug-resistant cancer cell lines, i.e., MCF7-R and LCC6-MDR.
These second-generation fluoro-taxoids exhibit single-digit nano-
molar IC50 values (except for 1d, 1e and 1g against LCC6-MDR, 1h
for both cell lines, and 2q against LCC6-MDR), which are two orders
of magnitude more potent than paclitaxel in average. Thus, it is
clear that these second-generation fluoro-taxoids possess the
ability to effectively modulate multidrug-resistance caused by
overexpression of P-glycoprotein and other efflux pumps. Fluoro-
taxoids 1 and 2 exhibit, in general, comparable cytotoxicity against
all cancer cell lines examined. However, the potency of 30-
difluoromethyl-taxoids 1 against MCF7-S and LCC6-WT is slightly
higher and more uniform than that of 30-trifluoromethyl-taxoids 2,
in average, with different substitution patterns. On the contrary,
for multidrug-resistant cell lines, MCF7-R and LCC6-MDR, fluoro-
taxoids 2 show more uniform activity than fluoro-taxoids 1.
For fluoro-taxoids 1, cytotoxicity against multidrug-resistant
cell lines, MCF7-R and LCC6-MDR, depends on the nature of meta
substituents of the C2-benzoate moiety, i.e., the potency increases
in the order: F < MeO < Cl < N3. In contrast, no clear trend is
observed for fluoro-taxoids 2 against these multidrug-resistant cell
lines. However, the introduction of 3-azidobenzoyl group to 30-
trifluoromethyl-taxoids (2m–q) clearly decreases the potency
against LCC6-WT cell line. It should be noted that 10-acyl groups
play an important role in increasing the potency against multi-
drug-resistant cell lines (2m–p vs. 2q), while the potency against
drug-sensitive cell lines is independent of this substitution at the
C10 position.
Scheme 4.
prepared using the methods previously reported by us [19], as
shown in Schemes 5 and 6, respectively.
Novel fluoro-taxoids (1a–p and 2a–p) were synthesized in good
to excellent yields through the Ojima-Holton coupling of
lactams, 3 and 4, with 2,10-modified-baccatins 5 using LiHMDS as
a base at ꢀ40 8C in THF, followed by deprotection of silyl groups by
HF/pyridine (Scheme 7).
b-
2.2. Biological activities of second-generation 30-difluoromethyl- and
30-trifluoromethyl-taxoids
Among these second-generation fluoro-taxoids examined,
fluoro-taxoid 1n (R1 = n-propanoyl; X = N3) appears to be the
most potent compound with the resistance factor (R/S ratio) of only
2.9–3.0 against two sets of drug-sensitive and drug-resistant
human breast cancer cell lines. Further preclinical studies on these
novel fluoro-taxoids are actively underway in these laboratories.
The second-generation fluoro-taxoids 1a–p and 2a–q were
evaluated for their in vitro cytotoxicity against several human
cancer cell lines, i.e., breast carcinoma cell lines (MCF7-S and LCC6-
WT) and their corresponding drug-resistant cell lines (MCF7-R and
Scheme 5.

820
L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
Scheme 6.
3. Experimental
used as the internal standard for 1H and 13C NMR spectra, while
CFCl3 as the standard for 19F NMR spectra. Melting points were
measured on a Thomas Hoover Capillary melting point apparatus.
Optical rotations were measured on a Perkin-Elmer Model 241
polarimeter. TLC was performed on Merck DC-alufolien with
Kieselgel 60F-254 and column chromatography was carried out on
silica gel 60 (Merck; 230–400 mesh ASTM). Chiral HPLC analysis
for the determination of enantiomeric purity was carried out with
a Waters HPLC assembly consisting of a Waters M45 solvent
delivery system, a Waters Model 680 gradient controller, and a
Water M440 detector (at 254 nm) using a DAICEL-CHIRACEL OD
chiral column (25 cm ꢁ 0.46 cm i.d.), employing hexan/2-propanol
(99.5/0.5, v/v) as the solvent system with a flow rate of 1.0 mL/min.
High resolution mass spectra were obtained at the Mass Spectro-
metry Laboratory, University of Illinois at Urbana-Champaign,
Urbana, IL.
3.1. General method
1H, 13C and 19F NMR spectra were recorded on a Varian 300, 400
or 500 MHz NMR spectrometer in CDCl3. Tetramethylsilane was
3.2. Materials
The chemicals were purchased from Aldrich Co. and Sigma and
purified before use by standard methods. Tetrahydrofuran was
freshly distilled under nitrogen from sodium metal and benzo-
phenone. Dichloromethane was distilled immediately prior to use
under nitrogen from calcium hydride. (3R,4R)-1-tert-Butoxycar-
bonyl-3-triisopropylsiloxy-4-difluoromethylazetidin-2-one
(3)
[19], (3R,4R)-1-tert-butoxycarbonyl-3-triisopropylsiloxy-4-tri-
fluoromethylazetidin-2-one (4) [19], 2-debenzoyl-2-(3-chloro-
benzoyl)-7-triethylsilyl-10-deacetyl-10-propanoylbaccatin III (5-
2c) [19], and 2-debenzoyl-2-(3-azidobenzoyl)-7-triethylsilyl-10-
deacetyl-10-propanoylbaccatin III (5-2d) [19], 2-debenzoyl-2-(3-
chlorobenzoyl)-10-propanoyl-30-dephenyl-30-difluoromethyldo-
cetaxel (1j) [19], 2-debenzoyl-2-(3-azidobenzoyl)-10-propanoyl-
30-dephenyl-30-trifluoromethyldocetaxel (2n) [19] were prepared
by the previously reported methods.
3.3. 2-Debenzoyl-2-(3-methoxybenzoyl)-10-acetyl-30-dephenyl-30-
difluoromethyldocetaxel (1a)
A typical experimental procedure is described for the synthesis
of 1a as follows: 2-(3-methoxybenzoyl)-7-TES-10-propanoylbac-
catin III (5-1a, 19 mg, 0.031 mmol) and (3R,4R)-difluoromethyl-
b
-lactam 3 (30 mg, 0.076 mmol) were dissolved in THF (1.0 mL).
The mixture was cooled to ꢀ40 8C and LiHMDS (1M THF solution,
62 L) was added. The reaction mixture was stirred for 2 h, and
quenched with 1.0 mL of saturated aqueous NH4Cl, the aqueous
m
Scheme 7.

L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
821
Table 1
In vitro cytotoxicity (IC50, nM)a of 30-difluoromethyl-taxoids (1a–p)
Taxoid
R1
X
MCF7-Sb
(breast)
MCF7-Rc
(breast)
R/Sd
LCC6-WTb
(breast)
LCC6-MDRe
(breast)
R/Sd
H460f
(lung)
HT-29g
(colon)
Paclitaxel
1.7
300
176
215
12
3.1
346
–
112
–
4.9
3.6
Docetaxel
1a
1.0
215
–
–
1.0
Ac
MeO
MeO
MeO
MeO
F
0.34
1.14
0.45
0.81
0.44
0.53
0.52
0.59
0.40
0.44
0.31
0.26
0.32
0.32
0.37
1.69
4.16
4.05
4.51
6.59
5.33
7.24
8.13
11.38
6.48
5.20
2.96
2.08
1.68
0.96
1.44
2.56
0.26
0.69
0.69
1.03
0.52
0.88
0.69
0.86
0.31
0.52
0.21
0.13
0.22
0.39
0.29
0.26
5.57
4.92
7.06
10.2
10.0
4.63
10.6
12.6
5.80
4.71
3.87
1.82
1.57
1.15
1.69
2.06
21
0.38
0.40
0.40
0.30
0.20
0.41
0.20
0.30
0.49
0.30
0.36
0.25
0.48
0.27
0.52
0.23
0.52
0.59
0.43
0.44
0.35
0.86
0.35
0.43
1.94
0.43
0.58
0.29
0.57
0.37
0.40
0.36
1b
Et–CO
3.5
10
8.1
7.1
10
9.9
19
3.5
1c
Me2N–CO
MeO–CO
Ac
1d
1e
13
14
16
19
16
12
1f
Et–CO
F
1g
Me2N–CO
MeO–CO
Ac
F
15
15
19
1h
1i
F
Cl
1j
Et–CO
Cl
9.1
1k
Me2N–CO
MeO–CO
Ac
Cl
9.5
18
14
1l
Cl
8.0
5.3
3.0
3.9
1.5
1m
1n
1o
N3
N3
N3
N3
7.1
Et–CO
2.9
5.8
7.9
Me2N–CO
MeO–CO
1p
a
The concentration of compound inhibits 50% of the growth of a cancer cell line after 72 h drug exposure.
Human breast carcinona.
b
c
d
e
f
Multidrug-resistant human breast carcinoma.
R/S = drug-resistance factor = IC50 (drug-resistant cell line)/IC50 (drug-sensitive cell line).
Multidrug resistant human breast carcinoma.
Human non-small cell lung carcinoma.
g
Human caucasian colon adenocarcinoma.
layer was extracted with ethyl acetate, and the combined organic
quenched with 10 mL saturated aqueous NaHCO3, extracted with
ethyl acetate. The combined organic layers were washed with
saturated aqueous CuSO4 and brine, dried over anhydrous MgSO4
and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (hexane/ethyl
acetate = 1/1) to afford 15.2 mg (44% yield for two steps) of
phases were washed with brine and dried over anhydrous MgSO4.
The crude product was purified on silica gel column (hexanes/
EtOAc = 1/1) to give the desired coupling product, 2-debenzoyl-2-
(3-methoxybenzoyl)-7-triethylsilyl-10-propanoyl-20-triisopro-
pylsilyl-30-dephenyl-30-difluoromethyldocetaxel (12a, 29.6 mg).
To a solution of 7-TES-20-TIPS-fluoro-taxoid 12a (29.6 mg) in
2.0 mL of a 1:1 mixture of pyridine/CH3CN was added 0.10 mL of
HF-pyridine at 0 8C. The reaction mixture was allowed to warm to
room temperature and stirred for 26 h. The reaction was then
desired fluoro-taxoid 1a as a white solid: mp 181 8C; [
(c = 0.76, CHCl3): 1H NMR (CDCl3, 400 MHz):
1.14 (3H, s, H-17-
a]
20-79
D
d
CH3), 1.25 (3H, s, H-16-CH3), 1.29 (9H, s, Boc), 1.67 (3H, s, H-19-
CH3), 1.69 (1H, bs, OH), 1.89 (4H, m, H-18-CH3, H-6b), 2.24 (4H, m,
Table 2
In vitro cytotoxicity (IC50 nM)a of 30-trifluoromethyl-taxoids (2a–q)
Taxoid
R1
X
MCF7-Sb
(breast)
MCF7-Rc
(breast)
R/Sd
LCC6-WTb
(breast)
LCC6-MDRe
(breast)
R/Sd
H460f
(lung)
HT-29g
(colon)
Paclitaxel
1.7
300
176
215
28
3.1
346
–
112
–
4.9
3.6
Docetaxel
2a
1.0
215
–
–
1.0
Ac
MeO
MeO
MeO
MeO
F
0.32
0.19
0.57
0.17
0.45
0.68
0.32
0.31
0.40
0.34
0.12
0.65
0.47
0.38
0.47
0.47
0.57
8.8
0.33
0.45
0.28
0.27
0.38
0.82
0.32
0.39
0.22
0.39
0.27
0.29
1.18
1.09
1.27
1.09
1.18
3.99
4.24
4.48
3.99
5.93
4.27
5.57
5.81
4.96
2.54
2.55
5.08
4.00
2.56
3.52
4.00
12.3
12
9
0.38
0.41
0.35
0.38
0.49
0.59
0.5
0.69
0.54
0.68
0.53
1.11
1.15
0.76
0.85
0.85
1.11
0.45
0.68
0.50
0.40
0.50
0.40
0.70
2b
Et–CO
Me2NCO
MeOCO
Ac
2.16
1.84
2.88
5.58
3.78
2.64
4.88
5.04
3.28
1.02
4.72
3.85
1.61
2.61
2.92
7.45
11
2c
3.2
16
15
16
2d
17
13
2e
2f
Et–CO
Me2NCO
MeOCO
Ac
F
5.6
8.3
16
13
9.6
5.2
2g
F
17
15
23
2h
2i
F
0.61
0.5
Cl
2j
Et–CO
Me2NCO
MeOCO
Ac
Cl
6.5
9.4
18
0.63
0.42
0.43
0.20
0.20
0.30
0.20
0.20
2k
Cl
8.5
7.3
8.2
4.2
5.6
6.2
2l
Cl
2m
2n
2o
N3
N3
N3
N3
N3
3.4
2.3
2.8
3.7
Et–CO
Me2NCO
MeOCO
H
2p
2q
13
10
a
The concentration of compound inhibits 50% of the growth of a cancer cell line after 72 h drug exposure.
