Trifluoromethyl- and difluoromethyl-β-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids

Article abstract of DOI:10.1016/j.jfluchem.2003.12.001

Enantiopure 1-acyl-3-hydroxyl-4-CF₂H-azetidin-2-ones and 1-acyl-3-hydroxy-4-CF₃-azetidin-2-ones serve as versatile intermediates for the syntheses of CF₂- and CF₃-containing α-hydroxy-β-amino acids, dipeptides,

Full text of DOI:10.1016/j.jfluchem.2003.12.001

Journal of Fluorine Chemistry 125 (2004) 487–500
Trifluoromethyl- and difluoromethyl-b-lactams as useful building
blocks for the synthesis of fluorinated amino acids, dipeptides,
and fluoro-taxoids
Larisa Kuznetsova, Ioana Maria Ungureanu, Antonella Pepe,
Ilaria Zanardi, Xinyuan Wu, Iwao Ojima*
Department of Chemistry, State University of New York at Stony Brook, Graduate Chemistry Bldg. 739, Stony Brook, NY 11794-3400, USA
Received 21 October 2003; received in revised form 21 October 2003; accepted 2 December 2003
Abstract
Enantiopure 1-acyl-3-hydroxyl-4-CF2H-azetidin-2-ones and 1-acyl-3-hydroxy-4-CF3-azetidin-2-ones serve as versatile intermediates for
the syntheses of CF2- and CF3-containing a-hydroxy-b-amino acids, dipeptides, and taxoid anticancer agents. Both enantiomers of
3-hydroxy-4-CF2H-b-lactams can be obtained in high yields through the diethylaminosulfur trifluoride (DAST) reaction of the corresponding
enantiopure 4-formyl-b-lactam that is prepared through [2 þ 2] cycloaddition of acetoxyketene to a 3-methyl-2-butenaldimine, followed by
enzymatic optical resolution and ozonolysis. (þ)-3-Hydroxy-4-CF3-b-lactams and (À)-3-hydroxy-4-CF3-b-lactams can also be readily
obtained in enantiopure form through [2 þ 2] cycloaddition of a CF3-imine with a ketene, followed by enzymatic optical resolution. Practical
processes for the preparations of these enantiopure 3-hydroxy-4-Rf-b-lactams as well as their synthetic applications are described.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Fluorine-containing; b-Lactam; a-Hydroxy-b-amino acid; Dipeptide; Taxoid; Enzymatic optical resolution; Enantiopure; Trifluoromethyl;
Difluoromethyl
1. Introduction
vitro and in vivo, of protein structures and drug-protein
interactions by taking advantage of the fact that fluorine
is virtually absent in the living tissue [33–35]. Therefore,
fluorine-containing a-hydroxy-b-amino acids are expected
to serve as important and useful bioactive compounds for
medicinal chemistry and chemical biology. However, only a
limited number of methods for the synthesis of enantiopure
fluorine-containing a-hydroxy-b-amino acids have been
reported to date [32,36–40].
As a part of our continuing efforts on the development and
expansion of the b-Lactam Synthon Method (b-LSM), we
became interested in applying the b-LSM to the syntheses of
fluorine-containing a-hydroxy-b-amino acids and their con-
geners for obvious reasons mentioned above. To this end, we
have to develop first efficient method(s) for the synthesis of
the corresponding enantiopure N-acyl-b-lactams.
Besides the utility of fluorine-containing b-lactams as
versatile synthetic intermediates, they may have intrinsic
importance as a pharmacophore of various therapeutic
agents since the b-lactam skeleton is found in numerous
pharmacologically active molecules possessing antibacterial
[41], antifungal [42], antitumor [43] and plasma cholesterol
lowering [44,45] activities.
a-Hydroxy-b-amino acids are structural patterns present
in a large number of biologically active compounds such as
paclitaxel (antitumor agent) [1–3], bestatin [4–6] (inhibitor
of aminopeptidases; immunological response modifier),
microginin [7] (ACE inhibitor; KNI inhibitors), and kinos-
tatins (HIV-1 protease inhibitors) [8,9] (Fig. 1). Accordingly,
in the past decade extensive studies have been performed for
the development of efficient methods for the synthesis of
enantiopure a-hydroxy-b-amino acids [10–30].
It has been shown that the introduction of fluorine(s),
difluoromethyl, or trifluoromethyl group to bioactive mole-
cules very often brings about substantially improved phar-
macological properties because of increased membrane
permeability, enhanced hydrophobic binding, stability
against metabolic oxidation, etc. [31,32]. The introduction
of fluorine(s) into the bioactive molecules as marker(s) also
provide a unique and valuable tool for 19F NMR studies, in
* Corresponding author. Tel.: þ1-631-632-7947; fax: þ1-631-632-7942.
E-mail address: iojima@notes.cc.sunysb.edu (I. Ojima).
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.12.001

488
L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
AcO
O
OH
O
Ph
O
Ph
NH
O
O
H2N
N
COOH
OH
NH
Ph
O
H
OAc
HO
OBz
OH
Bestatin
O
OH
OH
Paclitaxel
S
N
Ph
O
NH
O
OH
O
O
H
H
NH
N
N
N
H
N
CO2H
N
H
S
O
NH2
O
O
Microginin
Kinostatin (KNI)-227
OH
Fig. 1. Examples of bioactive compounds containing a hydroxy-b-amino acid unit.
O
O
Rf
O
Rf
O
O
N
OH
O
N
OMe
H
H
OH
OP
a
b
PO
O
Rf
Rf = CF2H, CF3
N
Boc
d
c
e
O
O
Rf
O
R
O
Rf
O
OMe
O
N
N
H
O
N
N
O
O
H
H
H
OP
OP
O
R2
O
O
O
OH
O
O
NH O
OH
a. hydrolysis
b. methanolysis
c. coupling with§ -amino ester
d. coupling with α-amino ester
e. ring-opening coupling with baccatin
O
Rf
OAc
O
O
HO
X
Scheme 1.
We describe here the practical processes for the prepara-
tion of enantiopure N-acyl-3-hydroxyl-4-Rf-b-lactams
(Rf ¼ CF2H, CF3) and their applications for the syntheses
of the corresponding Rf-containing a-hydroxy-b-amino
acids, dipeptides, and taxoids. Scheme 1 illustrates repre-
sentative transformations of N-t-Boc-3-PO-4-Rf-b-lactams
(P ¼ hydroxyl protecting group).
First, racemic cis-1-PMP-3-AcO-4-(2-methyl-1-propenyl)-
azetidin-2-one (2) (PMP ¼ p-methoxyphenyl) was synthe-
sized through [2 þ 2] ketene-imine cycloaddition in 10–20 g
scale [48]. Acetoxyketene generated in situ from acetoxy-
acetyl chloride and triethylamine was reacted with N-PMP-
3-methyl-2-butenaldimine (1) to give racemic cis-b-lactam
2 in good yield (Scheme 2). Then, the enzymatic optical
resolution of b-lactam 2 was carried out using the ‘‘PS-
Amano’’ lipase in a buffer solution at 50 8C and pH 7 to
2. Results and discussion
O
2.1. Synthesis of enantiopure 3-hydroxy-4-CF2H-b-lactams
AcO
N
Cl
AcO
O
The enantioselective synthesis of (3R,4S)-3-TIPSO-4-(2-
methyl-1-propenyl)azetidin-2-one was previously reported
by our laboratory using chiral enolate–imine cycloconden-
sation [46]. In the present work, we investigated the efficacy
of enzymatic optical resolution of racemic cis-3-AcO-4-(2-
methyl-1-propenyl)azetidin-2-ones using the commercially
available ‘‘PS-Amano’’ lipase, which was successfully
employed by Sih and co-workers for the optical resolution
of cis-3-AcO-4-phenylazetidin-2-ones [47].
CH2Cl2
N
-78oC-RT
Et3N,
PMP
MeO
overnight
1
(±)
2
AcO
AcO
O
HO
O
PS-Amano
+
N
N
N
buffer pH 7.0
10% CH3CN
O
PMP
PMP
PMP
(±)
2
2(+)
3(-)
Scheme 2.

L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
489
F
F
TIPSO
TIPSO
iii. 73%
AcO
O
TIPSO
F
F
F
i, ii
v
N
N
N
NH
68%
iv. 86%
85%
PMP
PMP
PMP
O
O
O
5(+)
6(+)
2(+)
4(+)
F
F
HO
O
TIPSO
TIPSO
O
TIPSO
iii. 94%
iv. 71%
F
i, ii
v
N
NH
N
N
quant.
88%
PMP
PMP
PMP
O
O
6(-)
3(-)
5(-)
4(-)
i) KOH, THF, 0 oC; ii) TIPSCl, Et3N, DMAP; iii) O3, MeOH/CH2Cl2, -78 oC; iv)DAST,CH2Cl2;
v) CAN, H2O/CH3CN, -15 oC.
Scheme 3.
afford kinetically resolved (3R,4S)-3-AcO-b-lactam 2(þ)
(>99% ee) and (3S,4R)-3-hydroxy-b-lactam 3(À) (96–
99% ee) with extremely high enantiopurity [49] (Scheme 2).
Since the acetyl group would not be tolerated in the
diethylaminosulfur trifluoride (DAST) reaction, which
was planned to introduce difluoromethyl group later in
the synthesis [50], the protecting group of the 3-hydroxyl
moiety of b-lactam 2 was changed to triisopropylsilyl
(TIPS). The resulting (3R,4S)-1-PMP-3-TIPSO-4-(2-
methyl-1-propenyl)azetidin-2-one (4(þ)) was subjected to
ozonolysis to give (3R,4S)-1-PMP-3-TIPSO-4-formylazeti-
din-2-one, which was immediately reacted with DAST to
afford the corresponding 4-difluoromethylazetidin-2-one
(5(þ)) in high yield. Finally the PMP group was removed
using cerium ammonium nitrate (CAN) to give enantiopure
(3R,4R)-3-TIPSO-4-difluoromethylazetidin-2-one (6(þ))
(Scheme 3). In a similar manner, (3S,4S)-3-hydroxy-b-lac-
tam 3(À) was converted to enantiopure (3S,4S)-3-TIPSO-4-
difluoromethylazetidin-2-one (6(À)) (Scheme 3).
temperature for this reaction. It was also found that acet-
oxyketene that should have been generated in situ did not
react with CF3-imine 7 well, for some reason. Accordingly,
it was necessary to use benzyloxyacetyl chloride as the
ketene precursor for the reaction with CF3-imine 7. The
use of benzyloxyketene for the reaction with CF3-imines
has been reported by us [48,51] and others [40]. Thus, the
[2 þ 2] ketene-imine cycloaddition proceeded smoothly
at 40 8C to give racemic cis-3-benzyloxy-4-trifluoro-
methylazetidin-2-one 8(Æ) in moderate yield. The b-lactam
8(Æ) was converted to the corresponding cis-3-acetoxy-b-
lactam 10(Æ) through hydrogenolysis, followed by acetyla-
tion in good overall yield (Scheme 4).
The enzymatic optical resolution of the racemic 3-AcO-4-
CF3-b-lactam 10(Æ) under the same conditions as those
described for the resolution of racemic b-lactam 2(Æ) (PS-
Amano, 50 8C, pH 7) gave kinetically resolved (3R,4R)-3-
AcO-4-CF3-b-lactam 10(þ) in high yield (42%/50% in
theory). However, the corresponding (3S,4S)-3-hydroxy-4-
CF3-b-lactam 9(À) was not isolated at all, presumably due to
the further hydrolysis of the b-lactam ring of this product
under these conditions. Changing the pH to 6 (slower
reaction) or 8 (faster reaction) did not solve this problem.
Fortunately, we found that this over-reaction was control-
lable by lowering the reaction temperature. Thus, reaction at
0–5 8C at pH 7 for 12 h gave b-lactam 9(À) with 97% ee in
good yield (36%/50% in theory) in addition to b-lactam
10(þ). The results are summarized in Table 1. 3-AcO-4-
CF3-b-lactam 10(þ) and 3-hydroxy-4-CF3-b-lactam
9(À), thus obtained, were converted the corresponding
2.2. Synthesis of enantiopure 3-hydroxy-4-CF3-b-lactams
For the synthesis of 4-trifluoromethyl-b-lactams we
employed a different strategy, i.e., introducing the trifluoro-
methyl moiety from the very beginning at the imine stage
for the [2 þ 2] ketene-imine cycloaddition. Because of the
reduced nucleophilicity of the nitrogen of N-PMP-trifluoro-
acetaldimine (7) the reaction was found to require much
higher temperature than those of usual aldimines to achieve
a high conversion. We found that 40 8C is the optimal
BnO
O
CF3
CF3
AcO
CF3
HO
O
CF3
iii
i
ii
N
N
N
PMP
N
98%
74%
83%
PMP
O
PMP
PMP
7
cis-9(±)
cis-10(±)
cis-8(±)
i) PhCH2OCH2COCl, Et3N, CH2Cl2, 40 oC; ii) H2, Pd/C, MeOH, 45oC;
iii) Ac2O, DMAP, Py, CH2Cl2
Scheme 4.

