Design, synthesis, and biological evaluation of new-generation taxoids

Article abstract of DOI:10.1021/jm800086e

Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistan

Full text of DOI:10.1021/jm800086e

J. Med. Chem. 2008, 51, 3203–3221
3203
Design, Synthesis, and Biological Evaluation of New-Generation Taxoids
Iwao Ojima,*,†,‡ Jin Chen,† Liang Sun,† Christopher P. Borella,† Tao Wang,† Michael L. Miller,† Songnian Lin,†
Xudong Geng,† Larisa Kuznetsova,† Chuanxing Qu,† David Gallager,† Xianrui Zhao,† Ilaria Zanardi,‡ Shujun Xia,§
Susan B. Horwitz,§ Jon Mallen-St. Clair,¶ Jennifer L. Guerriero,¶ Dafna Bar-Sagi,¶ Jean M. Veith,# Paula Pera,# and
Ralph J. Bernacki#
Department of Chemistry, State UniVersity of New York at Stony Brook, Stony Brook, New York 11794-3400, Institute of Chemical Biology &
Drug DiscoVery, State UniVersity of New York at Stony Brook, Stony Brook, New York 11794-3400, Department of Molecular Pharmacology,
Albert Einstein College of Medicine, Bronx, New York 10461, Department of Molecular Genetics and Microbiology, State UniVersity of New
York at Stony Brook, Stony Brook, New York 11794-5222, and Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, New York 14263
ReceiVed January 29, 2008
Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were
synthesized and their structure-activity relationships studied. A number of these taxoids exhibited
exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no
difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent
taxoids were termed “third-generation taxoids”. 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031)
exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in ꢀ-tubulin
as well, wherein the drug resistance is mediated by the ꢀ-tubulin mutation. These taxoids were found to
possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar
to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four
pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited
excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon
tumor xenografts in mice.
Introduction
has been shown that treatment with these drugs often produces
undesirable side effects as well as drug resistance.3 Therefore,
it is important to develop new taxane anticancer agents with
fewer side effects, superior pharmacological properties, and
improved activity against various classes of tumors, especially
against drug-resistant human cancer.
Cancer is one of the most common lethal diseases in the
world. In the U.S. cancer is now the leading cause of death in
people under the age of 85.1,2 Among a variety of chemothera-
peutic drugs paclitaxel and docetaxel are currently two of the
most widely used drugs in the fight against cancer, especially
for the treatment of ovarian, breast, and lung cancers as well as
Kaposi’s sarcoma.3,4 Further clinical applications are ongoing
against different types of cancers as well as for combination
therapies with other anticancer drugs.3 These “taxane” anticancer
drugs bind to the ꢀ-tubulin subunit, accelerate the polymerization
of tubulin, and stabilize the resultant microtubules, thereby
inhibiting their depolymerization.5,6 This results in the arrest
of the cell division cycle mainly at the G2/M stage, leading to
apoptosis through the cell-signaling cascade. Although both
paclitaxel and docetaxel possess potent antitumor activity, it
Accordingly, extensive structure-activity relationship (SARa)
studies on paclitaxel and its congeners have been performed in
different laboratories for discovery and development of better
taxane anticancer agents.4,7–16 In the course of our SAR study
on taxoids, we found that (i) the C3′-phenyl group was not an
essential component for their potent activity and (ii) the
modifications of the C10 position with certain acyl groups as
well as the replacement of the phenyl group with an alkenyl or
alkyl group at the C3′ position made compounds 1-2 orders
of magnitude more potent than the parent drugs (paclitaxel and
docetaxel) against drug-resistant human breast cancer cell lines.
These highly potent taxoids were termed “second-generation
taxoids”.17 Furthermore, we found that introduction of a
substituent (e.g., MeO, N3, Cl, F, etc.) to the meta position of
the C2-benzoyl group of the second-generation taxoids enhanced
the activities 2-3 orders of magnitude higher than the parent
drugs against drug-resistant human breast cancer cell lines.14,15
We describe here a full account of our work on the synthesis,
biological evaluations, and SAR of a series of novel new
generation taxoids bearing various substituents at the C2, C10,
C3′, and C3′N positions.
* To whom correspondence should be addressed. Phone: 631-632-1339.
Fax: 631-632-7942. E-mail: iojima@notes.cc.sunysb.edu.
†
Department of Chemistry, State University of New York at Stony
Brook.
‡
Institute of Chemical Biology & Drug Discovery, State University of
New York at Stony Brook.
§
Albert Einstein College of Medicine.
Department of Molecular Genetics and Microbiology, State University
¶
of New York at Stony Brook.
#
Department of Pharmacology & Therapeutics, Roswell Park Cancer
Institute.
a Abbreviations: DAB, 10-deacetylbaccatin III; IC50, half-maximal
inhibitory concentration; LiHMDS, lithium hexamethyldisilazide; NMO,
N-methylmorpholine N-oxide; PBS, phosphate buffered saline; PDA,
photodiode array; Pgp, P-glycoprotein; R/S, resistance factor (the ratio of
the IC50 value against the drug-resistant cell line to that against the drug-
sensitive cell line); RT-PCR, reverse transcriptase-polymerase chain
reaction; SAR, structure-activity relationship; SCID, severe combined
immunodeficiency; TEA, triethylamine; TES, triethylsilyl; TIPS, triisopro-
pylsilyl; TLC, thin layer chromatography; TPAP, tetrapropylammonium
perruthenate; WT, wild type.
Chemical Synthesis
Second-generation taxoids bearing different aromatic acyl
groups at the C10 position were synthesized by applying the
procedure developed by Georg.18 The C7 hydroxy group of 10-
deacetylbaccatin III (DAB, 1) was selectively protected as a
triethylsilyl ether using triethylsilyl chloride (TESCl) and
10.1021/jm800086e CCC: $40.75
2008 American Chemical Society
Published on Web 05/09/2008

3204 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
Scheme 1a
a Reagents and conditions: (i) (a) TESCl, imidazole, (b) LiHMDS, AcCl, 95% in two steps; (ii) LiHMDS, THF, 95%; (iii) N2H4 ·H2O, EtOH, 85%.
Scheme 2a
Table 1. Synthesis of Taxoids 6
taxoid
R
yield (%) (for two steps)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
Bz
90
90
87
80
92
90
92
97
80
80
60
85
97
80
80
2-MeO(C6H4)CO
3-MeO(C6H4)CO
4-MeO(C6H4)CO
3,4-(MeO)2(C6H3)CO
1-naphthoyl
a Reagents and conditions: (i) (a) RCl, TEA, DMAP, CH2Cl2 or (b) ROH,
DIC, DMAP, CH2Cl2 or (c) RCl, LiHMDS, THF, -20 °C (75-98%); (ii)
HF/pyridine, pyridine/MeCN (80-97%).
2-naphthoyl
Cbz
2-MeO(C6H4)CH2CO
3-MeO(C6H4)CH2CO
4-MeO(C6H4)CH2CO
(C6H5)(CH2)2CO
2-MeO(C6H4)(CH2)2CO
3-MeO(C6H4)(CH2)2CO
4-MeO(C6H4)(CH2)2CO
imidazole in DMF. The resulting 7-TES-DAB was acetylated
specifically at the C10 position to give 7-TES-baccatin III (2)
in excellent yield (95% for two steps)8,17,19 An isoserine moiety
wasintroducedtotheC13positionof2throughtheOjima-Holton
coupling of 2 with N-t-Boc-ꢀ-lactam 3a7,20 under the standard
conditions in the presence of LiHMDS in THF at -40 °C to
afford the corresponding taxoid 4 (Scheme 1).21,22
The selective removal of the acetyl group at the C10 position
of 4 with hydrazine was possible when the hydroxyl group at
the C2′ position was protected as a TIPS ester. This selective
deacetylation under mild conditions gave the desired C2′-TIPS-
7-TES-10-OH-taxoid 5 in high yield (Scheme 1).
Taxoid 5 served as the key intermediate for the syntheses of
a number of second-generation taxoids, bearing different acyl
groups at the C10 position. The acylation of the C10 position
of 5 was carried out using either an acid chloride with
triethylamine (TEA) and DMAP or a carboxylic acid with DIC
and DMAP (Scheme 2). For the introduction of a Cbz group,
CbzCl and LiHMDS were used (Scheme 2). Yields for the
acylation reactions were 75-98% (see Supporting Information
for details). The deprotection of C2′-TIPS and 7-TES groups
with HF-pyridine in pyridine/acetonitrile (1:1) proceeded
smoothly to give desired 10-acyl second-generation taxoids
6a-o in 80-97% yields (Scheme 2). Results are summarized
in Table 1.
Novel second-generation taxoids, bearing substituents at the
meta position of the C-2-benzoyl group, were synthesized
(Scheme 5) from the corresponding C2-modified DABs 10 (see
Schemes 3 and 4). The protection of the C7, C10, and C13
hydroxy groups of DAB with TES made it possible to selectively
remove the C2-benzoyl moiety with sodium bis(2-methoxy-
ethoxy)aluminumhydride, giving 7,10,13-tris-TES-2-debenzoyl-
DAB 8 in excellent yield.23,24 The esterification of the C2-OH
of 8 with 3-substituted benzoic acids (R1 ) F, Cl, MeO, Me,
N3, vinyl) with DIC and DMAP gave various C2-modified tris-
TES-DABs 9a-f in 80-90% yields. Removal of all TES groups
of 9a-f with HF-pyridine followed by selective protection of
the C7 hydroxyl group of the resulting baccatin gave 2-modified
DABs 10a-f. Subsequent selective acylation at the C10 position
of 10a-f afforded the corresponding 2,10-modified DABs
11a-l in 71-95% yields (Scheme 3). Results are summarized
in Table 2.
The same strategy was applied to the introduction of
2-methoxybenzoyl group at the C10 position but did not work
well. Thus, we employed an alternative method, which is shown
in Scheme 4. Selective oxidation of the C13 position of 10b
using TPAP and NMO provided 13-oxobaccatin 12. The C10
position was then acylated with 2-methoxylbenzoyl chloride in
the presence of DMAP to afford 10-(2-methoxybenzoyl)-13-
oxobaccatin 13. Reduction of the C13 ketone with NaBH4 gave
the desired 2-(3-methoxybenzoyl)-10-(2-methoxybenzoyl)bac-
catin 11k in reasonable yield.
The Ojima-Holton coupling reactions of baccatins 11a-l
with ꢀ-lactams 3a-f in the presence of LiHMDS as a base17,25
proceeded smoothly to give the corresponding taxoids 14 (see
Table 3 for structures). Enantiopure ꢀ-lactams with various C4
substituents were readily obtained through efficient chiral ester
enolate-imine cyclocondensations15,17,20,22,25,26 or [2 + 2]
ketene-imine cycloaddition, followed by enzymatic optical
resolution.27 The deprotection of the silyl groups with HF/
pyridine gave desired taxoids 14a-p and 15c-e,g in 65-95%
yields (for two steps) (Scheme 5). In addition, taxoid 14g (SB-
T-121303) (R1 ) MeO, R2 ) propanoyl, R3 ) 2-methylpropen-
1-yl) was subjected to hydrogenation on Pd/C to afford 15g
(R3 ) 2-methylpropyl) in quantitative yield (Scheme 5). Results
are summarized in Table 3.
We also investigated the effects of the C3′N substituents on
the cytotoxicity of second-generation taxoids. Modification of

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3205
Scheme 3a
a Reagents and conditions: (i) TESCl, imidazole, DMF, room temp, 96%; (ii) sodium bis(2-methoxyethoxy)aluminumhydride, THF, -10 °C, 97%; (iii)
DIC, DMAP, CH2Cl2, 85-90%; (iv) HF/pyridine, pyridine/MeCN; (v) TESCl, imidazole, DMF, room temp, 2 h; (vi) LiHMDS, R2COCl, THF.
Scheme 4a
Pgp+) human breast cancer cell lines, and selected taxoids were
also assayed for their potency against human breast cancer cell
line MCF7 (Pgp-) and human ovarian cancer cell line NCI/
ADR (Pgp+). Cytotoxicity assay results of taxoids 6a-o bearing
various aromatic groups in the acyl moieties at the C10 position
against LCC6-WT and LCC6-MDR cell lines are summarized
in Table 5.
As Table 5 shows, all taxoids assayed exhibit activities similar
to or slightly better than that of paclitaxel against LCC6-WT,
while their activities against LCC6-MDR are 2 orders of
magnitude better than that of paclitaxel for more than a half of
this series of taxoids. The most noteworthy feature revealed in
this assay can be seen in the dramatic decrease in the R/S ratio,
i.e., the ratio of the IC50 value against the drug-resistant cell
line to that against the drug-sensitive cell line (paclitaxel’s R/S
value is 112 in this assay), which is an excellent indicator to
see the level of drug resistance associated with drugs. A majority
of the taxoids in this series exhibit an R/S ratio at or below 3,
and taxoid 6d demonstrates almost no difference against drug-
resistant and drug-sensitive cell lines with an R/S ratio of 1.2.
In general, taxoids with a substituted or unsubstituted benzoyl
group (6a-e) or 2-phenylpropanoyl group (6m-o) are highly
potent against LCC6-MDR, while taxoids with an arylacetyl
substituents (6i-k) show reduced activity against LCC6-MDR
although 4 out of 7 taxoids in this group (6h-k) are more potent
than paclitaxel against LCC6-WT. Taxoids 6a and 6d that bear
a benzoyl group and a 4-methoxybenzoyl group, respectively,
at C10 possess highest potencies against LCC6-MDR (IC50
values of 4.8 and 4.7 nM, respectively). Taxoid 6k, bearing a
4-methoxyphenyl acetyl group at C10, is the least potent (IC50
) 38.4 nM) against LCC6-MDR, but 6k possesses the highest
potency against LCC6-WT. Interestingly, elongation of the alkyl
chain of 6i-k just by one carbon restores high potency against
LCC6-MDR.
a Reagents and conditions: (i) TPAP, NMO, 4 Å molecular sieves,
CH2Cl2, 25 °C, 99%; (ii) 2-MeO-BzCl, DMAP, TEA, CH2Cl2, 100%; (iii)
NaBH4, MeOH/THF, 80% at 50% conversion.
the C3′N position can be made by using enantiopure ꢀ-lactams
bearing various N-acyl or N-carbalkoxy groups. These ꢀ-lactams
were readily obtained by reacting NH-free 3-TBSO- or 3-TIPSO-
ꢀ-lactam with acid chlorides or chloroformates. The resulting
ꢀ-lactams 16a-h were coupled with 10-deacetyl-10-propanoyl-
baccatin III or baccatin 11b using 1.5-2 equiv of ꢀ-lactam
16a-h to complete the reactions in excellent yields. Subsequent
deprotection of silyl groups with HF/pyridine gave desired
taxoids 17a-l in good to excellent yields. Hydrogenation of
selected 17 on Pd/C gave the corresponding 3′-(2-methylpro-
pyl)taxoids 18 in quantitative yields (Scheme 6). Results are
summarized in Table 4.
10-Propanoyl taxoids bearing different acyl or carboalkoxy
groups at the C3′N position were assayed for their cytotoxicity
against LCC6-WT (Pgp-), LCC6-MDR (Pgp+), MCF7 (Pgp-),
and NCI/ADR (Pgp+) human cancer cell lines, and results are
summarized in Table 6. As Table 6 shows, most of C3′N-
modified taxoids possess better cytotoxicity against LCC6-WT
and MCF7 cell lines and 1-2 orders of magnitude higher
potency against drug-resistant LCC6-MDR and NCI/ADR cell
lines compared with paclitaxel. Two taxoids (17d and 17e),
bearing cyclopent-2-en-1-yl and cyclohex-2-en-1-yl groups,
Evaluation of Biological Activities
Cytotoxicity of New Generation Taxoids against Human
Breast and Ovarian Cancer Cell Lines. New second-genera-
tion taxoids, thus obtained, were evaluated for their cytotoxicity
against drug-sensitive (LCC6-WT, P-glycoprotein negative,
Pgp-) and drug-resistant (LCC6-MDR, P-glycoprotein positive,

3206 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
Scheme 5a
a Reagents and conditions: (i) 3a-f (1.2-1.5 equiv), LiHMDS, THF, -40 °C, 30 min; (ii) HF/pyridine, pyridine/MeCN, 0 °C to room temp, 18 h; (iii)
H2/Pd-C, EtOAc/MeOH, room temp, 24 h.
Table 2. 2,10-Modified Baccatins 11
exhibit remarkable potency against drug-resistant (Pgp+) cancer
R1
R2
yield (%)
cell lines, LCC6-MDR, and NCI/ADR, i.e., 2-3 orders of
magnitude higher potencies than those of paclitaxel and doc-
etaxel. In more than several cases, the R/S ratios are less than
3 and even become less than 1 in three cases (14g for LCC6-
WT:LCC6-MDR and MCF7:NCI/ADR and 15g for LCC6-WT:
LCC6-MDR). In these three cases, it can be said that the Pgp-
mediated MDR is completely circumvented by new taxoids 14g
and 15g. In addition to 14g and 15g, 14e and 14l also show
excellent R/S ratios, i.e., 14e, R/S ratios of 1.3 and 1.2 for LCC6-
WT:LCC6-MDR and MCF7:NCI/ADR, respectively; 14l, R/S
ratios of 1.0 for LCC6-WT:LCC6-MDR. Accordingly, we haVe
defined these new-generation taxoids, which can Virtually
circumVent the Pgp-mediated MDR, as the “third-generation”
taxoids. It is interesting to point out that the same C2-benzoyl
group modifications to the taxoids, bearing cycloalkanoyl or
carbalkoxy groups at the C3′N position, do not have recogniz-
able effects on potency except for taxoids 18h and 18m, which
exhibit subnanomolar IC50 values against LCC6-WT and MCF7.
Taxoid 18m also shows very high potency against drug-resistant
LCC6-MDR (2.6 nM) and NCI/ADR (1.18 nM) cell lines.
For the effects of the meta substituents of the C2-benzoyl
moiety, the potency decreases in the order F > Cl > N3 > MeO
. CH2dCH- against LCC6-WT (Pgp-), while the order
changes to MeO > N3 > Cl > F . CH2dCH- against LCC6-
MDR (Pgp+). Apparently, the former order is more or less
reflecting the ability of a taxoid with such a modification to
bind microtubules. On the other hand, the latter order reflects
the effects of these substituents on the MDR reversal activity
of taxoids or simply indicates the extent of interaction of taxoids
with Pgp in the reverse order. In both case, the m-vinyl
substitution of the C2-benzoyl moiety (14f) resulted in the least
potent taxoid in this comparison. The introduction of a m-methyl
group to the C2-benzoyl moiety (14a) does not seem to have a
recognizable positive effect.
baccatin
11a
11b
11c
11d
11e
11f
11g
11h
11i
Me
MeO
F
Cl
N3
CH2dCH-
MeO
MeO
MeO
MeO
MeO
MeO
MeCO
MeCO
EtCO
EtCO
EtCO
EtCO
EtCO
c-PrCO
MeOCO
PhCH2OCO
94
77
84
77
84
67
95
84
92
94
80
98
11j
11k
11l
2-MeO(C6H4)CO
4-MeO(C6H4)CH2CO
Table 3. Second- and Third-Generation Taxoids 14 and 15
yield for
two steps (%)
txoid
R1
R2
R3
14a Me
MeCO
MeCO
EtCO
EtCO
EtCO
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
80
72
84
70
71
80
69
77
80
70
95
70
65
80
71
83
89
80
70
73
14b MeO
14c
F
14d Cl
14e N3
14f CH2dCH- EtCO
14g MeO
14h MeO
14i MeO
14j MeO
14k MeO
14l MeO
14m MeO
14n MeO
14o MeO
14p MeO
EtCO
c-PrCO
MeOCO
PhCH2OCO
2-MeO(C6H4)CO
4-MeO(C6H4)CH2CO Me2CdCH-
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
CH2dCHCH2-
(E)-CH3CHdCH-
CH2dCH(CH2)2-
(S)-2,2-Me2-c-Pr-
Me2CHCH2-
15c
F
15d Cl
15e N3
15g MeO
Me2CHCH2-
Me2CHCH2-
Me2CHCH2-
For the C3′ position, 2-methylprop-1-enyl and 2-methylpropyl
are the best substituents for potency so far. However, the
introduction of allyl, (E)-prop-1-enyl, but-3-enyl, or (S)-2,2-
dimethylcyclopropyl group provided very potent taxoids
(14m-p), especially with the (S)-2,2-dimethylcyclopropyl group
(14p) appearing to have a beneficial effect, comparable to those
of 2-methylprop-1-enyl and 2-methylpropyl groups.
For the C10 modifications, the potency decreases in the order
4-MeO(C6H4)CH2CO ∼ 2-MeO(C6H4)CO > MeOCO ∼ Ac >
cyclo-PrCO ∼ EtCO > PhCH2OCO (Cbz) against LCC6-WT,
while the order changes to 4-MeO(C6H4)CH2CO > 2-
MeO(C6H4)CO ∼ EtCO > MeOCO > Cbz > Ac < c-Pr against
LCC6-MDR. However, the decreasing order further changes
against MCF7 and NCI/ADR, i.e., Cbz > EtCO > MeOCO >
exhibit high potency against all four cell lines examined, and
the R/S ratios are 9.2-15. The observed cytotoxicity values for
17d and 17e are comparable to those for the parent second-
generation taxoids, 6x (SB-T-1213)17 and 6′x (SB-T-1103),17
shown in Table 2 for comparison. These results indicate that
the t-Boc group at the C3′N position, which is the “gold
standard”, can be replaced by these cycloalkenoyl groups
without losing potency.
Cytotoxicity assay results of second-generation taxoids bear-
ing a modified C2-benzoyl group at its meta position are
summarized in Table 7. The IC50 values of paclitaxel, docetaxel,
6x, 6′x, and 19 (SB-T-1214) are also listed for comparison.17
As Table 7 shows, a majority of these new second-generation
taxoids (14 and 15), bearing a t-Boc group at the C3′N position,