Human breast carcinona.
b
c
d
e
f
Multidrug-resistant human breast carcinoma.
R/S = drug-resistance factor = IC50 (drug-resistant cell line)/IC50 (drug-sensitive cell line).
Multidrug resistant human breast carcinoma.
Human non-small cell lung carcinoma.
g
Human caucasian colon adenocarcinoma.

822
L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
H-10-CH3, H-14b), 2.35 (1 H, m, H-14a), 2.38 (3H, s, 4-OAc), 2.45
(1H, d, J = 3.6 Hz, OH) 2.55 (1H, ddd, J = 2.8, 5.6, 15.5 Hz, H-6a),
3.38 (1H, d, J = 4.0 Hz, OH-20), 3.81 (1H, d, J = 6.8 Hz, H-3), 3.89 (3H,
s, 2-m-MeO), 4.16 (1H, d, J = 8.4 Hz, H-20b), 4.35 (1H, d, J = 8.4 Hz,
H-20a), 4.42 (2H, m, H-7, H-30), 4.62 (1H, d, J = 2.4 Hz, H-20), 4.95
(1H, bd, J = 7.6 Hz, H-5), 5.01 (1H, d, J = 10 Hz, NH), 5.66 (1H, d,
J = 7.2 Hz, H-2), 5.85 (1H, ddd, J = 5.6, 56.0, 56.0 Hz, CF2H), 6.24
(1H, t, J = 8.4 Hz, H-13), 6.29 (1H, s, H-10), 7.14 (1H, dd, J = 2.4,
8.4 Hz, arom.), 7.40 (1H, t, J = 8.0 Hz, arom.), 7.65 (1H, s, arom.),
3.6. 2-Dephenyl-2-(3-methoxybenzoyl)-10-methoxycarbonyl-30-
dephenyl-30-difluoromethyldocetaxel (1d)
Yield 71% for two steps; 1H NMR (300 MHz, CDCl3):
d1.18 (3H, s,
H-17), 1.27 (3H, s, H-16), 1.32 (9H, s, Boc), 1.72 (3H, s, H-19), 1.82–
1.97 (1H, m, H-6b), 1.94 (3H, s, H-18), 2.22–2.68 (7H, m, H-4OAc,
H-6a, H-14, 7-OH), 3.40 (1H, bd, J = 5 Hz, 20-OH) 3.82 (1H, d,
J = 7 Hz, H-3), 3.90 (3H, s, 2-m-MeO), 3.93 (3H, s, H-10 MeO), 4.20
(1H, d, J = 8.1 Hz, H-20b), 4.38–4.55 (3H, m, H-20a, H-7), 4.66 (2H,
s, H-20, H-30), 4.96–5.06 (2H, m, H-5, NH-30), 5.70 (1H, d, J = 7 Hz, H-
2), 5.88 (1H, ddd, J = 6.3, 56.4, 56.4 Hz, H-30 CF2H), 6.14 (1H, s, H-
10), 6.28 (1H, dd, J = 8.4, 8.4 Hz, H-13), 7.18 (1H, d, J = 7.2 Hz,
arom.), 7.44 (1H, dd, J = 7.8, 7.8 Hz, arom.), 7.68 (1H, m, arom.), 7.75
7.71 (1H, d, J = 8.0 Hz, arom.); 13C NMR (CDCl3, 100 MHz):
d 9.7,
15.0, 21.0, 22.1, 22.7, 26.9, 28.2, 35.7, 35.8, 43.5, 45.9, 55.0 (m),
55.6, 58.8, 68.7, 72.4, 73.2, 75.7, 76.7, 76.9, 79.3, 81.2 81.4, 84.7,
114.3 (m), 114.4, 120.9, 122.9, 129.9, 130.5, 133.5, 142.1, 155.2,
159.9, 167.3, 170.5, 171.5, 172.6, 203.9; 19F NMR (CDCl3,
(1H, d, J = 7.8 Hz, arom.); 13C (75.5 MHz, CDCl3):
d 9.8, 15.1, 22.2,
282 MHz):
d
ꢀ125.7 (ddd, J = 10.9, 54.7, 285.1 Hz), ꢀ128.2 (ddd,
22.8, 27.0, 28.3, 35.7, 35.9, 43.5, 45.9, 54.9 (m), 55.6, 55.9, 58.9,
68.7, 72.0, 73.2, 75.3, 76.7, 77.5, 78.4, 79.3, 81.4, 84.7, 114.3 (m),
114.4, 120.9, 122.9, 129.9, 130.4, 133.1, 142.9, 155.1, 155.9, 159.8,
J = 9.3, 56.7, 285.1 Hz); HRMS (FAB+, m/z): Calcd. for
C
41H53F2NO16ꢂH+, 854.3405. Found: 854.3430.
167.2, 170.4, 172.4, 203.9; 19F (282 MHz, CDCl3):
d
ꢀ125.69 (ddd,
3.4. 2-Dephenyl-2-(3-methoxybenzoyl)-10-propanoyl-30-dephenyl-
30-difluoromethyldocetaxel (1b)
1F, J = 12.1, 55.8, 292.7 Hz), ꢀ128.2 (ddd, 1F, J = 9.02, 55.8,
283.4 Hz); HRMS (FAB+, m/z): Calcd. for C41H53F2NO17ꢂH+,
870.3354. Found: 868.3349.
Yield 38% for two steps; mp 168 8C; [
CHCl3); 1H NMR (400 MHz, CDCl3):
1.15 (3H, s, H-17), 1.26 (6H,
a]
20-56 (c = 0.80,
D
d
3.7. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-acetyl-30-dephenyl-30-
m, H-16, H-10 EtCO), 1.29 (9H, s, Boc), 1.58 (1H, bs, OH), 1.67 (3H,
s, H-19), 1.69 (1H, bs, OH), 1.88 (4H, m, H-6b, H-18), 2.25 (2H, m,
H-14), 2.39 (3H, s, 4OAc), 2.54 (3H, m, H-6a, H-10 EtCO), 3.36 (1H,
d, J = 4.0 Hz, OH), 3.82 (1H, d, J = 6.8 Hz, H-3), 3.89 (3H, s, 2-m-
MeO), 4.16 (1H, d, J = 8.4 Hz, H-20b), 4.36 (1H, d, J = 8.4 Hz, H-
20a), 4.42 (2H, m, H-7, H-30), 4.62 (1H, d, J = 3.6 Hz, H-20), 4.96
(1H, d, J = 7.6 Hz, H-5), 5.01 (1H, d, J = 10.0 Hz, NH), 5.66 (1H, d,
J = 6.8 Hz, H-2), 5.85 (1H, ddd, J = 6.0, 56, 56 Hz, CF2H), 6.25 (1H,
dd, J = 10, 10 Hz, H-13), 6.30 (1H, s, H-10), 7.14 (1H, d, J = 8.0 Hz,
arom.), 7.40 (1H, t, J = 8.0 Hz, arom.), 7.65 (1H, s, arom.), 7.72 (1H,
difluoromethyldocetaxel (1e)
Yield 68% for two steps; 1H NMR (CDCl3, 400 MHz):
d1.15 (3H, s,
H-17-CH3), 1.25 (3H, s, H-16-CH3), 1.31 (9H, s, Boc), 1.67 (3H, s, H-
19-CH3), 1.85–1.91 (4H, m, H-18-CH3, H-6b), 2.25 (3H, s, H-10-
CH3CO), 2.27–2.37 (2H, m, H-14), 2.41 (3H, s, H-4-OAc), 2.47 (1H, d,
J = 4 Hz, OH), 2.52–2.60 (1H, m, H-6a), 3.39 (1H, d, J = 5.2 Hz, 20-
OH), 3.81 (1H, d, J = 7 Hz, H-3), 4.15 (1H, d, J = 8.4 Hz, H-20b), 4.31
(1H, d, J = 8.4 Hz, 20-Ha), 4.38–4.45 (2H, m, H-7, H-30), 4.63 (1H, d,
J = 4.4 Hz, H-20), 4.95–4.98 (1H, m, H-5), 5.03 (1H, d, J = 9.6 Hz, NH),
5.64 (1H, d, J = 7 Hz, H-2), 5.87 (1H, ddd, J = 5.6, 56.4, 56.4 Hz,
CF2H), 6.24 (1H, dd, J = 8.8, 8.8 Hz, H-13), 6.29 (1H, s, H-10), 7.30
(1H, dd, J = 2, 8 Hz, arom.), 7.48–7.53 (1H, m, arom.), 7.81 (1H, d,
J = 8.4 Hz, arom.), 7.92 (1H, d, J = 8 Hz, arom.); 13C NMR (CDCl3,
d, J = 8.0 Hz, arom.); 13C (100 MHz, CDCl3):
d 9.2, 9.8, 15.0, 22.2,
22.7, 26.9, 27.8, 28.2, 35.7, 35.8, 43.5, 45.9, 55.0 (m), 55.6, 58.8,
68.7, 72.4, 73.2, 75.3, 75.5, 76.9, 79.3, 81.3, 81.4, 84.7, 114.3 (t,
J
CF = 230 Hz), 114.4, 120.9, 122.9, 129.9, 130.5, 133.8, 141.9,
154.5, 159.9, 167.3, 170.5, 172.3, 174.8, 203.9; 19F (282 MHz,
100 MHz):
d 9.6, 14.9, 20.9, 22.0, 22.5, 26.8, 28.0, 35.4, 35.6, 43.3,
CDCl3):
d
ꢀ125.7 (ddd, J = 10.9, 56.6, 287.1 Hz), ꢀ128.2 (ddd, J = 9,
45.7, 54.6 (m), 58.6, 68.4, 72.2, 72.9, 75.5, 75.6, 76.3, 79.4, 81.3,
81.4, 84.4, 114.0 (m), 117.1 (d, JCF = 24 Hz), 120.8 (d, JCF = 21 Hz),
122.9, 125.9, 130.4 (d, JCF = 7.5 Hz), 133.1, 141.9, 154.9, 162.3
(JCF = 246 Hz), 165.9, 170.2, 171.1, 172.2, 203.3; NMR, (CDCl3,
57, 286 Hz); HRMS (FAB+, m/z): Calcd. for C42H55F2NO16ꢂH+,
868.3562. Found: 868.3582.
3.5. 2-Dephenyl-2-(3-methoxybenzoyl)-10-dimethylcarbamoyl-30-
dephenyl-30-difluoromethyldocetaxel (1c)
282 MHz):
d
-111.8, ꢀ126.3 (ddd, 1F, J = 9.9, 67.2, 216.5 Hz), ꢀ128.2
(ddd, 1F, J = 6.8, 42.4, 216.5 Hz); HRMS (FAB+, m/z): Calcd. for
C
40H50F3NO15ꢂH+, 842.3205. Found: 842.3190.