490
L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
Table 1
Enzymatic optical resolution of racemic cis-3-AcO-4-CF3-b-lactam 10(Æ)
b-Lactam
pH
Temperature (8C)
Time
10(þ)
9(À)
Yield (%)
ee (%)
Yield (%)
ee (%)
cis-10(Æ)
cis-10(Æ)
7
7
50
4 days
12 h
42
45
100
–
–
0–5
99.9
36
97
AcO
CF3
TIPSO
CF3
HO
O
CF3
TIPSO
O
CF3
(À)-N-PMP-(À)-b-lactam 9(À) (vide supra). Thus, the reac-
tion of b-lactam 13(þ) with the ‘‘PS-Amano’’ lipase at
25 8C and pH 7 reached the 50% conversion in 3 h to afford
3-AcO-b-lactam 13(þ) and 3-hydroxy-b-lactam 14(À) in
excellent yields (Scheme 6).
i
iii
ii
N
O
N
H
N
N
100%
84%
95%
PMP
O
PMP
PMP
11(+)
12(+)
9(+)
10(+)
TIPSO
O
CF3
TIPSO
O
CF3
HO
O
CF3
iii
ii
N
N
N
PMP
H
PMP
2.3. Synthesis of enantiopure 1-acyl-3-hydroxy-4-Rf-b-
lactams
12(-)
11(-)
9(-)
80% in 2 steps
i) KOH, THF, -5oC; ii) TIPSCl, Et3N, CH2Cl2; iii) CAN, CH3CN/H2O, -10 ºC.
As it has been well documented [52], the b-Lactam
Synthon Method is exploiting the unique nature of this
four-membered cyclic amide with ring strain for its facile
ring-opening reactions [53]. When the nitrogen of this
strained cyclic amide is acylated (including carbalkoxy,
carbamoyl, thiocarbamoyl, and sulfonyl groups besides
the standard acyl groups), the resulting b-lactam ring
becomes highly activated for nucleophilic attacks. We and
others have been successfully exploiting this unique feature
of N-acyl-b-lactams in organic syntheses and medicinal
chemistry [53]. Scheme 7 illustrates readily available pos-
sible N-acyl-b-lactams through N-acylation of NH-free
3-PO-4-Rf-b-lactams (P ¼ hydroxyl protecting group).
Scheme 5.
(3R,4R)-3-TIPSO-4-CF3-b-lactam 12(þ) and (3S,4S)-3-
TIPSO-4-CF3-b-lactam 12(À) in a manner similar to that
described for the preparation of 3-TIPSO-4-CF2H-b-lactams
6(þ) and 6(À) (vide supra) (Scheme 5).
We also investigated another route to enantiopure b-
lactams 12(þ) and 12(À) as well as an efficient route to
enantiopure
3-hydroxy-4-CF3-azetidin-2-one
(14(À))
through enzymatic optical resolution of racemic cis-3-acet-
oxy-4-CF3-azetidin-2-one (13(Æ)), which was readily
obtained by the removal of the PMP group from racemic
b-lactam 10(Æ) with CAN. Gratifyingly, we found that the
enzymatic resolution of b-lactam 13(Æ) using the ‘‘PS-
Amano’’ lipase proceeded much faster than that of N-
PMP-b-lactam 10(Æ), i.e., the 50% conversion was reached
in 8 h at 3 8C to give (þ)-3-AcO-4-CF3-b-lactam 13(þ)
as well as (À)-3-hydroxy-4-CF3-azetidin-2-one (14(À))
without the ring-opening over-reaction (Scheme 6). It
was further found that (À)-b-lactam (14(À)) was stable
even at 25 8C under the reaction conditions. This makes
a sharp contrast to the labile nature of the corresponding
PO
O
Rf
N
NHR
PO
O
Rf
PO
O
Rf
O
N
NR1R2
N
ClCO2R
base
O
RN=C=O
R
O
O
ClCONR1R2
base
PO
O
Rf
N
H
RCOCl
base
RN=C=S
PO
Rf
PO
Rf
RSO2Cl
base
AcO
O
CF3
H
AcO
O
CF3
H
HO
O
CF3
H
N
N
R
NHR
PS-Amano
O
O
PO
O
Rf
+
N
N
buffer pH 7.0
10% CH3CN
N
O
S
N
R
S
A: 3 ºC, 8 h
B: 25 ºC, 1 h
cis-13(±)
13(+)
14(-)
O
O
Scheme 6.
Scheme 7.

L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
491
Table 2
Syntheses of N-acy1-3-TIPSO-4-Rf-b-lactams
Entry
NH-b-lactam
Configuration
Rf
Condition
N-Acyl-b-lactam
R
Yield (%)
1
2
3
4
5
6
7
6(À)
3S,4S
3S,4S
3S,4S
3S,4S
3R,4R
3R,4R
3R,4R
CF2H
CF2H
CF2H
CF2H
CF3
i
15a(À)
15b(À)
15c(À)
15d(À)
16a(þ)
16b(þ)
16c(þ)
t-Boc
Cbz
80
60
66
54
87
60
15
6(À)
i
6(À)
i
Tosyl
4-F-Bz
t-Boc
Cbz
6(À)
i
14(þ)
14(þ)
14(þ)
i
CF3
ii
ii
CF3
Tosyl
Table 2 lists a series of N-acyl-3-TIPSO-3-Rf-b-lactams
15 (Rf ¼ CF2H) and 16 (Rf ¼ CF3) prepared through acyla-
tion, including carbalkoxylation and sulfonylation, of
3-TIPSO-4-CF2H-azetidin-2-one (6(À)) and 3-TIPSO-4-
CF3-azetidin-2-one (12(þ)) as examples (t-Boc ¼ t-butoxy-
carbonyl; Cbz ¼ carbobenzoxy; Ts ¼ p-toluenesulfonyl;
yields are not optimized).
2.5. Synthesis of CF2H- and CF3-containing dipeptides
through ring-opening coupling of N-acyl-b-lactams with
amino acid esters
We carried out the ring-opening coupling of (3S,4S)- and
(3R,4R)-N-acyl-b-lactams, 15 and 16, with various (S)-a-
amino acid methyl esters, glycine methyl ester, and b-
alanine ethyl ester, which were generated in situ from the
corresponding hydrochlorides in dichloromethane in the
presence of N-methylmorpholine (NMM). Since these cou-
pling reactions do not need any peptide coupling reagents
such N,N-dicyclohexylcarbodiimide (DCC) and N,N-diiso-
propylcarbodiimide (DIC), the ‘‘atom economy [54] is
extremely high. The reactions gave the corresponding Rf-
containing dipeptides, 19–22, in good to quantitative yields.
Results are summarized in Table 4.
2.4. Synthesis of enantiopure CF2H- and CF3-containing
a-hydroxy-b-amino acid methyl esters
Enantiopure a-hydroxy-b-amino acid methyl esters bear-
ing a CF2H group or a CF3 group at the C-3 position, 17
(Rf ¼ CF2H) or 18 (Rf ¼ CF3), were readily synthesized
through a facile methanolysis of N-acyl-3-TIPSO-4-Rf-b-
lactams, 15 or 16, in the presence of triethylamine and a
catalytic amount of 4-(N,N-dimethylamino)pyridine
(DMAP) at ambient temperature in good to quantitative
yields. Results are summarized in Table 3 (yields are not
optimized).
As Table 4 shows, the rate and yield of the coupling
reaction highly depends on the bulkiness of amino acid
esters. N-Tosyl-4-CF2H-b-lactam 15c (entries 4-7) and
N-(4-F-benzoyl)-4-CF2H-b-lactam 15d (entry 8) are highly
Table 3
Syntheses of CF2H- and CF3-containing a-hydroxy-b-amino acid methyl esters
Entry
b-Lactam
Configuration
Rf
R
b-Rf-a-TIPSO-b-amino ester
Configuration
Yield (%)
1
2
3
4
5
6
15a(À)
15b(À)
15c(À)
16a(þ)
16b(þ)
16c(þ)
3S,4S
3S,4S
3S,4S
3R,4R
3R,4R
3R,4R
CF2H
CF2H
CF2H
CF3
t-Boc
Cbz
17a(À)
17b(À)
17c(À)
18a(þ)
18b(þ)
18c(þ)
2S,3S
2S,3S
2S,3S
2R,3R
2R,3R
2R,3R
98
78
Tosyl
t-Boc
Cbz
87
70
CF3
58
CF3
Tosyl
100