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3207
Scheme 6a
a Reagents and conditions: (i) LiHMDS, THF, -40 °C, 30 min; (ii) HF/pyridine, pyridine/MeCN, 0 °C to room temp, 18 h (61-86% for two steps); (iii)
H2, Pd/C, EtOAc, room temp, 24 h (90-92%).
Table 4. C3′N-Modified Second-Generation Taxoids 17 and 18
taxoid
R1
R4
yield (%)a
Table 5. Cytotoxicity of Second-Generation Taxoids with Modifications
at C10 (IC50, nM)a
17a
17b
17c
17d
17e
17f
17g
17h
17i
H
H
H
H
H
H
H
H
cyclobutyl
cyclopentyl
cyclohexyl
cyclopent-1-enyl
cyclohex-1-enyl
cyclopentyloxy
cyclohexyloxy
cyclopropyl
cyclobutyl
86
78
85
80
75
85
80
66
H
61
17j
17k
17l
18b
18c
18f
18g
18h
18k
18m
H
H
H
H
H
H
H
MeO
MeO
MeO
cyclopentyl
cyclohexyl
cyclohexyloxy
cyclopentyl
cyclohexyl
cyclopentyloxy
cyclohexyloxy
cyclopropyl
cyclohexyl
77
81
77
98b
98b
98b
98b
98b
98b
60c
cyclopentyloxy
a Yield for two steps unless otherwise noted. b Yield for hydrogenation.
c Yield for three steps.
4-MeO(C6H4)CH2CO > Ac > 2-MeO(C6H4)CO ∼ EtCO
against MCF7, while EtCO
. MeOCO > Cbz >
4-MeO(C6H4)CH2CO > Ac > 2-MeO(C6H4)CO ∼ EtCO
against NCI/ADR. These results suggest that the cancer cell
types including Pgp overexpression are sensitive to the C10
substitution. Nevertheless, the difference in potency for these
cases is within the factor of 10. Accordingly, all these highly
potent new taxoids are very good candidates for further
preclinical studies.
Cytotoxicity of New-Generation Taxoids against Pac-
litaxel-Resistant Cancer Cells with Point Mutations in
Tubulin. Multidrug resistance to paclitaxel arises from the
overexpression of ATP-binding cassette (ABC) transporters,28
but other drug-resistance mechanisms are also involved in
paclitaxel resistance.29 One of the significant mechanism is
associated with alterations of its cellular target, tubulin/micro-
tubule.30–35 In this regard, two paclitaxel-resistant sublines
1A9PTX10 and 1A9PTX22, derived from 1A9 cell line, have
been reported.34 The parental 1A9 is a clone of the human
ovarian carcinoma cell line A-2780. Point mutations in class I
ꢀ-tubulin in both 1A9PTX10 and 1A9PTX22 have been
identified by sequence analysis.34 Thus, the cytotoxicity of new-
generation taxoids against these two paclitaxel-resistant cell lines
would provide critical information about their ability to deal
with drug resistance other than MDR. Selected new-generation
taxoids, 19, 14g, and 15g, were assayed against both drug-
resistant cell lines and the parental cell line. As Table 8 shows,
all three taxoids exhibit extremely potent activity, especially
a Concentration of compound that inhibits 50% (IC50, nM) of the growth
of human tumor cell line after 72 h of drug exposure. R/S: resistance factor
) (IC50 for drug resistant cell line, R)/(IC50 for drug-sensitive cell line, S).
b LCC6-WT: human breast carcinoma cell line (Pgp-). c LCC6-MDR: mdr1
transduced cell line (Pgp+).

3208 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
Table 6. Cytotoxicity of Second-Generation Taxoids with C3′N Modifications (IC50, nM)a
taxoid
R1
R2
LCC6-WTb
3.1
LCC6-MDRc
346
R/Sd
MCF7e
NCI/ADRf
R/Sd
paclitaxel
6x
6′x
17a
17b
18b
17c
18c
17d
17e
17f
18f
112
1.7
0.18
0.35
1.2
1.1
2.3
1.0
1.5
0.4
0.3
1.4
1.3
1.4
1.4
300
4.0
5.1
41
22
29
176
22
15
34
20
12
18
13
15
13
6.1
6.8
6.4
10
t-Boc
t-Boc
2-Me-prop-1-enyl
2-Me-propyl
2-Me-prop-1-enyl
2-Me-prop-1-enyl
2-Me-propyl
2-Me-prop-1-enyl
2-Me-propyl
2-Me-prop-1-enyl
2-Me-prop-1-enyl
2-Me-prop-1-enyl
2-Me-propyl
cyclobutyl
cyclopentyl
cyclopentyl
cyclohexyl
1.3
1.1
6.3
1.3
5.8
1.2
1.2
0.94
2.6
1.2
4.8
34
19
64
13
32
14
11
12
14
15
18
26
17
10
10
5.5
12
9.2
13
5.4
13
3.8
18
19
cyclohexyl
cyclopent-1-enyl
cyclohex-1-enyl
cyclopentyloxy
cyclopentyloxy
cyclohexyloxy
cyclohexyloxy
6.0
3.8
8.6
8.8
8.9
14
17g
18g
2-Me-prop-1-enyl
2-Me-propyl
a Concentration of compound that inhibits 50% (IC50, nM) of the growth of human tumor cell line after 72 h of drug exposure. b LCC6-WT: human breast
carcinoma cell line (Pgp-). c LCC6-MDR: mdr1 transduced cell line (Pgp+). d R/S: resistance factor ) (IC50 for drug resistant cell line, R)/(IC50 for drug-
sensitive cell line, S). e MCF7: human breast carcinoma cell line. f NCI/ADR: multidrug resistant human ovarian carcinoma cell line.
Table 7. Cytotoxicity of Second-Generation Taxoids with C2-Meta Modifications (IC50, nM)a
taxoid
R1
R2
R3
R4
LCC6-WTb LCC6-MDRc
R/Sd
112
120
MCF7e NCI/ADRf
R/Sd
178
235
22
21
20
paclitaxel Ph
docetaxel t-BuO
6x
6′x
Ph
Ph
MeCO
H
H
H
H
H
H
Me
3.1
1.0
346
120
1.7
1.0
300
235
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
c-Pr
Me2CdCH-
Me2CHCH2-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
Me2CdCH-
CH2dCHCH2-
(E)-CH3CHdCH- EtCO
CH2dCH(CH2)2- EtCO
(S)-2,2-Me2-c-Pr- EtCO
Me2CHCH2-
Me2CHCH2-
Me2CHCH2-
Me2CHCH2-
Me2CdCH-
Me2CdCH-
EtCO
EtCO
c-PrCO
MeCO
MeCO
EtCO
EtCO
EtCO
EtCO
EtCO
c-PrCO
MeOCO
0.18
0.35
0.20
0.8
4.0
5.1
3.9
5.0
2.3
19
14a
14b
14c
14d
14e
14f
14g
14h
14i
1.5
0.6
0.5
0.8
0.9
2.9
1.0
1.0
0.6
1.2
0.4
0.4
1.2
1.2
0.9
0.48
0.4
0.8
1.1
0.9
1.1
1.6
1.1
6.9
1.23
0.6
1.0
0.76
5.8
3.9
6.3
2.9
MeO
F
2.7
2.1
1.3
1.2
7.1
0.9
2.9
1.6
1.8
0.9
0.4
8.4
4.1
5.4
1.1
2.4
2.9
2.4
0.8
17.2
15
4.5
4.2
1.6
1.3
2.4
0.90
2.9
2.7
1.5
2.3
1.0
7.0
3.4
6.0
2.3
3.0
3.6
2.2
0.89
0.8
Cl
N3
0.9
1.1
1.2
CH2dCH-
MeO
MeO
MeO
MeO
MeO
0.36
0.33
0.92
0.4
0.2
1.1
0.6
0.8
1.4
1.5
3.3
1.8
8.7
3.5
7.5
3.0
3.0
14j
14k
14l
PhCH2OCO
2-MeO(C6H4)CO
4-MeO(C6H4)CH2CO MeO
14m
14n
14o
14p
15c
15d
15e
15g
17h
17i
17j
17k
17l
18h
18k
18m
EtCO
MeO
MeO
MeO
MeO
F
10.9
2.0
0.6
7.7
1.5
3.9
2.5
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
EtCO
Cl
N3
1.0
0.36
0.5
0.8
0.3
2.1
0.43
7.8
8.8
9.5
2.1
1.19
15.6
11
32
9.7
9.7
30
9.3
6.9
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
16
9.4
10
6.1
12.0
22
c-Bu
c-pentyl Me2CdCH-
11
42
14.8
13
12
c-hexyl Me2CdCH-
1.8
17.5
c-hex-O Me2CdCH-
1.44
0.4
0.7
14
11.8
6.5
c-Pr
c-hexyl
Me2CHCH2-
Me2CHCH2-
12
3.4
c-pent-O Me2CHCH2-
2.6
0.17
1.18
a Concentration of compound that inhibits 50% (IC50, nM) of the growth of human tumor cell line after 72 h of drug exposure. b LCC6-WT: human breast
carcinoma cell line (Pgp-). c LCC6-MDR: mdr1 transduced cell line (Pgp+). d R/S: resistance factor ) (IC50 for drug resistant cell line, R)/(IC50 for drug-
sensitive cell line, S). e MCF7: human breast carcinoma cell line. f NCI/ADR: multidrug resistant human ovarian carcinoma cell line.

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3209
Table 8. Cytotoxicity of New Generation Taxoids against 1A9PTX10
cancer cell lines. In addition, taxoid 19 did not show any
appreciable cytotoxicity against primary pancreatic ductal cells
up to 10 µM concentration. This is a very impressive finding.
and 1A9PTX22 Cell Lines (IC50, nM)a
Preliminary in Vivo Antitumor Activity against Pancre-
atic Cancer CFPAC-1 Xenograft in Nude Mice. Encouraged
by remarkable in vitro cytotoxicity, a preliminary study on the
in vivo antitumor activity of taxoid 19 against CFPAC-1
xenograft in nude mice was undertaken. Animals were inocu-
lated with 1 million CFPAC-1 pancreatic cancer cells that
express high levels of mdr1 in each flank. After the tumor size
had become 100 mm3 on day 19, three intravenous injections
of 19 (20 mg/kg × 3, 60 mg/kg total dose in Tween-80/EtOH/
PBS) were made in 3-day intervals, i.e., days 19, 22, and 25.
The treatment was highly efficacious, causing complete reduc-
tion in tumor volume. After 8 weeks tumors were recovered
from the xenograft and subjected to histopathological analysis.
The analysis of the stained tissues revealed that only inflam-
matory infiltrate and fibrotic issue remained and no trace of
cancer cells. Consequently, taxoid 19 can be considered a very
promising lead compound for potential treatment of pancreatic
cancer.
taxoids
A-2780
1A9PTX10
R/Sb
1A9PTX22
R/Sb
paclitaxel 1.38 ( 0.05 532.95 ( 3.18 386
19
14g
15g
a Concentration of compound that inhibits 50% (IC50, nM) of the growth
of human tumor cell line after 72 h of drug exposure. b R/S: resistance factor
) (IC50 for drug resistant cell line, R)/(IC50 for drug-sensitive cell line, S).
160.70 ( 14.70 116
0.44 ( 0.04
0.76 ( 0.01
0.25 ( 0.01
9.00 ( 0.77 20.4
3.65 ( 0.21 4.8
4.91 ( 0.53 19.6
3.94 ( 0.03
3.88 ( 0.54
2.10 ( 0.13
9.0
5.1
8.4
against drug-resistant cell lines 1A9PTX10 and 1A9PTX22, with
2 orders of magnitude higher potency than paclitaxel. The results
clearly demonstrate that these second- and third-generation
taxoids possess capability of effectively circumventing the
paclitaxel drug resistance arising from point mutations in
tubulins/microtubules besides MDR. This makes the new-
generation taxoids even more attractive.
Cytotoxicity of New-Generation Taxoids against Pancre-
atic Cancer Cell Lines. Currently there are no effective
chemotherapeutic treatments for pancreatic cancer and the 5-year
survival rate is less than 5%.36 Pancreatic cancer is refractive
to conventional therapy, and the expression of various multidrug
resistance proteins is believed to be a major factor for the
extensive drug resistance.37–39 We carried out a RT-PCR
analysis of the expression of multidrug resistance genes in
lysates of pancreatic cancer cell lines and found that CFPAC-1
and PANC-1 cell lines expressed mdr1, mrp1, mrp2, and lrp
genes, responsible for multidrug resistance, while MIA PaCa-2
and BxPC-3 cell lines expressed mrp1, mrp2, and lrp genes.40
Accordingly, it was of particular interest for us to examine the
efficacy of new generation taxoids against highly multidrug-
resistant pancreatic cancer cell lines. Thus, two taxoids, 19 and
14g were evaluated for their cytotoxicity against four pancreatic
cancer cell lines, MIA PaCa-2, CFPAC-1, BxPC-3, and PANC-1.
Microtubule Polymerization Assay. The activities of 19,
14g, and 14i (SB-T-1213031) were evaluated in two in vitro
tubulin polymerization assays. Paclitaxel was also used as the
standard for comparison purposes. Changes in absorbance in
this spectrophotometric assay provide a direct measure of
turbidity, hence indicating the extent of tubulin polymerization.
Taxoids 19, 14g, and 14i induced tubulin polymerization in the
absence of GTP in a manner similar to paclitaxel (see Figures
1 and 2). The microtubules formed with these new generation
taxoids as well as paclitaxel were stable against Ca2+-induced
depolymerization. As Figure 1 shows, taxoids 19 and 14g
promote rapid polymerization of tubulin at a faster rate than
paclitaxel. The turbidity of the tubulin solution treated by 19
or 14g reaches a plateau quickly and does not change with time.
This observation may imply that there is a difference in structure
between microtubules formed with the new-generation taxoids
and those with paclitaxel. Third-generation taxoid 14g causes
spontaneous tubulin polymerization, reaching >90% of a plateau
within 5 min from onset, while it takes about 12 min for second-
generation taxoid 19 to reach the same point.
In a similar manner, the activity of taxoid 14i was
compared with that of paclitaxel in a tubulin polymerization
assay using a protocol for tubulin preparation slightly
different from that used for the experiments presented in
Figure 1. As Figure 2 shows, this assay reveals a remarkable
difference in the speed of tubulin polymerization between
the third-generation taxoid 14i and paclitaxel. Taxoid 14i
causes instantaneous polymerization of tubulin, completing
the polymerization within 2 min, while paclitaxel promotes
the polymerization much more slowly.
Table 9. Cytotoxicity of 19 and 14g against Pancreatic Cancer Cell
Lines (IC50, nM)a
taxoids
MIA PaCa-2
CFPAC-1
BxPC-3
PANC-1
19
14g
0.92
0.68
0.83
0.89
1.04
3.03
3.68
22.6
a Concentration of compound that inhibits 50% (IC50, nM) of the growth
of human tumor cell line after 72 h of drug exposure.
As Table 9 shows, new-generation taxoids 19 and 14g exhibit
excellent cytotoxicity against four pancreatic cancer cell lines
with subnanomolar to single-digit nanomolar IC50 values except
one case for 14g against PANC-1. It is worth mentioning that
the third-generation taxoid 14g, which possesses superior
potency (>10 times) over the second-generation taxoid 19
against Pgp+ (i.e., mdr1) human ovarian cancer cell line NCI/
ADR (see Table 3), exhibits lower potency than taxoid 19
against BxPC-3 and PANC-1 cell lines, especially against the
latter (22.6 vs 3.68 nM). The results may suggest that taxoid
14g cannot modulate a combination of multidrug-resistant
proteins so efficiently as Pgp alone. Nevertheless, 14g is still
highly cytotoxic to PANC-1. On the other hand, taxoid 19
demonstrates remarkably high potency against all four pancreatic
Electron Microscopy Analysis. The microtubules formed
with new-generation taxoids (19, 14g, and 14i) were analyzed
further by electron microscopy for their morphology and
structure in comparison with those formed by using GTP
and paclitaxel. The electron micrographs of microtubules formed
with three taxoids, paclitaxel, and GTP are summarized in Figure
3. As parts A and B of Figure 3 show, GTP and paclitaxel form
long and straight microtubules. The microtubules formed with
a second-generation taxoid 19 (Figure 3C) are shorter than those
with GTP or paclitaxel. In contrast, the morphology of the
microtubules formed by the action of third-generation taxoids
14g and 14i is unique in that those microtubules are very short
and numerous (parts D and E of Figure 3). The microtubules

3210 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
Figure 1. Tubulin polymerization with 19, 14g, and paclitaxel:
microtubule protein 1 mg/mL, 37 °C, GTP 1 mM, drug 10 µM.
Figure 2. Tubulin polymerization with 14i and paclitaxel: microtubule
protein 1 mg/ml, 37 °C, drug 10 µM.
with taxoid 14g appear to have more curvature than those with
14i. It is worth mentioning that discodermolide (another potent
anticancer drug candidate, stabilizing microtubules41–44) forms
microtubules with characteristics similar to those formed with
14g and 14i, i.e., short and numerous (Figure 3F). It is strongly
suggested that the formation of short and numerous microtubules
is related to the instantaneous rapid polymerization of tubulin
observed with these third-generation taxoids as well as
discodermolide.
Figure 3. Electromicrographs of microtubules (20000×): (A) GTP;
(B) paclitaxel; (C) 19; (D) 14g; (E) 14i; (F) discodermolide.
Antitumor Activity of Taxoid 19 in Vivo against Pgp+
DLD-1 Human Colon Tumor Xenograft. Taxoid 19 has
recently emerged as one of the leading candidates among the
second- and third-generation taxoids being studied in the Ojima
laboratory, especially in connection with tumor-targeting drug
delivery using taxoid conjugates with ω3 fatty acids.45 Accord-
ingly, this taxoid was evaluated for its efficacy against a drug-
resistant human colon tumor xenograft (Pgp+) DLD-1 in severe
combined immune deficient mice (SCID). Taxoid was admin-
istered intravenously at three doses 3 times using a 3-day
regimen (q3d × 3, on days 5, 8, and 11), starting from day 5
after DLD-1 subcutaneous tumor implantation. Results are
summarized in Table 10.
As Table 6 shows, taxoid 19 exhibits remarkable antitumor
activity in sharp contrast to paclitaxel. As anticipated, paclitaxel
is ineffective against this highly drug-resistant (Pgp+) tumor
at its optimal dose (60 mg/kg total dose). The best result for
taxoid 19 was obtained at 60 mg/kg total dose (20 mg/kg × 3),
wherein complete regression of the DLD-1 tumor was achieved
in 5 of 5 mice (tumor growth delay greater than 150 days).
Systemic toxicity profile shows that there was only 3-5%
weight loss during day 15 to day 20, and the drug was very
well tolerated by animals. At 30 mg/kg total dose (10 mg/kg ×
Table 10. Antitumor Effect of Taxoid 19 Delivered iv to SCID Mice
Bearing a Pgp+ Human Colon Tumor Xenograft, DLD-1
iv
total dose
(mg/kg)
growth
cured mice/
groupd
treatmenta
delayb (day)
toxicityc
control
vehicle
paclitaxel
19
19
19
0
0
60
30
60
120
0
0
0
0
0
2
0/10
0/5
0/5
0/5
5/5
3/5
4
8
37
>150
>150
a Treatment given iv to SCID mice on day 5 after DLD-1 human colon
tumor implant and continued as noted. All drugs were formulated in
Tween/EtOH. b Based on comparison of each group vs control using the
Cox-Mantel test. c Number of animals that either died or lost greater than
20% body weight. d SCID mice with no palpable tumor on day 167, end of
experiment.
3), tumor growth delay of 37 days was observed, but all animals
died before day 60. At 120 mg/kg total dose (40 mg/kg × 3),
two animals died because of the drug’s toxicity. Nevertheless,
three animals survived till the end of the experiment on day
167 (tumor growth delay less than 150 days). Thus, the total
dose of 60 mg/kg (20 mg/kg × 3) appears to be optimal for
taxoid 19. The highly promising in vivo antitumor activity of