Yield 54% for two steps; mp 167 8C; [
1H NMR (300 MHz, CDCl3):
1.16 (3H, s, H-17), 1.25 (3H, s, H-16),
a]
20-64 (c = 1.3, CHCl3);
D
d
3.8. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-propanoyl-30-dephenyl-30-
1.29 (9H, s, Boc), 1.67 (3H, s, H-19), 1.71 (1H, bs, OH), 1.90 (1H, m,
H-6b), 1.91 (3H, s, H-18), 2.25 (2H, m, H-14), 2.39 (3H, s, H-4OAc),
2.54 (1H, ddd, J = 4.8, 8.0, 14.8 Hz, H-6a), 2.96 (3H, s, 10-Me2NCO),
3.05 (3H, s, 10-Me2NCO), 3.18 (1H, bs, OH), 3.40 (1H, bs, 20-OH),
3.81 (1H, d, J = 7 Hz, H-3), 3.90 (3H, s, 2-m-MeO), 4.17 (1H, d,
J = 8.4 Hz, H-20b), 4.35 (1H, d, J = 8.4 Hz, H-20a), 4.48 (2H, m, 7H,
30H), 4.63 (1H, J = 4 Hz 20H), 4.97 (1H, d, J = 8 Hz, H-5), 5.03 (1H, d,
J = 10.4 Hz, NH), 5.65 (1H, d, J = 7 Hz, H-2), 5.85 (1H, ddd, J = 5.6,
55.6, 55.6 Hz, CF2H), 6.25 (2H, m, H-10, H-13), 7.14 (1H, dd, J = 2.8,
7.2 Hz, arom.), 7.40 (1H, dd, J = 8, 8 Hz, arom.), 7.65 (1H, m, arom.),
difluoromethyldocetaxel (1f)
Yield 60% for two steps; 1H NMR (400 MHz, CDCl3):
d 1.14 (3H, s,
17-CH3), 1.21 (3H, s, 16-CH3), 1.24 (9H, s, Boc), 1.29 (s, 3H, 10-
CH2CH3), 1.60 (1H, bs, OH), 1.63 (3H, s, 19-CH3), 1.87 (1H, m, 6-Hb),
1.89 (3H, s, 18-CH3), 2.20–2.54 (8H, m, 10-CH2CH3, 6-Ha, 4-Ac, 14-
Ha, 14-Hb), 3.40 (1H, bs, OH), 3.82 (1H, d, J = 7 Hz, 3-H), 4.15 (1H, d,
J = 8 Hz, 20-Hb), 4.31 (1H, d, J = 8 Hz, 20-Ha), 4.43 (2H, m, 7-H, 30-
H), 4.63 (1H, d, J = 4 Hz, 20-H), 4.96 (1H, d, J = 8 Hz, H-5), 5.00 (1H, d,
J = 10 Hz, NH), 5.64 (1H, d, J = 7 Hz, 2-H), 5.82 (1H, ddd, J = 6, 55,
55 Hz, CF2H), 6.24 (1H, m, 13-H), 6.30 (1H, s, 10-H), 7.32 (1H, m),
7.49 (1H, m), 7.60 (1H, m), 7.92 (1H, m); 13C NMR (100 MHz,
7.72 (1H, d, J = 8.0 Hz, arom.); 13C (100 MHz, CDCl3):
d 9.6, 15.1,
22.5, 22.7, 27.1, 28.2, 35.6, 35.7, 36.2, 36.9, 43.5, 45.8, 54.8 (m),
55.6, 58.8, 68.6, 72.7, 73.3, 75.4, 76.3, 76.7, 79.4, 81.2, 81.5, 84.9,
114.3 (m), 114.4, 120.9, 122.9, 129.9, 130.5, 133.9, 142.4, 155.2,
CDCl3): d 9.2 (CH2CH3), 9.7 (19-CH3), 15.0 (18-CH3), 22.1 (17-CH3),
22.6 (4-Ac), 26.9 (16-CH3), 27.7 (CH2CH3), 28.1 (Boc), 35.5 (14-
CH2), 35.8 (6-CH2), 43.4 (15-C), 45.8 (3-CH), 54.4 (m, 30-CH), 58.8
(8-C), 68.7 (20-CH), 72.4 (13-CH), 73.1 (7-CH), 75.5 (2-CH), 75.6
(10-CH), 76.5 (20-CH2), 76.9 (1-C), 79.3 (Boc), 81.3 (4-C), 84.7 (5-
CH), 114.3 (q, JCF = 242 Hz, CF2H), 117.2 (d, JCF = 28 Hz, arom.),
156.3, 159.9, 167.3, 170.4, 172.6, 205.8; 19F (282 MHz, CDCl3):
d
ꢀ125.7 (ddd, J = 10.9, 54.7, 285.1 Hz), ꢀ128.3 (ddd, J = 10.9, 54.7,
285.1 Hz); HRMS (FAB+, m/z): Calcd. for C42H56F2N2O16ꢂH+,
883.3671. Found: 883.3690.

L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
823
121.1(d, JCF = 26 Hz, arom.), 126.2 (arom.), 130.7 (d, JCF = 7 Hz
arom.), 131.4 (arom.), 133.4 (11-C), 142.0 (12-C), 155.2 (Boc), 164.0
(d, JCF = 246 Hz, CF arom.), 166.2 (2-benz), 170.5 (4-Ac), 172.6 (10-
arom.), 7.60 (1H, m, arom.), 8.04 (1H, m, arom.), 8.10 (m, 1H,
arom.);13C NMR (CDCl3, 75 MHz):
9.5 (19-CH3), 14.8 (18-CH3),
d
20.8 (10-Ac), 21.8 (17-CH3), 22.3 (4-Ac), 26.6 (16-CH3), 27.9 (Boc),
35.3 (14-CH2), 35.5 (6-CH2), 43.1 (15-C), 45.6 (3-CH), 54.6 (m, 30-
CH), 58.5 (8-C), 68.5 (20-CH), 72.2 (13-CH), 72.8 (7-CH), 75.3 (10-
CH), 75.4 (2-CH), 76.3 (20-CH2), 79.1 (1-C), 80.9 (Boc), 81.0 (4-C),
84.4 (5-CH), 114.0 (t, JCF = 244 Hz, CF2H), 128.3 (arom.), 130.1
(arom.), 130.4 (arom.), 130.8 (arom.), 133.0 (arom.), 133.7 (11-C),
134.8 (CIV arom.), 141.9 (12-C), 155.0 (Boc), 165.8 (2-benz), 170.3
(10-Ac), 171.2 (4-Ac), 172.3 (10-C), 203.5 (9-C); 19F NMR (CDCl3,
C), 174.8 (10-prop), 203.8 (9-C); 19F NMR (282 MHz, CDCl3):
d
ꢀ111.6 (m, 1 F, CAr–F), ꢀ126.2 (ddd, 1 F, J = 12, 55, 286 Hz),ꢀ127.0
(ddd, 1F, J = 9, 55, 286 Hz). HRMS (ES+, m/z): Calcd. for
C
41H52NO15F3ꢂH+, 856.3367. Found: 856.3374.
3.9. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-dimethylcarbamoyl-30-
dephenyl-30-difluoromethyldocetaxel (1g)
282 MHz):
d
ꢀ126.5 (ddd, J = 13, 57, 287 Hz), ꢀ127.4 (ddd, J = 9, 57,
Yield 84% for two steps; 1H NMR (CDCl3, 300 MHz):
d
1.18 (3H, s,
285 Hz); HRMS (ES+, m/z): Calcd. for C40H50ClF2NO15ꢂH+, 858.2910.
17-CH3), 1.27 (3H, s, 16-CH3), 1.34 (9H, s, Boc), 1.70 (3H, s, 19-CH3),
1.86–1.94 (1H, m, 6-Hb), 1.94 (3H, s, 18-CH3), 2.25–2.38 (2H, m,
14-H), 2.44 (3H, s, 4-Ac), 2.52–2.62 (1H, m, 6-Ha), 2.99 (3H, s,
NMe), 3.07 (3H, s, NMe), 3.25 (1H, bs), 3.35 (1H, bs, 20-OH), 3.84
(1H, d, J = 7.2 Hz, 3-H), 4.18 (1H, d, J = 8.4 Hz, 20-Hb), 4.34 (1H, d,
J = 8.4 Hz, 20-Ha), 4.44–4.45 (2H, m, 7-H, 30-H), 4.67 (1H, bs, 20-H),
5.01 (1H, d, J = 7.8 Hz, H-5), 5.07 (1H, d, J = 10 Hz, NH), 5.66 (1H, d,
J = 7.2 Hz, 2-H), 5.90 (1H, ddd, J = 6.6, 55.8, 55.8 Hz, CH2H), 6.25–
6.31 (2H, m, 10-H, 13-H), 7.31–7.38 (1H, m, arom.), 7.49–7.56 (1H,
m, arom.), 7.84 (1H, d, J = 8.7 Hz, arom.), 7.96 (1H, d, J = 8.1 Hz,
Found: 858.2923.
3.12. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-propanoyl-30-dephenyl-
30-difluoromethyldocetaxel (1j)
Yield 75% for two steps; 1H NMR (CDCl3, 300 MHz):
d 1.20–1.28
(9H, m, 16-CH3, 17-CH3, CH3CH2), 1.33 (9H, s, Boc), 1.60 (1H, bs,
OH) 1.69 (3H, m, 19-CH3), 1.91 (4H, m, 18-CH3, H-6b), 2.30 (2H, m,
H-14a, H-14b), 2.43 (3H, s, 4Ac), 2.56 (3H, m, CH2CO, H-6a), 3.47
(1H, d, J = 5 Hz, OH-20), 3.84 (1H, d, J = 7 Hz, H-3), 4.15 (1H, d,
J = 8 Hz, H-20b), 4.32 (1H, d, J = 8 Hz, H-20a), 4.44 (2H, m, H-30, H-
7), 4.66 (1H, d, J = 5 Hz, H-20), 4.98 (1H, m, H-5), 5.08 (d, 1H,
J = 10 Hz, NH), 5.64 (1H, d, J = 7 Hz, H-2), 5.98 (1H, ddd, J = 6, 56,
56 Hz, CF2H), 6.25 (1H, m, H-13), 6.33 (1H, s, H-10), 7.47 (1H, m,
arom.), 7.62 (1H, m, arom.), 8.04 (1H, m, arom.), 8.18 (1H, m,
arom.); 13C NMR (CDCl3, 75.5 MHz):
d 9.3, 14.9, 22.3, 22.4, 26.9,
27.9, 35.4, 35.6, 36.3, 36.7, 43.2, 45.5, 54.5 (m), 58.5, 68.4, 72.0,
72.9, 76.0, 76.3, 77.2, 79.2, 81.3, 81.4, 84.7, 114.0 (q, JCF = 242 Hz,
CF2H), 117.1 (d, J = 24 Hz), 120.8 (d, J = 21 Hz), 125.9, 130.4 (d,
J = 10 Hz), 131.2, 133.4, 142.3, 155.0, 156.1, 163.0 (d, J = 219 Hz),
165.9, 170.3, 172.4, 205.5; HRMS (FAB+, m/z): Calcd. for
C41H53F3N2O15ꢂH+, 871.3471. Found: 871.3465.
arom.); 13C NMR (CDCl3, 75 MHz):
d 9.3 (CH2CH3), 9.8 (19-CH3),
15.1 (18-CH3), 22.1 (17-CH3), 22.6 (4-Ac), 26.9 (16-CH3), 27.8
(CH2CH3), 28.2 (Boc), 35.6 (6-CH2), 35.8 (14-CH2), 43.4 (15-C), 45.9
(3-CH), 54.8 (m, 30-CH), 58.7 (8-C), 68.9 (20-CH), 72.5 (13-CH), 73.1
(7-CH), 75.5 (2-CH), 75.6 (10-CH), 76.5 (20-CH2), 79.4 (1-C), 81.2
(Boc), 81.3 (4-C), 84.7 (5-CH), 114.3 (t, JCF = 244 Hz, CF2H), 128.5
(arom.), 130.4 (arom.), 130.6 (arom.), 131.1 (arom.), 133.4 (arom.),
134.0 (11-C), 135.1 (arom.), 142.1 (12-C), 155.3 (Boc), 166.0 (2-
benz), 170.6 (4-Ac), 172.6 (10-C), 174.9 (10-prop.), 203.8 (9-C); 19F
3.10. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-methoxycarbonyl-30-
dephenyl-30-difluoromethyldocetaxel (1h)
Yield 79% for two steps; 1H NMR (CDCl3, 400 MHz):
d1.15 (3H, s,
Me), 1.25 (3H, s, Me), 1.30 (9H, s, Boc), 1.69 (3H, s, Me), 1.88–1.76
(1H, m), 1.92 (3H, s, Me), 2.21–2.36 (3H, m, H14), 2.40 (3H, s, Ac),
2.44 (1H, m, H6b), 2.57 (1H, ddd, J = 6.8, 9.6, 15.2 Hz, H6a), 3.39
(1H, bs, OH), 3.89 (1H, d, J = 7 Hz, H3), 3.87 (3H, s, OMe), 4.15 (1H, d,
J = 8.4 Hz, H20b), 4.31 (1H, d, J = 8.4 Hz, H20a), 4.34–4.45 (2H, m,
H7, H30), 4.63 (1H, m, H20), 4.96 (1H, d, J = 8 Hz, H-5), 5.10 (1H, d,
J = 10 Hz, NH), 5.87 (1H, ddd, J = 6, 56, 56 Hz, CF2H), 6.12 (1H, s,
H10), 6.24 (1H, dd, J = 10 Hz, H13), 7.32 (1H, ddd, J = 1.2, 8,
16.4 Hz,), 7.53–7.47 (1H, m), 7.81 (1H, d, J = 9.6 Hz), 7.92 (1H, d,
NMR (CDCl3, 282 MHz):
d
ꢀ126.0 (ddd, J = 12, 55, 283 Hz), ꢀ128.0
(ddd, J = 9, 55, 286 Hz); HRMS (ES+, m/z): Calcd. for
C
41H52ClF2NO15ꢂH+, 872.3066. Found: 872.3055.