492
L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
Table 4
Ring-opening coupling of N-acyl-b-lactams with amino acid esters
Entry
b-Lactam
Configuration
Rf
R
Amino ester
Reaction time (h)
Dipeptide
Isolated yield (%)
1
2
15a(À)
15a(À)
15a(À)
15c(À)
15c(À)
15c(À)
15c(À)
15d(À)
16b(þ)
16b(þ)
3S,4S
3S,4S
3S,4S
3S,4S
3S,4S
3S,4S
3S,4S
3S,4S
3R,4R
3R,4R
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
CF3
t-Boc
t-Boc
t-Boc
Tosyl
Tosyl
Tosyl
Tosyl
4-F-Bz
Cbz
(S)-Phe-OMe
Gly-OMe
24
18
18
12
12
12
12
12
96
48
19a
19b
21a
19c
19d
19e
19f
No reaction
62
50
3
b-Ala-OEt
4
(S)-Val-OMe
(S)-Leu-OMe
(S)-Met-OMe
(S)-Phe-OMe
(S)-Phe-OMe
(S)-Phe-OMe
b-Ala-OEt
82
5
94
6
89
83
7
8
19g
20a
22b
100
65
9
10
CF3
Cbz
65
reactive, giving the corresponding dipeptides in high yields
regardless of the bulkiness of the amino acid esters used. N-t-
Boc-4-CF2H-b-lactam 15a and N-Cbz-4-CF3-b-lactam 16b
are modestly reactive. Thus, the reactions of these b-lactams
are very sensitive to the bulkiness of the amino acid esters
employed. In a publication from our laboratory, we have
reported that the bulkiness of the hydroxyl group of N-acyl-
3-hydroxy-4-substituted-b-lactams imposes significant
effects on the reactivity of the b-lactam in the ring-opening
coupling with a-amino acid esters, i.e., the N-t-Boc-b-lac-
tams with free hydroxyl group at C-3 is the most reactive,
followed by t-Boc group as the hydroxyl protecting group,
and TIPS group is the worst [55]. Accordingly, it is surely
anticipated that the reactivity of these N-acyl-4-Rf-b-lac-
tams would increase substantially by using a free hydroxyl
group or a less bulky acyl group than TIPS, such as acetyl,
Cbz and t-Boc, as the hydroxyl protection group at C3.
On the basis of the results presented in Table 4 as well as
our previous works [55,56], we can readily envision the
versatile utility of the N-acyl-3-PO-4-Rf-lactams (P ¼
hydroxyl protecting group) for the syntheses of Rf-contain-
ing dipeptides, depsipeptides, peptidomimetics, and key
synthetic building blocks for Rf-containing hydroxyethy-
lene, dihyroxylethylene, and hydroxyethylamine dipeptide
isosteres. Scheme 8 exemplifies the possible transformations
of N-t-Boc-3-PO-4-Rf-lactams.
anticancer agents [50,57], we applied the ring-opening
coupling of (3R,4R)-N-t-Boc-3-TIPSO-4-Rf-b-lactams,
15a and 16a, with baccatins for the syntheses of two new
fluoro-taxoids.
Thus, the reactions of (3R,4R)-N-t-Boc-3-TIPSO-4-
CF2H-b-lactam 15a and (3R,4R)-N-t-Boc-3-TIPSO-4-CF3-
b-lactam 16a with 2-debenzoyl-2-(3-chlorobenzoyl)-10-
deacetyl-10-propanyl-baccatin (23) and with 2-debenzoyl-
2-(3-azidobenzoyl)-10-deacetyl-10-propanoylbaccatin (24),
respectively, were carried out in the presence of LiHMDS as
the base in THF at À40 8C. The subsequent removal of the
silyl protecting groups by HF/pyridine gave the correspond-
ing new fluoro-taxoids 25 and 26 in fairly good overall yields
(Scheme 9).
Cytotoxicity of the two new fluoro-taxoids were evaluated
in vitro against two human breast cancer cell lines and the
corresponding drug-resistant cell lines. The IC50 values were
determined through 72 h exposure of the fluoro-taxoids to
R
f
2
2
R
R
f
O
R
f
O
R
3
R
OCO-NH
3
3
3
COOR
*
R
OCO-NH
N
H
COO–Resin
*
R
OCO-NH
N
O
1
H
OR
OH
R
f
R
f
O
3
CHO
3
COOR
R
OCO-NH
3
R OCO-NH
N
H
O
OH
2
R
R
f
O
R
f
O
3
COOR
1
3
3
*
R
O
R
R
OCO-NH
OCO-NH
3
N
H
COOR
f
3
*
R
OCO-NH
OH
2
OH
R
N
R
f
O
R
f
O
O
COOR
3
COOR
3
3
*
R
N
H
COOR
3
R
OCO-NH
2
OH
R
OH
R
f
R
f
O
2.6. Synthesis of CF2H- and CF3-containing taxoid
anticancer agents through ring-opening coupling of
N-acyl-b-lactams with baccatins
3
O
COOR
3
COOR
3
*
R
OCO-NH
S
R
OCO-NH
N
4
OH
NHCOOR
OH
R
R
f
f
O
O
3
R
COOR
f
3
O
COOR
3
3
3
*
R
OCO-NH
N
H
COOR
R
OCO-NH
O
3
R
OCO-NH
N
N
4
OH
4
OH
NHCOOR
NHCOOR
OH
As a part of our continuing work on the synthesis and
structure-activity relationship study (SAR) of fluoro-taxoid
Scheme 8.

L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
493
O
O
In conclusion, practical methods for the syntheses of
enantiopure N-acyl-3-hydroxy-4-Rf-b-lactams (Rf ¼ CF2H,
CF3) have been successfully developed by means of [2 þ 2]
ketene-imine cycloaddition, followed by enzymatic optical
resolution, N-acylation (including carbamoylation and sulfo-
nylation as well), and other manipulations. Facile methano-
lysis of these enantiopure N-acyl-3-hydroxy-4-Rf-b-lactams
gave the corresponding Rf-containing a-hydroxy-b-amino
acid methyl esters in good to quantitative yields. Ring-
opening coupling of these b-lactams with amino acid esters
and baccatins afforded the corresponding Rf-containing
dipeptides and taxoids, respectively in good overall yields.
The two new fluoro-taxoids synthesized exhibited excellent
cytotoxicity against human breast cancer cell lines, espe-
cially against the drug-resistant cell lines, MCF7-R and
LCC6-MDR, which were two orders of magnitude more
potent than paclitaxel. On the basis of the results described
above, we can easily envision the wide applicability of
enantiopure N-acyl-3-hydroxy-4-Rf-b-lactams for the synth-
eses of Rf-containing bioactive compounds. Further studies
on the applications of fluorine-containing b-lactams coupled
with the b-Lactam Synthon Method (b-LSM) are actively
underway in these laboratories.
TIPSO
O
CF H
2
O
OTES
N
Boc
15a(+)
(1.8 equiv.)
O
HO
i. 92%
OAc
O
O
HO
ii. 75%
O
Cl
23
O
O
OH
O
O
NH
O
O
HF C
2
O
OAc
O
O
HO
OH
25
Cl
O
O
TIPSO
OTES
CF
3
O
N
O
Boc
16a(+)
(1.8 equiv.)
O
HO
i. 96%
OAc
O
O
HO
ii. 84%
O
N
24
3
O
O
OH
O
O
NH
O
3. Experimental
O
F C
3
O
OAc
O
O
HO
OH
26
3.1. General method
N
3
NMR spectra were recorded on a Bruker AC-250 NMR
spectrometer or a Varian 300 NMR spectrometer or Varian
400 NMR spectrometer using tetramethylsilane as the inter-
nal standard. 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 on
silica gel 60 (Merck; 230–400 mesh ASTM). Chiral HPLC
analysis for the determination of enantiomeric excess was
carried out with a Waters HPLC assembly consisting
of a Waters M45 solvent delivery system, A Waters
Model 680 gradient controller, and a Waters M440 detector
(at 254 nm), using a DAICEL-CHIRACEL OD chiral col-
umn (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
o
i) LiHMDS, THF, -40 C; ii) HF/Py, Py/CH CN, 25 uC.
3
Scheme 9.
the cancer cells by means of the method developed by
Skehan et al. [58]. As Table 5 shows, the new fluoro-taxoids,
25 and 26, possess more than two orders of magnitude higher
cytotoxicity than paclitaxel against the drug-resistant cell
lines, MCF7-R and LCC6-MDR, and several times higher
potency than paclitaxel against the drug-sensitive cell lines,
MCF7-S and LCC6-WT. Thus, these two fluro-taxoids are
highly promising additions to the arsenal of the ‘‘second-
generation taxoid anticancer agents’’, and warrant further
evaluations in vivo.
Table 5
In vitro cytotoxicity (IC50 nM)a of fluoro-taxoids
Taxoid
MCF7-S
(breast)
MCF7-R
(breast)
R/Sb
LCC6-WT
(breast)
LCC6-MDR
(breast)
R/Sb
H460
HT-29
(ovarian)
(colon)
Paclitaxel
1.8
0.6
0.4
484
6.4
2.6
269
11
3.4
0.6
1.2
216
3.1
1.6
64
5.5
0.3
0.2
3.6
0.5
0.4
25
26
5.2
1.3
6.5
a The concentration of compound which inhibits 50% (IC50) of the growth of the human tumor cell line after 72 h drug exposure.
b R/S ¼ drug-resistance factor ¼ IC50 (drug-resistant cell line)/IC50 (drug-sensitive cell line).

494
L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
1.0 ml/min. HPLC analysis for determination of isomeric
ratio was carried out with the same Water HPLC assembly
using 5 m Spherical Silica column employing hexane/2-
propanol/dichloromethane (15/1/1, v/v/v) as the solvent
system with a flow rate 1.0 ml/min, or hexane/2-propanol/
dichloromethane (10/1/1, v/v/v) as the solvent system with a
flow rate 1.4 ml/min. Elemental analysis were performed
at M-H-W Laboratory, Phoenix, AZ. High resolution
mass spectra were obtained from the Mass Spectrometry
Laboratory, University of Illinois at Urbana-Champaign,
Urbana, IL.
conditions except for the longer reaction time (40 h) and less
amount of the ‘‘PS-Amano’’ lipase (10 g), 8.104 g (45%/
50% in theory) of (3R,4S)-3-AcO-b-lactam 2(þ) (>99% ee)
and 5.344 g (34%/50% in theory) of (3R,4S)-3-hydroxy-b-
lactam 3(À) (96% ee) were obtained.
3.4. 1-(4-Methoxyphenyl)-3-acetoxy-4-
trifluoromethylazetidin-2-one (10(Æ))
To a solution of (500 mg, 4.1 mmol) 4-dimethylamino-
pyridine (DMAP), 3.4 ml of pyridine, and (3.42 g,
13.1 mmol) of racemic 3-hydroxy-b-lactam 9(Æ) in 6 ml
of CH2Cl2, was added dropwise (2.24 ml, 23.76 mmol)
acetic anhydride. The mixture was stirred overnight at
RT. The reaction mixture was then poured into a mixture
of 140 ml 6N HCl, 210 ml of ice, and 430 ml ether. The
organic layer was washed with 2N HCl and the combined
aqueous layers extracted with ether. The combined organic
layers were washed with saturated aqueous NaHCO3 and
dried over MgSO4, filtered, and concentrated in vacuo to
3.2. Materials
The chemicals were purchased from Aldrich and Sigma
and purified before use by standard methods. Tetrahydro-
furan was freshly distilled under nitrogen from sodium
metal and benzophenone. Dichloromethane was distilled
immediately prior to use under nitrogen from calcium
hydride. 1-(4-Methoxyphenyl)-3-acetoxy-4-(2-methyl-1-
propenyl)azetidin-2-one (2(Æ)) [48], 1-(4-methoxyphenyl)-
3-triisopropylsiloxy-4-formylazetidin-2-one (5(þ)) [50],
1-(4-methoxyphenyl)-3-benzyloxy-4-trifluoromethyla-
zetidin-2-one (10(Æ)) [51,59], 1-(4-methoxyphenyl)-3-
hydroxy-4-trifluoromethylazetidin-2-one (9(Æ)) [51],
2-debenzoyl-2-(3-chlorobenzoyl)-7-triethylsilyl-10-dea-
cetyl-10-propanoylbaccatin III (23) [60], and 2-debenzoyl-2-
(3-azidobenzoyl)-7-triethylsilyl-10-deacetyl-10-propanoyl-
baccatin III (24) [60] were prepared by the previously
reported methods.
1
afford 2.9 g (74%) of the product 10 as a white solid: H
NMR (300 MHz, CDCl3): d 2.19 (s, 3H), 3.97 (s, 3H),
4.74 (q, J ¼ 5:1 Hz, 1H), 6.17 (d, J ¼ 5:4 Hz, 1H), 6.09
(d, J ¼ 9:0 Hz, 2H), 6.39 (d, J ¼ 9:0 Hz, 2H); 19F NMR
(282 MHz, CDCl3): d À69.6 (d, J ¼ 6:2 Hz).
3.5. (3R,4R)-1-(4-Methoxyphenyl)-3-acetoxy-4-
trifluoromethylazetidin-2-one (10(þ))
A solution of (431 mg, 1.42 mmol) 3-acetoxy-b-lactam in
4 ml of CH3CN and 20 ml of buffer solution at pH7 (653 mg,
4.8 mmol of KH2PO4 and 540 mg, 3.1 mmol of K2HPO4)
was added 431 mg of PS-Amano at 3 8C. The reaction was
monitored by NMR to reach a 1:1 ratio of products. After the
reaction mixture was filtrated and extracted with ethyl ether
several times, dried over MgSO4 and concentrated. The
crude material was purified by flash chromatography to give
194 mg of 10(þ) as white solid in 45% (50% in theory)
yeild: 1H NMR (300 MHz, CDCl3): d 2.19 (3H, s), 3.97 (3H,
s), 4.74 (1H, q, J ¼ 5:1 Hz), 6.17 (1H, d, J ¼ 5:4 Hz),
6.09 (2H, d, J ¼ 9:0 Hz), 6.39 (2H, d, J ¼ 9:0 Hz); 19F
NMR (282 MHz, CDCl3): d À69.6 (d, J ¼ 6:2 Hz), MS
(FABþ, m/z): Calcd. for C13H12F3NO4Hþ, 304.07; Found,
303.9%.
3.3. (3S,4R)-1-(4-Methoxyphenyl)-3-acetoxy-4-(2-methyl-
1-propenyl)azetidin-2-one (2)
To 90.2 mg of racemic 1-(4-methoxyphenyl)-3-acetoxy-
4-(2-methyl-1-propenyl)azetidin-2-one (2(Æ)) suspended in
3.6 ml of 0.2 M sodium phosphate buffer (pH ¼ 7:5) and
0.4 ml of acetonitrile was added 80 mg of the ‘‘PS Amano’’
lipase, and the mixture was vigorously stirred at 50 8C. After
22 h, the 1H NMR showed the conversion of the reaction was
50%. The reaction mixture was filtered through Celite and
extracted with CH2Cl2 (10 ml 3Â). The combined organic
layers were dried over MgSO4 and concentrated in vacuo.
The residue was purified by chromatography on silica
gel (hexanes/EtOAc ¼ 4/1) to give (3R,4S)-1-(4-methoxy-
phenyl)-3-acetoxy-4-(2-methyl-1-propenyl)azetidin-2-one
(2(þ)) (42.1 mg, 47% yield, 96.6% ee) and (3S,4R)-1-
(4-methoxyphenyl)-3-hydroxy-4-(2-methyl-1-propenyl)-
azetidin-2-one (3(À)) (37.1 g, 47% yield, 99.8% ee).
The enantiopurity of the b-lactams was determined by
chiral HPLC at the OH-b-lactam stage using a DAICEL-
CHIRACEL OD chiral column (25 cm  0:46 cm i.d.),
employing hexane/2-propanol (97/3, v/v) as the solvent
system with a flow rate of 1.0 ml/min.
3.6. (3R,4R)-1-(4-Methoxyphenyl)-3-hydroxy-4-
trifluoromethylazetidin-2-one (9(þ))
To a solution of b-lactam 10 (1.19 g, 3.94 mmol) in 79 ml
of THF was added 1 M aqueous solution of potassium
hydroxide (11.8 ml, 11.8 mmol) and the mixture was stirred
for 1.5 h at 3 8C. The reaction was quenched with aqueous
saturated NH4Cl solution (30 ml), and the aqueous layer was
extracted with EtOAc (60 ml 3Â). The combined extracts
were washed with brine, dried over anhydrous MgSO4 and
concentrated in vacuo to afford a white solid (982 mg,
When this process was carried out in a large scale using
18.13 g of racemic 3-AcO-b-lactam (2(þ)), under the same