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3211
2′-Triisopropyl-3′-dephenyl-3′-(2-methyl-1-propenyl)-7-trieth-
ylsilyldocetaxel (5). To a solution of 4 (31 mg, 0.03 mmol) in 3
mL of EtOH was added 1 mL of N2H4 ·H2O, and the mixture was
allowed to stir for 1 h. The reaction was quenched with saturated
aqueous NH4Cl and extracted two times with EtOAc. The combined
organic layers were washed with water and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The resulting crude
solid was purified by flash chromatography on silica gel (hexanes/
EtOAc ) 3/1) to afford 5 (25 mg, 85% yield) as a white solid: 1H
(300 MHz, CDCl3) δ 0.54 (m, 6 H), 0.85 (m, 9 H), 1.04 (m, 24
H), 1.15 (s, 3 H), 1.33 (s, 9 H), 1.64 (s, 6 H), 1.74 (m, 4 H), 2.34
(m, 1 H), 2.37 (s, 3 H), 3.90 (d, J ) 7.5 Hz, 1 H), 4.20 (d, J ) 8.7
Hz, 1 H), 4.30 (d, 8.7 Hz, 1 H), 4.42 (m, 2 H), 4.80 (m, 2 H), 4.92
(d, J ) 8.1, 1 H), 5.11 (d, J ) 1.8 Hz, 1 H), 5.33 (d, J ) 8.4 Hz,
1 H), 5.63 (d, J ) 7.5 Hz, 1 H), 6.15 (t, J ) 8.1 Hz, 1 H), 7.47
(dd, J ) 8.1 Hz, 7.2 Hz, 2 H), 7.59 (dd, J ) 7.2 Hz, 8.1 Hz, 1 H),
8.09 (d, J ) 7.2 Hz, 2 H).
Preparation of 2′,7-Protected Taxoid 5A. Method A. To a
solution of 5, 3 equiv of DMAP, and 3 equiv of triethylamine in
CH2Cl2 was added 3 equiv of the corresponding acid chloride. The
solution was allowed to stir for 12-72 h at 25-40 °C, diluted with
EtOAc, and quenched with saturated aqueous NaHCO3. The organic
layer was washed with water and brine, dried over MgSO4, filtered,
and concentrated. The resulting solid was purified by flash
chromatography on silica gel to afford the corresponding coupling
product, 2′-triisopropyl-3′-dephenyl-3′-(2-methyl-1-propenyl)-7-tri-
ethylsilyl-10-acyldocetaxel (5A).
19 warrants further preclinical evaluation of this second-
generation taxoid.
Experimental Section
General Methods. 1H and 13C NMR spectra were measured on
a Varian 300, 400, or 500 MHz NMR spectrometer or a Bruker
AC-250 NMR spectrometer. Melting points were measured on a
Thomas-Hoover capillary melting point apparatus and are uncor-
rected. Specific optical rotations were measured on a Perkin-Elmer
model 241 polarimeter. IR spectra were recorded on a Perkin-Elmer
model 1600 FT-IR spectrophotometer. TLC was performed on
Merck DC-alufolien with Kieselgel 60F-254, and column chroma-
tography was carried out on silica gel 60 (Merck, 230-400 mesh
ASTM). Purity was determined with a Waters HPLC assembly
consisting of dual Waters 515 HPLC pumps, a PC workstation
running Millennium 32, and a Waters 996 PDA detector, using a
Phenomenex Curosil-B column, employing CH3CN/water (2/3) as
the solvent system with a flow rate of 1 mL/min. High-resolution
mass spectra were obtained at the Mass Spectrometry Laboratory,
University of Illinois at Urbana-Champaign, Urbana, IL, or the
Mass Spectrometry Facility, University of California, Riverside,
Riverside, CA.
Materials. The chemicals were purchased from Aldrich-Sigma
Co. and used as received or purified before use by standard methods.
Tetrahydrofuran was freshly distilled from sodium metal and
benzophenone. Dichloromethane was also distilled immediately
prior to use under nitrogen from calcium hydride. N,N-Dimethyl-
formamide (DMF) was distilled over 4 Å molecular sieves under
reduced pressure. 4-(N,N-Dimethylamino)pyridine (DMAP) was
uses as received. 10-Deacetylbaccatin III (DAB, 1) was obtained
from Indena, SpA, Italy. 7-Triethylsilylbaccatin III (2),46,47 (3R,4S)-
1-tert-butoxycarbonyl-3-triisopropylsiloxy-4-(2-methylprop-1-enyl)
azetidin-2-one (3a),7,20 (3R,4S)-1-tert-butoxycarbonyl-3-triisopro-
pylsiloxy-4-(2-methylpropyl)azetidin-2-one (3b),14,48 (3R,4S)-1-
(tert-butoxycarbonyl)-3-triisopropylsiloxy-4-(prop-2-enyl)azetidin-
2-one (3c),49 (3R,4S)-1-(tert-butoxycarbonyl)-3-triisopropylsiloxy-
4-[(E)-prop-1-enyl]azetidin-2-one(3d),7(3R,4S)-1-(tert-butoxycarbonyl)-
3-triisopropylsiloxy-4-(3-butenyl)azetidin-2-one (3e),49 (3R,4S)-1-
(tert-butoxycarbonyl)-3-triisopropylsiloxy-4-[(S)-2,2-dimethylcy-
clopropyl]azetidin-2-one (3f),26 7,10,13-tri(triethylsilyl)-10-deacetyl-
baccatin III (7),23,49 7,10,13-tri(triethylsilyl)-2-debenzoyl-10-
deacetylbaccatin III (8),49,50 7-triethylsilyl-10-deacetyl-10-pro-
panoylbaccatin,17 and 3′-dephenyl-3′-(2-methyl-1-propenyl)-10-
(cyclopropanecarbonyl)docetaxel (19)17 were prepared by the
literature methods.
Method B. To a solution of 5, 3 equiv of DMAP, and 3 equiv
of the corresponding acid in CH2Cl2 was added 3 equiv of DIC.
The solution was allowed to stir for 12-72 h at 25 °C, diluted
with EtOAc, and quenched with saturated aqueous NaHCO3. The
organic layer was washed with water and brine, dried over MgSO4,
filtered, and concentrated. The resulting solid was purified by flash
chromatography on silica gel to afford the desired coupling product
5A.
Preparation of Taxoids 6 through Deprotection of 5A. A
typical procedure is described for the synthesis of 3′-dephenyl-3′-
(2-methyl-1-propenyl)-10-(2-methoxybenzoyl)docetaxel (6b). To a
solution of 10 mg (0.01 mmol) of 2′-triisopropyl-3′-dephenyl-3′-
(2-methyl-1-propenyl)-7-triethylsilyl-10-(2-methoxybenzoyl)doce-
taxel (5A-b) in 1 mL of pyridine/acetonitrile (1/1) was added
dropwise 0.1 mL of HF/pyridine at 0 °C, and the mixture was stirred
at room temperature overnight. The reaction was quenched with
saturated aqueous NaHCO3. The mixture was then diluted with ethyl
acetate, washed with saturated CuSO4 solution and water, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(hexanes/EtOAc ) 1/1) to afford 5 mg (90% yield) of taxoid 6b
Synthesis of C10-Modified Taxoids 6. C-10 modified second-
generation taxoids 6 were synthesized using the route illustrated
in Scheme 1 via key intermediates 4 and 5, followed by acylation
and deprotection. Typical procedures for the preparation of 4 and
5 as well as those for acylation and deprotection are described
below.
20
as a white solid: mp 150-158 °C; [R]D -75 (c 0.010, CDCl3);
1H NMR (250 MHz, CDCl3) δ 1.20 (m, 6 H), 1.31 (s, 9 H), 1.54
(s, 3 H), 1.63 (s, 3 H), 1.82 (m, 1 H), 1.84 (s, 3 H), 2.01 (s, 3 H),
2.36 (s, 3 H), 2.57 (m, 2 H), 3.39 (bs, 1 H), 3.89 (m, 4 H), 4.20
(m, 2 H), 4.31 (d, J ) 8.1 Hz, 1 H), 4.48 (m, 1 H), 4.63 (m, 2 H),
4.98 (d, J ) 8.7 Hz, 1 H), 5.25 (m, 1 H), 5.70 (d, J ) 6.9 Hz, 1
H), 6.12 (m, 1 H), 6.47 (s, 1 H), 7.00 (m, 2 H), 7.54 (m, 4 H), 8.22
(m, 3 H); 13C (63 MHz, CDCl3) δ 9.6, 15.0, 18.6, 21.9, 22.4, 25.7,
26.6, 28.2, 35.6, 43.3, 45.7, 51.6, 55.9, 58.7, 72.2, 72.4, 73.8, 75.2,
75.6, 78.0, 79.3, 80.0, 81.1, 84.5, 112.1, 120.3, 120.63, 128.6, 129.2,
130.2, 132.7, 133.0, 133.7, 134.6, 160.0, 165.8, 167.0, 170.1, 170.5,
203.8. HRMS (FAB) m/z calcd for C49H61NO16 ·H+: 920.4069.
Found: 920.4068 (∆ ) 0.1 ppm). Other taxoids 6a and 6c-o were
prepared in the same manner, and characterization data are shown
below.
7-Triethylsilyl-10-acetyl-2′-triisopropyl-3′-dephenyl-3′-(2-meth-
ylprop-1-enyl)docetaxel (4). To a solution of 7-triethylsilylbaccatin
III (2)46,47 (86 mg, 0.12 mmol) and 4-(2-methylprop-1-enyl)-ꢀ-
lactam 37,20 (82 mg, 0.20 mmol) in 5 mL of dry THF was added
1 M LiHMDS (0.20 mL, 0.20 mmol) in THF dropwise at -40 °C,
and the solution was stirred at the same temperature for 30 min.
The reaction was quenched with saturated aqueous NH4Cl, and the
aqueous layer was extracted with CH2Cl2. The combined extracts
were dried over anhydrous MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (hexane/
EtOAc ) 6:1) to afford 4 (125 mg, 95% yield) as a white solid:
1H (300 MHz, CDCl3) δ 0.54 (m, 6 H), 0.85 (m, 9 H), 1.04 (m, 24
H), 1.15 (s, 3 H), 1.33 (s, 9 H), 1.64 (s, 6 H), 1.74 (m, 4 H), 2.16
(s, 3 H), 2.35 (s, 3 H), 2.49 (m, 1 H), 3.90 (d, J ) 7.5 Hz, 1 H),
4.20 (d, J ) 8.7 Hz, 1 H), 4.30 (d, 8.7 Hz, 1 H), 4.43 (m, 2 H),
4.80 (m, 2 H), 4.92 (d, J ) 8.1 Hz, 1 H), 5.33 (d, J ) 8.4 Hz, 1
H), 5.63 (d, J ) 7.5 Hz, 1 H), 6.08 (t, J ) 8.1 Hz, 1 H), 6.35 (s,
1 H), 7.47 (dd, J ) 8.1 Hz, 7.2 Hz, 2 H), 7.59 (dd, J ) 7.2 Hz, 8.1
Hz, 1 H), 8.09 (d, J ) 7.2 Hz, 2 H).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-benzoyldocetaxel (6a).
90% (two steps); white solid; mp 140-143 °C; 1H NMR (250 MHz,
CDCl3) δ 1.12 (s, 3 H), 1.22 (s, 3 H), 1.35 (s, 9 H), 1.58 (s, 3 H),
1.70 (s, 3 H), 1.76 (s, 3 H), 1.85 (m, 1 H), 1.96 (s, 3 H) 2.37 (s, 3
H), 2.60 (m, 2 H), 3.38 (m, 1 H), 3.89 (d, J ) 7.0 Hz, 1 H), 4.21
(m, 2 H), 4.32 (d, J ) 8.3 Hz, 1 H), 4.52 (m, 1 H), 4.76 (m, 2 H),
4.98 (d, J ) 8.0 Hz, 1 H), 5.30 (m, 1 H), 5.71 (d, J ) 7.0 Hz, 1
H), 6.21 (m, 1 H), 6.56 (s, 1 H), 7.47 (dd, J ) 7.3 Hz, 7.8 Hz, 4

3212 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
H), 7.58 (m, 2 H), 8.10 (m, 4 H); 13C (63 MHz, CDCl3) δ 9.6,
15.0, 18.6, 22.1, 22.4, 23.5, 25.7, 26.9, 28.2, 35.7, 42.3, 43.3, 45.8,
51.6, 58.7, 72.3, 72.4, 73.8, 75.1, 76.0, 79.2, 80.1, 81.1, 84.5, 120.6,
128.5, 128.7, 129.1, 129.2, 130.0, 130.2, 132.9, 133.7, 142.9, 166.4,
167.0, 170.1, 172.1, 203.6. HRMS (FAB) m/z calcd for
C48H59NO15 ·H+: 890.3963. Found: 890.3966 (∆ ) -0.3 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(3-methoxybenzoyl)-
docetaxel (6c). 87% (two steps); white solid; mp 154-159 °C;
[R]20D -75 (c 0.010, CDCl3); 1H NMR (250 MHz, CDCl3) δ 1.20
(s, 3 H), 1.37 (s, 15 H), 1.54 (s, 3 H), 1.63 (s, 3 H), 1.82 (m, 1 H),
1.84 (s, 3 H), 2.36 (s, 3 H), 2.57 (m, 2 H), 3.39 (bs, 1 H), 3.89 (m,
4 H), 4.20 (m, 2 H), 4.31 (d, J ) 8.1 Hz, 1 H), 4.48 (m, 1 H), 4.63
(m, 2 H), 4.98 (d, J ) 8.7 Hz, 1 H), 5.25 (m, 1 H), 5.70 (d, J ) 6.9
Hz, 1 H), 6.12 (m, 1 H), 6.54 (s, 1 H), 7.02 (m, 1 H), 7.44 (m, 6
H), 8.02 (m, 2 H); 13C (63 MHz, CDCl3) δ 9.6, 15.0, 18.6, 22.1,
22.4, 25.7, 26.8, 28.2, 33.4, 35.7, 43.3, 45.8, 51.6, 55.4, 58.7, 72.3,
73.8, 75.1, 76.1, 79.2, 80.0, 81.1, 84.5, 105.1, 114.1, 120.1, 120.6,
122.3, 128.7, 129.2, 129.6, 130.2, 130.4, 132.8, 133.7, 159.6, 166.3,
167.0, 169.7, 169.8, 170.1, 170.4, 203.5. HRMS (FAB) m/z calcd
for C49H61NO16 ·H+: 920.4069. Found: 920.4068 (∆ ) 0.1 ppm).
HPLC analysis using a Phenomenex Curosil-B column: CH3CN/
water (2/3) as the solvent system with a flow rate of 1 mL/min;
UV (230 and 254 nm) showed g95% purity.
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(4-methoxybenzoyl)-
docetaxel (6d). 80%; white solid; mp 148-156 °C; [R]20D -45 (c
0.010, CDCl3); 1H NMR (250 MHz, CDCl3) δ 1.25 (s, 3 H), 1.35
(s, 9 H), 1.55 (s, 3 H), 1.70 (s, 6 H), 1.77 (s, 3 H), 1.82 (m, 1 H),
1.95 (s, 3 H), 2.37 (s, 3 H), 2.57 (m, 2 H), 3.39 (bs, 1 H), 3.88 (m,
4 H), 4.21 (m, 2 H), 4.31 (d, J ) 8.1 Hz, 1 H), 4.55 (m, 1 H), 4.76
(m, 2 H), 4.98 (d, J ) 8.7 Hz, 1 H), 5.23 (m, 1 H), 5.75 (d, J ) 6.6
Hz, 1 H), 6.21 (m, 1 H), 6.54 (s, 1 H), 6.94 (d, J ) 6.5 Hz, 2 H),
7.48 (m, 3 H), 8.03 (d, J ) 9 Hz, 2 H), 8.11 (d, J ) 6.5 Hz, 2 H);
13C (63 MHz, CDCl3) δ 9.6, 15.0, 18.6, 22.1, 22.4, 25.7, 26.8,
28.2, 33.4, 35.7, 43.3, 45.8, 51.6, 55.4, 58.7, 72.3, 73.8, 75.1, 76.1,
79.2, 80.0, 81.1, 84.5, 105.1, 114.1, 120.1, 120.6, 121.3, 128.7,
129.2, 129.6, 130.2, 131.4, 132.8, 133.7, 159.6, 166.3, 167.4, 169.8,
170.0, 170.1, 170.7, 203.6. HRMS (FAB) m/z calcd for
C49H61NO16 ·H+: 920.4069. Found: 920.4068 (∆ ) 0.1 ppm). HPLC
analysis using a Phenomenex Curosil-B column: CH3CN/water (2/
3) as the solvent system with a flow rate of 1 mL/min; UV (230
and 254 nm) showed g95% purity.
203.9. HRMS (FAB) m/z calcd for C52H61NO15 ·H+: 940.4128.
Found: 940.4124 (∆ ) 0.4 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(2-napthoyl)doce-
taxel (6g). 92%; white solid; mp 165-170 °C; 1H NMR (250 MHz,
CDCl3) δ 1.32 (s, 3 H), 1.35 (s, 9 H), 1.39 (s, 3 H), 1.57 (s, 3 H),
1.72 (s, 3 H), 1.76 (s, 3 H), 1.95 (m, 1 H), 1.98 (s, 3 H), 2.38 (s,
3 H), 2.50 (m, 2 H), 3.39 (bs, 1 H), 3.92 (d, J ) 7.0 Hz, 1 H), 4.23
(m, 2 H), 4.31 (d, J ) 8.3 Hz, 1 H), 4.55 (m, 1 H), 4.77 (m, 2 H),
4.99 (d, J ) 8.8 Hz, 1 H), 5.25 (m, 1 H), 5.73 (d, J ) 6.8 Hz, 1
H), 6.23 (m, 1 H), 6.63 (s, 1 H), 7.51 (m, 5 H), 7.99 (m, 6 H), 8.65
(s, 1 H); 13C (63 MHz, CDCl3) δ 9.6, 14.2, 15.1, 18.6, 22.2, 22.4,
25.7, 26.9, 28.2, 35.7, 43.3, 45.8, 51.6, 58.7, 72.3, 73.4, 73.8, 75.1,
76.2, 79.2, 80.0, 81.1, 84.5, 120.6, 125.2, 126.3, 126.8, 127.8, 128.4,
128.6, 129.2, 129.5, 130.2, 131.8, 132.4, 132.9, 133.7, 135.9, 138.0,
142.9, 155.5, 166.6, 167.0, 170.1, 203.6. HRMS (FAB) m/z calcd
for C52H61NO15 ·H+: 940.4128. Found: 940.4124 (∆ ) 0.4 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-benzyloxycarbonyl-
docetaxel (6h). 97%, white solid; mp 145-150 °C; 1H NMR (300
MHz. CDCl3) δ 1.15 (s, 3 H), 1.23 (s, 3 H), 1.34 (s, 9 H), 1.60 (bs,
1 H), 1.70 (s, 3 H), 1.76 (s, 6 H), 1.85 (m, 1 H), 1.89 (s, 3 H), 2.36
(s, 3 H), 2.54 (m, 2 H), 3.36 (bs, 1 H), 4.19 (m, 2 H), 4.30 (d, J )
8.7 Hz, 1 H), 4.40 (m, 1 H), 4.76 (m, 2 H), 4.96 (d, J ) 7.8 Hz,
1 H), 5.23 (s, 2 H), 5.31 (d, J ) 7.5 Hz, 1 H), 5.67 (d, J ) 6.9 Hz,
1 H), 6.16 (m, 2 H), 7.40 (m, 7 H), 7.61 (dd, J ) 7.2 Hz, 7.5 Hz,
1 H), 8.10 (d, J ) 7.5 Hz, 2 H); 13C NMR (63 MHz, CDCl3) δ
9.5, 15.1, 18.5, 21.8, 22.4, 25.7, 26.5, 28.2, 35.5, 35.6, 43.1, 45.6,
51.6, 58.2, 58.6, 70.6, 72.1, 72.3, 73.8, 75.0, 78.4, 79.2, 80.0, 81.0,
84.4, 120.6, 128.5, 128.6, 128.7, 129.2, 130.1, 132.5, 133.7, 134.7,
137.9, 143.5, 155.3, 155.5, 166.9, 170.1, 173.0, 203.9. HRMS
(FAB) m/z calcd for C49H61NO16 ·H+: 920.4069. Found: 920.4068
(∆ ) 0.1 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(2-methoxyphenyl-
acetyl)docetaxel (6i). 80% (for two steps); white solid; mp
1
148-149 °C; H NMR (250 MHz. CDCl3) δ 1.04 (s, 3 H), 1.13
(s, 3 H), 1.35 (s, 9 H), 1.58 (s, 3 H), 1.66 (s, 3 H), 1.76 (s, 3 H),
1.88 (s, 4 H), 2.34 (s, 3 H), 2.39 (m, 2 H), 2.50 (m, 1 H), 3.39 (bs,
1 H), 3.81 (m, 4 H), 4.19 (m, 2 H), 4.32 (m, 2 H), 4.75 (m, 2 H),
4.94 (d, J ) 7.5 Hz, 1 H), 5.29 (m, 1 H), 5.64 (d, J ) 6.8 Hz, 1
H), 6.14 (t, J ) 7.5 Hz, 1 H), 6.29 (s, 1 H), 6.92 (m, 2 H), 7.27 (m,
2 H), 7.46 (m, 2 H), 7.56 (m, 1 H), 8.09 (d, J ) 7.0 Hz, 2 H); 13
C
NMR (63 MHz, CDCl3) δ 9.5, 14.2, 15.1, 18.5, 21.6, 22.4, 25.7,
26.4, 28.2, 30.9, 35.6, 40.1, 43.1, 45.8, 51.5, 55.7, 58.8, 61.2, 72.0,
72.3, 73.7, 74.9, 75.0, 75.8, 79.1, 81.0, 84.4, 87.5, 114.0, 114.6,
120.1, 120.6, 122.5, 128.6, 129.6, 130.4, 130.5, 132.7, 142.5, 159.6,
169.7, 170.5, 172.9, 203.4. HRMS (FAB) m/z calcd for
C50H63NO16 · H+: 934.4225. Found: 934.4229 (∆ ) -0.4 ppm).
HPLC analysis using a Phenomenex Curosil-B column: CH3CN/
water (2/3) as the solvent system with a flow rate of 1 mL/min;
UV (230 and 254 nm) showed g95% purity.
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(3,4-dimethoxyben-
zoyl)docetaxel (6e). 92% (for two steps); white solid; mp 159-165
1
°C; H NMR (250 MHz, CDCl3) δ 1.25 (s, 6 H), 1.33 (s, 12 H),
1.70 (s, 3 H), 1.76 (s, 3 H), 1.95 (m, 4 H), 2.42 (s, 3 H), 2.66 (m,
2 H), 3.37 (bs, 1 H), 3.88 (m, 1 H), 3.93 (s, 3 H), 3.95 (s, 3 H),
4.18 (m, 2 H), 4.32 (d, J ) 8.5 Hz, 1 H), 4.51 (m, 1 H), 4.76 (m,
2 H), 4.98 (d, J ) 8.0 Hz, 1 H), 5.31 (m, 1 H), 5.71 (d, J ) 6.8
Hz, 1 H), 6.21 (t, J ) 8.0 Hz, 1 H), 6.53 (s, 1 H), 6.92 (d, J ) 8.5
Hz, 1 H), 7.44 (dd, J ) 7.3 Hz, 8.0 Hz, 2 H), 7.57 (m, 2 H), 7.73
(d, J ) 8.5 Hz, 1 H), 8.11 (d, J ) 7.0 Hz, 2 H); 13C NMR (63
MHz, CDCl3) δ 9.5, 14.2, 15.0, 18.6, 22.1, 22.4, 25.7, 26.9, 28.2,
29.7, 35.6, 43.3, 45.8, 51.6, 56.0, 56.1, 58.7, 72.3, 73.8, 75.1, 75.9,
79.2, 80.0, 81.1, 84.5, 110.4, 112.4, 120.6, 121.5, 124.1, 128.7,
129.2, 130.2, 132.9, 133.7, 138.0, 142.8, 148.8, 153.7, 155.5, 166.2,
167.0, 170.1, 173.1, 203.8. HRMS (FAB) m/z calcd for
C50H63NO17 ·H+: 950.4174. Found: 950.4174 (∆ ) 0.0 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(1-naphthoyl)doce-
taxel (6f). 90% (two steps); white solid; mp 162-164 °C; 1H NMR
(250 MHz, CDCl3) δ 1.21 (s, 3 H), 1.28 (s, 3 H), 1.35 (s, 9 H),
1.73 (s, 3 H), 1.77 (s, 6 H), 1.93 (m, 1 H), 2.00 (s, 3 H), 2.38 (s,
3 H), 2.68 (m, 2 H), 3.37 (bs, 1 H), 3.92 (d, J ) 7.0 Hz, 1 H), 4.23
(m, 2 H), 4.33 (d, J ) 8.3 Hz, 1 H), 4.58 (m, 1 H), 4.77 (m, 2 H),
5.00 (d, J ) 8.0 Hz, 1 H), 5.33 (m, 1 H), 5.73 (d, J ) 7.0 Hz, 1
H), 6.23 (t, J ) 7.0 Hz, 1 H), 6.69 (s, 1 H), 7.57 (m, 6 H), 7.90 (d,
J ) 7.5 Hz, 1 H), 8.10 (m, 3 H), 8.32 (d, J ) 6.5 Hz, 1 H), 8.89
(d, J ) 8.3 Hz, 1 H); 13C NMR (63 MHz, CDCl3) δ 9.6, 15.1,
15.6, 18.6, 22.2, 22.4, 25.7, 26.8, 28.2, 35.7, 43.3, 45.8, 51.6, 58.7,
72.3, 72.4, 73.8, 75.1, 76.0, 79.2, 80.0, 81.1, 84.5, 120.6, 124.5,
125.7, 126.1, 126.4, 128.0, 128.6, 128.7, 129.2, 130.2, 130.8, 131.4,
133.0, 133.7, 134.1 138.0, 143.0, 155.5, 167.0, 167.5, 170.2, 173.0,
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(3-methoxyphenyl-
acetyl)docetaxel (6j). 80% (for two steps); white solid; mp
1
145-150 °C; H NMR (250 MHz, CDCl3) δ 1.07 (s, 3 H), 1.18
(s, 3 H), 1.34 (s, 9 H), 1.59 (s, 3 H), 1.67 (s, 3 H), 1.73 (s, 3 H),
1.76 (s, 3 H) 1.86 (s, 3 H), 1.86 (m, 1 H), 2.17 (m, 4 H), 2.37 (s,
3 H), 2.39 (m, 2 H), 2.55 (m, 1 H), 3.34 (bs, 1 H), 3.79 (m, 4 H),
4.19 (m, 1 H), 4.32 (d, J ) 8.4 Hz, 1 H), 4.39 (m, 1 H), 4.73 (m,
2 H), 4.94 (d, J ) 8.1 Hz, 1 H), 5.30 (m, 1 H), 5.64 (d, J ) 6.8
Hz, 1 H), 6.13 (t, J ) 8.1 Hz, 1 H), 6.30 (s, 1 H), 6.88 (m, 2 H),
7.27 (m, 2 H), 7.46 (m, 2 H), 7.60 (m, 1 H), 8.09 (d, J ) 7.3 Hz,
2 H); 13C NMR (250 MHz, CDCl3) δ 9.5, 14.5, 15.1, 18.4, 21.6,
22.4, 25.7, 26.4, 28.2, 30.9, 35.6, 40.1, 43.1, 45.6, 51.5, 55.7, 58.8,
61.2, 72.0, 72.3, 73.7, 74.9, 75.0, 75.8, 79.1, 81.0, 84.4, 87.5, 114.0,
114.6, 120.1, 120.6, 122.7, 128.6, 129.6, 130.2, 130.5, 132.5, 142.5,
159.6, 168.9, 170.5, 172.9, 203.6. HRMS (FAB) m/z calcd for
C50H63NO16 · H+: 934.4225. Found: 934.4229 (∆ ) -0.4 ppm).
HPLC analysis using a Phenomenex Curosil-B column: CH3CN/
water (2/3) as the solvent system with a flow rate of 1 mL/min;
UV (230 and 254 nm) showed g95% purity.
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-(4-methoxyphenyl-
acetyl)docetaxel (6k). 60% (for two steps); white solid; mp
1
145-150 °C; H NMR (250 MHz. CDCl3) δ 1.07 (s, 3 H), 1.18