3.13. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-dimethylcarbamoyl-30-
dephenyl-30-difluoromethyldocetaxel (1k)
J = 7.6 Hz); 13C NMR (CDCl3, 100 MHz):
d
9.8, 15.3, 22.2, 22.8, 26.9,
Yield 56% for two steps; 1H NMR (400 MHz, CDCl3):
d 1.14 (3H, s,
28.3, 35.6, 35.9, 43.4, 45.9, 54.7 (m), 55.9, 58.9, 68.7, 72.4, 73.1,
75.6, 76.6, 78.3, 79.4, 81.3, 81.6, 84.7, 114.3 (q, JCF = 242 Hz, CF2H),
117.3 (d, JCF = 23 Hz), 121.0 (d, JCF = 21 Hz), 126.2, 130.6 (d,
17-CH3), 1.24 (3H, s, 16-CH3), 1.30 (9H, s, Boc), 1.66 (3H, s, 19-CH3),
1.87 (1H, m, 6-Hb), 1.90 (3H, s, 18-CH3), 2.28 (2H, m, H-14), 2.40
(3H, s, 4-Ac), 2.53 (1H, m, 6-Ha), 2.95 (3H, s, NMe), 3.03 (3H, s,
NMe), 3.20 (1H, bs, OH), 3.50 (1H, d, J = 4 Hz, 20-OH), 3.80 (1H, d,
J = 7 Hz, H-3), 4.14 (1H, d, J = 8.4 Hz, H-20b), 4.28 (1H, d, J = 8.4 Hz,
H-20a), 4.40 (2H, m, H-7, H-30), 4.63 (1H, bs, 20-H), 4.98 (1H, bd,
J = 6 Hz, NH), 5.09 (1H, d, J = 10 Hz, H-5), 5.60 (1H, d, J = 7 Hz, 2-H),
5.85 (1H, ddd, J = 6, 56, 56 Hz, CF2H), 6.23 (1H, m, 13-H), 6.24 (1H, s,
10-H), 7.45 (1H, m, arom.), 7.56 (1H, m, arom.), 7.99 (1H, m, arom.),
J
CF = 7.6 Hz), 131.4 (d, JCF = 5 Hz), 133.0, 142.9, 155.2, 155.8,
162.5 (d, JCF = 246 Hz), 166.2, 170.5, 172.5, 203.8; 19F NMR, (CDCl3,
282 MHz):
d
ꢀ111.6 (bs, 1F), ꢀ126.0 (ddd, 1F, J = 12.1, 55.1,
278.4 Hz), ꢀ128.0 (ddd, 1F, J = 9, 68.6, 283.7 Hz); HRMS (FAB+, m/
z): Calcd. for C40H50F3NO16ꢂH+, 858.3154. Found; 858.3160.
3.11. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-acetyl-30-dephenyl-30-
8.11 (1H, m, arom.); 13C NMR (100 MHz, CDCl3):
d 9.69 (19-CH3),
difluoromethyldocetaxel (1i)
15.2 (18-CH3), 22.6 (16-CH3), 22.7 (4-Ac), 27.2 (17-CH3), 28.4 (Boc),
35.7 (6-CH2), 35.7 (NMe), 36.3 (NMe), 36.9 (14-CH2), 43.3 (15-C),
45.8 (3-CH), 54.9 (m, 30-CH), 58.7 (8-C), 68.7 (20-CH), 72.7 (13-CH),
73.1 (7-CH), 75.8 (2-CH), 76.3 (10-CH), 76.5 (20-CH2), 79.5 (1-C),
81.2 (4-C), 81.4 (Boc), 84.4 (5-CH), 114.2 (t, JCF = 244 Hz, CF2H,),
128.5 (arom.), 130.1 (arom.), 130.6 (arom.), 131.5 (arom.), 133.6
(arom.), 133.9 (11-C), 134.9 (arom.), 142.4 (12-C), 155.1 (Boc),
156.2 (10-carb), 166.0 (2-benz), 170.0 (4-Ac), 171.4 (10-C), 205.5
20
Yield 59% for two steps; mp 164–166 8C, [
a
]
ꢀ57 (CHCl3, c
D
0.96); 1H NMR (CDCl3, 400 MHz):
d
1.16 (3H, s, 16-CH3), 1.27 (3H, s,
17-CH3), 1.33 (9H, s, Boc), 1.69 (3H, s, 19-CH3), 1.91 (4H, m, 18-CH3,
H-6b), 2.27 (3H, s, 10-Ac), 2.30 (2H, m, H-14), 2.37 (s, 3H, 4-Ac),
2.60 (2H, m, 6-Ha, OH), 3.60 (1H, bs, OH), 3.83 (1H, d, J = 7 Hz, 3-H),
4.17 (1H, d, J = 8 Hz, H-20b), 4.33 (1H, d, J = 8 Hz, H-20a), 4.50 (2H,
m, H-30, H-7), 4.66 (1H, bs, H-20), 4.99 (1H, bd, J = 7.8 Hz, H-5), 5.07
(1H, d, J = 10 Hz, NH), 5.65 (1H, d, J = 7 Hz, H-2), 5.90 (1H, dd,
J = 57 Hz, CF2H), 6.21 (1H, m, H-13), 6.30 (1H, s, H-10), 7.48 (1H, m,
(9-C); 19F NMR, (282 MHz, CDCl3)
d
ꢀ126.0 (ddd, J = 12, 55,
286 Hz), ꢀ127.9 (ddd, J = 9, 58, 286 Hz); HRMS (ES+, m/z): Calcd. for
C
41H53N2O15F2ClꢂH+,887.3181. Found: 887.3222.

824
L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
3.14. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-methoxycarbonyl-30-
141.8, 155.0, 166.2, 170.4, 171.2, 172.4, 203.6; 19F (282 MHz,
dephenyl-30-difluoromethyldocetaxel (1l)
CDCl3):
d
ꢀ126.2 (ddd, J = 12, 55, 287 Hz), ꢀ127.9 (ddd, J = 9, 55,
287 Hz); HRMS (FAB+, m/z): Calcd. for C41H52F2N4O15ꢂH+, 879.3470.
Yield 86% for two steps; white solid; mp 143–145 8C; [
a]
20-38
Found: 879.3457.
D
(CHCl3, c = 0.26); 1H NMR (400 MHz, CDCl3):
d
1.14 (3H, s, 17-CH3),
1.24 (3H, s, 16-CH3), 1.30 (9H, s, Boc), 1.68 (3H, s, 19-CH3), 1.88 (1H,
m, 6-Hb), 1.90 (3H, s, 18-CH3), 2.60–2.10 (7H, m, 7-OH, 14-Ha, 14-
Hb, 4-Ac, 6-Ha), 3.40 (1H, bd, J = 5 Hz, 20-OH), 3.79 (1H, d, J = 7 Hz,
3-H), 3.87 (3H, s, OMe), 4.14 (1H, d, J = 8 Hz, 20-Hb), 4.30 (1H, d,
J = 8 Hz, 20-Ha), 4.37 (2H, m, 7-H, H-30), 4.62 (1H, d, J = 2.4 Hz, 20-
H), 4.97 (2H, m, 5-H, NH), 5.62 (1H, d, 2-H), 5.87 (1H, ddd, J = 5.6,
56, 56 Hz, CF2H), 6.11 (1H, s, 10-H), 6.23 (1H, m, H-13), 7.45 (1H, m,
arom.), 7.60 (1H, m, arom.), 8.00 (1H, m, arom.), 8.12 (1H, m,
arom.); 13C NMR (100 MHz, CDCl3): ( 9.7 (19-CH3), 15.1 (18-CH3),
22.0 (17-CH3), 22.6 (4-Ac), 26.8 (16-CH3), 28.2 (Boc), 35.5 (6-CH2),
35.8 (14-CH2), 43.3 (15-C), 45.8 (3-CH), 54.0 (m, 30-CH), 55.8
(OMe), 58.5 (8-C), 68.7 (20-CH), 72.3 (13-CH), 73.0 (7-CH), 75.5 (2-
CH), 76.5 (20-CH2), 76.9 (10-CH), 78.4 (Boc), 79.4 (1-C), 81.2 (4-C),
84.6 (5-CH), 114.2 (t, JCF = 244 Hz, CF2H), 128.5 (arom.), 130.4
(arom.), 130.6 (arom.), 131.0 (arom.), 133.0 (arom.), 134.0 (11-C),
135.0 (arom.), 143.0 (12-C), 154.8 (10-carb), 155.9 (Boc), 166.0 (2-
benz), 170.6 (4-Ac), 171.8 (10-C), 203.9 (9-C); HRMS (ES+, m/z):
Calcd. for C40H50NO16F2ClꢂH+,874.2864. Found: 874.2892.
3.17. 2-Dephenyl-2(3-azidobenzoyl)-10-dimethylcarbamoyl-30-
difluoromethyldocetaxel (1o)
Yield 37 % for two steps; mp 175 8C; [
1H NMR (300 MHz, CDCl3):
1.18 (3H, s, 17-CH3), 1.26 (3H, s, 16-
a]
20-50 (c = 1.3, CHCl3);
D
d
CH3), 1.32 (9 H, s, Boc), 1.67 (1H, bs, OH), 1.71 (3H, s, H-19), 1.95
(4H, m, 6-Hb, 18CH3), 2.32 (2H, m, H-14), 2.41 (3H, s, 4-Ac), 2.58
(1H, m, 6-Ha), 3.00 (3H, s, Me2NCO), 3.08 (3H, s, Me2NCO), 3.25
(1H, bs, OH), 3.43 (1H, bs, OH), 3.84 (1H, d, J = 7 Hz, 3-H), 4.19 (1H,
d, J = 8.4 Hz, 20-Hb), 4.36 (1H, d, J = 8.4 Hz, 20-Ha), 4.49 (2H, m, 7-
H, 30-H), 4.67 (1H, d, J = 4, 20-H), 5.01 (1H, d, J = 8.4 Hz, 5-H), 5.08
(1H, d, J = 10 Hz, NH), 5.67 (1H, d, J = 7 Hz, 2-H), 5.88 (1H, ddd,
J = 6.0, 56.4, 56.4, CF2H), 6.25 (2H, m, 10-H, 13-H), 7.25 (1H, m,
arom.), 7.51 (1H, m, arom.), 7.86 (1H, m, arom.), 7.92 (1H, d,
J = 7.5 Hz, arom.); 13C (100 MHz, CDCl3):
d9.4, 14.9, 22.3, 22.5, 26.8,
27.9, 35.3, 35.4, 36.0, 36.6, 43.2, 45.5, 54.5 (m), 58.5, 68.3, 72.4,
72.9, 75.6, 76.6, 77.2, 79.2, 80.9, 81.1, 84.7, 114.0 (t, JCF = 244 Hz),
120.1, 124.4, 126.7, 130.2, 130.8, 133.4, 140.8, 142.3, 154.9, 156.1,
166.2, 170.4, 172.4, 205.5; 19F (282 MHz, CDCl3):
d
ꢀ126.2 (ddd,
3.15. 2-Debenzoyl-2-(3-azidobenzoyl)-10-acetyl-30-dephenyl-30-
J = 12, 55, 287 Hz), ꢀ127.9 (ddd, J = 9, 55, 296 Hz); HRMS (FAB+, m/
difluoromethyldocetaxel (1m)
z): Calcd. for C41H53F2N5O15ꢂH+, 894.3579. Found: 894.3571.