L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
495
1
95% yield): H NMR (300 MHz, CDCl3): d 3.43 (bd) 3.80
combined organic layers were washed with water and
saturated Na2SO3 to afford 13(Æ) (519 mg, 75%): 1H
NMR (300 MHz, CDCl3): d 2.17 (3H, s), 4.35 (1H,
q, J ¼ 6:0 Hz), 6.05 (1H, dd, J ¼ 1:5, 4.5 Hz), 7.37
(1H, bs).
(3H, s), 4.62 (1H, dq, J ¼ 5:4 Hz), 5.27 (1H, d, J ¼ 5:4 Hz),
6.88 (2H, d, J ¼ 9:0 Hz), 7.40 (2H, d, J ¼ 9:0 Hz); 19F
NMR (282 MHz, CDCl3): d À68.9 (d, J ¼ 6:2 Hz), MS
(FABþ, m/z): Calcd. for C11H10F3NO3Hþ, 262.06; Found,
261.98.
3.10. (3R,4R)-3-Acetoxy-4-trifluoromethylazetidin-
2-one (13(þ))
3.7. (3R,4R)-1-(4-Methoxyphenyl)-3-triisopropylsiloxy-4-
trifluoromethylazetidin-2-one (11)
To a solution of (400 mg, 1.42 mmol) 3-acetoxy-b-lactam
13(Æ) in 4 ml of CH3CN and 20 ml of buffer solution at pH7
(653 mg, 4.8 mmol of KH2PO4 and 540 mg, 3.1 mmol of
K2HPO4) was added 431 mg of PS-Amano at 3 8C. The
reaction was monitored by NMR. The reaction mixture was
filtrated and extracted with ethyl ether several times, dried
over MgSO4 and concentrated. The crude product was
purified by flash chromatography on silica gel to give
To a solution of 982 mg (3.8 mmol) of 9, 2.4 ml
(15.2 mmol) of triethylamine, and 100 mg of DMAP in
76 ml CH2Cl2, was added 1.6 ml (7.5 mmol) of TIPSCl at
room temperature. The reaction mixture was stirred for
18 h and quenched with water. The reaction mixture was
diluted with 300 ml EtOAc and the organic layer was
washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The crude material was purified
by flash chromatography on silica gel to yield 11 (1.59 g,
100%): 1H NMR (300 MHz, CDCl3): d 1.04–1.42 (21H, m)
3.79 (3H, s), 4.58 (1H, q, J ¼ 5:4 Hz), 5.27 (1H, d,
J ¼ 4:8 Hz), 6.87 (2H, d, J ¼ 9:0 Hz), 7.40 (2H, d,
J ¼ 9:0 Hz); 13C NMR (75.5 MHz, CDCl3): d 12.1, 17.9,
18.0, 55.7, 58.3 (q, J ¼ 31:8 Hz, CF3), 76.3, 114.7,
119.5, 130.1, 157.3, 165.6; 19F NMR (282 MHz, CDCl3):
d À68.7 (d, J ¼ 6:2 Hz), MS (FABþ, m/z): Calcd. for
C20H30F3NO3SiÁHþ, 418.19; Found, 418.09.
1
13(þ) as a white solid in 45% (50% in theory) yield; H
NMR (300 MHz, CDCl3): d 2.17 (3H, s), 4.35 (1H, q,
J ¼ 6:0 Hz), 6.05 (1H, dd, J ¼ 1:5, 4.5 Hz), 7.37 (1H, bs);
13C NMR(100 MHz, CDCl3):d 20.1, 53.5(q, J ¼ 31, 63 Hz),
73.8, 125.0 (q, J ¼ 277, 553 Hz), 164.7, 169.0, MS
(FABþ, m/z): Calcd. for C6H6F3NO3Hþ, 198.03; Found,
197.97.
3.11. (3R,4R)-3-Hydroxy-4-trifluoromethylazetidin-
2-one (14(þ))
3.8. (3R,4R)-3-Triisopropylsiloxy-4-trifluoromethyl-
azetidin-2-one (12)
Yield 43% (50% in theory); 1H NMR (400 MHz,
CD3COCD3): d 4.32 (1H, m), 5.24 (1H, m), 5.75 (1H, d,
J ¼ 8:0 Hz), 7.92 (1H, bs); 13C NMR (100 MHz,
CD3COCD3): d 54.3 (q, J ¼ 31, 63 Hz), 77.5, 125.0
(q, J ¼ 277, 553 Hz), 169.2.
To a solution (825 mg, 1.96 mmol) of (þ)-cis-l-(4-metho-
xyhenyl)-3-TIPS-4-trifluoromethyl-azetidin-2-one 11
(825 mg, 1.96 mmol) in 60 ml of acetonitrile at À10 8C
was slowly added a solution of cerium ammonium nitrate
(4.3 g, 7.9 mmol) in 60 ml of water over a 2 h period. The
mixture was stirred for additional 30 min at À10 8C and
diluted with 20 ml of ether. The aqueous layer was extracted
with two 20 ml portions of ether, and the combined organic
layers were washed with water and saturated Na2SO3 to
3.12. (3S,4S)-1-(tert-Butoxycarbonyl)-3-triisopropylsiloxy-
4-difluoromethylazetidin-2-one (15a(À))
To a solution of NH-b-lactam 6(À) (1.0 g, 3.4 mmol),
di-tert-butyldicarbonate (890 mg, 4.08 mmol), and DMAP
(207 mg, 1.7 mmol) in 20 ml of dichloromethane triethyl-
amine (1.42 ml, 10.2 mmol) was added dropwise at room
temperature. The mixture was stirred for 3 h and the reaction
was quenched with a saturated solution of NH4Cl. The
aqueous layer was extracted with dichloromethane the
combined organic layers were treated with brine and
MgSO4. After evaporation of the solvent in vacuo, the crude
product was purified on a silica gel column with hexane
ethyl acetate (6:1) to afford the 15a as white solid (1.08 g,
1
afford 12 (519 mg, 84%): H NMR (300 MHz, CDCl3): d
1.13–1.26 (21H, m), 4.17 (1H, q, J ¼ 5:1 Hz), 5.87 (1H, dd,
J ¼ 1:5, 4.7 Hz) 6.70 (1H, bs); 13C NMR (75.5 MHz,
CDCl3): d 12.1, 17.7, 17.8, 55.2 (q, J ¼ 32:7 Hz, CF3),
76.9, 165.0; 19F NMR (282 MHz, CDCl3): d À72.2
(d, J ¼ 7:3 Hz).
3.9. 3-Acetoxy-4-trifluoromethylazetidin-2-one (13(Æ))
1
80%). H NMR (300 MHz, CDCl3): d 1.21 (21H, m), 1.5
To a solution of 3-AcO-4-trifluoromethylazetidin-2-one
(2.8 g, 9.2 mmol) in 385 ml of acetonitrile at À10 8C was
slowly added a solution of cerium ammonium nitrate
(19.2 g, 35 mmol) in 386 ml of water over a period of
2 h. The mixture was stirred for addition 30 min at
À10 8C and diluted with 20 ml of ether. The aqueous layer
was extracted with two 20 ml portions of ether, and the
(9H, s), 4.30 (1H, m), 5.15 (1H, dd, J ¼ 0:9, 6.3 Hz),
6.04 (1H, ddd, J ¼ 55, 54, 5 Hz, CF2H); 13C NMR
(75.5 MHz, CDCl3): d 12.0, 17.8, 28.1, 57.6 (dd, J ¼ 21,
30 Hz), 76.3, (d, J ¼ 4:5 Hz, CF2H), 84.5, 113.8 (t,
J ¼ 242 Hz, CF2H), 147.8, 165.0; 19F NMR (282 MHz,
CDCl3): d À122.0 (ddd, J ¼ 295, 52, 9 Hz), À127.0 (ddd,
J ¼ 298, 55, 9 Hz).