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3213
(s, 3 H), 1.34 (s, 9 H), 1.59 (s, 3 H), 1.67 (s, 3 H), 1.73 (s, 3 H),
1.76 (s, 3 H), 1.86 (s, 3 H), 1.86 (m, 1 H), 2.17 (m, 4 H), 2.37 (s,
3 H), 2.39 (m, 2 H), 2.55 (m, 1 H), 3.34 (bs, 1 H), 3.79 (m, 4 H),
4.19 (m, 1 H), 4.32 (d, J ) 8.4 Hz, 1 H), 4.39 (m, 1 H), 4.73 (m,
2 H), 4.94 (d, J ) 8.1 Hz, 1 H), 5.30 (m, 1 H), 5.64 (d, J ) 6.9
Hz, 1 H), 6.15 (t, J ) 8.1 Hz, 1 H), 6.30 (s, 1 H), 7.03 (d, J ) 9.0
Hz, 2 H), 7.45 (m, 2 H), 7.58 (m, 1 H), 8.10 (d, J ) 7.3 Hz, 2 H),
8.26 (d, J ) 9.0 Hz, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.5,
14.2, 15.1, 18.5, 21.6, 22.4, 25.7, 26.4, 28.2, 30.9, 35.6, 40.1, 43.1,
45.8, 51.5, 55.7, 58.8, 61.2, 72.0, 72.3, 73.7, 74.9, 75.0, 75.8, 79.1,
81.0, 84.4, 87.5, 114.0, 114.6, 120.1, 120.6, 122.5, 128.6, 129.6,
130.4, 130.5, 132.7, 142.5, 159.6, 169.7, 170.5, 172.9, 203.4. HRMS
(FAB) m/z calcd for C50H63NO16 ·H+: 934.4225. Found: 934.4229
(∆ ) -0.4 ppm).
Hz 2 H); 13C NMR (63 MHz, CDCl3) δ 9.5, 14.9, 18.6, 22.4, 25.7,
26.6, 28.2, 30.0, 35.6, 36.1, 43.2, 45.6, 51.6, 55.3, 58.6, 72.2, 72.3,
73.8, 75.0, 75.5, 79.2, 81.1, 84.4, 113.9, 117.6, 120.6, 128.6, 129.2,
130.2, 132.2, 132.8, 133.7, 138.0, 142.6, 158.2, 167.0, 170.1, 173.1,
173.6, 203.8. HRMS (FAB) m/z calcd for C51H65NO16 ·H+:
948.4382. Found: 948.4382 (∆ ) 0.0 ppm).
Preparation of 7,10,13-Tri-TES-2-Modified Baccatins (9). A
typical procedure is described for the preparation of 7,10,13-
tri(triethylsilyl)-2-debenzoyl-2-(3-fluorobenzoyl)-10-deacetylbacca-
tin III (9c). To a solution of baccatin 8 (200 mg, 0.255 mmol),
3-fluorobenzoic acid (179 mg, 1.28 mmol), and DMAP (31 mg,
0.255 mmol) in 4 mL of dichloromethane was added 1,3-
diisopropylcarbodiimide (DIC) (193.1 mg, 1.53 mmol), and the
mixture was stirred at 40 °C for 40 h. The resulting precipitate
was filtered off and washed with ethyl acetate (30 mL). The filtrate
was washed with saturated sodium bicarbonate solution (10 mL ×
2), dried over anhydrous magnesium sulfate, and concentrated in
vacuo. Column chromatography of the residue on silica gel using
hexanes/ethyl acetate (7/1) as eluant gave 9c as a white solid (183
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-hydrocinnamoyldoc-
etaxel (6l). 85% (for two steps); white solid; mp 150-155 °C; 1H
NMR (250 MHz, CDCl3) δ 1.13 (s, 3 H), 1.21 (s, 3 H), 1.56 (s, 12
H), 1.68 (s, 3 H), 1.72 (s, 3 H), 1.86 (s, 3 H), 1.88 (m, 1 H), 2.16
(s, 3 H), 2.38 (m, 2 H), 2.85 (m, 2 H), 3.20 (m, 2 H), 3.35 (bs, 1
H), 3.7 (m, 1 H), 4.20 (m, 2 H), 4.34 (d, J ) 8.3 Hz, 1 H), 4.45
(m, 1 H), 4.77 (m, 2 H), 4.94 (d, J ) 7.5 Hz, 1 H), 5.31 (bs, 1 H),
5.66 (d, J ) 7.0 Hz, 1 H), 6.27 (m, 2 H), 7.17 (m, 5 H), 7.47 (dd,
J ) 7.8 Hz, 8.3 Hz, 2 H), 7.60 (m, 1 H), 8.09 (d, J ) 7.8 Hz, 2 H);
13C NMR (63 MHz, CDCl3) δ 9.5, 15.0, 18.6, 22.4, 25.7, 26.6,
28.2, 30.0, 35.6, 36.1, 43.2, 45.6, 51.6, 55.3, 58.6, 72.2, 72.3, 73.8,
75.0, 75.5, 79.2, 81.1, 113.9, 117.6, 120.6, 128.6, 129.2, 130.2,
132.2, 133.7, 138.0, 142.6, 158.2, 167.0, 170.1, 173.1, 173.6, 203.8.
HRMS (FAB) m/z calcd for C50H63NO15 ·H+: 918.4276. Found:
918.4276 (∆ ) 0.0 ppm).
1
mg, 79%): mp 93-95 °C; H NMR (CDCl3) δ 0.60 (m, 18 H),
0.98 (m, 27 H), 1.09 (s, 3 H), 1.16 (s, 3 H), 1.57 (bs, 1 H), 1.62 (s,
3 H), 1.85 (m, 1 H), 1.96 (s, 3 H), 2.14 (m, 2 H), 2.26 (s, 3 H),
2.50 (m, 1 H), 3.83 (d, J ) 6.9 Hz, 1 H), 4.10 (d, J ) 8.1 Hz, 1
H), 4.24 (d, J ) 8.1 Hz, 1 H), 4.39 (dd, J ) 10.4, 6.9 Hz, 1 H),
4.92 (m, 2 H), 5.17 (s, 1 H), 5.56 (d, J ) 7.0 Hz, 1 H), 7.29 (m,
1 H), 7.43 (dd, J ) 13.6, 8.0 Hz, 1 H), 7.76 (d, J ) 9.2 Hz, 1 H),
7.87 (d, J ) 7.7 Hz, 1 H); 13C NMR (CDCl3) δ 4.8, 5.2, 5.9, 6.9,
10.4, 14.6, 20.6, 22.3, 26.3, 37.2, 39.8, 42.9, 46.9, 58.2, 68.2, 72.6,
75.7, 75.9, 76.5, 79.6, 80.7, 84.0, 116.6, 117.0, 120.3, 120.7, 125.6,
130.1, 130.3, 131.7, 131.9, 132.4, 135.6, 139.5, 160.6, 164.5, 165.6,
169.9, 205.6. HRMS (FAB, DCM/NBA) m/z calcd for
C47H77O10SiF·H+: 905.4887. Found: 905.4869 (∆ ) 2.0 ppm).
Other 7,10,13-tri-TES-2-modified baccatins 9a, 9b, and 9d-f
were prepared in the same manner, and characterization data are
summarized in the Supporting Information.
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-[3-(2-methoxyphe-
nyl)propanoyl]docetaxel (6m). 97%; white solid; mp 155-159
1
°C; [R]20 -45 (c 0.050, CDCl3); H NMR (250 MHz, CDCl3) δ
D
1.13 (s, 3 H), 1.24 (s, 3 H), 1.35 (s, 9 H), 1.67 (s, 3 H), 1.75 (s, 3
H), 1.88 (s, 4 H), 2.01 (s, 3 H), 2.35 (s, 3 H), 2.48 (m, 2 H), 2.79
(m, 2 H), 2.94 (m, 2 H), 3.33 (m, 1 H), 3.82 (m, 4 H), 4.20 (m, 2
H), 4.30 (d, J ) 8.5 Hz, 1 H), 4.38 (m, 1 H), 4.75 (m, 2 H), 4.96
(d, J ) 8.0 Hz, 1 H), 5.31 (m, 1 H), 5.64 (d, J ) 7.0 Hz, 1 H),
6.19 (m, 1 H), 6.29 (s, 1 H), 6.82 (m, 2 H), 7.19 (m, 2 H), 7.45 (m,
2 H), 7.59 (m, 1 H), 8.10 (d, J ) 7.3 Hz 2 H); 13C NMR (63 MHz,
CDCl3) δ 9.5, 15.0, 18.6, 21.9, 22.4, 25.7, 26.0, 26.6, 28.2, 30.9,
31.6, 33.4, 34.0, 35.6, 43.2, 45.7, 51.6, 55.2, 58.6, 72.2, 72.4, 73.8,
75.1, 75.4, 79.2, 80.0, 81.1, 84.4, 87.3, 105.1, 110.2, 120.4, 120.6,
127.7, 128.5, 128.6, 129.2, 130.0, 130.2, 132.9, 133.7, 137.9, 142.5,
155.4, 157.5, 167.0, 170.1, 173.5, 203.8. HRMS (FAB) m/z calcd
for C51H65NO16 ·H+: 948.4382. Found: 948.4382 (∆ ) 0.0 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-[3-(3-methoxyphe-
nyl)propanoyl]docetaxel (6n). 80%; white solid; mp 159-164 °C;
1H NMR (250 MHz, CDCl3) δ 1.12 (s, 3 H), 1.23 (s, 3 H), 1.35 (s,
9 H), 1.55 (s, 3 H), 1.60 (s, 3 H), 1.75 (s, 3 H), 1.87 (s, 3 H), 1.88
(m, 1 H), 2.35 (s, 3 H), 2.49 (m, 2 H), 2.81 (m, 2 H), 2.94 (m, 2
H), 3.34 (m, 1 H), 3.79 (s, 3 H), 3.81 (m, 1 H), 4.20 (m, 2 H), 4.29
(d, J ) 8.3 Hz, 1 H), 4.38 (m, 1 H), 4.75 (m, 2 H), 4.92 (d, J ) 8.0
Hz, 1 H), 5.30 (bs, 1 H), 5.66 (d, J ) 7.0 Hz, 1 H), 6.19 (m, 1 H),
6.29 (s, 1 H), 6.79 (m, 3 H), 7.20 (m, 1 H), 7.47 (m, 2 H), 7.53 (m,
1 H), 8.15 (d, J ) 7.5 Hz 2 H); 13C NMR (63 MHz, CDCl3) δ 9.5,
14.9, 18.6, 21.9, 22.4, 25.7, 26.6, 28.2, 30.9, 33.4, 35.6, 35.7, 36.3,
43.2, 45.6, 51.6, 55.2, 58.6, 72.2, 73.7, 75.0, 75.6, 79.2, 81.1, 84.4,
105.2, 111.8, 114.0, 120.6, 128.6, 129.2, 129.5, 130.2, 132.8, 133.7,
141.8, 142.7, 166.9, 169.7, 170.1, 171.3, 173.0, 203.8. HRMS
(FAB) m/z calcd for C51H65NO16 ·H+: 948.4382. Found: 948.4382
(∆ ) 0.0 ppm).
Preparation of 7-TES-2-(3-substituted benzoyl)-10-acylbac-
catins 11. A typical procedure is described for the preparation of
7-triethylsilyl-2-debenzoyl-2-(3-fluorobenzoyl)-10-deacetyl-10-pro-
panoylbaccatin III (11c). (a) To a solution of 9c (181 mg, 0.200
mmol) in 10 mL of pyridine/acetonitrile (1:1) was added dropwise
HF/pyridine (70:30, 1.5 mL) at 0 °C, and the mixture was stirred
at room temperature for 17 h. To the reaction mixture was added
ethyl acetate (100 mL) and saturated aqueous sodium carbonate
(15 mL). The organic layer was separated and washed with saturated
aqueous copper sulfate (10 mL × 3) and water (10 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to afford
2-(3-fluorobenzoyl)-2-debenzoyl-10-deacetylbaccatin III (7-OH-
10c) as a white solid (106 mg, 94%).
(b) To a solution of baccatin 7-OH-10c thus obtained (105 mg,
0.187 mmol) and imidazole (54 mg, 0.789 mmol) in dry DMF (3.1
mL) was added chlorotriethylsilane (0.10 mL, 0.592 mmol)
dropwise at room temperature. The reaction mixture was stirred at
room temperature for 2 h and diluted with ethyl acetate (60 mL).
The reaction mixture was then washed with water (5 mL × 3) and
brine (10 mL), dried over MgSO4, and concentrated in vacuo.
Column chromatography of the residue on silica gel (hexanes/ethyl
acetate ) 2/1 to 1/1) gave 7-TES-2-(3-fluorobenzoyl)-2-debenzoyl-
10-deacetylbaccatin III (10c) as a white solid (105 mg, 84% yield):
1
mp 118-120 °C; H NMR (CDCl3) δ 0.55 (m, 6 H), 0.92 (m, 9
H), 1.06 (s, 6 H), 1.61 (bs, 1 H), 1.71 (s, 3 H), 1.89 (m, 1 H), 2.06
(s, 3 H), 2.21 (s, 1 H), 2.25 (s, 1 H), 2.27 (s, 3 H), 2.47 (m, 1 H),
3.93 (d, J ) 7.0 Hz, 1 H), 4.13 (d, J ) 7.1 Hz, 1 H), 4.28 (m, 2
H), 4.39 (dd, J ) 10.5, 6.6 Hz, 1 H), 4.84 (t, J ) 7.8 Hz, 1 H),
4.95 (d, J ) 8.3 Hz, 1 H), 5.16 (s, 1 H), 5.55 (d, J ) 7.0 Hz, 1 H),
7.29 (m, 1 H), 7.44 (dd, J ) 13.6, 7.8 Hz, 1 H), 7.77 (d, J ) 8.9
Hz, 1 H), 7.88 (d, J ) 7.7 Hz, 1 H); 13C NMR (CDCl3) δ 5.1, 6.7,
9.9, 15.2, 18.5, 22.5, 28.8, 37.2, 38.5, 42.6, 46.9, 57.9, 67.8, 72.9,
74.5, 75.2, 76.4, 78.8, 80.6, 84.2, 116.7, 117.0, 120.5, 120.8, 125.8,
125.9, 130.2, 130.3, 134.9, 160.5, 164.5, 165.8, 170.7, 210.2. HRMS
(FAB, DCM/NBA) m/z calcd for C35H49O10FSi·H+: 677.3157.
Found: 677.3177 (∆ ) -2.9 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-10-[3-(4-methoxyphe-
nyl)propanoyl]docetaxel (6o). 80%; white solid; mp 169-172 °C;
1H NMR (250 MHz, CDCl3) δ 1.12 (s, 3 H), 1.23 (s, 3 H), 1.35 (s,
9 H), 1.68 (s, 3 H), 1.76 (s, 3 H), 1.86 (s, 6 H), 1.88 (m, 1 H), 2.35
(s, 3 H), 2.48 (m, 2 H), 2.79 (m, 2 H), 2.94 (m, 2 H), 3.33 (d, J )
6.5 Hz, 1 H), 3.78 (s, 3 H), 3.81 (m, 1 H), 4.20 (m, 2 H), 4.30 (d,
J ) 8.5 Hz, 1 H), 4.42 (m, 1 H), 4.75 (m, 2 H), 4.96 (d, J ) 8.0
Hz, 1 H), 5.31 (bs, 1 H), 5.66 (d, J ) 7.0 Hz, 1 H), 6.17 (m, 1 H),
6.29 (s, 1 H), 6.82 (d, J ) 8.5 Hz, 2 H), 7.13 (d, J ) 8.5 Hz, 2 H),
7.47 (dd, J ) 7.3 Hz, 7.8 Hz, 2 H), 7.60 (m, 1 H), 8.10 (d, J ) 7.3