Yield 53% for two steps; white solid; mp 173 8C; [
a
]
20-46
3.18. 2-Dephenyl-2(3-azidobenzoyl)-10-methoxycarbonyl-30-
D
(c = 0.81, CHCl3); 1H NMR (CDCl3, 300 MHz):
d
1.14 (3H, s, H-17),
difluoromethyldocetaxel (1p)
1.24 (3H, s, H-16), 1.29 (9H, s, Boc), 1.65 (1H, bs, OH), 1.67 (3H, s, H-
19), 1.89 (4H, m, CH3-18, H-6b), 2.25 (4H, m, H-10-CH3, H-14b),
2.32 (1H, m, H-14a), 2.39 (3H, s, 4-OAc), 2.55 (3H, m, H-6a, COCH2),
3.41 (1H, d, J = 4.8 Hz, OH-20), 3.82 (1H, d, J = 7.2 Hz, H-3), 4.16 (1H,
d, J = 8.0 Hz, H-20b), 4.32 (1H, d, J = 8.0 Hz, H-20a), 4.43 (2H, m, H-
7, H-30), 4.62 (1H, d, J = 2.4 Hz, H-20), 4.96 (1H, bd, J = 9.6 Hz, H-5),
5.04 (1H, d, J = 10 Hz, NH0), 5.65 (1H, d, J = 8.0 Hz, H-2), 5.85 (1H,
ddd, J = 5.6, 56.0, 56.0 Hz, CF2H), 6.21 (1H, t, J = 7.6 Hz, H-13), 6.29
(1H, s, H-10), 7.22 (1H, d, J = 7.6 Hz, arom.), 7.48 (1H, t, J = 8.0 Hz,
arom.), 7.83 (1H, s, arom.), 7.88 (1H, d, J = 8.0 Hz, arom.); 13C NMR
Yield 70 % for two steps; mp 156–158 8C; [
CHCl3); 1H NMR (300 MHz, CDCl3):
1.17 (3H, s, CH3-17), 1.26 (3H,
a]
20-42 (c = 2.4,
D
d
s, CH3-16), 1.31 (9H, s, Boc), 1.71 (3H, s, CH3-19), 1.75 (2H, m), 1.87
(1H, m, H-6a), 1.94 (3H, s, CH3-18), 2.32 (2H, m, H-14), 2.41 (3H, s,
H-4OAc), 2.56 (1H, m, H-6b), 3.57 (1H, bs, OH), 3.84 (1H, d, J = 7 Hz,
H-3), 4.17 (1H, d, J = 8.4 Hz, H-20b), 4.36 (1H, d, J = 8.4 Hz, H-6a),
4.43 (2H, m, H-7, H-30), 4.65 (1H, m, H-20), 5.03 (1H, d, J = 8.4 Hz, H-
5), 5.16 (1H, d, J = 10 Hz, NH), 5.89 (ddd, J = 6.0, 56.4, 56.4 Hz,
CF2H), 6.14 (1H, s, H-10), 6.24 (1H, dd, J = 9, 9 Hz H-13), 7.24 (1H, d,
J = 8.1 Hz, arom.), 7.51 (1H, dd, J = 8.1, 8.1 Hz, arom.), 7.86 (1H, s,
arom.), 7.92 (1H, d, J = 7.5 Hz, arom.); 13C (75 MHz, CDCl3):
d 9.5,
14.9, 21.8, 22.5, 26.5, 27.9, 35.3, 35.5, 43.1, 45.5, 54.5 (m), 55.6,
58.5, 68.4, 71.9, 72.8, 75.4, 76.3, 78.1, 79.1, 80.8, 80.9, 84.4, 114.0 (t,
(CDCl3, 75.5 MHz): d 9.8, 15.1, 21.0, 22.1, 22.6, 26.9, 28.2, 35.6, 35.8,
43.4, 45.9, 54.8 (m), 58.7, 68.9, 72.5, 73.1, 75.6, 75.7, 76.5, 79.4,
81.2, 81.3, 84.7, 114.3 (t, JCF = 244 Hz) 120.1, 124.4, 126.7, 130.4,
130.6, 133.4, 140.8, 142.1, 155.3, 166.0, 170.6, 172.6, 174.9, 203 8;
19F NMR, (CDCl3, 282 MHz):
d
ꢀ126.6 (ddd, J = 9, 42, 216 Hz),
J
CF = 244 Hz) 120.1, 124.4, 126.7, 130.2, 130.7, 132.7, 140.8, 142.8,
ꢀ128.1 (ddd, J = 6, 42, 216 Hz); HRMS (FAB+, m/z): Calcd. for
155.0, 155.7, 166.2, 170.5, 172.4, 203.8; 19F (282 MHz, CDCl3):
d
C
40H50F2N4O15ꢂH+, 865.3314. Found: 865.3310.
ꢀ126.2 (ddd, J = 9, 55, 283 Hz), ꢀ128.0 (ddd, J = 9, 55, 287 Hz);
HRMS (FAB+, m/z): Calcd. for C40H50F2N4O16ꢂH+, 881.3263. Found:
881.3261.
3.16. 2-Dephenyl-2(3-azidobenzoyl)-10-propanoyl-30-
difluoromethyldocetaxel (1n)
3.19. 2-Debenzoyl-2-(3-methoxybenzoyl)-10-acetyl-30-dephenyl-30-
Yield 79 % for two steps; mp 149 8C; [
a
]
20-50 (c = 4.5, CHCl3);
trifluoromethyldocetaxel (2a)
D
1H NMR (300 MHz, CDCl3):
d
1.16 (3H, s, CH3-17), 1.26 (6H, m, CH3-
16, H-10 CH3CH2CO), 1.32 (9H, s, Boc), 1.69 (3H, s, H-19), 1.79 (1H,
bs, OH), 1.91 (4H, m, H-6a, H-18), 2.32 (2H, m, H-14), 2.42 (3H, s, H-
4OAc), 2.61 (3H, m, H-6b, H-10 CH3CH2CO), 3.52 (1H, d, J = 5.1 Hz,
OH), 3.85 (1H, d, J = 7.2 Hz, H-3), 4.17 (1H, d, J = 8.4 Hz, H-20a), 4.35
(1H, d, J = 8.4 Hz, H-20b), 4.46 (2H, m, H-7, H-30), 4.65 (1H, d,
J = 4.2 Hz, H-20), 4.99 (1H, d, J = 8.7 Hz, H-5), 5.13 (1H, d, J = 10.2 Hz,
NH-30), 5.67 (1H, d, J = 6.9, H-2), 5.88 (1H, ddd, J = 6.0, 56, 56 Hz,
CF2H), 6.24 (1H, t, J = 7.2, H-13), 6.33 (1H, s, H-10), 7.25 (1H, d,
J = 7.8, arom.), 7.51 (1H, t, J = 7.8 Hz, arom.), 7.84 (1H, s, arom.), 7.90
Yield 36 % for two steps; white solid; mp 191 8C; [
(c = 0.7, CHCl3); 1H NMR (CDCl3, 300 MHz):
1.15 (3H, s, CH3-17),
a]
20-72
D
d
1.25 (3H, m, CH3-16), 1.30 (9H, s, Boc), 1.67 (3H, s, CH3-19), 1.70
(bs, 1 H, OH), 1.88 (4H, m, H-6b, CH3-18), 2.25 (3H, s, 10-OAc), 2.32
(2H, m, H-14), 2.37 (3H, s, 4-OAc), 2.47 (1H, bs, OH), 2.56 (1H, m, H-
6a), 3.38 (1H, bs, OH), 3.81 (1H, d, J = 7 Hz, H-3), 3.89 (3H, s, MeO),
4.17 (1H, d, J = 8.4 Hz, H-20b), 4.36 (1H, d, J = 8.4 Hz, H-20a), 4.42
(1H, m, H-7), 4.71 (1H, m, H-20), 4.77 (1H, m, H-30), 4.95 (1H, d,
J = 8.4, H-5), 5.20 (1H, d, J = 10 Hz, NH0), 5.66 (1H, d, J = 7 Hz, H-2),
6.29 (2H, m, H-10, H-13), 7.15 (1H, d, J = 7.5 Hz), 7.41 (1H, d,
J = 8 Hz), 7.65 (1H, s), 7.72 (1H, m); 13C NMR (CDCl3, 75.5 MHz):
d
9.6, 14.8, 20.8, 21.9, 22.3, 26.7, 27.9, 35.4, 35.5, 43.2, 45.6, 53.8 (m),
55.3, 58.6, 68.0, 72.1, 73.4, 74.9, 75.4, 76.5, 79.0, 81.2, 81.4, 84.4,
(1H, d, J = 7.8, arom.); 13C (100 MHz, CDCl3):
22.5, 26.6, 27.5, 27.9, 35.3, 35.5, 43.2, 45.6, 54.5 (m), 58.5, 68.4,
72.1, 72.9, 75.3, 75.4, 76.3, 79.1, 80.4, 80.9, 84.5, 113.9 (t,
d 8.9, 9.5, 14.8, 21.9,
J
CF = 244 Hz) 120.1, 124.4, 126.7, 130.2, 130.7, 133.2, 140.8,

L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
825
114.1, 120.7, 122.7, 125.0 (q, JCF = 280 Hz), 129.7, 130.2, 133.4,
9.7, 15.1, 22.1, 22.5, 26.9, 28.1, 35.6, 35.8, 43.4, 45.8, 54.2 (m), 55.5,
55.8, 58.8, 68.3, 72.3, 73.6, 76.7, 76.9, 78.4, 79.2, 81.5, 81.7, 84.6,
114.3, 120.9, 122.9, 125.0 (q, JCF = 280 Hz), 129.9, 130.4, 133.3,
142.6, 154.9, 155.9, 159.9, 167.3, 170.4, 171.9, 203.9; 19F NMR
(CDCl3, 282 MHz):
for C41H52F3NO17ꢂH+, 888.3260. Found: 888.3242.
141.6, 154.6, 159.7, 167.1, 170.2, 171.2, 171.8, 203.5; 19F NMR
(CDCl3, 282 MHz):
d
ꢀ73.8 (d, J = 9.0 Hz); HRMS (FAB+, m/z): Calcd.
for C41H52F3NO16ꢂH+, 872.3311. Found: 872.3321.
d
–73.8 (d, J = 7.3 Hz); HRMS (FAB+, m/z): Calcd.
3.20. 2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-30-
dephenyl-30-trifluoromethyldocetaxel (2b)
3.23. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-acethyl-30-dephenyl-30-
Yield 43% for two steps; white solid; mp 156 8C; [
a
]
20-57
trifluoromethyldocetaxel (2e)
D
(c = 0.54, CHCl3): 1H NMR (CDCl3, 300 MHz):
d
1.15 (3H, s, CH3-16),
1.23 (6H, m, C-17, 10-CH3CH2CO), 1.30 (9H, s, Boc), 1.68 (3H, s, CH3-
19), 1.70 (1H, ds, OH), 1.88 (4H, m, H-6b, CH3-18), 2.26 (2H, m, H-
14), 2.37 (3H, s, 4-OAc), 2.54 (4H, m, H-6a, 10-CH3CH2CO, OH), 3.81
(1H, d, J = 7 Hz, H-3), 3.89 (3H, s, MeO), 4.17 (1H, d, J = 8.4 Hz, H-
20b), 4.36 (1H, d, J = 8.4 Hz, H-20a), 4.42 (1H, dd, J = 4.0, 10.4 Hz, H-
7), 4.70 (1H, bs, H-20), 4.77 (1H, m, H-30), 4.96 (1H, d, J = 8.0, H-5),
5.20 (1H, d, J = 10.8 Hz, NH0), 5.66 (1H, d, J = 7 Hz, H-2), 6.26 (1H,
dd, J = 9, 9 Hz, H-13), 6.30 (1H, s, H-10), 7.15 (1H, d, J = 8.8 Hz), 7.40
(1H, dd, J = 8, 8 Hz), 7.84 (1H, s), 7.65 (1H, s), 7.72 (1H, d, J = 7.2 Hz);
Yield 79% for two steps; white solid; mp 140–142 8C; [a D
(CHCl3, c = 0.26) 1H NMR (400 MHz, CDCl3):
1.14 (3H, s, 17-CH3),
]
20-44
d
1.24 (3H, s, 16-CH3) 1.30 (9H, s, Boc), 1.60 (1H, bs, OH), 1.67 (3H, s,
19-CH3), 1.80 (1H, m, H-6b), 1.88 (3H, s, 18-CH3), 2.24 (3H, s, 10-Ac),
2.30 (2H, m, H-14a, H-14b), 2.38 (3H, s, 4-Ac), 2.42 (1H, bs, OH), 2.60
(1H, m, H-6a), 3.40 (1H, bs, OH), 3.80 (1H, d, J = 7 Hz, H-3), 4.15 (1H,
d, J = 8 Hz, H-20b), 4.31 (1H, d, J = 8 Hz, H-20a), 4.40 (1H, dd, J = 7,
10 Hz H-7), 4.70 (1H, d, J = 1.2 Hz, H-20), 4.80 (1H, m, H-30), 4.95 (1H,
d, J = 8 Hz, H-5), 5.20 (1H, d, J = 10 Hz, NH), 5.63 (1H, d, J = 7 Hz, H-2),
6.28 (2H, m, H-13, H-10), 7.32 (1H, m, arom.), 7.50 (1H, m, arom.),
7.80 (1H, m, arom.), 7.92 (1H, d, J = 8 Hz, arom.); 13C NMR (100 MHz,
13C NMR (CDCl3, 75.5 MHz):
d 9.3, 9.7, 15.1, 22.3, 22.6, 27.0, 27.9,
28.2, 35.7, 35.8, 43.5, 45.9, 53.8 (m), 55.9, 58.9, 68.4, 72.5, 73.7,
75.3, 75.6, 76.9, 79.3, 81.6, 81.7, 84.8, 114.4, 121.0, 123.0, 125.0 (q,
JCF = 280 Hz), 130.1, 130.5, 133.8, 141.8, 154.9, 159.8, 167.4, 170.5,
CDCl3): d 9.75 (19-CH3), 15.0 (18-CH3), 21.0 (10-Ac), 22.1 (17-CH3),
22.5 (4-Ac), 26.9 (16-CH3), 28.1 (Boc), 35.6 (14-CH2), 35.7 (6-CH2),
43.4 (15-C), 45.8 (3-CH), 54.0 (m, C30), 58.8 (8-C), 68.3 (20CH), 72.3,
73.4 (2-CH), 75.6 (10-CH), 76.6 (20-CH2), 77.6 (7-CH), 79.3 (1-C),
81.4 (Boc), 81.6 (4-CH), 84.6 (5-CH), 117.4 (JCF = 23 Hz, arom.), 121.1
(JCF = 20 Hz, arom.), 124 (q, JCF = 280 Hz CF3), 126.2 (arom.), 130.7 (d,
JCF = 7 Hz, arom.), 131.0 (arom.), 133.5 (11-C), 141.9 (12-C), 154.8
(Boc), 163.1 (d, JCF = 90 Hz, CF arom.), 166.1 (2-benz), 170.4 (10-Ac),
171.4 (4-Ac), 171.9 (10-C), 203.6 (9-C); HRMS (ES+, m/z): Calcd. for
172.1, 174.9, 203.9; 19F NMR (CDCl3, 282 MHz):