496
L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
3.13. (3S,4S)-1-Benzyloxycarbonyl-3-triisopropylsiloxy-4-
difluoromethyazetidin-2-one (15b(À))
(2 ml, 2 mmol). The reaction mixture was allowed to stir
for 30 min then of CbzCl (0.155 ml, 1.03 mmol) was added.
After 1 h the reaction was quenched with water and
extracted with ethyl acetate three times. The crude material
was purified by flash chromatography on silica gel to give
274 mg 16b(þ) in 60% yield as yellow oil: 1H NMR
(400 MHz, CDCl3): d 1.01–1.23 (21H, m), 4.55 (1H, q,
J ¼ 4:8 Hz), 5.28 (3H, m), 7.34 (5H, m).
Yield 60%; 1H NMR (400 MHz, CDCl3): d 1.10 (21H, m),
1.5 (s, 9H), 4.30 (1H, m), 5.15 (1H, d, J ¼ 0:6 Hz), 5.28 (2H,
m), 6.04 (ddd, J ¼ 55, 54, 5 Hz, 1H, CF2H). 7.4 (5H, m); 13
C
NMR (75.5 MHz, CDCl3): d 12.0, 17.8, 57.6 (dd, J ¼ 21,
30 Hz), 68.9, (t, J ¼ 179 Hz, CF2H), 84.5, 113.8 (t,
J ¼ 244 Hz, CF2H), 122.6, 122.2, 128.3, 128.6, 128.7,
128.8, 128.9, 129.0, 134.8, 140.1, 164.5.
3.18. (3R,4R)-1-(4-Methylbenzenesulfonyl)-3-
triisopropylsiloxy-4-trifluoromethylazetidin-2-one (16c(þ))
3.14. (3S,4S)-1-(4-Methylbenzenesulfonyl)-3-
triisopropylsiloxy-4-difluoromethyazetidin-2-one (15c(À))
1
Yield 15%; H NMR (300 MHz, CDCl3): d 0.87–1.12
(21H, m), 3.66 (3H, s), 4.46 (1H, q, J ¼ 5:2 Hz), 5.14 (1H, d,
20
Yield 66%; ½aŠ
À 85:7ꢀ (c 0.84, CHCl3); 1H NMR
J ¼ 5:1 Hz), 6.75 (2H, d, J ¼ 9 Hz), 6.28 (2H, d, J ¼ 9 Hz).
D
(CDCl3, 300 MHz): d 7.89 (2H, d, J ¼ 8:4 Hz), 7.34 (2H,
d, J ¼ 8:4 Hz), 5.83 (1H, ddd, J ¼ 4:8, 54 Hz), 5.22 (1H, d,
J ¼ 6 Hz), 4.51–4.46 (1H, m), 2.43 (3H, s), 1.15–1.01 (21H,
m); 13C NMR (CDCl3, 75.5 MHz): 163.9, 145.81, 135.5,
130.1, 128, 113.4 (dd, J ¼ 244 Hz), 76.8, 60 (dd, J ¼ 20:6,
29.8 Hz), 22, 17.8, 12; 19F NMR (282 MHz, CDCl3): d
À121.9 (ddd, 1F, J ¼ 6:2, 51.9, 295.6 Hz),À125.2 (ddd,
1F, J ¼ 9:3, 55, 296.9 Hz). HRMS (FABþ, m/z): Calcd.
for C20H31F2NO4SSiÁHþ, 448.1784. Found: 448.1794.
3.19. (2S,3S)-3-(N-tert-Butoxycarbonylamino)-4,4-
difluoro-2-triisopropylsiloxybutanoic acid methyl ester
(17a(À))
A
mixture of t-Boc-b-lactam 15a(À) (37 mg,
0.094 mmol), triethylamine (21 ml, 0.15 mmol) and a cata-
lytic amount of DMAP (8 mg, 0.065 mmol) in methanol
(1 ml) was stirred for 30 h. Methanol was evaporated and the
crude product was purified by flash chromatography on
silica gel to afford 17a(À) as colorless oil (39 mg, 98%
3.15. (3S,4S)-1-(4-Fluorobenzoyl)-3-triisopropylsiloxy-4-
difluoromethyazetidin-2-one (15d(À))
20
yield); [a]D þ21.88 (c 1.375, CHCl3); IR (neat): n 3440,
2940, 2867, 1760, 1720, 1490; 1H, NMR (400 MHz,
CDCl3): d 1.10 (21H, m), 1.40 (9H, s), 3.70 (3H, s), 4.3
(1H, bd, J ¼ 10 Hz), 4.66 (1H, s), 5.07 (1H, bd, J ¼ 10 Hz),
5.82 (1H, dt, J ¼ 56, 4 Hz, CF2H); 13C NMR (100 MHz,
CDCl3): d 12.7, 18.2, 28.5, 52.6, 55.7 (t, J ¼ 24 Hz, C-3),
70.5, 80.6, 114.2 (t, J ¼ 243 Hz, CF2H), 155.3, 171.3; 19F
NMR (282 MHz, CDCl3): d À126.4 (ddd, J ¼ 287, 56,
9 Hz), À130.0 (ddd, J ¼ 284, 56, 9 Hz). HRMS (FABþ,
m/z): Calcd. for C19H37F2NO5SiÁHþ, 426.2482. Found:
426.2492.
20
Yield 54%; ½aŠ
À 53:4ꢀ (c 0.58, CHCl3); 1H NMR
D
(CDCl3, 250 MHz): d 1.24–1.07 (21H, m), 4.75–4.64
(1H, m), 5.21 (1H, d, J ¼ 6 Hz), 6.16 (1H, ddd, J ¼ 5,
55 Hz), 7.26–7.06 (2H, m), 7.99 (2H, dd, J ¼ 5, 7.5 Hz); 13
C
NMR (CDCl3, 75.5 MHz): d 12, 17.8, 22, 60 (dd, J ¼ 20:6,
29.8 Hz), 76.8, 113.4 (dd, J ¼ 244 Hz), 128, 130.1, 135.5,
145.81, 162.9, 163.5; 19F NMR (282 MHz, CDCl3): À103.9
(sl, 1F), À122.9 (ddd, 1F, J ¼ 12:1, 54.8, 298.9 Hz), À127.7
(ddd, 1F, J ¼ 5:9, 54.8, 298.9 Hz). HRMS (FABþ, m/z):
Calcd. for C20H28F3NO3SiÁHþ, 416.1864. Found: 416.1872.
3.20. (2S,3S)-3-(N-Benzyloxycarbonylamino)-4,4-difluoro-
2-triisopropylsiloxybutanoic acid methyl ester (17b(À))
3.16. (3R,4R)-1-(tert-Butoxycarbonyl)-3-
triisopropylsiloxy-4-trifluoromethylazetidin-2-one (16a(þ))
Yield 78%; colorless oil; IR (neat): n 3440, 3353, 2940,
2867, 1760–1710; 1H, NMR (400 MHz, CDCl3): d 1.10
(21H, m), 3.69 (3H, s), 4.38 (1H, m), 4.68 (1H, s), 5.10 (1H,
d, J ¼ 12 Hz), 5.14 (1H, d, J ¼ 12 Hz), 5.35 (1H, d,
J ¼ 10 Hz), 5.87 (1H, dt, J ¼ 56, 4.4 Hz, CF2H), 7.34
(5H, m); 13C NMR (100 MHz, CDCl3): d 12.7, 18.2, 52.6,
56.2 (t, J ¼ 24 Hz, C-3), 67.6, 70.4, 114.0 (t, J ¼ 243 Hz,
CF2H), 128.4, 128.6, 128.7,136.1, 155.9, 171.0.
20
Yield 87%; ½aŠ
þ 66:2ꢀ (c 1.51, CHCl3); 1H NMR
D
(300 MHz, CDCl3): d 1.12–1.22 (21H, m), 1.52 (9H, s),
4.48 (1H, q, J ¼ 5:7 Hz), 5.20 (1H, d, J ¼ 6:0 Hz); 13C
NMR (75.5 MHz, CDCl3): d 12.0, 17.7, 17.8, 28.1, 57.3 (q,
J ¼ 32:9 Hz, CF3), 76.4, 85.0, 164.9; 19F NMR (282 MHz,
CDCl3): d À70.0 (d, J ¼ 6:2 Hz). HRMS (FABþ, m/z):
Calcd. for C18H32F3NO4SiÁHþ, 412.2126. Found: 412.2128.
3.17. (3R,4R)-1-Benzyloxycarbonyl-3-triisopropylsiloxy-
4-trifluoromethylazetidin-2-one (16b(þ))
3.21. (2R,3R)-3-(N-4-Methylbenzenesulfonylamino)-4,4-
difluoro-2-triisopropylsiloxybutanoic acid methyl ester
(17c(À))
To
1.03 mmol) in 5 ml of THF under nitrogen atmosphere at
a
solution of N-H-b-lactam 14(þ) (322 mg,
1
Yield 87%, colorless oil; H NMR (CDCl3, 300 MHz):
1.18–1.06 (21H, m), 2.48 (3H, s), 3.67 (3H, s), 4.02–3.86
À78 8C was added dropwise 1 M solution of LiHMDS