3214 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
(c) To a solution of 10c (104 mg, 0.154 mmol) in dry THF (11
mL) was added LiHMDS (1.0 M in THF, 0.17 mL, 0.17 mmol)
dropwise at -40 °C. The mixture was stirred at -40 °C for 5 min.
Then freshly distilled chlorotriethylsilane (0.016L, 0.1844 mmol)
was added dropwise and the reaction mixture was stirred for 30
min. Then, to the reaction mixture was added aqueous saturated
NH4Cl (10 mL) and ethyl acetate (100 mL), and the organic layer
was separated and washed with brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo. Column chroma-
tography of the residue on silica gel (hexanes/ethyl acetate ) 3/1)
The resulting solid was purified by column chromatography on silica
gel (hexane/EtOAc ) 3:1) to give 10k (60 mg, 40% yield, 80%
1
yield based on 50% conversion) as a white solid: H (300 MHz,
CDCl3) δ 0.58 (m, 6 H), 0.91 (q, J ) 7.8 Hz, 9 H), 1.10 (s, 3 H),
1.12 (s, 3 H), 1.37 (s, 3 H), 1.92 (m, 2 H), 1.97 (bs, 1 H), 2.19 (s,
3 H), 2.30 (s, 3 H), 2.55 (m, 1 H), 3.54 (m, 1 H), 3.85 (m, 7 H),
3.94 (d, J ) 6.9 Hz, 1 H), 4.15 (d, J ) 7.8 Hz, 1 H), 4.34 (d, J )
7.8 Hz, 1 H), 4.53 (dd, J ) 6.6 Hz, 3.6 Hz, 1 H), 4.84 (m, 1H),
4.97 (d, J ) 7.8 Hz, 1 H), 5.66 (d, J ) 6.9 Hz, 1 H), 6.69 (s, 1 H),
6.95-7.07 (m, 2 H), 7.14-7.19 (m, 1 H), 7.28-7.42 (m, 2 H),
7.65-7.73 (m, 2 H), 8.01 (m, 1 H).
Synthesis of Second- and Third-Generation Taxoids 14
through the Ojima-Holton Coupling of Baccatins 11 with
ꢀ-Lactams 3a-f. A typical procedure is described for the
synthesis of 2-debenzoyl-2-(3-methylbenzoyl)-10-acetyl-3′-
dephenyl-3′-(2-methylprop-1-enyl)docetaxel (14a). (a) To a
solution of baccatin 11a (50 mg, 0.071 mmol) and ꢀ-lactam 3a
(41.1 mg, 0.099 mmol) in 3 mL of dry THF was added a 1.0 M
solution of LiHMDS in THF (0.099 mL, 0.099 mmol) dropwise
at -40 °C, and the solution was stirred at the same temperature
for 30 min. The reaction was quenched with aqueous saturated
ammonium chloride, and the aqueous layer was extracted with
dichloromethane. The combined extracts were dried over
anhydrous magnesium sulfate and concentrated in vacuo. The
residue was purified on a silica gel column (hexanes/EtOAc )
6/1) to afford the coupling product, 7-TES-2′-TIPS-14a (67 mg,
84% yield), as a white solid.
gave 11c as a white solid (95 mg, 84%): mp 194-196 °C; [R]20
D
1
-74 (c 0.39, CHCl3); H NMR (CDCl3) δ 0.56 (q, J ) 7.8 Hz, 6
H), 0.89 (t, J ) 7.8 Hz, 9 H), 1.00 (s, 3 H), 1.20 (m, 7 H), 1.64 (s,
3 H), 1.83 (m, 1 H), 2.16 (s, 3 H), 2.25 (m, 3 H), 2.40 (m, 4 H),
3.85 (d, J ) 6.8 Hz, 1 H), 4.09 (d, J ) 8.2 Hz, 1 H), 4.25 (d, J )
8.2 Hz, 1 H), 4.45 (dd, J ) 10.2, 6.7 Hz, 1 H), 4.79 (t, J ) 8.0 Hz,
1 H), 4.93 (d, J ) 9.4 Hz, 1 H), 5.57 (d, J ) 7.1 Hz, 1 H), 6.45 (s,
1 H), 7.29 (m, 1 H), 7.44 (dd, J ) 13.6, 8.0 Hz, 1 H), 7.74 (d, J
) 8.7 Hz, 1 H), 7.86 (d, J ) 7.7 Hz, 1 H); 13C NMR (CDCl3) δ
5.3, 6.7, 6.94, 9.2, 9.9, 14.9, 20.1, 22.5, 26.8, 27.7, 37.2, 38.3, 42.7,
47.2, 58.5, 67.8, 72.3, 75.2, 75.5, 76.4, 78.8, 80.7, 84.2, 116.7,
117.0, 120.5, 120.8, 125.9, 130.2, 130.3, 131.6, 131.7, 132.6, 144.1,
165.8, 170.6, 172.8, 202.3. HRMS (FAB) m/z calcd for
C38H53O11FSi·H+: 733.3419. Found: 733.3418 (∆ ) +0.2 ppm).
Other 7-TES-2-(3-substituted-benzoyl)-10-acylbaccatins (11a,
11b, and 11d-k) were prepared in the same manner, and
characterization data are summarized in the Supporting Information.
Preparation of 2-Debenzoyl-2-(3-methoxybenzoyl)-7-trieth-
ylsilyl-10-deacetyl-10-(2-methoxybenzoyl)baccatin III (11k). (a)
To a solution of 104 mg (0.16 mmol) of 2-debenzoyl-2-(3-
methoxybenzoyl)-7-triethylsilyl-10-deacetyl baccatin III (10b) in
2 mL of CH2Cl2 was added 21 mg (0.17 mmol) of N-methylmor-
pholine N-oxide (NMO) and 20 mg of 4 Å molecular sieves. After
the mixture was stirred for 10 min, 37 mg (0.01 mmol) of
tetrapropylammonium perruthenate (TPAP) was added and the
mixture was allowed to stir for 4 h. The reaction mixture was then
filtered and concentrated in vacuo to give 2-debenzoyl-2-(3-
methoxybenzoyl)-7-triethylsilyl-10-deacetyl-13-oxo-baccatin III
(12) (104 mg, 99% yield) as a white solid: 1H (300 MHz, CDCl3)
δ 0.49 (m, 6 H), 0.95 (m, 9 H), 1.15 (s, 3 H), 1.22 (s, 3 H), 1.24
(m, 1H), 1.71 (s, 3 H), 1.84 (m, 2 H), 2.10 (s, 3 H), 2.17 (s, 3 H),
2.47 (m, 1 H), 2.60 (d, J ) 19.8 Hz, 1 H), 2.89 (d, J ) 19.8 Hz,
1H), 3.85 (m, 6 H), 4.11 (d, J ) 8.7 Hz, 1 H), 4.35 (m, 4 H), 4.90
(d, J ) 8.1 Hz, 1 H), 5.31 (d, J ) 1.8 Hz, 1 H), 5.62 (d, J ) 6.6
Hz, 1 H), 7.13 (dd, J ) 8.4 Hz, 2.7 Hz, 1 H), 7.38 (t, J ) 5.4 Hz,
1 H), 7.58 (s, 3 H), 7.64 (d, J ) 7.5 Hz, 1 H). HRMS: m/e calcd
for C44H58O13Si·H+: 823.3725. Found: 823.3723 (∆ ) -0.2 ppm).
(b) To a solution of 104 mg (0.159 mmol) of 12, DMAP (59
mg, 0.477 mmol), and triethylamine (48 mg, 0.477 mmol) in 2 mL
of CH2Cl2 was added 2-methoxylbenzoyl chloride (81 mg, 0.477
mmol). The mixture was allowed to stir overnight, and the reaction
was quenched with saturated aqueous NaHCO3 and extracted three
times with EtOAc. The combined organic layers were washed with
water and brine, dried over MgSO4, filtered, and concentrated. The
resulting solid was purified by column chromatography on silica
gel (hexanes/EtOAc ) 8/1) to give 2-debenzoyl-2-(3-methoxyben-
zoyl)-7-triethylsilyl-10-deacetyl-10-(2-methoxybenzoyl)-13-oxo-
(b) To a solution of 7-TES-2′-TIPS-14a (65.0 mg, 0.058 mmol),
thus obtained, in 4 mL pyridine/acetonitrile (1/1) was added
dropwise HF/pyridine (70/30, 0.5 mL) at 0 °C. The mixture was
stirred at room temperature overnight. The reaction was quenched
with saturated aqueous NaHCO3. The reaction mixture was diluted
with EtOAc, washed with aqueous saturated CuSO4 and water, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(hexanes/EtOAc ) 1/1) to afford 14a (47 mg, 96% yield, 81% yield
for two steps) as a white solid: mp 145-148 °C; [R]20 -85 (c
D
0.011, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.14 (s, 3 H), 1.25
(s, 3 H), 1.34 (s, 9 H), 1.67 (s, 3 H), 1.75 (d, J ) 3.6 Hz, 6 H),
1.89 (s, 3 H), 2.23 (s, 3 H), 2.37 (m, 9 H), 2.52 (m, 2 H), 3.80 (d,
J ) 7.2 Hz, 1 H), 4.18 (m, 2 H), 4.30 (d, J ) 8.7 Hz, 1 H), 4.42
(m, 1 H), 4.75 (m, 2 H), 4.96 (d, J ) 7.8 Hz, 1 H), 5.29 (m, 2 H),
5.64 (d, J ) 7.2 Hz, 1H), 6.16 (t, J ) 8.7 Hz, 1 H), 6.30 (s, 1 H),
7.37 (m, 2 H), 7.90 (m, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.5,
14.9, 18.5, 20.8, 21.3, 21.8, 22.3, 25.7, 26.6, 28.2, 35.6, 43.2, 25.6,
58.4, 72.1, 72.3, 73.7, 74.9, 75.6, 76.46, 79.1, 81.1, 84.4, 120.7,
127.3, 128.5, 129.1, 130.8, 132.8, 134.4, 138.3, 142.6, 155.4, 167.0,
170.0, 171.3, 203.7. HRMS (FAB) m/z calcd for C44H59NO15 ·Na+:
864.3782. Found: 864.3803 (∆ ) -2.4 ppm).
Other taxoids 14b-p, 15c-e, and 15 g were prepared in the
same manner, and characterization data are shown below.
2-Debenzoyl-2-(3-methoxybenzoyl)-10-acetyl-3′-dephenyl-3′-
(2-methylprop-1-enyl)docetaxel (14b). White solid; 72% (for two
1
steps); mp 142-144 °C; [R]25 -72 (c 0.70, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 1.15 (s, 3H), 1.26 (s, 3H), 1.34 (s, 9H), 1.68
(s, 3H), 1.74 (s, 3H), 1.77 (s, 3H), 1.90 (s, 3H), 1.92 (m, 1H), 2.24
(s, 3H), 2.35 (s, 3H), 2.38 (m, 2H), 2.54 (m, 1H), 3.81 (d, J ) 6.9
Hz, 1H), 3.87 (s, 3H), 4.18 (d, J ) 8.4 Hz, 1H), 4.35 (d, J ) 8.4
Hz, 1H), 4.43 (dd, J ) 6.6, 10.5 Hz, 1H), 4.75 (br s, 2H), 4.97 (d,
J ) 8.1 Hz, 1 H), 5.32 (s, 1H), 5.66 (d, J ) 7.2 Hz, 1H), 6.18 (t,
J ) 8.4 Hz, 1H), 6.30 (s, 1H), 7.14 (dd, J ) 2.1, 8.1 Hz, 1H), 7.38
(t, J ) 7.8 Hz, 1H), 7.64 (s, 1H), 7.70 (d, J ) 7.8 Hz, 1H); 13C
NMR (75.0 MHz, CDCl3) δ 9.5, 15.0, 18.5, 20.9, 21.8, 22.4, 25.7,
26.7, 28.2, 29.7, 35.6, 43.2, 45.6, 51.5, 55.4, 58.6, 72.2, 72.3, 73.7,
75.1, 75.6, 76.4, 79.1, 80.0, 81.1, 84.4, 114.6, 120.2, 122.6,
122.6, 129.6, 130.4, 132.8, 137.9, 142.7, 143.5, 159.7, 166.8,
170.0, 171.3, 173.1, 203.8. HRMS (DCM/NBA/NACL) calcd
for C44H59NO16Na +: 880.3766. Obtained: 880.3732 (∆ ) -3.9
ppm). HPLC analysis using a Phenomenex Curosil-B column:
CH3CN/water (2/3) as the solvent system with a flow rate of 1
mL/min; UV (230 and 254 nm) showed g95% purity.
1
baccatin III (13) (125 mg, 100%) as a white solid: H (300 MHz,
CDCl3) δ 0.58 (m, 6 H), 0.91 (q, J ) 7.8 Hz, 9 H), 1.10 (s, 3 H),
1.12 (s, 3 H), 1.37 (s, 3 H), 1.92 (m, 1 H), 1.97 (bs, 1 H), 2.19 (s,
3 H), 2.30 (s, 3 H), 2.55 (m, 1 H), 2.64 (d, J ) 19.8 Hz, 1 H), 2.93
(s, J ) 19.8 Hz, 1 H), 3.54 (m, 3 H), 3.85 (m, 8 H), 3.97 (d, J )
6.6 Hz, 1 H), 4.13 (d, J ) 8.1 Hz, 1 H), 4.35 (d, J ) 8.7 Hz, 1 H),
4.54 (dd, J ) 6.6 Hz, 3.9 Hz, 1 H), 4.93 (d, J ) 8.1 Hz, 1 H), 5.73
(d, J ) 6.6 Hz, 1 H), 6.82 (s, 1 H), 6.66-7.07 (m, 3 H), 7.14-7.19
(m, 2 H), 7.28-7.42 (m, 1 H), 7.48-7.68 (m, 1 H), 8.01 (m, 1 H).
(c) To a solution of 13 (125 mg, 0.159 mmol) in 6 mL of MeOH/
THF (3/2) at 0 °C was added NaBH4 (100 mg, 6.36 mmol), and
the solution was allowed to stir for 5 h. The reaction was quenched
with saturated NH4Cl and extracted three times with CH2Cl2. The
organic layer was dried over MgSO4, filtered, and concentrated.