d –73.8 (d,
J = 7.3 Hz); HRMS (FAB+, m/z): Calcd. for C42H54F3NO16ꢂH+,
886.3467. Found: 886.3486.
3.21. 2-Debenzoyl-2-(3-methoxybenzoyl)-10-dimethylcarbamoyl-
30-dephenyl-30-trifluoromethyldocetaxel (2c)
Yield 66 % for two steps; white solid; mp 164 8C; [a D
]
20-58
C
40H49NO15F4ꢂH+, 860.3117. Found: 860.3107. 19F NMR, (CDCl3,
(c = 3.6, CHCl3); 1H NMR (CDCl3, 400 MHz):1.15(3H, s, CH3-17,)1.24
(3H, s, CH3-16), 1.29 (9H, s, Boc), 1.67 (3H, s, CH3-19), 1.78 (bs, 1 H,
OH), 1.89 (4H, m, H-6b, CH3-18), 2.24 (2H, m, H-14), 2.36 (3H, s, 4-
OAc), 2.53 (1H, ddd, J = 2.8, 5.6, 15.2 Hz, H-6a), 2.96 (3H, s, N-CH3),
3.04 (3H, s, N-CH3), 3.21 (1H, bs, OH), 3.55 (1H, bs, OH), 3.80 (1H, d,
J = 7 Hz, H-3), 3.89 (s, 3 H, MeO), 4.17 (1H, d, J = 8.4 Hz, H-20b), 4.35
(1H, d, J = 8.4 Hz, H-20a), 4.45 (1H, m, H-7), 4.70 (1H, s, H-20), 4.77
(1H, m, H-30), 4.96 (1H, d, J = 8 Hz, H-5), 5.28 (1H, d, J = 10.4 Hz, NH0),
5.65 (1H, d, J = 7 Hz, H-2), 6.27 (2H, m, H-10, H- 13), 7.13 (1H, dd,
J = 2.8, 8.4 Hz, arom.), 7.39 (1H t, J = 8.0 Hz, arom.), 7.64 (1H, s,
282 MHz)
d
ꢀ73.8 (d, J = 9 Hz), ꢀ111.61 (q, J = 6 Hz).
3.24. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-propanoyl-30-
dephenyl-30-trifluoromethyldocetaxel (2f)
Yield 85% for two steps; white solid, mp 128–130 8C; [a]
20-28
D
(CHCl3, c = 0.34); 1H NMR (400 MHz, CDCl3):
d 1.14 (3H, s, 16-CH3),
1.23 (3H, t, CH2CH3), 1.24 (3H, s, 16-CH3), 1.55 (9H, s, Boc), 1.67
(3H, s, 19-CH3), 1.88 (4H, s, H-6b, 18-CH3), 2.30 (2H, m, H-14a, H-
14b), 2.38 (3H, s, 4-Ac), 2.60 (4H, m, OH, H-6a, CH2CH3), 3.32 (1H, d,
J = 4 Hz, 20-OH), 3.82 (1H, d, J = 7 Hz, H-3), 4.15 (1H, d, J = 8 Hz, H-
20b), 4.31 (1H, d, J = 8 Hz, H-20), 4.40 (1H, m, H-7), 4.70 (1H, dd,
J = 5, 1.2 Hz, H-20), 7.80 (1H, m, arom.), 4.80 (1H, m, H-30), 4.96 (1H,
d, J = 8 Hz, H-5), 5.19 (1H, d, J = 10 Hz, NH), 5.63 (1H, d, J = 7 Hz, H-
2), 6.21 (1H, m, H-13), 6.30 (1H, s, H-10), 7.32 (1H, m, arom.), 7.50
arom.), 7.71 (1H, d, J = 8.0 Hz, arom.); 13C NMR (CDCl3, 75.5 MHz):
d
9.6, 15.1, 22.5, 22.7, 27.1, 28.1, 35.6, 35.8, 36.3, 36.9, 43.5, 45.8, 54.0
(m), 55.5, 58.8, 68.3, 72.6, 73.6, 75.4, 76.3, 76.7, 79.3, 81.2, 81.6, 84.9,
114.3, 120.9, 122.9, 125.0 (q, JCF = 280 Hz), 129.9, 130.5, 133.9, 142.2,
154.8, 156.3, 159.9, 167.3, 170.3, 171.9, 205.7; 19F NMR (CDCl3,
282 MHz):
C
d
–72.8 (d, J = 7.3 Hz); HRMS (FAB+, m/z): Calcd. for
(1H, m, arom.), 7.92 (1H, m, arom.); 13C NMR (100 MHz CDCl3):
d
42H55F3N2O16ꢂH+, 901.3576. Found: 901.3586.
9.2 (CH2CH3), 9.7 (19-CH3), 15.0 (18-CH3), 22.1 (17-CH3), 22.5 (4-
Ac), 26.9 (16-CH3), 27.8 (CH2CH3), 28.1 (Boc), 35.6 (14-CH2), 35.7
(6-CH2), 43.6 (15-C), 45.8 (3-CH), 54.1 (m, 30-CH), 58.8 (8-C), 68.3
(20-CH), 72.4 (7-CH), 73.5 (2-CH), 75.4 (10-CH), 75.6 (13-CH), 76.6
(20-CH2), 79.4 (1-C), 81.4 (4-C), 81.6 (Boc), 84.6 (5-CH), 117.3 (d,
JCF = 16 Hz, arom.), 121.0 (d, JCF = 21 Hz, arom.), 124.7 (q,
JCF = 280 Hz, CF3), 126.2 (arom.), 130.7 (d, JCF = 8 Hz, arom.),
131.4 (arom.), 133.6 (11-C), 141.8 (12-C), 154.8 (Boc), 163.0 (d,
JCF = 247 Hz, CF arom.), 166.4 (2-ben), 170.5 (4-Ac), 171.9 (10-C),
174.8 (10-prop), 203.7 (9-C); HRMS (ES+, m/z): Calcd. for
3.22. 2-Debenzoyl-2-(3-methoxybenzoyl)-10-methoxycarbonyl-30-
dephenyl-30-trifluoromethyldocetaxel (2d)
Yield 90 % for two steps; white solid; mp 201 8C; [
(c = 1.2, CHCl3); 1H NMR (CDCl3, 400 MHz):
1.15 (3H, s, CH3-17,)
a]
20-50
D
d
1.24 (3H, s, CH3-16), 1.30 (9H, s, Boc), 1.69 (3H, s, CH3-19), 1.72 (1H,
bs, OH), 1.88 (1H, m, H-6b), 1.91 (s, 3H, CH3-18), 2.26 (1H, m, H-
14a), 2.35 (m, 1 H, H-14b), 2.39 (3H, s, 4-OAc), 2.45 (1H, bs, OH),
2.56 (3H, m, H-6a), 3.40 (1H, bs, OH), 3.79 (1H, d, J = 7.0 Hz, H-3),
3.87 (3H, s, 10-MeO), 3.89 (s, 3H, 2-m-MeO), 4.17 (1H, d, J = 8.5 Hz,
H-20b), 4.36 (1H, d, J = 8.5 Hz, H-20a), 4.39 (1H, dd, J = 4.0, 11.0 Hz,
H-7), 4.70 (1H, bs, H-20), 4.77 (1H, m, H-30), 4.95 (1H, d, J = 7.5 Hz,
H-5), 5.21 (1H, d, J = 10.0 Hz, NH0), 5.66 (1H, d, J = 7 Hz, H-2), 6.11
(1H, s, H-10), 6.26 (1H, dd, J = 8, 8 Hz, H- 13), 7.24 (1H, dd, J = 2.5,
8.0 Hz, arom.), 7.38 (1H, dd, J = 7.5, 7.5 Hz, arom.), 7.65 (1H s,
C
41H51NO15F4H+, 874.3273. Found: 874.3316. 19F NMR, (CDCl3,
282 MHz)
73.8 (d, J = 6 Hz), ꢀ111.6 (q, J = 6 Hz).
d
3.25. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-dimethylcarbomoyl-30-
dephenyl-30-trifluoromethyldocetaxel (2g)
Yield 88 % for two steps; white solid; mp 175 8C; [
(c = 4.4, CHCl3); 1H NMR (CDCl3, 400 MHz):
1.15 (3H, s, CH3-17,)
a]
20-59
D
arom.), 7.72 (1H d, J = 8.0 Hz, arom.); 13C NMR (CDCl3, 100 MHz):
d
d

826
L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
1.25 (3H, s, CH3-16), 1.30 (9H, s, Boc), 1.66 (3H, s, CH3-19), 1.73 (1H,
bs, OH), 1.88 (1H, m, H-6b), 1.90 (3H, s, CH3-18), 2.20–2.37 (2H, m,
H-14a,b), 2.38 (3H, s, 4-OAc), 2.53 (1H, m, H-6a), 2.96 (3H, s,
N(Me)2), 3.04 (3H, s, N(Me)2), 3.20 (1H, s, OH), 3.51 (1H, bs, OH),
3.80 (1H, d, J = 7.2 Hz, H-3), 4.15 (1H, d, J = 8.4 Hz, H-20b), 4.29 (1H,
d, J = 8.4 Hz, H-20a), 4.44 (1H, dd, J = 4.4, 10.8 Hz, H-7), 4.71 (1H, bs,
H-20), 4.78 (1H, m, H-30), 4.97 (1H, d, J = 8.0 Hz, H-5), 5.27 (1H, d,
J = 10.4 Hz, NH0), 5.62 (1H, d, J = 7.2 Hz, H-2), 6.26 (2H, m, H-13, H-
10), 7.31 (1H, ddd, J = 1.6, 7.6, 7.6 Hz, arom.), 7.48 (1H, m, arom.),
7.80 (1H, d, J = 9.2 Hz, arom.), 7.92 (1H, d, J = 7.6 Hz, arom.); 13C
203.9 (9-C); HRMS (ES+, m/z): Calcd. for C40H49NO15F3ClꢂH+,
876.2821. Found: 876.2815. 19F NMR (282 MHz, CDCl3)
d
ꢀ73.8
(d, J = 9 Hz).
3.28. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-propanoyl-30-dephenyl-
30-trifluoromethyldocetaxel (2j)
Yield 72% for two steps; white solid, mp 154–157 8C; [
(CHCl3, c = 0.015); 1H NMR (400 MHz, CDCl3):
1.14 (3H, s, 17-
a]
20-58
D
d
CH3), 1.20 (6H, m, 16-CH3, CH3CH2), 1.30 (9H, s, Boc), 1.67 (3H, s,
19-CH3), 1.88 (4H, m, 18-CH3, 6-Hb), 2.25 (2H, m, 14-Ha, 14-Hb),
2.38 (3H, s, 4-Ac), 2.55 (3H, m, CH2CH3, 6-Ha), 3.51 (1H, bs, 20-OH),
3.81 (1H, d, J = 7 Hz, H-3), 4.15 (1H, d, J = 8 Hz, H-20b), 4.29 (1H, d,
J = 8 Hz, H-20a), 4.40 (1H, m, H-7), 4.70 (1H, bs, H-20), 4.77 (1H, m,
H-30), 4.96 (1H, d, J = 9 Hz, H-5), 5.26 (1H, d, J = 10 Hz, NH), 5.60
(1H, d, J = 7 Hz, H-2), 6.23 (1H, m, H-13), 6.30 (1H, s, H-10), 7.44
(1H, m, arom.), 7.58 (1H, m, arom.), 8.00 (1H, m, arom.), 8.11 (1H,
NMR (CDCl3, 75.5 MHz):
d 9.6, 15.1, 22.4, 22.5, 27.1, 28.1, 35.6,
35.7, 36.2, 36.9, 43.4, 45.8, 54.1 (m), 58.7, 68.3, 72.7, 73.5, 75.7,
76.3, 76.6, 79.4, 81.4, 81.5, 84.9, 117.3 (d, JCF = 22.0 Hz), 121.0 (d,
J
CF = 20.5 Hz), 124.0 (q, JCF = 280 Hz), 126.2, 130.6 (d, JCF = 7.6 Hz),
131.5 (d, CF = 7.6 Hz), 133.9, 142.3, 154.9, 156.3, 163.0 (d,
CF = 246 Hz), 166.2, 170.4, 171.9, 205.6; 19F NMR (CDCl3,
J
J
282 MHz):
C
d
–73.7 (d, J = 7.3 Hz); HRMS (FAB+, m/z): Calcd. for
41H52F4N2O15ꢂH+, 889.3377. Found: 889.3383.