L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
497
(1H, m), 4.64 (1H, sl), 5.49 (1H, d, J ¼ 9:3 Hz), 5.88 (1H,
dd, J ¼ 3:9, 55.5 Hz), 7.36 (2H, d, J ¼ 8:1 Hz), 7.82 (2H, d,
J ¼ 8:1 Hz); 13C NMR (CDCl3, 100 MHz): 12.3, 17.8, 21.5,
52.4, 57.7 (dd, J ¼ 23 Hz), 69.8, 113.5 (dd, J ¼ 245:8 Hz),
127.2, 129.6, 137.4, 143.7, 170.6; 19F NMR (282 MHz,
CDCl3): À125.3 (ddd, 1F, J ¼ 8:5, 53.6, 284 Hz),À129.0
(ddd, 1F, J ¼ 18:4, 55, 287 Hz).
0.15 mmol) at ambient temperature. The mixture was stirred
for 12 h. The reaction mixture was diluted with CH2Cl2 and
washed with saturated solution of NaHCO3. The organic
layer was dried over MgSO4, and concentrated in vacuo to
20
afford 30 mg of 19b in 62% yield as colorless oil: [a]D
À12.848 (c 1.635, CHCl3); IR (neat): n 3417, 2947, 2869,
1
1760–1693; H NMR (400 MHz, CDCl3): d 1.10 (18H, s),
1.12 (3H, m), 1.20 (9H, s), 3.78 (3H, s), 4.00 (1H, dd,
J ¼ 18, 5 Hz), 4.10 (1H, dd J ¼ 18, 5 Hz) 4.33 (1H, m), 4.40
(1H, d, J ¼ 4 Hz), 5.70 (1H, d, J ¼ 10 Hz), 5.93 (1H, m);
13C NMR (100 MHz, CDCl3): d 12.4, 18.2, 28.5, 41.2, 52.7,
55.2 (t, J ¼ 21 Hz), 71.5, 80.4, 113.8 (t, J ¼ 243 Hz, CF2H),
155.2, 169.6, 171.5; 19F NMR (282 MHz, CDCl3): À126.6
(ddd, J ¼ 286, 55, 9 Hz), À128.6 (ddd, J ¼ 286, 55, 18 Hz).
HRMS (FABþ, m/z): Calcd. for C21H40F2N2O6SiÁHþ,
483.2697. Found: 483.2703.
3.22. (2R,3R)-3-N-tert-Butoxycarbonylamino-4,4,4-
trifluoro-2-triisopropylsiloxybutanoic acid methyl
ester (18a(þ))
20
Yield 70% yield; colorless oil; [a]D À23.68 (c 1.99,
CHCl3); IR (neat): n 3446, 2947, 2869, 1766, 1732, 1496,
1
1161; H NMR (300 MHz, CDCl3): d 1.11–1.38 (21H, m),
1.50 (9H, s), 3.79 (3H, s), 4.69 (1H, q, J ¼ 8:1 Hz), 4.86
(1H, s), 5.26 (1H, d, J ¼ 10:5 Hz); 13C NMR (100 MHz,
CDCl3): d 12.8, 18.0, 28.3, 52.7, 55.1 (q, J ¼ 29:6 Hz, CF3),
70.2, 81.0, 122.9, 125.8, 155.1, 170.9; 19F NMR (282 MHz,
CDCl3): d À73.4 (d, J ¼ 7:3 Hz). HRMS (FABþ, m/z):
Calcd. for C19H36F3NO5SiÁHþ, 444.2388. Found: 444.2393.
3.26. [(2S,3S)-4,4-Difluoro-3-(4-methylbenzenesulfonyl-
amino)-2-triisopropylsiloxybutanoyl]-(S)-valine methyl
ester (19c)
1
Yield 82%; colorless oil H NMR (CDCl3, 400 MHz): d
3.23. (2R,3R)-3-N-Benzyloxycarbonylamino-4,4,4-
trifluoro-2-triisopropylsiloxybutanoic acid methyl ester
(18b(þ))
1.12–0.85 (27H, m), 2.19–2.13 (1H, m), 2.41 (3H, s), 3.72
(3H, s), 3.87–3.79 (1H, m), 4.15–3.91 (1H, m), 4.47–4.43
(1H, m), 5.87 (1H, dd, J ¼ 1:6, 54.8 Hz), 6.62 (1H, d,
J ¼ 8:4 Hz), 7.28–7.23 (3H, m), 7.79 (2H, d,
J ¼ 8:4 Hz); 13C NMR (CDCl3, 100.5 MHz): d 11.9,14.3,
17.8, 18.6, 21.6, 31, 52.2, 56.9 (dd, J ¼ 25 Hz), 60.4, 69.9,
113.1 (dd, J ¼ 244:8 Hz), 127.2, 129.5, 137.7, 143.5, 170.6,
171.1; 19F NMR (282 MHz, CDCl3): À126.2 to À126.5 (m,
2F). HRMS (FABþ, m/z): Calcd. for C26H44F2N2O6SSiÁHþ,
579.2730. Found: 579.2723.
20
Yield 58% yield; colorless oil; [a]D À19.48 (c 1.08,
CHCl3); IR (neat): n 3442, 2947, 2867, 1762, 1730, 1500,
1
1163; H NMR (400 MHz, CDCl3): d 1.04–1.17 (21H, m),
3.68 (3H, s), 4.69 (1H, q, J ¼ 8:2 Hz), 4.81 (1H, s), 5.12
(2H, s), 5.45 (1H, d, J ¼ 9:6 Hz), 7.30–7.39 (5H, m);
13C NMR (100 MHz, CDCl3): d 12.8, 18.0, 52.7, 55.3
(q, J ¼ 30:4 Hz), 67.8, 70.1, 128.3, 128.5, 128. 8, 136.1,
155.9, 170.7; 19F NMR (282 MHz, CDCl3): d À73.5
(d, J ¼ 7:1 Hz). HRMS (FABþ, m/z): Calcd. for
C22H34F3NO5SiÁHþ, 478.2231. Found: 478.2235.
3.27. [(2S,3S)-4,4-Difluoro-3-(4-methylbenzenesulfonyl-
amino)-2-triisopropylsiloxybutanoyl]-(S)-leucine methyl
ester (19d)
3.24. (2R,3R)-3-(N-4-Methylbenzenesulfonylamino)-4,4,4-
trifluoro-2-triisopropylsiloxybutanoic acid methyl ester
(18c(þ))
Yield 94%; colorless oil; 1H NMR (CDCl3, 400 MHz): d
1.03–089 (28H, m), 1.65–1.52 (2H, m), 2.4 (3H, s), 3.71
(3H, s), 3.85–3.81 (1H, m), 4.12–4.08 (1H, m), 4.58–4.51
(1H, m), 5.85 (1H, dd, J ¼ 54:4 Hz), 7.07 (1H, d,
J ¼ 8:4 Hz), 7.29 (2H, d, J ¼ 8:4 Hz), 7.79 (2H, d,
J ¼ 8:4 Hz); 13C NMR (CDCl3, 100 MHz): d 11.9, 17.8,
21.6, 21.9, 22.7, 24.8, 41.4, 50.4, 52.3, 57.2 (dd,
J ¼ 21:3 Hz), 69.8, 113 (dd, J ¼ 245:6 Hz), 127.2, 129.5,
137.7, 143.5, 170.4, 172.2; 19F NMR (282 MHz, CDCl3): d
À126.4 to À126.7 (m, 2F). HRMS (FABþ, m/z): Calcd. for
C27H46F2N2O6SSiÁHþ, 593.2887. Found: 593.2900.
20
100% yield; colorless oil; [a]D þ53.48 (c 0.88, CHCl3);
1
IR (neat): n 3440, 2945, 2867, 1768, 1514, 1249, 1139; H
NMR (400 MHz, CDCl3): d 1.04–1.27 (21H, m), 3.79 (3H,
s), 4.58 (1H, q, J ¼ 5:4 Hz), 5.27 (1H, d, J ¼ 5:2 Hz), 6.87
(2H, d, J ¼ 7:0 Hz), 7.40 (2H, d, J ¼ 7:0 Hz); 13C NMR
(100 MHz, CDCl3): d 12.1, 17.7, 17.8, 29.9, 55.7, 58.5 (q,
J ¼ 31:9 Hz), 76.3, 114.6, 119.4, 130.0, 157.2, 165.5; 19F
NMR (282 MHz, CDCl3): d À68.7 (d, J ¼ 5:6 Hz).
3.28. [(2S,3S)-4,4-Difluoro-3-(4-methylbenzenesulfonyl-
amino)-2-triisopropylsiloxybutanoyl]-(S)-methionine
methyl ester (19e)
3.25. [(2S,3S)-3-tert-Butoxycarbonylamino-4,4-difluoro-
2-triisopropylsiloxybutanoyl]glycine methyl ester (19b)
To the solution of b-lactam 15a(À) (40 mg, 0.1 mmol)
and glycine methyl ester (16 mg, 0.13 mmol) in 1 ml of
CH2Cl2 was added dropwise N-methylmorpholine (16 ml,
Yield 89%; colorless oil; 1H NMR (CDCl3, 400 MHz): d
1.08–0.89 (21H, m), 2.06 (3H, s), 2.14–1.97 (2H, m), 2.4
(3H, s), 2.49–2.42 (2H, m), 3.74 (3H, s), 3.88–3.82 (1H, m),

498
L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
4.14–4.11 (1H, m), 4.72–4.66 (1H, m), 5.88 (1H, dd,
J ¼ 1:6, 54.4 Hz), 6.53 (1H, d, J ¼ 9:6 Hz), 7.29 (2H, d,
J ¼ 8:4 Hz), 7.4 (1H, d, J ¼ 8 Hz), 7.79 (2H, d,
J ¼ 8:4 Hz); 13C NMR (CDCl3, 100.5 MHz): d 12, 15.4,
17.8, 21.6, 29.6, 31.3, 51.1, 52.6, 57.1 (dd, J ¼ 20:6 Hz),
69.9, 113.1 (dd, J ¼ 245:5 Hz), 127.2, 129.5, 137.7, 143.6,
170.5, 171.2; 19F NMR (282 MHz, CDCl3): d À126.4 to
À126.7 (m, 2F). HRMS (FABþ, m/z): Calcd. for
C26H44F2N2O6S2SiÁHþ, 611.2451. Found: 611.2451.
(1H, d, J ¼ 3:2 Hz), 4.62 (1H, m), 4.83 (1H, q, J ¼ 6:8 Hz),
5.08 (1H, d, J ¼ 12 Hz), 5.15 (1H, d, J ¼ 12 Hz), 6.12 (1H,
d, J ¼ 10 Hz), 7.10 (2H, d, J ¼ 6:4 Hz), 7.33 (10H, m); 13C
NMR (100 MHz, CDCl3): d 12.5, 17.9, 18.0, 38.2, 52.1,
53.4, 55.7 (q, J ¼ 29:6 Hz), 67.7, 71.4, 127.4, 128.3, 128.5,
128.7, 128.8, 129.2, 135.8, 136.1, 155.7, 170.8, 171.5; 19F
NMR (282 MHz, CDCl3): d À71.7 (d, J ¼ 9:0 Hz). HRMS
(FABþ, m/z): Calcd. for C31H43F3N2O6SiÁHþ, 625.2915.
Found: 625.2930.
3.29. (2S,3S)-2-[4,4-Difluoro-3-(4-
methylbenzenesulfonylamino)-2-
triisopropylsiloxybutanoyl]-(S)-phenylalanine
methyl ester (19f)
3.32. [(2S,3S)-3-N-tert-Butoxycarbonylamino-4,4-
difluoro-2-triisopropylsiloxybutanoyl]-b-alanine
ethyl ester (21a)
20
Yield 50%; colorless oil; [a]D þ20.858 (c 0.815, CHCl3);
Yield 83%; colorless oil; 1H NMR (CDCl3, 400 MHz): d
0.94–0.89 (21H, m), 3.39 (3H, s), 2.97 (1H, dd, J ¼ 5:6,
14 Hz), 3.16 (1H, dd, J ¼ 5:6, 14 Hz), 3.68 (3H, s), 3.84–
3.76 (1H, m), 4.11 (1H, d, J ¼ 5:2 Hz), 4.92–4.87 (1H, m),
5.69 (1H, ddd, J ¼ 1:6, 54.4 Hz), 6.53 (1H, d, J ¼ 9:2 Hz),
7.1–7.07 (3H, m), 7.29–7.22 (5H, m), 7.79 (2H, d,
J ¼ 8:4 Hz); 13C NMR (CDCl3, 100 MHz): d 11.9, 17.7,
21.5, 37.9, 52.2, 57.1 (dd, J ¼ 20:6 Hz), 69.8, 112.9
(dd, J ¼ 245:6 Hz), 127.1, 127.2, 128.6, 128.9, 129.5,
135.1, 137.7, 143.5, 170.2, 170.8; 19F NMR (282 MHz,
CDCl3): d À125.9 to À126.3 (m, 2F). HRMS (FABþ,
m/z): Calcd. for C30H44F2N2O6SSiÁHþ, 627.2730. Found:
627.2747.
IR (neat): n 3427, 2964, 2869, 1760–1693; 1H NMR
(400 MHz, CDCl3): d 1.00–1.24 (24H, m), 1.43 (9H, s),
2.49 (2H, m), 3.46 (1H, m), 3.58 (1H, m), 4.14 (2H, m) 4.32
(2H, m), 5.76–6.00 (2H, m); 13C NMR (100 MHz, CDCl3): d
12.4, 14.5, 18.2, 33.8, 34.6, 55.2 (t, J ¼ 21 Hz), 61.0, 71.4,
80.3, 113.9 (t, J ¼ 243 Hz, CF2H), 155.2, 171.2, 172.3; 19
F
NMR (282 MHz, CDCl3): d À126.8 (ddd, J ¼ 286, 55,
9 Hz), À128.5 (ddd, J ¼ 286, 55, 18 Hz). HRMS (FABþ,
m/z): Calcd. for C23H44F2N2O6Si.Naþ, 533.2829. Found:
533.2848.
3.33. [(2R,3R)-3-N-Benzyloxycarbonylamino-4,4,4-
trifluoro-2-triisopropylsiloxybutanoyl]-b-alanine ethyl
ester (22b)
3.30. [(2S,3S)-4,4-Difluoro-3-(4-fluorobenzoylamino)-
2-triisopropylsiloxybutanoyl]-(S)-phenylalanine methyl
ester (19g)
Yield 65%; colorless oil; [a]D20-26.98 (c 0.89, CHCl3); IR
(neat): n 3421, 2947, 2867, 1730, 1500, 1271, 1182, 1141;
1H NMR (400 MHz, CDCl3): d 1.09 (21H, m), 1.24 (t,
J ¼ 7:2 Hz, 3H), 2.48 (3H, m), 3.46 (1H, m), 3.58 (1H, m),
4.13 (2H, m), 4.44 (1H, d, J ¼ 3:2 Hz), 4.60 (1H, m), 5.09
(1H, d, J ¼ 12 Hz), 5.17 (1H, d, J ¼ 12 Hz), 6.19 (1H, d,
J ¼ 10 Hz), 7.33 (5H, m); 13C NMR (100 MHz, CDCl3): d
12.3, 14.3, 18.0, 33.7, 34.6, 55.7 (q, J ¼ 28:9 Hz), 61.0,
67.7, 71.5, 128.3, 128.5, 128.7, 136.1, 155.7, 170.8, 172.2;
19F NMR (282 MHz, CDCl3): d À71.7 (d, J ¼ 7:3 Hz).
HRMS (FABþ, m/z): Calcd. for C26H41F3N2O6SiÁHþ,
563.2759. Found: 563.2772.
Yield 100%; colorless oil; 1H NMR (CDCl3, 250 MHz): d
0.98–0.86 (21H, m), 3.05 (dd, J ¼ 5:3, 14 Hz), 3.16 (dd,
J ¼ 5:2, 14 Hz), 3.71 (3H, s), 4.76 (d, 1H, J ¼ 5 Hz), 4.39
(1H, d, J ¼ 5 Hz), 4.99–4.84 (2H, m), 5.92 (1H, dd,
J ¼ 55 Hz), 7.15–7.07 (3H, m), 7.32–7.22 (5H, m),
7.75 (1H, d, J ¼ 7:5 Hz), 7.92–7.87 (2H, m); 13C NMR
(CDCl3, 62.9 MHz): d 6.7, 12.6, 24.5, 32.6, 47.09, 47.8
(dd, J ¼ 20:1 Hz), 108.3 (dd, J ¼ 243 Hz), 65.3, 110.5
(d, J ¼ 15:7 Hz), 113, 122.2, 123.6, 124.4, 124.5 (d,
J ¼ 9:5 Hz), 129.9, 159.8 (d, J ¼ 251:6 Hz), 163.1(d,
J ¼ 326 Hz), 165.9; 19F NMR (282 MHz, CDCl3): d
À107.8 (sl, 1F), À126.5 to À126.9 (m, 2F). HRMS
(FABþ, m/z): Calcd. for C30H41F3N2O5SiÁHþ, 595.2810.
Found: 595.2811.
3.34. 2-Debenzoyl-2-(3-chlorobenzoyl)-10-propanoyl-
30-dephenyl-30-difluoromethyldocetaxel (25)
2-(3-Chlorobenzoyl)-7-TES-10-propanoylbaccatin 23
[60] (31 mg, 0.042 mmol) and b-lactam 15a(þ) (23 mg,
0.058 mmol) were dissolved in THF (1 ml, c ¼ 0:042 M).
The mixture was cooled to À40 8C, and LiHMDS (1 M THF
solution, 76 ml) was added. The solution was stirred for 2 h,
and the reaction was quenched with 1 ml of NH4Cl, and the
aqueous layer was extracted with ethyl acetate. The com-
bined organic layers were washed with brine and dried over
MgSO4. The crude was purified on silica gel column to yield
44 mg (92%) of 7-TES-20-TIPS-25 as a white solid: 1H
3.31. [(2R,3R)-3-(N-Benzyloxycarbonylamino)-4,4,4-
trifluoro-2-triisopropylsiloxybutanoyl]-(S)-phenylalanine
methyl ester (20a)
20
Yield 65%; colorless oil; [a]D þ6.88 (c 1.76, CHCl3); IR
1
(neat): n 3404, 2947, 2867, 1730, 1500, 1143; H NMR
(400 MHz, CDCl3): d 1.01 (21H, m), 3.08 (1H, dd,
J ¼ 7:2 Hz), 3.19 (1H, dd, J ¼ 5:2 Hz), 3.71 (3H, s), 4.47