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3215
2-Debenzoyl-2-(3-fluorobenzoyl)-10-deacetyl-10-propanoyl-3′-
dephenyl-3′-(2-methylprop-1-enyl)docetaxel (14c). White solid;
84% (for two steps); mp 137-139 °C; [R]20D -78 (c 0.45, CHCl3);
1H NMR (CDCl3) δ 1.13 (s, 3 H), 1.19 (m, 6 H), 1.33 (m, 9 H),
1.66 (s, 3 H), 1.75 (s, 6 H), 1.89 (s, 3 H), 2.34 (m, 5 H), 2.52 (m,
4 H), 3.37 (m, 1 H), 3.80 (d, J ) 7.0 Hz, 1 H), 4.12 (m, 2 H), 4.29
(d, J ) 8.5 Hz, 1 H), 4.42 (m, 1 H), 4.76 (m, 1 H), 4.96 (d, J ) 8.1
Hz, 1 H), 5.29 (m, 1 H), 5.63 (d, J ) 7.2 Hz, 1 H), 6.16 (t, J ) 8.4
Hz, 1 H), 6.30 (s, 1 H), 7.29 (m, 1 H), 7.43 (m, 1 H), 7.77 (d, J )
9.1 Hz, 1 H), 7.89 (d, J ) 7.8 Hz, 1 H); 13C NMR (CDCl3) δ 9.1,
9.5, 14.9, 18.5, 21.8, 22.3, 25.7, 26.6, 27.6, 28.2, 35.5, 43.1, 45.6,
51.6, 58.5, 72.2, 73.7, 75.4, 76.3, 77.6, 79.2, 79.9, 81.0, 84.4, 116.8,
117.1, 120.6, 125.9, 130.3, 130.4, 132.8, 138.0, 142.6, 155.4, 165.7,
170.0, 174.6, 203.7; 19F NMR (CDCl3, using Freon as standard) δ
-112.1. HRMS (FAB) m/z calcd for C44H58O15FN·H+: 860.3869.
Found: 860.3870 (∆ ) -0.1 ppm).
2-Debenzoyl-2-(3-chlorobenzoyl)-10-deacetyl-10-propanoyl-
3′-dephenyl-3′-(2-methylprop-1-enyl)docetaxel (14d). White solid;
70% (for two steps); mp 142-144 °C; [R]20D -89 (c 0.090, CHCl3);
1H NMR (CDCl3) δ 1.13 (s, 3 H), 1.21 (m, 7 H), 1.33 (s, 9 H),
1.66 (m, 3 H), 1.74 (m, 7 H), 1.82 (s, 3 H), 2.45 (m, 5 H), 2.52 (m,
3 H), 3.80 (d, J ) 7.1 Hz, 1 H), 4.12 (m, 2 H), 4.27 (d, J ) 8.3
Hz, 1 H), 4.40 (dd, J ) 10.6, 6.5 Hz, 1 H), 4.75 (m, 2 H), 4.96 (d,
J ) 8.2 Hz, 1 H), 5.30 (d, J ) 9.2 Hz, 1 H), 5.60 (d, J ) 7.1 Hz,
1 H), 6.13 (t, J ) 8.6 Hz, 1 H), 6.30 (s, 1 H), 7.40 (t, J ) 7.8 Hz,
1 H), 7.56 (d, J ) 8.3 Hz, 1 H), 7.97 (d, J ) 7.7 Hz, 1 H), 8.10 (s,
1 H); 13C NMR (CDCl3) δ 9.0, 9.5, 14.9, 18.6, 21.8, 22.3, 25.6,
26.5, 27.5, 28.1, 35.5, 41.2, 43.1, 45.6, 51.6, 58.4, 72.2, 72.3, 73.7,
75.4, 75.5, 76.3, 79.2, 79.9, 81.0, 84.4, 120.5, 128.3, 130.0, 130.2,
131.0, 132.7, 133.6, 134.7, 137.9, 142.6, 155.4, 165.5, 169.9, 173.1,
174.6, 203.7. HRMS: m/e calcd for C44H58O15NCl·H+: 876.3573.
Found: 876.3573 (∆ ) 0.0 ppm).
2-Debenzoyl-2-(3-azidobenzoyl)-10-deacetyl-10-propanoyl-3′-
dephenyl-3′-(2-methylprop-1-enyl)docetaxel (14e). White solid;
71% (for two steps); mp 128-130 °C; [R]20D -71 (c 0.44, CHCl3);
1H NMR (CDCl3) δ 1.14 (s, 3 H), 1.25 (m, 9 H), 1.34 (s, 9 H),
1.66-1.73 (m, 12 H), 1.89 (s, 3 H), 2.37 (m, 5 H), 2.52 (m, 4 H),
3.32 (bs, 1 H), 3.81 (d, J ) 6.9 Hz, 1 H), 4.12 (m, 2 H), 4.30 (d,
J ) 8.1 Hz, 1 H), 4.40 (dd, J ) 10.6, 6.8 Hz, 1 H), 4.74 (m, 2 H),
4.96 (d, J ) 8.2 Hz, 1 H), 5.29 (m, 1 H), 5.64 (d, J ) 7.0 Hz, 1
H), 6.13 (t, J ) 9.0 Hz, 1 H), 6.31 (s, 1 H), 7.23 (d, J ) 7.5 Hz,
1 H), 7.46 (t, J ) 7.9 Hz, 1 H), 7.78 (s, 1 H), 7.86 (d, J ) 7.8 Hz,
1 H); 13C NMR (CDCl3) δ 9.0, 9.5, 15.0, 18.6, 21.8, 22.5, 25.7,
26.6, 27.6, 28.2, 35.5, 43.2, 45.6, 51.6, 58.6, 72.2, 72.6, 73.7, 75.4,
76.4, 79.2, 81.0, 84.5, 87.3, 120.1, 120.5, 124.3, 126.8, 130.2, 132.7,
140.8, 166.0, 170.1, 174.6, 203.8. HRMS: m/e calcd for
C44H58O15N4 ·H+: 883.3977. Found: 883.3987 (∆ ) -1.1 ppm).
HPLC analysis using a Phenomenex Curosil-B column: CH3CN/
water (2/3) as the solvent system with a flow rate of 1 mL/min;
UV (230 and 254 nm) showed g95% purity.
3′-Dephenyl-3′-(2-methylprop-1-enyl)-2-debenzoyl-2-(3-allyl-
benzoyl)-10-propanoyldocetaxel (14f). White solid; 80% (for two
steps), mp 118-120 °C; 1H NMR (300 MHz, CDCl3) δ 1.15 (s, 3
H), 1.21 (t, J ) 7.4 Hz, 3 H), 1.23 (s, 3 H), 1.34 (s, 9 H), 1.68 (s,
3 H), 1.75 (s, 3 H), 1.77 (s, 3 H), 1.86 (m, 1 H), 1.90 (s, 3 H), 2.36
(s, 6 H), 2.39 (m, 2 H), 2.37 (s, 3 H), 2.53 (m, 3 H), 3.36 (bs, 1 H),
3.83 (d, J ) 6.9 Hz, 1 H), 4.19 (m, 3 H), 4.32 (d, J ) 8.4 Hz, 1
H), 4.43 (dd, J ) 6.6, 10.5 Hz, 1 H), 4.74 (d, J ) 3.0 Hz, 1 H),
4.97 (d, J ) 8.4 Hz, 1 H), 5.34 (br d, J ) 10.8 Hz, 2 H), 5.67 (d,
J ) 6.9 Hz, 1 H), 5.85 (d, J ) 17.4 Hz, 1 H), 6.18 (t, J ) 8.4 Hz,
1 H), 6.32 (s, 1 H), 6.76 (dd, J ) 10.5, 17.4 Hz, 1 H), 7.44 (t, J )
7.8 Hz, 1 H), 7.63 (d, J ) 7.5 Hz, 1 H), 7.98 (d, J ) 7.8 Hz, 1 H),
8.17 (s, 1 H); 13C NMR (63 MHz, CDCl3) δ 9.0, 9.5, 15.0, 18.5,
20.9, 22.4, 25.7, 26.7, 28.2, 29.7, 35.5, 35.6, 43.2, 45.6, 51.5, 58.6,
72.2, 72.9, 75.1, 75.4, 79.2, 80.0, 81.1, 84.4, 115.4, 120.6, 127.8,
128.9, 129.4, 131.3, 135.9, 138.1, 155.4, 159.7, 165.4, 166.9, 170.0,
171.9, 178.5, 203.8. HRMS (FAB) m/z calcd for C46H61NO15 ·Na+:
890.3981. Found: 890.3939 (∆ ) -4.7 ppm). HPLC analysis using
a Phenomenex Curosil-B column: CH3CN/water (2/3) as the solvent
system with a flow rate of 1 mL/min; UV (230 and 254 nm) showed
95% purity.
2-Debenzoyl-2-(3-methoxybenzoyl)-10-deacetyl-10-propanoyl-
3′-dephenyl-3′-(2-methylprop-1-enyl)docetaxel (14g). White solid;
69% (for two steps); mp 130-132 °C; [R]20D -75 (c 0.080, CHCl3);
1H NMR (CDCl3) δ 1.13 (s, 3 H), 1.28 (m, 8 H), 1.33 (s, 9 H),
1.66 (m, 3 H), 1.73 (s, 3 H), 1.75 (s, 3 H), 1.89 (m, 5 H), 2.37 (m,
6 H), 2.52 (m, 3 H), 3.80 (d, J ) 6.9 Hz, 1 H), 3.86 (s, 3 H), 4.12
(m, 2 H), 4.32 (d, J ) 8.5 Hz, 1 H), 4.40 (dd, J ) 10.6, 6.8 Hz, 1
H), 4.72 (m, 2 H), 4.96 (d, J ) 8.3 Hz, 1 H), 5.30 (d, J ) 7.6 Hz,
1 H), 5.64 (d, J ) 7.0 Hz, 1 H), 6.16 (t, J ) 8.6 Hz, 1 H), 6.30 (s,
1 H), 7.13 (d, J ) 7.9 Hz, 1 H), 7.33 (t, J ) 8.0 Hz, 1 H), 7.62 (s,
1 H), 7.68 (d, J ) 7.6 Hz, 1 H); 13C NMR (CDCl3) δ 9.0, 9.5,
14.9, 18.5, 21.8, 22.4, 25.7, 26.6, 27.5, 28.2, 35.5, 43.2, 45.6, 51.5,
55.3, 58.5, 72.2, 72.3, 73.7, 75.1, 75.4, 76.2, 79.1, 79.9, 81.1, 84.4,
114.6, 120.1, 120.6, 122.5, 129.6, 130.4, 132.9, 137.8, 142.5, 155.4,
159.6, 166.8, 170.0, 174.0, 174.6, 203.8. HRMS m/e calcd for
C45H61O16N · H+: 872.4069. Found: 872.4072 (∆ ) -0.4 ppm).
HPLC analysis using a Phenomenex Curosil-B column: CH3CN/
water (2/3) as the solvent system with a flow rate of 1 mL/min;
UV (230 and 254 nm) showed g95% purity.
3′-Dephenyl-3′-(2-methylprop-1-enyl)-2-debenzoyl-2-(3-meth-
oxybenzoyl)-10-(cyclopropanecarbonyl)docetaxel (14h). 77% (for
two steps); mp 144-146 °C; [R]25D -74 (c 0.92, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.16 (s, 3H), 1.26 (s, 3H), 1.34 (s, 9H), 1.66
(m, 4H), 1.67 (s, 3H), 1.74 (s, 3H), 1.77 (s, 3H), 1.82 (m, 2H),
1.89 (s, 3H), 2.34 (s, 3H), 2.38 (m, 2H), 2.54 (m, 1H), 3.36 (br s,
1H), 3.81 (d, J ) 7.2 Hz, 1H), 3.87 (s, 3H), 4.18 (d, J ) 9.0 Hz,
1H), 4.20 (s, 1H), 4.34 (d, J ) 8.4 Hz, 1H), 4.41 (dd, J ) 6.6, 11.1
Hz, 1H), 4.79 (m, 2H), 4.97 (d, J ) 9.0 Hz, 1 H), 5.31 (br s, 1H),
5.66 (d, J ) 6.9 Hz, 1H), 6.18 (t, J ) 9.0 Hz, 1H), 6.30 (s, 1H),
7.14 (d, J ) 8.1 Hz, 1H), 7.37 (t, J ) 7.8 Hz, 1H), 7.64 (s, 1H),
7.70 (d, J ) 7.5 Hz, 1H); 13C NMR (75.0 MHz, CDCl3) δ 9.5,
13.0, 15.0, 18.5, 21.9, 22.4, 25.7, 26.7, 28.2, 29.7, 35.5, 35.6, 43.2,
45.6, 51.5, 55.4, 58.6, 72.2, 72.4, 73.7, 75.1, 75.4, 76.4, 79.2, 80.0,
81.1, 84.4, 114.6, 120.1, 120.6, 122.6, 129.6, 130.4, 132.9, 137.9,
142.7, 155.4, 159.7, 166.8, 170.0, 171.9, 175.1, 203.9. HRMS
(DCM/NBA/NACL) calcd for C46H61NO16Na+: 906.3909. Ob-
tained: 906.3888 (∆ ) -2.3 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-2-debenzoyl-2-(3-meth-
oxybenzoyl)-10-(methoxycarbonyl)docetaxel (14i). White solid;
80% (for two steps); mp 132-138 °C; 1H NMR (300 MHz, CDCl3)
δ 1.15 (s, 3 H), 1.25 (m, 12 H), 1.68 (m, 6 H), 1.89 (m, 1 H), 1.93
(s, 3 H), 2.17 (s, 3 H), 2.35 (s, 3 H), 2.57 (m, 1 H), 3.78 (d, J )
6.9 Hz, 1 H), 3.87 (bs, 7 H), 4.20 (m, 2 H), 4.36 (m, 2 H), 4.73
(m, 2 H), 4.95 (d, J ) 7.8 Hz, 1 H), 5.31 (d, J ) 7.0, 1 H), 5.65
(d, J ) 6.9 Hz, 1 H), 6.17 (m, 2 H), 7.12 (dd, J ) 7.8 Hz, 2.4 Hz,
1 H), 7.37 (t, J ) 7.8 Hz, 1 H), 7.63 (s, 1 H), 7.68 (d, J ) 4.5 Hz,
1 H), 8.01 (s, 1 H); 13C NMR (63 MHz, CDCl3) δ 9.4, 15.0, 18.5,
21.7, 22.4, 25.7, 26.6, 28.2, 30.9, 33.3, 35.6, 43.1, 45.6, 51.5, 55.4,
55.6, 58.6, 72.1, 72.3, 73.7, 75.1, 78.3, 79.1, 80.0, 81.1, 84.4, 105.1,
114.6, 120.1, 120.6, 122.5, 129.6, 130.4, 132.5, 137.9, 143.5, 155.8,
159.7, 166.8, 170.1, 176.4, 204.0. HRMS (FAB) m/z calcd for
C51H65NO17 ·H+: 964.4331. Found: 964.4366 (∆ ) 3.7 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-2-debenzoyl-2-(3-meth-
oxybenzoyl)-10-(benzyloxycarbonyl)docetaxel (14j). White solid;
70% (for two steps); mp 145-150 °C; 1H NMR (300 MHz, CDCl3)
δ 1.15 (s, 3 H), 1.25 (m, 12 H), 1.69 (m, 6 H), 1.89 (m, 1 H), 1.95
(s, 3 H), 2.16 (s, 3 H), 2.35 (s, 3 H), 2.56 (m, 1 H), 3.36 (d, J )
6.9 Hz, 1 H), 3.78 (d, J ) 7.2 Hz, 1 H), 3.87 (s, 3 H), 4.19 (m, 2
H), 4.33 (d, J ) 8.7 Hz, 1 H), 4.40 (m, 1 H), 4.72 (m, 2 H), 4.95
(d, J ) 7.5 Hz, 1 H), 5.23 (s, 2 H), 5.31 (d, J ) 7.8 Hz, 1 H), 5.65
(d, J ) 7.2 Hz, 1 H), 6.14 (m, 2 H), 7.12 (dd, J ) 7.2 Hz, 1.8 Hz,
1 H), 7.34 (m, 6 H), 7.63 (s, 1 H), 7.68 (d, J ) 7.8 Hz, 1 H).
HRMS (FAB) m/z calcd for C50H63NO17 ·H+: 950.4174. Found:
950.4164 (∆ ) -1.1 ppm). HPLC analysis using a Phenomenex
Curosil-B column: CH3CN/water (2/3) as the solvent system with
a flow rate of 1 mL/min; UV (230 and 254 nm) showed g95%
purity.
3′-Dephenyl-3′-(2-methyl-1-propenyl)-2-debenzoyl-2-(3-meth-
oxybenzoyl)-10-(2-methoxybenzoyl)docetaxel (14k). White solid;
95% (for two steps); mp 143-145 °C; 1H NMR (300 MHz, CDCl3)
δ 1.28 (s, 3 H), 1.31 (s, 3 H), 1.34 (s, 9 H), 1.60 (m, 1 H), 1.71 (s,