m, arom.); 13C NMR (100 MHz, CDCl3):
d 9.09 (CH2CH3), 9.62 (19-
CH3), 14.8 (18-CH3), 21.9 (17-CH3), 22.3 (4-Ac), 26.7 (16-CH3), 27.6
(CH2CH3), 28.0 (Boc), 35.4 (6-CH2), 35.6 (14-CH2), 43.2 (15-C), 45.7
(3-CH), 54.0 (m, 30-CH), 58.5 (8-C), 68.1 (20-CH), 72.1 (13-CH), 73.2
(7-CH), 75.2 (10-CH), 75.4 (2-CH), 76.3 (20-CH2), 79.1 (1-C), 81.1
(Boc), 81.3 (4-C), 84.4 (5-CH), 124.0 (q, JCF = 280 Hz, CF3), 128.1
(arom.), 129.9 (arom.), 130.3 (arom.), 130.7 (arom.), 133.2 (arom.),
133.6(11-C), 134.7 (arom.), 141.4 (12-C), 154.5 (Boc), 165.3 (2-
benz), 170.0 (4-Ac), 171.5 (10-C), 174.4 (10-prop.), 203.3 (9-C);
HRMS (ES+, m/z): Calcd. for C41H51NO15F3ClꢂH+, 890.2978. Found:
3.26. 2-Debenzoyl-2-(3-fluorobenzoyl)-10-methoxycarbonyl-30-
dephenyl-30-trifluoromethyldocetaxel (2h)
Yield 74 % for two steps; white solid; mp 169 8C; [
(c = 3.7, CHCl3); 1H NMR (CDCl3, 400 MHz):
1.15 (3H, s, CH3-17,)
a]
20-47
D
d
1.24 (3H, s, CH3-16), 1.30 (9H, s, Boc), 1.69 (3H, s, CH3-19), 1.73 (1H,
bs, OH), 1.83 (1H, m, H-6b), 1.91 (s, 3H, H-18), 2.25 (2H, m, H-
14a,b), 2.38 (3H, s, 4-OAc), 2.57 (1H, m, H-6a), 3.40 (1H, bs, OH),
3.78 (1H, d, J = 7 Hz, H-3), 3.87 (3H, s, 10-MeO), 4.15 (1H, d,
J = 8.4 Hz, H-20b), 4.30 (1H, d, J = 8.4 Hz, H-20a), 4.38 (1H, dd,
J = 4.1, 11.0 Hz, H-7), 4.71 (1H, bs, H-20), 4.77 (1H, m, H-30), 4.95
(1H, d, J = 7.6 Hz, H-5), 5.28 (1H, d, J = 11.6 Hz, NH0), 5.63 (1H, d,
J = 7 Hz, H-2), 6.11 (1H, s, H-10), 6.25 (1H, t, J = 8, 8 Hz, H- 13), 7.31
(1H, ddd, J = 2.4, 8, 8 Hz, arom.), 7.49 (1H, m, arom.), 7.79 (1H, d,
J = 8.8 Hz, arom.), 7.91 (1H, d, J = 8.0 Hz, arom.); 13C NMR (CDCl3,
890.2979. 19F NMR (CDCl3, 282 MHz)
d
ꢀ73.8 (d, J = 9 Hz).
3.29. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-dimethylcarbamoyl-30-
dephenyl-30-trifluoromethyldocetaxel (2k)
Yield 58% for two steps; white solid; mp 175–177 8C; [
(CHCl3, c = 0.60); 1H NMR (400 MHz, CDCl3):
1.14 (3H, s, 17-CH3),
a]
20-62
D
d
75.5 MHz):
d
9.6, 15.1, 22.1, 22.5, 26.8, 28.1, 35.6, 35.8, 43.3, 45.9,
1.24 (3H, s, 16-CH3), 1.30 (9H, s, Boc), 1.66 (3H, s, 19-CH3), 1.87 (1H,
m, H-6b), 1.90 (3H, s, 18-CH3), 2.28 (2H, m, H-14a, H-14b), 2.38
(3H, s, 4-Ac), 2.50 (1H, m, H-6a), 2.96 (3H, s, NMe), 3.04 (3H, s,
NMe), 3.20 (1H, bs, OH), 3.45 (1H, bs, 20-OH), 3.80 (1H, d, J = 7 Hz,
H-3), 4.14 (1H, d, J = 8 Hz, H-20b), 4.29 (1H, d, J = 8 Hz, 20-Ha), 4.42
(1H, dd, J = 7, 11 Hz, H-7), 4.70 (1H, bs, H-20), 4.78 (1H, m, H-30),
4.98 (1H, bd, J = 9 Hz, H-5), 5.20 (1H, d, J = 10.4 Hz, NH), 5.60 (1H, d,
J = 7 Hz, H-2), 6.24 (2H, m, H-13, H-10), 7.45 (1H, m, arom.), 7.56
(1H, m, arom.), 7.99 (1H, m, arom.), 8.11 (1H, m, arom.); 13C NMR
54.0 (m), 55.8, 58.8, 68.3, 72.3, 73.3, 75.6, 76.6, 78.3, 79.3, 81.3,
81.6, 84.6, 117.3 (d, JCF = 22.8 Hz), 120.0 (d, JCF = 21.3 Hz), 124.0 (q,
JCF = 280 Hz), 126.2, 130.7 (d, JCF = 7.6 Hz), 131.5 (d, JCF = 6.8 Hz),
133.17, 142.7, 154.9, 155.9, 163.0 (d, JCF = 246 Hz), 166.2, 170.5,
171.9, 203.9; 19F NMR, (CDCl3, 282 MHz):
d –73.7 (d, J = 7.1 Hz);
HRMS (FAB+, m/z): Calcd. for C40H49F4NO16ꢂH+, 876.3060. Found:
876.3068.
3.27. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-acethyl-30-dephenyl-30-
(100 MHz, CDCl3): d 9.56 (19-CH3), 15.1 (18-CH3), 22.4 (16-CH3),
trifluoromethyldocetaxel (2i)
22.5 (4-Ac), 27.1 (17-CH3), 28.1 (Boc), 35.6 (6-CH2), 35.7 (NMe),
36.3 (NMe), 36.9 (14-CH2), 43.3 (15-C), 45.8 (3-CH), 54.9 (m, 30-
CH), 58.7 (8-C), 68.7 (20-CH), 72.7 (13-CH), 73.5 (7-CH), 75.8 (2-
CH), 76.3 (10-CH), 76.5 (20-CH2), 79.5 (1-C), 81.4 (4-C), 81.5 (Boc),
84.9 (5-CH), 124.2 (q, JCF = 280 Hz, CF3), 128.5 (arom.), 130.3
(arom.), 130.6 (arom.), 131.0 (arom.), 133.8 (arom.), 133.9 (11-C),
134.9 (arom.), 142.4 (12-C), 155.0 (Boc), 156.2 (10-carb), 166.0 (2-
benz), 170.4 (4-Ac), 171.9 (10-C), 205.6 (9-C); HRMS (ES+, m/z):
Calcd. For C41H52N2O15F3ClH+, 905.3087. Found: 905.3115. 19F
Yield 60% for two steps; mp 148–150 8C; [
c = 0.49); 1H NMR (400 MHz, CDCl3):
1.14 (3H, s, 17-CH3), 1.30
a]
20-53.06 (CHCl3,
D
d
(3H, s, 16-CH3), 1.55 (9H, s, Boc), 1.84 (3H, s, 19-CH3), 1.88 (1H, m,
6-Hb), 1.90 (1H, s, 18-CH3), 2.28 (3H, s, 10-Ac), 2.30 (2H, m, 14-Ha,
14-Hb), 2.38 (3H, s, 4-Ac), 2.46 (1H, bs, OH), 2.60 (1H, m, H-6a),
3.37 (1H, bs, 20-OH), 3.80 (1H, d, J = 7 Hz, H-3), 4.14 (1H, d, J = 8 Hz,
H-20b), 4.29 (1H, d, J = 8 Hz, H-20a), 4.40 (1H, m, H-7), 4.70 (1H, bs,
H-20), 4.80 (1H, m, H-30), 4.96 (1H, d, J = 8 Hz, H-5), 5.18 (1H, d,
J = 10 Hz, NH), 5.60 (1H, d, J = 7 Hz, 2-H), 6.24 (1H, m, 13-H), 6.28
(1H, s, H-10), 7.45 (1H, m, arom.), 7.59 (1H, m, arom.), 8.00 (1H, d,
NMR, (CDCl3, 282 MHz)
d
ꢀ73.8 (d, J = 9.6 Hz).
3.30. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-methoxycarbonyl-30-
dephenyl-30-trifluoromethyldocetaxel (2l)
J = 8 Hz, arom.), 8.13 (1H, s, arom.); 13C NMR (100 MHz, CDCl3):
d
9.7 (19-CH3), 15.0 (18-CH3), 21.0 (10-Ac), 22.1 (17-CH3), 22.4 (4-
Ac), 26.9 (16-CH3), 28.1 (Boc), 35.6 (6-CH2), 35.8 (14-CH2), 43.4
(15-C), 45.8 (3-CH), 55.8 (m, 30-CH), 58.8 (8-C), 68.3 (20CH), 72.2
(13-CH), 72.4 (7-CH), 73.5 (10-CH), 75.6 (2-CH), 76.5 (20-CH2), 79.4
(1-C), 81.4 (Boc), 81.6 (4-C), 84.6 (5-CH), 124.0 (q, JCF = 280 Hz,
CF3), 128.5 (arom.), 130.3 (arom.), 130.6 (arom.), 131.0 (arom.),
133.5 (arom.), 133.9 (11-C), 135.1 (CIV arom.), 141.9 (12-C), 154.8
(Boc), 166.0 (2-benz), 170.4 (10-Ac), 171.4 (4-Ac), 171.9 (10-C),
Yield 84% for two steps; white solid, mp 154–156 8C; [
(CHCl3, c = 0.18) 1H NMR (400 MHz, CDCl3):
1.14 (3H, s, 17-CH3),
a]
20-44
D
d
1.24 (3H, s, 16-CH3), 1.27 (9H, s, Boc), 1.68 (3H, s, 19-CH3), 1.88
(1H, m, 6-Hb), 1.91 (3H, s, 18-CH3), 2.28 (2H, m, 14-Ha, 14-Hb),
2.38 (3H, s, 4-Ac), 2.45 (1H, bs, OH), 2.56 (1H, m, 6-Ha), 3.40 (1H,
bs, OH), 3.78 (1H, d, J = 7 Hz, 3-H), 3.87 (3H, s, OMe), 4.14 (1H, d,
J = 7 Hz, 20-Hb), 4.29 (1H, d, J = 7 Hz, 20-Ha), 4.38 (1H, m, 7-H),

L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
827
4.70 (1H, bs, 20-H), 4.77 (1H, m, 30-H), 4.96 (1H, d, J = 8 Hz, H-5),
5.20 (1H, d, J = 10 Hz, NH), 5.61 (1H, d, J = 7 Hz, H-2), 6.11 (1H, s, H-
10), 6.24 (1H, m, H-13), 7.45 (1H, m, arom.), 7.58 (1H, d, J = 8 Hz,
arom.), 8.00 (1H, d, J = 8 Hz, arom.), 8.12 (1H, s, arom.), 13C NMR
1.26 (3H, s, CH3-16), 1.32 (9H, s, Boc), 1.69 (4H, s, CH3-19, OH), 1.92
(4H, m, H-6b, CH3-18), 2.29 (2H, m, H-14), 2.39 (3H, s, 4-OAc), 2.56
(1H, m, H-6a,), 2.98 (3H, s, N-CH3), 3.06 (3H, s, N-CH3), 3.22 (1H, bs,
OH), 3.43 (1H, bs, OH), 3.84 (1H, d, J = 7.0 Hz, H-3), 4.18 (1H, d,
J = 8.0 Hz, H-20b), 4.34 (1H, d, J = 8.0 Hz, H-20a), 4.48 (1H, m, H-7),
4.72 (1H, d, J = 3.5 Hz, H-20), 4.79 (1H, m, H-30), 4.99 (1H, d, J = 8 Hz,
H-5), 5.24 (1H, d, J = 10.0 Hz, NH0), 5.66 (1H, d, J = 7.0 Hz, H-2), 6.27
(1H, m, H-10, H-13), 7.24 (1H, d, J = 8.5 Hz, arom.), 7.49 (1H, dd,
J = 8.0, 8.0 Hz, arom.), 7.85 (1H, s, arom.), 7.91 (1H, d, J = 7.5 Hz,
(100 MHz, CDCl3):
d 9.7 (19-CH3), 15.1 (18-CH3), 22.0 (17-CH3),
22.4 (4-Ac), 26.8 (16-CH3), 28.1 (Boc), 35.5 (6-CH2), 35.8 (14-CH2),
43.3 (15-C), 45.8 (3-CH), 54.0 (m, 30-CH), 55.8 (OMe), 58.8 (8-C),
68.3 (20-CH), 72.3 (13-CH), 73.4 (7-CH), 75.6 (2-CH), 76.5 (10-CH),
76.9 (20-CH2), 79.4 (1-C), 81.3 (4-C), 81.6 (Boc), 84.6 (5-CH), 125.0
(q, JCF = 280 Hz, CF3), 128.5 (arom.), 130.1 (arom.), 130.6 (arom.),
131.0 (arom.), 133.1 (arom.), 133.9 (11-C), 135.1 (arom.), 142.7
(12-C), 154.8 (10-carb), 155.0 (Boc), 166.0 (2-benz), 170.4 (4-Ac),
arom.); 13C NMR (CDCl3, 75.5 MHz):
d 9.3, 14.9, 22.3, 22.4, 26.8,
27.9, 35.3, 35.4, 36.0 36.6, 43.2, 45.5, 53.6 (m), 58.5, 68.0, 72.3, 73.4,
75.5, 76.0, 76.3, 77.2, 79.2, 81.2, 84.7, 120.1, 124.4, 125.0 (q,
171.9 (10-C), 203.8 (9-C); 19F NMR (282MHz, CDCl3)
d
ꢀ73.8 (d,
JCF = 280 Hz) 126.7, 130.2, 130.7, 133.6, 140.9, 142.0, 154.6, 156.0,
J = 6 Hz); HRMS (ES+, m/z): Calcd. for C40H49NO16F3ClH+,
166.2, 170.2, 171.8, 205.4; 19F NMR (CDCl3, 282 MHz):