L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
499
NMR (CDCl3, 300 MHz): d 0.68 (6H, m, TES), 0.94 (9H, m,
3.35. 2-Debenzoyl-2-(3-azidobenzoyl)-7-triethylsilyl-10-
propanoyl-20-triisopropylsilyl-30-dephenyl-30-
TES), 1.15–1.30 (30H, m, H-17, H-16, TIPS, CH3), 1.32
(9H, s, Boc), 1.68 (3H, s, H-19), 1.90 (1H, m, H-6b), 2.10
(4H, m, H-18, H-14b), 2.30 (1H, m, H-14a), 2.40 (3H, s,
4-OAc), 2.55 (3H, m, H-6a, COCH2), 3.87 (1H, d, J ¼ 7 Hz,
H-3), 4.16 (1H, d, J ¼ 8:0 Hz, H-20b), 4.32 (1H, d,
J ¼ 8:0 Hz, H-20a), 4.42 (1H, m, H-30), 4.48 (1H, dd,
J ¼ 7, 10 Hz H-7), 4.87 (1H, bs, H-20), 4.95 (1H, bd,
J ¼ 7:0 Hz, H-5), 5.08 (1H, d, J ¼ 10 Hz, NH0), 5.64
(1H, d, J ¼ 7:0 Hz, H-2), 5.80 (dt, J ¼ 6:3, 56.0 Hz,
CF2H), 6.25 (1H, m, H-13), 6.38 (1H, s, H-10), 7.50 (1H,
t, J ¼ 8:0 Hz, arom), 7.60 (1H, m, arom), 8.00 (1H, m,
arom), 8.16 (1H, m, arom); 13C NMR (CDCl3, 75.5 MHz): d
202.0, 172.9, 171.1, 170.3, 166.0, 155.5, 140.6, 135.0,
133.8, 133.7, 131.2, 130.7, 130.3, 128.5, 84.5, 81.3,
80.9, 79.1, 76.7, 75.6, 75.0, 72.5, 72.1, 70.6, (d,
JCF ¼ 6 Hz), 58.6, 56.0 (t, JCF ¼ 24 Hz), 47.0, 43.5,
37.4, 35.4, 28.2, 27.8, 26.5, 22.9, 21.5, 18.2, 18.1, 14.5,
12.9, 10.3, 9.4, 7.0, 5.5; 19F NMR, (CDCl3, 282 MHz): d
À125.0 (ddd, J ¼ 9:0, 55, 283 Hz), À128.8 (ddd, J ¼ 9:0,
55, 283 Hz).
trifluoromethyldocetaxel (7-TES-20-TIPS-26)
1
Yield 96%; white solid; H NMR (CDCl3, 300 MHz): d
0.60 (6H, m, TES), 0.93 (9H, m, TES), 1.13–1.28 (30H, m,
H-17, H-16, TIPS, CH3), 1.33 (9H, s, Boc), 1.70 (3H, s, H-19),
1.91 (1H, m, H-6b), 2.05 (3H, s, H-18), 2.32 (2H, m, H-14),
2.37 (3H, s, 4-OAc), 2.52 (3H, m, H-6a, COCH2), 3.86 (1H, d,
J ¼ 6:9 Hz, H-3), 4.18 (1H, d, J ¼ 8:4 Hz, H-20b), 4.35
(1H,d, J ¼ 8:4 Hz, H-20a), 4.49 (1H, dd, J ¼ 3:6, 10.2 Hz,
H-7), 4.69 (1H, q, J ¼ 8:1 Hz, H-30), 4.95 (2H, m, H-20, H-5),
5.19 (1H, d, J ¼ 10:2 Hz, NH0), 5.70 (1H, d, J ¼ 6:9 Hz, H-
2), 6.25 (1H, t, J ¼ 9:6 Hz, H-13), 6.50 (1H, s, H-10), 7.22
(1H, dd, J ¼ 1:5, 7.8 Hz, arom), 7.50 (1H t, J ¼ 8:1 Hz,
arom), 7.85 (1H s, arom), 7.91 (1H d, J ¼ 8:1 Hz, arom);
19F NMR, (CDCl3, 282 MHz): d À72.90 (d, J ¼ 6:2 Hz).
3.36. 2-Debenzoyl-2-(3-azidobenzoyl)-10-propanoyl-30-
dephenyl-30-trifluoromethyldocetaxel (26)
1
To a solution of 7-TES-20-TIPS-25 (44 mg) in 4 ml of a
1:1 mixture of pyridine and CH3CN at 0 8C was added
0.5 ml of HF-pyridine. The reaction was allowed to warm to
room temperature and stirred for 26 h. The reaction mixture
was then quenched with 1 ml of NaHCO3, and extracted
with ethyl acetate. The combined organic layers washed
with CuSO4 and brine, dried over MgSO4 and concentrated.
The residue was purified by chromatography on silica gel
using hexane/ethyl acetate (1/1) as eluant to afford 18 mg
(75% yield) of 25 as a white solid: 1H NMR (CDCl3,
300 MHz): d 1.26 (9H, m, H-17, H-16, CH3), 1.33 (9H,
s, Boc), 1.69 (3H, s, H-19), 1.91 (4H, m, H-18, H-6b), 2.30
(2H, m, H-14a, H-14b), 2.43 (3H, s, 4-OAc), 2.55 (3H, m,
H-6a, COCH2), 3.48 (1H, d, J ¼ 5 Hz, OH-20), 3.86 (1H, d,
J ¼ 7 Hz, H-3), 4.16 (1H, d, J ¼ 8:0 Hz, H-20b), 4.32 (1H,
d, J ¼ 8:0 Hz, H-20a), 4.44 (2H, m, H-7, H-30), 4.66 (1H,
dd, J ¼ 5 Hz, H-20), 5.00 (1H, bd, J ¼ 7:0 Hz, H-5), 5.08
(1H, d, J ¼ 10 Hz, NH0), 5.64 (1H, d, J ¼ 7:0 Hz, H-2),
5.80 (dt, J ¼ 6:3, 56.0 Hz, CF2H), 6.25 (1H, m, H-13),
6.38 (1H, s, H-10), 7.50 (1H, t, J ¼ 8:0 Hz, arom), 7.60 (1H,
m, arom), 8.00 (1H, m, arom), 8.16 (1H, m, arom);
13C NMR (CDCl3, 75.5 MHz): d 9.3, 9.8, 15.1, 22.1,
22.6, 27.8, 28.2, 26.9, 35.6, 35.8, 43.4, 45.9, 54.8
(t, JCF ¼ 24 Hz), 58.7, 68.9 (JCF ¼ 6 Hz), 72.5, 73.1,
75.6, 75.7, 76.5, 79.4, 81.2, 81.3, 84.7, 114.3 (t,
JCF ¼ 244 Hz) 128.5, 130.4, 130.6, 131.1, 133.4, 134.0,
135.1, 142.1, 155.3, 166.0, 170.6, 172.6, 174.9, 203 8; 19F
NMR, (CDCl3, 282 MHz): d À126.0 (ddd, J ¼ 12,
55, 283 Hz), À128.0 (ddd, J ¼ 9, 55, 286 Hz). HRMS
(FABþ, m/z): Calcd. for C41H52ClF2NO15.Naþ, 894.2886.
Found: 894.2922.
Yield 84%; white solid; H NMR (CDCl3, 300 MHz): d
1.16 (3H, s, C-16), 1.25 (6H, m, C-17, CH3), 1.32 (9H, s,
Boc), 1.69 (3H, s, H-19), 1.69 (1H, ds, 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 ¼ 6:9 Hz, H-3), 4.18 (1H, d, J ¼ 8:7 Hz, H-20b), 4.34
(1H, d, J ¼ 8:7 Hz, H-20a), 4.45 (1H, dd, J ¼ 3:6, 10.2 Hz,
H-7), 4.72 (1H, s, H-5), 4.78 (1H, q, J ¼ 8:1 Hz, H-30), 4.98
(1H, d, J ¼ 8:1, H-20), 5.30 (1H, d, J ¼ 10:2 Hz, NH0), 5.67
(1H, d, J ¼ 7:2 Hz, H-2), 6.25 (1H, t, J ¼ 9:3 Hz, H-13),
6.32 (1H, s, H-10), 7.24 (1H, d, J ¼ 8:1 Hz), 7.50 (1H, t,
J ¼ 7:8 Hz), 7.84 (1H, s), 7.91 (1H, d, J ¼ 7:5 Hz); 13C
NMR (CDCl3, 75.5 MHz): d 9.0, 9.5, 14.2, 14.8, 21.9, 22.4,
26.6, 27.5, 27.9, 35.3, 35.5, 43.2, 45.6, 53.8 (q,
JCF ¼ 48 Hz), 58.5, 60.4, 68.1, 72.1, 73.3, 75.2, 75.4,
76.3, 76.6, 79.0, 81.1, 81.2, 84.5, 120.0, 124.5, 126.7,
130.2, 130.7, 133.3, 140.9, 141.6, 154.6, 166.2, 170.3,
171.8, 174.6, 203.5; 19F NMR, (CDCl3, 282 MHz): d
À73.78 (d, J ¼ 9:3 Hz). HRMS (FABþ, m/z): Calcd. for
C41H51F3N4O15ÁHþ, 897.3376. Found: 897.3406.
Acknowledgements
This research was supported by grants from National
Institutes of Health (NIGMS, NCI). Generous support from
Indena SpA, is also gratefully acknowledged. The authors
are grateful to Dr. Ralph J. Bernacki and Paul Pera, Roswell
Park Memorial Cancer Institute for carrying out the in vitro
cytotoxicity assay of the fluoro-taxoids.
In the same manner as described for the synthesis of
25, 7-TES-20-TIPS-26 and fluoro-taxoid 26 were obtained.
The characterization data of these taxoids are shown
below.
References
[1] D.G.I. Kingston, Chem. Commun. 10 (2001) 867–880.
[2] I. Ojima, S. Lin, T. Wang, Curr. Med. Chem. 6 (1999) 927–954.