3216 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
3 H), 1.75 (s, 3 H), 1.77 (s, 3 H), 1.91 (m, 1 H), 1.96 (s, 3 H), 2.37
(s, 3 H), 2.59 (m, 2 H), 3.35 (bs, 1 H), 3.88 (s, 3 H), 3.91 (s, 3 H),
4.22 (m, 2 H), 4.35 (d, J ) 8.4 Hz, 1 H), 4.51 (m, 1 H), 4.76 (m,
2 H), 4.98 (d, J ) 8.1 Hz,1 H), 5.32 (m, 1 H), 5.71 (d, J ) 6.9 Hz,
1 H), 6.21 (m, 1 H), 6.57 (s, 1 H), 6.99 (m, 2 H), 7.13 (dd, J ) 8.4
Hz, 1.8 Hz, 1 H), 7.36 (t, J ) 7.5 Hz, 1 H), 7.50 (m, 1 H), 7.65 (s,
1 H), 7.70 (d, J ) 7.5 Hz, 1 H), 7.99 (dd, J ) 7.8, 2.1 Hz, 1 H);
13C NMR (63 MHz, CDCl3) δ 9.56, 15.0, 18.5, 22.4, 25.7, 26.6,
28.2, 35.6, 43.3, 45.7, 55.4, 55.9, 58.7, 72.2, 72.4, 73.7, 75.2, 75.6,
79.2, 81.2, 84.5, 87.6, 105.0, 105.1, 112.1, 120.2, 120.3, 122.6,
129.7, 130.5, 132.7, 134.6, 159.7, 160.0, 165.9, 166.9, 170.1, 203.8.
HRMS (FAB) m/z calcd for C50H63NO17 ·H+: 950.4174. Found:
950.4149 (∆ ) -2.7 ppm).
3′-Dephenyl-3′-(2-methyl-1-propenyl)-2-debenzoyl-2-(3-meth-
oxybenzoyl)-10-(4-methoxyphenylacetyl)docetaxel (14l). White
solid; 70% (for two steps); mp 152-154 °C; 1H NMR (300 MHz,
CDCl3) δ 1.07 (s, 3 H), 1.18 (s, 3 H), 1.34 (s, 9 H), 1.59 (s, 3 H),
1.67 (s, 3 H), 1.73 (s, 3 H), 1.76 (s, 3 H) 1.86 (s, 3 H), 1.86 (m, 1
H), 2.17 (m, 4 H), 2.37 (s, 3 H), 2.39 (m, 2 H), 2.55 (m, 1 H), 3.34
(bs, 1 H), 3.79 (m, 4 H), 3.68 (s, 3 H), 4.19 (m, 1 H), 4.32 (d, J )
8.4 Hz, 1 H), 4.39 (m, 1 H), 4.73 (m, 2 H), 4.94 (d, J ) 8.1 Hz,
1 H), 5.30 (m, 1 H), 5.64 (d, J ) 6.9 Hz, 1 H), 6.15 (t, J ) 8.1 Hz,
1 H), 6.30 (s, 1 H), 6.86 (d, J ) 8.4 Hz, 2 H), 7.12 (dd, J ) 7.8
Hz, 2.1 Hz, 1 H), 7.24 (m, 2 H), 7.37 (t, J ) 7.5 Hz, 1 H), 7.63 (s,
1 H), 7.68 (d, J ) 7.8 Hz, 1 H); 13C NMR (63 MHz, CDCl3) δ
9.53, 14.2, 14.9, 18.5, 21.6, 22.4, 25.7, 26.4, 28.2, 30.9, 35.6, 40.1,
43.1, 45.6, 51.5, 55.2, 55.3, 58.5, 72.1, 72.3, 73.7, 75.0, 75.8, 79.0,
79.9, 81.0, 84.4, 87.5, 114.0, 114.6, 120.1, 120.6, 122.5, 129.6,
130.4, 130.5, 132.7, 142.5, 159.6, 166., 170.0, 172.0, 203.4, 206.9.
HRMS (FAB) m/z calcd for C51H65NO17 ·H+: 964.4331. Found:
964.4366 (∆ ) 3.7 ppm).
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(prop-2-enyl)docetaxel (14m). White solid; 65% (for two steps);
mp 127-130 °C; [R]20D -64 (c 0.25, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.13 (s, 3 H), 1.21 (m, 26 H), 1.66 (m, 3 H), 1.88 (s, 3
H), 2.20-2.37 (m, 5 H), 2.52 (m, 3 H), 3.39 (bs, 1 H), 3.80 (d, J
) 8.8 Hz, 1 H), 3.89 (s, 3 H), 4.12 (m, 2 H), 4.35 (m, 3 H), 4.61
(m, 1 H), 4.96 (m, 2 H), 5.63 (m, 1.25 H), 5.84 (d, J ) 5.8 Hz, 0.5
H), 6.06 (d, J ) 5.9 Hz, 0.25 H), 6.23 (t, J ) 8.8 Hz, 1 H), 6.30
(s, 1 H), 7.13 (d, J ) 5.8 Hz, 1 H), 7.38 (t, J ) 8.0 Hz, 1 H), 7.63
(s, 1 H), 7.70 (d, J ) 7.6 Hz, 1 H); 13C NMR (63 MHz, CDCl3)
δ 9.0, 9.6, 14.8, 21.9, 22.5, 26.7, 27.6, 28.0, 29.7, 35.5, 43.2, 45.7,
55.3, 58.6, 68.5, 72.2, 73.0, 75.1, 75.3, 79.0, 81.2, 84.5, 87.4, 103.1,
114.1, 120.7, 122.7, 129.8, 130.2, 133.3, 159.7, 167.1, 170.3, 170.7,
174.6, 203.6. HRMS (FAB) m/z calcd for C44H59NO16 ·H+:
858.3912. Found: 858.3880 (∆ ) -3.7 ppm).
15.3 Hz, 1 H), 5.66 (d, J ) 7.2 Hz, 1 H), 5.82 (m, 1H), 6.21 (t, J
) 8.7 Hz, 1 H), 6.31 (s, 1 H), 7.14 (dd, J ) 2.4, 8.1 Hz, 1 H), 7.39
(t, J ) 8.1 Hz, 1 H), 7.65 (s, 1 H), 7.72 (d, J ) 7.5 Hz, 1 H); 13
C
NMR (63 MHz, CDCl3) δ 9.0, 9.5, 14.9, 21.9, 22.6, 26.7, 27.6,
28.1, 29.7, 30.1, 31.4, 35.5, 35.6, 43.2, 45.6, 55.4, 58.6, 72.2, 72.5,
75.1, 75.4, 79.1, 79.8, 81.1, 84.4, 114.4, 115.8, 120.3, 122.7, 129.7,
130.4, 137.2, 155.4, 159.6, 166.9, 170.3, 170.0, 173.9, 174.6, 203.8.
HRMS (FAB) m/z calcd for C45H61NO16 ·Na+: 894.3870. Found:
894.3904 (∆ ) -3.1 ppm).
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-[(S)-2,2-dimethylcyclopropyl]docetaxel (14p). White solid; 83%
1
(for two steps); H NMR (CDCl3) δ 0.098 (t, J ) 4.6 Hz, 1 H),
0.62 (dd, J ) 8.5, 4.3 H), 1.11 (m, 10 H), 1.24 (s, 6 H), 1.31 (s, 9
H), 1.66 (s, 3 H), 1.83 (s, 1 H), 1.89 (s, 3 H), 2.34 (s, 3 H), 2.37
(m, 2 H), 2. 54 (m, 3 H), 3.34 (d, J ) 6.6 Hz, 1 H), 3.51 (t, J )
9.3 Hz, 1 H), 3.80 (d, J ) 7.0 Hz, 1 H), 3.85 (s, 3 H), 4.18 (d, J
) 8.4 Hz, 1 H), 4.32 (s, 1 H), 4.34 (d, J ) 8.4 Hz, 1 H), 4.43 (m,
1 H), 4.80 (d, J ) 8.9 Hz, 1 H), 4.97 (d, J ) 8.4 Hz, 1 H), 5.65 (d,
J ) 7.0 Hz, 1 H), 6.15 (t, J ) 8.6 Hz, 1 H), 6.30 (s, 1 H), 7.13 (dd,
J ) 8.0, 2.2 Hz, 1 H), 7.36 (t, J ) 8.0 Hz, 1 H), 7.63 (s, 1 H), 7.69
(d, J ) 7.5 Hz, 1 H); 13C NMR (CDCl3) δ 9.0, 9.5, 14.9, 17.1,
19.3, 20.1, 22.0, 22.6, 26.2, 26.5, 27.1, 27.5, 28.1, 33.2, 35.5, 43.2,
45.5, 55.3, 55.4, 58.5, 72.1, 72.7, 73.0, 75.1, 75.4, 76.4, 79.1, 79.8,
81.1, 84.4, 87.4, 114.4, 120.3, 122.6, 129.6, 130.4, 132.8, 142.6,
155.0, 159.6, 166.7, 169.7, 170.6, 174.6, 203.8. HRMS (FAB) m/z
calcd for C46H63NO16H+: 886.4225. Found: 886.4237 (∆ ) -1.3
ppm).
2-Debenzoyl-2-(3-fluorobenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropyl)docetaxel (15c). White solid; 89% (for two
1
steps): mp 138-140 °C; [R]20 -79 (c 0.47, CHCl3); H NMR
D
(CDCl3) δ 0.95 (s, 3 H), 0.97 (s, 3 H), 1.13 (s, 3 H), 1.28 (m, 18
H), 1.66 (m, 5 H), 2.37 (m, 6 H), 2.52 (m, 4 H), 3.21 (bs, 1 H),
3.80 (d, J ) 7.0 Hz, 1 H), 4.12 (m, 2 H), 4.29 (d, J ) 8.5 Hz, 1
H), 4.42 (m, 1 H), 4.57 (d, J ) 9.7 Hz, 1 H), 4.96 (d, J ) 10.1 Hz,
1 H), 5.61 (d, J ) 6.8 Hz, 1 H), 6.16 (t, J ) 8.4 Hz, 1 H), 6.30 (s,
1 H), 7.29 (m, 1 H), 7.43 (m, 1 H), 7.77 (d, J ) 9.1 Hz, 1 H), 7.89
(d, J ) 7.8 Hz, 1 H); 13C NMR (CDCl3) δ 9.1, 9.5, 14.9, 21.8,
22.4, 23.2, 24.7, 26.5, 27.6, 28.1, 35.5, 41.2, 43.2, 45.6, 51.3, 57.6,
72.2, 72.6, 73.0, 75.4, 75.5, 76.2, 79.2, 79.6, 81.0, 84.4, 116.8,
117.2, 120.6, 120.9, 126.0, 130.3, 130.4, 142.6, 155.5, 169.9, 174.0,
174.6, 203.7; 19F NMR (CDCl3, using Freon as the standard) δ
-112.1. HRMS (FAB) m/z calcd for C44H60O15FN·H+: 862.4025.
Found: 862.4022 (∆ ) + 0.4 ppm).
2-Debenzoyl-2-(3-chlorobenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropyl)docetaxel (15d). White solid; 80% (for two
1
steps); mp 143-145 °C; [R]20 -83 (c 0.12, CHCl3); H NMR
D
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-[(E)-prop-1-enyl]docetaxel (14n). White solid; 80% (for two
steps); mp 120-122 °C; [R]20D -100 (c 0.010, CHCl3). 1H NMR
(300 MHz, CDCl3) δ 1.14 (s, 3 H), 1.32 (s 3 H), 1.66 (s, 3 H),
1.73 (s 3 H), 1.75 (s, 3 H), 1.88 (s, 3 H), 2.36 (m, 6 H), 3.87 (s, 2
H), 4.12 (d, 2 H), 4.27 (m, 2 H), 4.40 (dd, J ) 10.6, 6.8 Hz, 1 H),
4.57 (b, 1 H), 4.86 (d, 1 H), 4.96 (d, J ) 8.1 Hz, 1 H), 5.60 (m, 2
H), 6.13 (t, J ) 8.8 Hz, 1 H), 6.30 (s, 1 H), 7.40 (t, J ) 7.8 Hz, 1
H), 7.56 (d, J ) 8.3 Hz, 1 H), 7.97 (d, J ) 7.7 Hz, 1 H), 8.10 (s,
1 H); 13C NMR (62.9 MHz, CDCl3) δ 4.5, 5.0, 10.4, 13.3, 17.3,
18.0, 22.2, 23.0, 23.6, 25.2, 31.0, 31.1, 38.7, 41.1, 50.9, 54.1, 67.7,
68.6, 70.6, 70.9, 73.2, 74.5, 76.6, 79.9, 110.0, 115.8, 118.1, 122.8,
124.3, 125.2, 128.0, 138.0, 149.0, 162.0, 165.6, 170.0, 199.0. HRMS
m/e calcd for C44H59NO16H+: 858.3912. Found: 858.3880 (∆ )
-3.7 ppm).
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(but-3-enyl)docetaxel (14o). White solid; 71% (for two steps);
mp 116-117 °C; [R]20D -37 (c 0.30, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.14 (s, 3 H), 1.23 (t, J ) 7.5 Hz, 3 H), 1.25 (s, 3 H),
1.30 (s, 9 H), 1.39 (m, 2 H), 1.67 (m, 3 H), 1.84 (m, 1 H), 1.88 (s,
3 H), 2.15 (m, 2 H), 2.33 (m, 2 H), 2.37 (s, 3 H), 2.53 (m, 3 H),
3.26 (bs, 1 H), 3.81 (d, J ) 6.9 Hz, 1 H), 3.89 (s, 3 H), 4.05 (m,
1 H), 4.18 (d, J ) 8.1 Hz, 1 H), 4.23 (s, 1 H), 4.36 (d, J ) 8.4 Hz,
1 H), 4.44 (dd, J ) 7.2, 10.2 Hz, 1 H), 4.64 (d, J ) 9.9 Hz, 1 H),
4.97 (d, J ) 8.7 Hz, 1 H), 5.05 (d, J ) 8.4 Hz, 1 H), 5.08 (d, J )
(CDCl3) δ 0.95 (m, 6 H), 1.12 (s, 3 H), 1.28 (m, 26 H), 1.66 (m,
6 H), 1.88 (s, 3 H), 2.37 (m, 6 H), 2.52 (m, 4 H), 3.21 (bs, 1 H),
3.80 (d, J ) 7.1 Hz, 1 H), 4.12 (m, 2 H), 4.27 (d, J ) 8.3 Hz, 1
H), 4.40 (dd, J ) 10.6, 6.8 Hz, 1 H), 4.57 (d, J ) 9.6 Hz, 1 H),
4.96 (d, J ) 8.1 Hz, 1 H), 5.60 (d, J ) 7.1 Hz, 1 H), 6.13 (t, J )
8.8 Hz, 1 H), 6.30 (s, 1 H), 7.40 (t, J ) 7.8 Hz, 1 H), 7.56 (d, J )
8.3 Hz, 1 H), 7.97 (d, J ) 7.7 Hz, 1 H), 8.10 (s, 1 H); 13C NMR
(CDCl3) δ 9.0, 9.5, 14.9, 21.8, 22.3, 23.2, 24.6, 26.5, 27.5, 28.1,
35.5, 41.2, 43.1, 45.6, 51.3, 58.4, 72.2, 72.6, 73.0, 75.4, 75.5, 76.2,
79.2, 79.6, 81.0, 84.4, 128.3, 130.0, 130.3, 131.0, 132.7, 133.6,
134.7, 142.6, 155.5, 165.5, 169.8, 174.0, 174.6, 203.7. HRMS m/e
calcd for C44H60O15NCl H+: 878.3730. Found: 878.3728 (∆ ) 0.2
ppm).
2-Debenzoyl-2-(3-azidobenzoyl)-10-propanoyl-3′-dephenyl-3′-
(2-methylpropyl)docetaxel (15e). White solid; 70% (for two steps);
1
mp 132-134 °C; [R]20 -70 (c 0.47, CHCl3); H NMR (CDCl3)
D
δ 0.95 (m, 6 H), 1.12 (s, 3 H), 1.28 (m, 26 H), 1.66 (m, 6 H), 1.88
(s, 3 H), 2.37 (m, 5 H), 2.52 (m, 4 H), 3.18 (bs, 1 H), 3.82 (d, J )
6.9 Hz, 1 H), 4.12 (m, 4 H), 4.31 (d, J ) 8.4 Hz, 1 H), 4.40 (dd,
J ) 10.2, 6.6 Hz, 1 H), 4.56 (d, J ) 9.6 Hz, 1 H), 4.97 (d, J ) 8.7
Hz, 1 H), 5.65 (d, J ) 6.9 Hz, 1 H), 6.14 (t, J ) 8.4 Hz, 1 H), 6.31
(s, 1 H), 7.23 (m, 1 H), 7.46 (t, J ) 7.8 Hz, 1 H), 7.88 (d, J ) 7.5
Hz, 1 H); 13C NMR (CDCl3) δ 9.0, 9.5, 14.9, 21.8, 22.5, 23.2,
24.7, 26.6, 27.6, 28.1, 35.5, 41.2, 43.2, 45.6, 51.4, 58.5, 72.2, 72.6,
73.0, 75.4, 75.5, 76.3, 78.0, 79.2, 79.7, 81.0, 84.4, 120.2, 124.3,

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3217
126.8, 130.1, 132.8, 140.8, 142.6, 155.5, 166.0, 170.1, 174.0, 174.6,
203.8. HRMS m/e calcd for C44H60N4O15 ·H+: 885.4133. Found:
885.4134 (∆ ) -0.1 ppm).
133.7, 139.0, 142.3, 166.9, 170.2, 172.8, 174.6, 174.9, 203.8. HRMS
m/e calcd for C44H57NO14 ·H+: 824.3857. Found: 824.3855 (∆ )
0.3 ppm).
Other taxoids 17b-l were synthesized in the same manner, and
characterization data are shown below.
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropyl)docetaxel (15g). White solid; 73% (for two
steps); mp 132-134 °C; [R]20D -110 (c 0.070, CHCl3); 1H NMR
(CDCl3) δ 0.95 (m, 6 H), 1.13 (s, 3 H), 1.28 (m, 8 H), 1.66 (m, 6
H), 1.88 (s, 3 H), 2.37 (m, 6 H), 2.52 (m, 4 H), 3.21 (bs, 1 H),
3.80 (d, J ) 6.9 Hz, 1 H), 3.86 (s, 3 H), 4.12 (m, 2 H), 4.30 (d, J
) 8.4 Hz, 1 H), 4.40 (dd, J ) 10.6, 6.8 Hz, 1 H), 4.57 (d, J ) 9.6
Hz, 1 H), 4.96 (d, J ) 8.1 Hz, 1 H), 5.63 (d, J ) 7.0 Hz, 1 H),
6.16 (t, J ) 8.4 Hz, 1 H), 6.30 (s, 1 H), 7.13 (d, J ) 7.9 Hz, 1 H),
7.33 (t, J ) 8.0 Hz, 1 H), 7.62 (s, 1 H), 7.68 (d, J ) 7.6 Hz, 1 H);
13C NMR (CDCl3) δ 9.0, 9.6, 14.9, 21.8, 22.5, 23.3, 24.7, 26.6,
27.6, 28.1, 35.5, 41.2, 43.2, 45.6, 51.2, 55.3, 58.5, 72.2, 72.6, 73.0,
75.4, 75.5, 76.2, 79.1, 79.7, 81.1, 84.4, 114.1, 120.4, 122.7, 129.6,
130.4, 132.9, 142.5, 155.4, 159.6, 166.8, 169.9, 174.0, 174.6, 203.8.
HRMS m/e calcd for C45H63O16N·H+: 874.4225. Found: 874.4224
(∆ ) 0.1 ppm). HPLC analysis using a Phenomenex Curosil-B
column: CH3CN/water (2/3) as the solvent system with a flow rate
of 1 mL/min; UV (230 and 254 nm) showed g95% purity.
10-Propanoyl-3′-dephenyl-3′-(2-methylprop-1-enyl)-3′N-(cy-
clopentanecarbonyl)docetaxel (17b). White solid; 78% (for two
1
steps); mp 150-152 °C; [R]20 -75.7 (c 3.75, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 0.98 (m, 6H), 1.16 (s, 3 H), 1.23 (m, 3 H),
1.26 (s, 9 H), 1.84-1.41 (m, 13 H), 1.88 (s, 3 H), 2.39 (s, 3 H),
2.43-2.59 (m, 3 H), 3.37 (d, J ) 5.7 Hz, 1 H), 3.80 (d, J ) 7.2
Hz, 1 H), 4.20 (m, 2 H), 4.30 (d, J ) 8.1, 1 H), 4.42 (m, 2 H), 4.97
(d, J ) 7.5 Hz, 1 H), 5.47 (d, J ) 9.4 Hz, 1 H), 5.68 (d, J ) 7.2
Hz, 1 H), 6.14 (m, 1 H), 6.30 (s, 1 H), 7.47 (t, 2 H), 7.60 (t, 1 H),
8.12 (d, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.0, 9.6, 14.9, 21.9,
22.0, 22.5, 23.3, 24.8, 25.8, 25.8, 26.7, 27.6, 29.7, 30.7, 35.6, 35.8,
41.0, 43.2, 45.6, 45.7, 49.6, 58.6, 72.2, 72.6, 72.9, 75.0, 75.4, 76.5,
79.1, 81.1, 84.4, 128.7, 129.2, 130.2, 133.1, 133.6,142.2, 166.9,
170.1, 173.8, 174.6, 176.3, 203.8. HRMS m/e calcd for
C45H59NO14 ·H+: 838.4014. Found: 838.4011 (∆ ) 0.3 ppm).
10-Propanoyl-3′-dephenyl-3′-(2-methylprop-1-enyl)-3′N-(cy-
clohexanecarbonyl)docetaxel (17c). White solid; 85% (for two
Alternative Method for the Synthesis of 15g through
Hydrogenation of 14g. To a reaction flask with activated Pd/C
(33 mg, 0.014 mmol) was added a solution of 14g (250 mg, 0.287
mmol) in 10 mL of EtOAc with several drops of MeOH under
hydrogen atmosphere. The suspension was stirred overnight, and
the reaction mixture was filtered through Celite. The filtrate was
condensed by a rotary evaporator and the residue was purified on
a silica gel column using hexanes/EtOAc (1/1) as the eluant to
afford 15 g (250 mg, 99.8% yield) as a white solid.
1
steps); mp 152-155 °C; [R]20 -78.3 (c 3.78, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 0.08 (s, 3 H), 1.13-1.18 (m, 6 H), 1.28 (s,
9 H), 1.60 (s, 3 H), 1.69 (br, s, 6 H) 1.72 (m, 1 H), 1.83 (s, 3 H),
2.29 (s, 3 H), 2.31 (s, 2 H), 2.44 (m, 3 H), 3.38 (br s, 1 H), 3.74
(d, J ) 6.9 Hz, 1 H), 4.10 (d, J ) 8.1 Hz, 1 H), 4.13 (br s 1 H),
4.22 (d, J ) 8.1 Hz, 1 H), 4.33 (dd, J ) 10.1, 7.5 Hz, 1 H), 4.67
(m, 2 H), 4.88 (d, J ) 9.3 Hz, 1 H), 5.23 (d, J ) 8.4 Hz, 1 H),
5.59 (d, J ) 6.9 Hz, 1 H), 6.06 (m, 1 H), 6.24 (s, 1 H), 7.37 (t, 2
H), 7.51 (t, 1 H), 8.01 (d, 2 H). HRMS m/e calcd for
C46H61NO14 ·H+: 852.4170. Found: 852.4172 (∆ ) -0.2 ppm).
10-Propanoyl-3′-dephenyl-3′-(2-methylprop-1-enyl)-3′N-de-
benzoyl-3′N-(cyclopent-1-ene-1-carbonyl)docetaxel (17d). White
solid; 80% (for two steps); mp 148-151 °C; [R]20D -70.3 (c 1.45,
Preparation of (3R,4S)-1-Acyl-3-trialkylsiloxy-4-(2-methyl-
prop-1-enyl)azetidin-2-ones (16). A typical procedure is described
for the preparation of (3R,4S)-1-cyclohexanecarbonyl-3-triisopro-
pylsiloxy-4-(2-methylprop-1-enyl)azetidin-2-one (16h). To a solu-
tion of (3R,4S)-3-triisopropylsiloxy-4-(2-methylprop-1-enyl)azetidin-
2-one20 (129 mg, 0.435mmol) and DMAP (53 mg, 0.435mmol) in
1 mL of CH2Cl2 was added triethylamine (0.6 mL, 4.35 mmol)
followed by the dropwise addition of cyclohexyl chloroformate
(0.14 mL, 0.652 mmol) at 0 °C. The mixture was stirred for 2 h at
room temperature, quenched with NH4Cl (5 mL), and extracted
with EtOAc (10 mL × 3), washed with brine, dried over MgSO4,
and concentrated in vacuo. Column chromatography of the residue
on silica gel (hexanes/EtOAc ) 20/1) afforded 16h (177 mg, 94%
1
CHCl3); H NMR (300 MHz, CDCl3) δ 1.08 (s, 3 H), 1.13-1.18
(m, 6 H), 1.28 (s, 9 H), 1.60 (s, 3 H), 1.69 (br, s, 6 H), 1.72 (m, 1
H), 1.83 (s, 3 H), 2.29 (s, 3 H), 2.31 (s, 2 H), 2.44 (m, 3 H), 3.82
(d, J ) 6.6 Hz, 1 H), 4.19 (d, J ) 8.7 Hz, 1H), 4.31 (m, 2H), 4.42
(m, 1 H), 4.96 (d, J ) 4.8 Hz, 1H), 5.10 (m, 1H), 5.38 (d, J ) 9.0
Hz, 1H), 5.67 (d, J ) 7.2 Hz, 1 H), 5.89 (d, J ) 8.1 Hz, 1 H), 6.19
(t, 1 H), 6.31 (s, 1 H), 6.51 (dd, 1 H), 7.47 (t, 2 H), 7.61 (t, 1 H),
8.09 (d, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.0, 9.5, 14.9, 18.6,
21.8, 22.4, 23.2, 25.8, 26.8, 27.6, 31.4, 33.1, 35.6, 35.8, 43.2, 45.6,
50.4, 58.6, 72.0, 72.2, 73.8, 75.0, 75.4, 76.5, 79.0, 81.0, 84.4, 87.5,
120.0, 128.6, 129.2, 130.1, 133.1, 133.7, 138.4, 139.2, 139.5, 142.2,
165.0, 166.8, 170.3, 172.7, 174.6, 203.8. HRMS m/e calcd for
C45H57NO14 ·H+: 836.3857. Found: 836.3858 (∆ ) -0.1 ppm).
10-Propanoyl-3′-dephenyl-3′-(2-methylprop-1-enyl)-3′N-de-
benzoyl-3′N-(cyclohex-1-ene-1-carbonyl)docetaxel (17e). White
1
yield) as a colorless oil: H NMR (300 MHz, CDCl3) δ 1.03 (m,
21 H). 1.14-1.50 (m, 6 H), 1.64-1.93 (m, 4 H), 1.76 (s, 3 H),
1.78 (s, 3 H), 2.91 (m, 1 H), 4.80 (dd, J ) 6.3 Hz, J ) 9.9 Hz, 1
H), 4.99 (d, J ) 6.3 Hz, 1 H), 5.22 (d, J ) 9.9 Hz, 1 H).
Other N-modified ꢀ-lactams 16a-g were prepared in the same
manner. (3R,4S)-3-tert-butyldimethylsiloxy-4-(2-methylprop-1-eny-
l)azetidin-2-one was prepared in the same manner as that described
for the corresponding 3-triisopropylsiloxy-ꢀ-lactam.20,22 Charac-
terization data (1H NMR) for 16a-g are summarized in the
Supporting Information.
solid; 75% (for two steps); mp 151-154 °C; [R]20 -67 (c 2.92,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 1.15 (s, 3 H), 1.13-1.18
(m, 6 H), 1.26 (s, 9 H), 1.60 (s, 3 H), 1.69 (br, s, 6 H), 1.72 (m, 1
H), 1.81 (s, 3H), 1.93 (s, 3 H), 2.16 (m, 4 H), 2.38 (s, 3 H),
2.45-2.59 (m, 3 H), 3.74 (d, J ) 6.9 Hz), 3.82 (d, J ) 6.6 Hz,
1H), 4.20 (d, J ) 8.4 Hz, 1 H), 4.30 (m, 2H), 4.41 (m, 1 H), 4.96
(d, J ) 7.8 Hz, 1 H), 5.06 (m, 1H), 5.11 (d, J ) 3.6 Hz, 1H), 5.37
(d, J ) 9.0 Hz, 1 H), 5.67 (d, J ) 7.2 Hz, 1 H), 5.93 (d, J ) 7.8
Hz, 1H), 6.18 (t, 1 H), 6.31 (s, 1 H), 6.60 (dd, 1H), 7.46 (t, 2 H),
7.60 (t, 1 H), 8.09 (d, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.0,
9.5, 14.9, 18.6, 21.4, 21.8, 22.0, 22.4, 24.2, 25.4, 25.8, 26.8, 27.6,
29.7, 30.9, 35.6, 35.8, 43.2, 45.6, 50.5, 58.6, 71.9, 72.2, 73.9, 75.0,
75.4, 79.1, 81.0, 84.4, 120.1, 128.6, 129.2, 130.1, 132.5, 133.0,
133.7, 134.7, 139.2, 142.3, 166.9, 168.4, 170.3, 172.8, 174.6, 203.8.
HRMS m/e calcd for C46H59NO14 ·H+: 850.4014. Found: 850.4018
(∆ ) -0.5 ppm).
Synthesis of Taxoids 17. Taxoids 17a-l were synthesized
through the Ojima-Holton coupling of 7-TES-10-deacetyl-10-
propanoylbaccatin17 or baccatin 11b with ꢀ-lactams 16a-h in the
same manner as that described above for the synthesis of 14a-p.
For example, 3′-dephenyl-3′-(2-methylprop-1-enyl)-3′N-debenzoyl-
3′N-cyclobutanecarbonyl-10-propanoyldocetaxel (17a) was obtained
in 86% yield for two steps as a white solid: mp 149-151 °C; [R]20
D
1
-72.6 (c 2.91, CHCl3); H NMR (300 MHz, CDCl3) δ 1.16 (s, 3
H), 1.21-1.26 (m, 15 H), 1.69 (s, 3 H), 1-2.00 (m, 10 H), 1.83
(s, 3 H), 2.09-2.21 (m, 5 H), 2.44-2.60 (m, 4 H), 2.92 (m, 1 H),
3.82 (d, J ) 6.6 Hz, 1 H), 4.32-4.19 (m, 3 H), 4.43 (m, 1 H), 4.97
(d, J ) 8.4 Hz, 1 H), 5.04 (m, 1H), 5.35 (d, J ) 8.7 Hz, 1H), 5.58
(d, J ) 8.4 Hz, 1 H), 5.68 (d, J ) 7.2 Hz, 1 H), 6.20 (t, 1 H), 6.31
(s, 1 H), 7.47 (t, 2 H), 7.61 (t, 1 H), 8.11 (d, 2 H); 13C NMR (63
MHz, CDCl3) δ 0, 9.5, 14.9, 18.6, 21.9, 22.4, 25.2, 25.5, 25.7,
26.7, 27.6, 29.7, 35.7, 39.7, 43.2, 45.6, 50.2, 58.6, 72.1, 72.2, 73.8,
75.0, 75.4, 76.4, 79.1, 81.0, 84.4, 120.0, 128.6, 129.2, 130.1, 133.1,
10-Propanoyl-3′-dephenyl-3′-(2-methylprop-1-enyl)-3′N-de-
benzoyl-3′N-(cyclopentyloxycarbonyl)docetaxel (17f). White solid;
85% (for two steps); mp 141-143 °C; [R]20D -74 (c 5.06, CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.08 (s, 3 H), 1.13-1.18 (m, 6 H),
1.28 (s, 9 H), 1.60 (s, 3 H), 1.69 (br, s, 6 H) 1.72 (m, 1 H), 1.83