d –72.8 (d,
892.2770. Found: 892.2780.
J = 9.0 Hz); HRMS (FAB+, m/z): Calcd. for C41H52F3N5O15ꢂNa+,
934.3304. Found: 934.3275.
3.31. 2-Debenzoyl-2-(3-azidobenzoyl)-10-acetyl-30-dephenyl-30-
trifluoromethyldocetaxel (2m)
3.34. 2-Debenzoyl-2-(3-azidobenzoyl)-10-methoxycarbonyl-30-
dephenyl-30-trifluoromethyldocetaxel (2p)
Yield 80% for two steps; white solid; mp 179 8C; [
(c = 2.2, CHCl3); 1H NMR (CDCl3, 500 MHz):
1.17 (3H, s, CH3-16),
a]
20-46
D
d
Yield 53% for two steps; white solid; mp 173 8C; [
(c = 1.4, CHCl3); 1H NMR (CDCl3, 500 MHz):
1.17 (3H, s, CH3-17,)
a]
20-42
D
1.27 (3H, m, CH3-17), 1.32 (9H, s, Boc), 1.69 (3H, s, CH3-19), 1.91
(4H, m, H-6b, CH3-18), 2.01 (1H, bs, OH), 2.27 (3H, s, 10-OAc),2.35
(1H, m, H-14), 2.39 (3H, s, 4-OAc), 2.58 (1H, ddd, J = 2.0, 6.5 Hz, H-
6a), 3.43(1H, bs, OH), 3.84 (1H, d, J = 7.0 Hz, H-3), 4.18 (1H, d,
J = 8.0 Hz, H-20b), 4.35 (1H, d, J = 8.0 Hz, H-20a), 4.44 (1H, dd,
J = 4.0, 10.5 Hz, H-7), 4.72 (1H, s, H-5), 4.78 (1H, q, J = 8.5 Hz, H-30),
4.98 (1H, d, J = 9.0 Hz, H-20), 5.24 (1H, d, J = 10.5 Hz, NH0), 5.67 (1H,
d, J = 7.0 Hz, H-2), 6.26 (1H, t, J = 9.0 Hz, H-13), 6.31 (1H, s, H-10),
7.24 (1H, d, J = 8.0 Hz), 7.50 (1H, t, J = 8.0 Hz), 7.85 (1H, s), 7.90 (1H,
d
1.26 (3H, s, CH3-16), 1.32 (9H, s, Boc), 1.63 (1H, bs, OH), 1.71 (3H, s,
CH3-19), 2.41 (4H, m, H-6b, CH3-18), 2.32 (2H, m, H-14), 2.41 (3H,
s, 4-OAc), 2.59 (1H, m, H-6a), 3.39 (1H, bs, OH), 3.82 (1H, d,
J = 7.0 Hz, H-3), 3.89 (3H, s, 10-MeO), 4.19 (1H, d, J = 8.0 Hz, H-20b),
4.35 (1H, d, J = 8.0 Hz, H-20a), 4.42 (1H, m, H-7), 4.72 (1H, bs, H-20),
4.78 (1H, m, H-30), 4.98 (1H, d, J = 8 Hz, H-5), 5.22 (1H, d, J = 10 Hz,
NH0), 5.69 (1H, d, J = 7.0 Hz, H-2), 6.13 (1H, s, H-10), 6.26 (1H, dd,
J = 9, 9 Hz, H- 13), 7.24 (1H, d, J = 7.5 Hz, arom.), 7.50 (1H, dd, J = 8,
d, J = 7.5 Hz); 13C NMR (CDCl3, 75.5 MHz):
d
9.9, 15.1, 21.2, 22.2,
8 Hz, arom.), 7.85 (1H, s, arom.), 7.92 (1H, d, J = 8.0 Hz, arom.); 13
NMR (CDCl3, 75.5 MHz): 9.5, 14.9, 21.8, 22.4, 26.6, 27.9, 29.7,
C
22.7, 27.0, 28.2, 35.7, 35.9, 43.5, 45.9, 53.3 (m), 58.4, 68.3, 72.3,
73.5, 75.7, 76.6, 77.5, 79.3, 81.4, 81.5, 84.7, 120.3, 124.6, 125.0 (q,
JCF = 280 Hz), 126.9, 130.4, 130.9, 133.5, 141.1, 141.8, 154.8, 166.3,
d
35.3, 35.5, 43.1, 45.5, 53.6 (m), 55.6, 58.5, 68.0, 71.9, 73.3, 75.4,
76.3, 78.1, 79.1, 81.1, 81.3, 84.4, 120.1, 124.0, 125.0 (q,
170.4, 171.3, 171.9, 203.5; 19F NMR (CDCl3, 282 MHz):
d
–73.7 (d,
JCF = 280 Hz), 126.8, 130.2, 130.7, 132.9, 140.9, 142.6, 154.6,
J = 6.2 Hz); HRMS (FAB+, m/z): Calcd. for C40H49F3N4O15ꢂH+,
155.7, 166.2, 170.3, 171.8, 203.7; HRMS (FAB+, m/z): Calcd. for
883.3219. Found: 883.3226.
C
40H49F3N4O16ꢂH+, 899.3168. Found: 899.3221.
3.32. 2-Debenzoyl-2-(3-azidobenzoyl)-10-propanoyl-30-dephenyl-
30-trifluoromethyldocetaxel (2n)
3.35. 2-Dephenyl-2(3-azidobenzoyl)-30-trifluoromethyldocetaxel
(2q)
Yield 80 % for two steps; white solid; mp 170 8C; [
a
]
20-47
Yield 47 % for two steps; mp 184 8C; [
1H NMR (300 MHz, CDCl3):
1.19 (3H, s, CH3-17), 1.24 (3H, s, CH3-
a]
20-27 (c = 0.60, CHCl3);
D
D
(c = 3.2, CHCl3); 1H NMR (CDCl3, 300 MHz):
d
1.16 (3H, s, CH3-17),
d
1.25 (6H, m, CH3-16, CH3), 1.32 (9H, s, Boc), 1.69 (3H, s, CH3-19),
1.69 (1H, bs, OH), 1.90 (4H, m, H-6b, H-18), 2.32 (2H, m, H-14),
2.39 (3H, s, 4-OAc), 2.56 (4H, m, H-6a, COCH2, OH), 3.55 (1H, bs,
OH), 3.84 (1H, d, J = 7 Hz, H-3), 4.18 (1H, d, J = 8.4 Hz, H-20b), 4.34
(1H, d, J = 8.4 Hz, H-20a), 4.45 (1H, m, H-7), 4.72 (1H, bs, H-20),
4.78 (1H, m, H-30), 4.98 (1H, d, J = 8.1 Hz, H-5), 5.30 (1H, d,
J = 10.2 Hz, NH0), 5.67 (1H, d, J = 7.2 Hz, H-2), 6.25 (1H, dd, J = 9,
9 Hz, H-13), 6.32 (1H, s, H-10), 7.24 (1H, d, J = 8.1 Hz), 7.50 (1H,
dd, J = 7.8, 7.8 Hz), 7.84 (1H, s), 7.91 (1H, d, J = 7.5 Hz); 13C NMR
16), 1.34 (9H, s, Boc), 1.64 (1H, bs, OH), 1.78 (3H, s, CH3-19), 1.88
(1H, m, H-6a), 1.94 (3H, s, CH3-18), 2.30 (2H, m, H-14), 2.41 (3H, s,
H-4OAc), 2.63 (1H, m, H-6b), 3.44 (1H, bs, OH), 3.96 (1H, d, J = 7 Hz,
H-3), 4.21 (1H, d, J = 8.4 Hz, H-20b), 4.28 (1H, dd, J = 4.5, 10.8 Hz, H-
7) 4.37 (1H, d, J = 8.4 Hz, H-20a) 4.71 (1H, bs, H-10), 4.79 (1H, m, H-
30), 4.98 (1H, d, J = 7.8 Hz H-5), 5.25 (2H, m, H-20, NH-30), 5.70 (1H,
d, J = 7 Hz, H-2), 6.26 (1H, dd, J = 9, 9 Hz, H-13), 7.23 (1H, d,
J = 7.8 Hz, arom.), 7.49 (1H, dd, J = 8, 8 Hz, arom.), 7.86 (1H, s,
arom.), 7.91 (1H, d, J = 7.8 Hz, arom.); 13C (75.5 MHz, CDCl3):
d 10.1,
(CDCl3, 75.5 MHz):
d
9.0, 9.5, 14.8, 21.9, 22.4, 26.6, 27.5, 27.8,
14.6, 21.3, 22.7, 26.6, 28.2, 35.4, 35.8, 43.3, 46.7, 53.9 (m), 57.9,
68.4, 72.2, 73.7, 74.7, 75.5, 76.9, 79.1, 81.4, 81.6, 84.4, 120.3, 124.7,
125.0 (q, JCF = 280 Hz), 127.0, 130.5, 131.0, 133.4, 140.8, 141.2,
35.3, 35.5, 43.2, 45.6, 53.8 (m), 58.5, 68.1, 72.1, 73.3, 75.2, 75.4,
76.3, 79.0, 81.1, 81.2, 84.5, 120.0, 124.0, 124.5 (q, JCF = 280 Hz),
126.7, 130.2, 130.7, 133.3, 140.9, 141.6, 154.6, 166.2, 170.3,
154.9, 166.4, 170.7, 171.9, 204.4; 19F NMR (282 MHz, CDCl3):
d
171.8, 174.6, 203.5; 19F NMR, (CDCl3, 282 MHz):
d
ꢀ73.8 (d,
ꢀ73.85 (d, J = 6.2 Hz); HRMS (FAB+, m/z): Calcd. for
J = 9.3 Hz); HRMS (FAB+, m/z): Calcd. for C41H51F3N4O15ꢂH+,
C
38H47F3N4O14ꢂNa+, 863.2933. Found: 863.2960.
897.3376. Found: 897.3406.
Acknowledgments
3.33. 2-Debenzoyl-2-(3-azidobenzoyl)-10-dimethylcarbamoyl-30-
dephenyl-30-trifluoromethyldocetaxel (2o)
This work has been supported by grants from the National
Institutes of Health (GM42798 and CA103314 to I.O.; CA 73872 to
R.J.B.). Generous support from Indena SpA, is gratefully acknowl-
edged.
Yield 77 % for two steps; white solid; mp 188 8C; [
(c = 1.7, CHCl3); 1H NMR (CDCl3, 300 MHz):
1.17 (3H, s, CH3-17,)
a]
20-51
D
d

828
L.V. Kuznetsova et al. / Journal of Fluorine Chemistry 129 (2008) 817–828
tion, and Future Directions; ACS Symposium Series 746, American Chemical
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