500
L. Kuznetsova et al. / Journal of Fluorine Chemistry 125 (2004) 487–500
[3] G.I. Georg, T.T. Chen, I. Ojima, D. Vyas, Taxane Anticancer Agents:
[32] V.P. Kukhar, V.A. Soloshonok, Fluorine-Containing Amino Acids:
Synthesis and Properties, Wiley, Chichester, 1994.
Basic Science and Current Status, vol. 583, The American Chemical
Society, Washington, DC, 1999.
[33] S.C. O’Hagan, S.L. Cobb, J.T.G. Hamilton, D. Cormac, C.D.
Murphy, Nature 416 (2002) 279.
[4] H. Umezawa, T. Aoyagi, H. Suda, M. Hamada, T. Takeuchi, J.
Antibiot. 29 (1976) 97–99.
[34] T.S. Gerhard, R. Mortishire-Smith, J. Pharm. Biol. Anal. (2003)
531–538.
[5] H. Suda, T. Takita, T. Aoyagi, H. Umezawa, J. Antibiot. 29 (1976)
600–601.
[35] M.-M.M.R. Martino, V. Gilard, Curr. Drug Metab. (2000) 271–303.
[36] S.Y. Kaneko, T. Kitazume, J. Org. Chem. 58 (1993) 2302–2312.
[37] K.H. Uneyama, H. Amii, Tetrahedron Lett. 39 (1998) 4079–4082.
[38] P.B. Fustero, E. Salavert, A. Navarro, M.C.R. de Arellano, A.S.
Fuentes, J. Org. Chem. 67 (2003) 4667–4679.
[6] W.H.H. Pearson, J. Org. Chem. 54 (1989) 4235.
[7] T.M. Okino, M. Murakami, K. Yamaguchi, Tetrahedron Lett. 34
(1993) 501.
[8] T.H. Mimoto, H. Takaku, S. Kisanuki, T. Fukazawa, K. Terashima,
R. Kato, S. Nojima, S. Misawa, T. Ueno, J. Imai, H. Enomoto, S.
Tanaka, H. Sakikawa, M. Shintani, H. Hayashi, Y. Kiso, Chem.
Pharm. Bull. 48 (2000) 1310–1326.
[39] S.I.V. Soloshonok, V.P. Kukhar, V.K. Svedas, J. Org. Chem. 63
(1998) 1878–1884.
[40] B.J.P. Abouabdellah, D. Bonnet-Delpon, T.T.T. Nga, J. Org. Chem.
62 (1997) 8826–8833.
[9] Y.Y. Kiso, S. Matsumoto, H. Mimoto, T. Kato, R. Nojima, S. Takaku,
H. Fukazawa, T. Kimura, T. Akaji, Arch. Pharm. 331 (1998) 87–89.
[10] J.-N. Denis, A.E. Greene, A.A. Serra, M.-J. Luche, J. Org. Chem. 51
(1986) 46–50.
[41] I.M. Page, Accounts Chem. Res. (1984) 144–151.
[42] H.M.E. Khalafallah, H.A. Soleman, J. Ind. Chem. Soc. 69 (1992)
318–320.
[11] L. Deng, E.N. Jacobsen, J. Org. Chem. 57 (1992) 4320–4323.
[12] A. Commerc¸on, D. Bezard, F. Bernard, J.D. Bourzat, Tetrahedron
Lett. 33 (1992) 5185–5188.
[43] J. Lukic, European Patent Application, E 9791 (1997) 580.
[44] W.G.A.D. Borthwick, T.M. Haley, M. Tomaszewski, W. Wang, Z.H.
Hu, J. Bedard, H.L. Jin, L. Yuen, T.S. Mansour, Bioorg. Med. Chem.
Lett. 8 (1998) 365–370.
[13] D.-M. Gou, Y.-C. Liu, C.-S. Chen, J. Org. Chem. 58 (1993) 1287–
1289.
[45] B.M. Ogilvie, M.A. Poupart, A. Abraham, A. Bhavsar, P. Bonneau, J.
Bordeleau, Y. Bousquet, C. Chabot, J.S. Duceppe, G. Fazal, S.
Goulet, C. GrandMaitre, I. Guse, T. Halmos, P. Lavallee, M. Leach,
E. Malenfant, J. Omeara, R. Plante, C. Plouffe, M. Poirier, F. Soucy,
C. Yoakim, R. Deziel, J. Med. Chem. 40 (1997) 4113–4135.
[46] I. Ojima, I. Habus, M. Zhao, M. Zucco, Y.H. Park, C.-M. Sun, T.
Brigaud, Tetrahedron 48 (1992) 6985–7012.
[14] C.R. Bonini, J. Chem. Soc., Chem. Commun. (1994) 2767.
[15] F.H. Grosjean, M. Larcheveque, J.J. Legendre, Y. Petit, Tetrahedron
50 (1994) 9325–9334.
[16] M.C. Pasto, A. Moyano, M.A. Pericas, A. Riera, J. Org. Chem. 61
(1996) 6033–6037.
[17] J.D. Bourzat, A. Commerc¸on, Tetrahedron Lett. 34 (1993) 6049–
6052.
[47] R. Brieva, J.Z. Crich, C.J. Sih, J. Org. Chem. 58 (1993) 1068–1075.
[48] S. Lin, X.D. Geng, C.X. Qu, R. Tynebor, D.J. Gallagher, E. Pollina,
J. Rutter, I. Ojima, Chirality 12 (2000) 431–441.
[18] G.I. Georg, Z.S. Cheruvallath, G.C.B. Harriman, M. Hepperle, H.
Park, Bioorg. Med. Chem. Lett. 3 (1993) 2467–2470.
[19] C.A. Palomo, J.I. Miranda, A. Mielgo, J.M. Odriozola, Tetrahedron
Lett. 34 (1993) 6325.
[49] X. Wu, SUNY Stony Brook, Stony Book, 2003.
[50] I. Ojima, S. Lin, J.C. Slater, T. Wang, P. Pera, R.J. Bernacki, C.
Ferlini, Bioorg. Med. Chem. 8 (2000) 1576–1585.
[20] R.A. Holton, J.H. Liu, Bioorg. Med. Chem. Lett. 3 (1993) 2475–
2478.
[51] I. Ojima, J.C. Slater, Chirality 9 (1997) 487–494.
[52] I. Ojima, Acc. Chem. Res. 28 (1995) 383–389, references cited
therein.
[21] I. Ojima, I. Habus, M. Zhao, G.I. Georg, R. Jayasinghe, J. Org.
Chem. 56 (1991) 1681–1684.
[22] I. Ojima, Y.H. Park, C.M. Sun, T. Brigaud, M. Zhao, Tetrahedron
Lett. 33 (1992) 5737–5740.
[53] I. Ojima, F. Delaloge, Chem. Soc. Rev. 26 (1997) 377–386.
[54] B.M. Trost, Accounts Chem. Res. 35 (2002) 695–705.
[55] I. Ojima, C.M. Sun, Y.H. Park, J. Org. Chem. 59 (1994) 1249–
1250.
[23] C.S. Swindell, M. Tao, J. Org. Chem. 58 (1993) 5889–5891.
[24] C. Mukai, I.J. Kim, E. Furu, M. Hanaoka, Tetrahedron 49 (1993)
8323–8336.
[56] I. Ojima, H. Wang, T. Wang, E.W. Ng, Tetrahedron Lett. 39 (1998)
923–926.
[57] I. Ojima, J.C. Slater, P. Pera, J.M. Veith, A. Abouabdellah,
[25] K. Hattori, H. Yamamoto, Tetrahedron 50 (1994) 2785–2792.
[26] F.A.R. Davis, R.E. Reddy, J. Org. Chem. 57 (1992) 6387.
[27] B.H.M. Norman, Tetrahedron Lett. 33 (1992) 6803.
[28] J.-N. Denis, A. Correa, A.E. Greene, J. Org. Chem. 56 (1991) 6939–
6942.
´ ´
J.-P. Begue, R.J. Bernacki, Bioorg. Med. Chem. Lett. 7 (1997)
209–214.
[58] P. Skehan, R. Streng, D. Scudierok, A. Monks, J. McMahon, D.
Vistica, J.T. Warren, H. Bokesch, S. Kenney, M.R. Boyd, J. Nat.
Cancer Inst. 82 (1990) 1107–1112.
[29] A. Dondoni, D. Perrone, T. Semola, Synthesis (1995) 181–186.
[30] C.D.-d.-V. Cativiela, J.A. Galvez, Tetrahedron: Asymmetry 7 (1996)
529.
´ ´
[59] A. Abouabdellah, J.-P. Begue, D. Bonnet-Delpon, Synlett (1996)
399–400.
[31] I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical Frontiers
of Fluorine Chemistry, ACS Symposium Series 639, American
Chemical Society, Washington, DC, 1996.
[60] I. Ojima, T. Wang, M.L. Miller, S. Lin, C. Borella, X. Geng, P. Pera,
R.J. Bernacki, Bioorg. Med. Chem. Lett. 9 (1999) 3423–3428.