3218 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
(s, 3 H), 2.29 (s, 3 H), 2.31 (s, 2 H), 2.44 (m, 3 H), 3.38 (br s, 1
H), 3.74 (d, J ) 6.9 Hz, 1 H), 4.10 (d, J ) 8.1 Hz, 1 H), 4.13 (br
s 1 H), 4.22 (d, J ) 8.1 Hz, 1 H), 4.33 (dd, J ) 10.1, 7.5 Hz, 1 H),
4.67 (m, 2 H), 4.88 (d, J ) 9.3 Hz, 1 H), 5.23 (d, J ) 8.4 Hz, 1
H), 5.59 (d, J ) 6.9 Hz, 1 H), 6.06 (m, 1 H), 6.24 (s, 1 H), 7.37
(t, 2 H), 7.51 (t, 1 H), 8.01 (d, 2 H); 13C NMR (63 MHz, CDCl3)
δ 9.0, 9.5, 14.9, 18.5, 21.9, 22.4, 23.6, 23.6, 25.7, 26.7, 27.5, 29.7,
32.6, 32.6, 35.6, 35.6, 43.2, 45.7, 51.9, 58.5, 72.1, 72.2, 73.7, 75.0,
75.4, 76.4, 77.9, 79.2, 81.1, 84.4, 120.5, 128.6, 129.2, 130.1, 133.0,
133.7, 138.2, 142.3, 156.1, 166.9, 170.2, 172.8, 174.6, 203.8. HRMS
m/e calcd for C45H59NO15 ·H+: 854.3963. Found: 854.3960 (∆ )
+ 0.3 ppm).
1 H), 4.96 (d, J ) 8.4 Hz, 1 H), 5.03 (dt, J ) 3.0, 8.7 Hz, 1 H),
5.36 (d, J ) 9.0 Hz, 1 H), 5.66 (d, J ) 6.9 Hz, 1 H), 5.72 (d, J )
8.1 Hz, 1 H), 6.13 (t, J ) 8.7 Hz, 1 H), 6.31 (s, 1 H), 7.13 (dd, J
) 7.5 Hz, J ) 2.1 Hz, 1 H), 7.37 (d, J ) 7.5 Hz, 2 H), 7.63 (s, 1
H), 7.69 (d, J ) 7.5 Hz, 1 H). HRMS m/e calcd for
C46H61O15N · H+: 868.4119. Found: 868.4122 (∆ ) -0.3 ppm).
HPLC analysis using a Phenomenex Curosil-B column: CH3CN/
water (2/3) as the solvent system with a flow rate of 1 mL/min;
UV (230 and 254 nm) showed g95% purity.
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropen-1-yl)-3′N-de-tert-butoxycarbonyl-3′N-(cyclo-
hexanecarbonyl)docetaxel (17k). White solid; 81% (for two steps);
1
10-Propanoyl-3′-dephenyl-3′-(2-methylprop-1-enyl)-3′N-de-
benzoyl-3′N-(cyclohexyloxycarbonyl)docetaxel (17g). White solid;
mp 151-153 °C; [R]20 -73.4 (c 14.3, CHCl3); H NMR (300
D
MHz, CDCl3) δ 1.14 (s, 3 H), 1.28 (m, 8 H), 1.33 (s, 9 H), 1.67
(m, 3 H), 1.73 (s, 3 H), 1.75 (s, 3 H), 1.89 (m, 5 H), 2.37 (m, H),
2.52 (m, 3 H), 3.80 (d, J ) 6.9 Hz, 1 H), 3.86 (s, 3 H), 4.18-4.23
(m, 2 H), 4.33 (d, J ) 8.7 Hz, 1 H), 4.41 (dt, J ) 11.1, 6.6 Hz, 1
H), 4.95 (d, J ) 7.8, 1 H), 5.03 (dt, J ) 2.7, 8.4 Hz, 1 H), 5.35 (d,
J ) 8.4 Hz, 1 H), 5.67 (d, J ) 6.9 Hz, 1 H), 5.72 (d, J ) 8.1 Hz,
1 H), 6.12 (t, J ) 9.0 Hz, 1 H), 6.31 (s, 1 H), 7.13 (dd, J ) 7.8 Hz,
J ) 2.1 Hz, 1 H), 7.37 (d, J ) 7.8 Hz, 2 H), 7.63 (s, 1 H), 7.69 (d,
J ) 7.8 Hz, 1 H). HRMS m/e calcd for C47H63O15N·H+: 882.4276.
Found: 882.4275 (∆ ) 0.1 ppm). HPLC analysis using a Phenom-
enex Curosil-B column: CH3CN/water (2/3) as the solvent system
with a flow rate of 1 mL/min; UV (230 and 254 nm) showed 95%
purity.
80% (for two steps); mp 142-144 °C; [R]20 -66.5 (c 5.00,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 1.08 (s, 3 H), 1.13-1.18
(m, 6 H), 1.28 (s, 9 H), 1.60 (s, 3 H), 1.69 (br, s, 6 H) 1.72 (m, 1
H), 1.83 (s, 3 H), 2.29 (s, 3 H), 2.31 (s, 2 H), 2.44 (m, 3 H), 3.38
(br s, 1 H), 3.74 (d, J ) 6.9 Hz, 1 H), 4.10 (d, J ) 8.1 Hz, 1 H),
4.13 (br s 1 H), 4.22 (d, J ) 8.1 Hz, 1 H), 4.33 (dd, J ) 10.1, 7.5
Hz, 1 H), 4.67 (m, 2 H), 4.88 (d, J ) 9.3 Hz, 1 H), 5.23 (d, J )
8.4 Hz, 1 H), 5.64 (d, J ) 7.0 Hz, 1 H), 6.18 (m, 1 H), 6.30 (s, 1
H), 7.46 (t, 2 H), 7.59 (t, 1 H), 8.09 (d, 2 H); 13C NMR (63 MHz,
CDCl3) δ 9.0, 9.5, 14.9, 18.5, 21.9, 22.4, 23.6, 23.7, 25.3, 25.7,
26.7, 27.5, 31.8, 35.6, 35.6, 43.2, 45.7, 51.8, 58.5, 72.1, 72.2, 73.7,
75.0, 75.4, 76.4, 79.2, 81.0, 84.4, 120.6, 128.6, 129.2, 130.1, 133.0,
133.7, 138.1, 142.3, 155.8, 166.9, 170.2, 172.8, 174.6, 203.8. HRMS
m/e calcd for C46H61NO15 ·H+: 868.4120. Found: 868.4120 (∆ )
-0.1 ppm).
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropen-1-yl)-3′N-de-tert-butoxycarbonyl-3′N-(cyclo-
hexyloxycarbonyl)docetaxel (17l). White solid; 77% (for two
1
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylprop-1-enyl)-3′N-de-tert-butoxycarbonyl-3′N-(cyclo-
steps); mp 141-143 °C; [R]20 -68 (c 10.1, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 1.13 (s, 3 H), 1.28 (m, 8 H), 1.33 (s, 9 H),
1.66 (m, 3 H), 1.73 (s, 3 H), 1.75 (s, 3 H), 1.89 (m, 5 H), 2.37 (m,
H), 2.52 (m, 3 H), 3.81 (d, J ) 7.2 Hz, 1 H), 3.87 (s, 3 H), 4.17
(d, 8.7 Hz, 1 H), 4.23 (d, J ) 3.0 Hz, 1 H), 4.34 (d, J ) 8.7 Hz),
4.42 (dd, J ) 10.8, 7.5 Hz, 1 H), 4.49 (m, 1 H), 4.79 (dt, J ) 3.0,
8.0 Hz, 1 H), 4.88 (d, J ) 8.7 Hz, 1 H), 4.96 (d, J ) 7.5 Hz, 2 H),
5.32 (d, J ) 8.0 Hz, 1 H), 5.66 (d, J ) 7.2 Hz, 1 H), 6.19 (t, J )
8.1 Hz, 1 H), 6.31 (s, 1 H), 7.13 (dd, J ) 7.8 Hz, J ) 2.1 Hz, 1 H),
7.37 (d, J )7.8 Hz, 2 H) 7.63 (s, 1 H), 7.69 (d, J ) 7.8 Hz, 1 H).
HRMS m/e calcd for C47H63O16N·H+: 898.4225. Found: 898.4226
(∆ ) -0.1 ppm). HPLC analysis using a Phenomenex Curosil-B
column: CH3CN/water (2/3) as the solvent system with a flow rate
of 1 mL/min; UV (230 and 254 nm) showed 95% purity.
propanecarbonyl)docetaxel (17h). White solid; 66% (for two
1
steps); mp 141-143 °C; [R]20 -66.6 (c 11.4, CHCl3); H NMR
D
(300 MHz, CDCl3): δ 1.14 (s, 3 H), 1.28 (m, 9 H), 1.67 (s, 3 H),
1.73 (s, 3 H), 1.77 (s, 3 H), 1.88 (m, 5 H), 2.35 (m, 5 H), 2.52 (m,
3 H), 3.80 (d, J ) 6.8 Hz, 1 H), 3.85 (s, 3 H), 4.17 (d, J ) 8.7, 1
H), 4.25 (d, J ) 3.2 Hz, 1 H), 4.33 (d, J ) 8.7 Hz), 4.41 (dd, J )
10.5 Hz, J ) 6.3 Hz, 1 H), 4.96 (d, J ) 8.1 Hz, 1 H), 5.03 (td, J
) 3.2, 8.8 Hz, 1 H), 5.37 (d, J ) 8.8 Hz, 1 H), 5.66 (d, J ) 6.8
Hz, 1 H), 5.92 (d, J ) 8.1 Hz, 1 H), 6.15 (t, J ) 8.4 Hz, 1 H), 6.30
(s, 1 H), 7.13 (dd, J ) 7.8 Hz, J ) 2.4 Hz, 1 H), 7.3 (t, J ) 7.8
Hz, 2 H) 7.62 (d, 2.4 Hz, 1 H), 7.68 (d, J ) 7.8 Hz, 1 H). HRMS
m/e calcd for C44H57NO15 ·H+: 840.3806. Found: 840.3802 (∆ )
-0.5 ppm). HPLC analysis using a Phenomenex Curosil-B column:
CH3CN/water (2/3) as the solvent system with a flow rate of 1
mL/min; UV (230 and 254 nm) showed g95% purity.
Synthesis of Taxoids 18 through Hydrogenation of 17. A
typical procedure is described for the synthesis of 10-propanoyl-
3′-dephenyl-3′-(2-methylpropyl)-3′N-debenzoyl-3′N-(cyclopentan-
ecarbonyl)docetaxel (18b). To a flask charged with activated 10%
Pd/carbon (2 mg, 0.002 mmol) and 17b (13 mg, 0.02 mmol) under
hydrogen atmosphere were added EtOAc (12.0 mL) and MeOH
(0.02 mL), and the suspension was stirred at room temperature for
24 h. The reaction mixture was filtered over Celite and the filtrate
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropen-1-yl)-3′N-de-tert-butoxycarbonyl-3′N-(cy-
clobutanecarbonyl)docetaxel (17i). White solid; 61% (for two
1
steps); mp 143-145 °C; [R]20 -70.4 (c 13.5, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 1.14 (s, 3 H), 1.28 (m, 8 H), 1.33 (s, 9 H),
1.67 (m, 3 H), 1.73 (s, 3 H), 1.75 (s, 3 H), 1.89 (m, 5 H), 2.37 (m,
H), 2.52 (m, 3 H), 2.91 (m, 1 H), 3.80 (d, J ) 6.9 Hz, 1 H), 3.85
(s, 3 H), 4.19 (d, J ) 8.4, 1 H), 4.25 (s, 1 H), 4.34 (d, J ) 8.4 Hz),
4.42 (t, J ) 7.2, 1 H), 4.96 (d, J ) 8.1 Hz, 1 H), 5.03 (dt, J ) 3.3,
8.9 Hz, 1 H), 5.35 (d, J ) 8.9 Hz, 1 H), 5.57 (d, J ) 8.1 Hz, 1 H),
5.67 (d, J ) 7.2 Hz, 1 H), 6.16 (t, J ) 8.7 Hz, 1 H), 6.31 (s, 1 H),
7.13 (dd, J ) 7.8 Hz, J ) 1.8 Hz, 1 H), 7.37 (t, J ) 7.8 Hz, 1 H)
7.63 (s, 1 H), 7.70 (d, J ) 7.8 Hz, 1 H). HRMS m/e calcd for
C45H59O15N·H+: 854.3962. Found: 854.3962 (∆ ) 0.1 ppm). HPLC
analysis using a Phenomenex Curosil-B column: CH3CN/water (2/
3) as the solvent system with a flow rate of 1 mL/min; UV (230
and 254 nm) showed 95% purity.
was concentrated in vacuo to afford 18b in quantitative yield as
1
white solid: mp 149-152 °C; [R]20 -114 (c 3.70, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 0.98 (m, 6H), 1.16 (s, 3 H), 1.23 (m,
3 H), 1.26 (s, 9 H), 1.84-1.41 (m, 13 H), 1.88 (s, 3 H), 2.39 (s, 3
H), 2.43-2.59 (m, 3 H), 3.37 (d, J ) 5.7 Hz, 1 H), 3.80 (d, J )
7.2 Hz, 1 H), 4.20 (m, 2 H), 4.30 (d, J ) 8.1, 1 H), 4.42 (m, 2 H),
4.97 (d, J ) 7.5 Hz, 1 H), 5.47 (d, J ) 9.4 Hz, 1 H), 5.68 (d, J )
7.2 Hz, 1 H), 6.14 (m, 1 H), 6.30 (s, 1 H), 7.47 (t, 2 H), 7.60 (t, 1
H), 8.12 (d, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.0, 9.6, 14.9,
21.9, 22.0, 22.5, 23.3, 24.8, 25.8, 25.8, 26.7, 27.6, 29.7, 30.7, 35.6,
35.8, 41.0, 43.2, 45.6, 45.7, 49.6, 58.6, 72.2, 72.6, 72.9, 75.0, 75.4,
76.5, 79.1, 81.1, 84.4, 128.7, 129.2, 130.2, 133.1, 133.6, 142.2,
166.9, 170.1, 173.8, 174.6, 176.3, 203.8. HRMS m/e calcd for
C45H61NO14 ·H+: 840.4170. Found: 840.4174 (∆ ) -0.4 ppm).
Other taxoids 18c, 18f-h, 18k, and 18m were synthesized in
the same manner, and characterization data are shown below.
10-Propanoyl-3′-dephenyl-3′-(2-methylpropyl)-3′N-debenzoyl-
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropen-1-yl)-3′N-de-tert-butoxycarbonyl-3′N-(cyclo-
pentanecarbonyl)docetaxel (17j). White solid; 77% (for two steps);
1
mp 136-138 °C; [R]20 -74.5 (c 14.1, CHCl3); H NMR (300
D
MHz, CDCl3) δ 1.14 (s, 3 H), 1.28 (m, 8 H), 1.33 (s, 9 H), 1.67
(m, 3 H), 1.73 (s, 3 H), 1.75 (s, 3 H), 1.89 (m, 5 H), 2.37 (m, H),
2.52 (m, 3 H), 3.80 (d, J ) 6.9 Hz, 1 H), 3.85 (s, 3 H), 4.19 (d, J
) 8.4, 1 H), 4.21 (s, 1 H), 4.32 (d, J ) 8.4 Hz), 4.41 (t, J)10.2,
3′N-cyclohexanecarbonyldocetaxel (18c). White solid; 100%; mp
1
133-135 °C; [R]20 -74 (c 4.21, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 1.08 (s, 3 H), 1.13-1.18 (m, 6 H), 1.28 (s, 9 H), 1.60 (s,

New Generation Taxoids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3219
3 H), 1.69 (br, s, 6 H) 1.72 (m, 1 H), 1.83 (s, 3 H), 2.29 (s, 3 H),
2.31 (s, 2 H), 2.44 (m, 3 H), 3.38 (br s, 1 H), 3.74 (d, J ) 6.9 Hz,
1 H), 4.10 (d, J ) 8.1 Hz, 1 H), 4.13 (br s 1 H), 4.22 (d, J ) 8.1
Hz, 1 H), 4.33 (dd, J ) 10.1, 7.5 Hz, 1 H), 4.67 (m, 2 H), 4.88 (d,
J ) 9.3 Hz, 1 H), 5.23 (d, J ) 8.4 Hz, 1 H), 5.59 (d, J ) 6.9 Hz,
1 H), 6.06 (m, 1 H), 6.24 (s, 1 H), 7.37 (t, 2 H), 7.51 (t, 1 H), 8.01
(d, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.0, 9.6, 14.9, 21.8, 22.0,
22.5, 23.3, 24.8, 25.6, 26.7, 27.6, 29.7, 35.6, 35.7, 41.0, 43.2, 45.5,
45.6, 49.2, 58.5, 72.2, 72.6, 72.8, 75.1, 75.4, 79.0, 81.1, 84.4, 128.6,
129.3, 130.2, 133.1, 133.6, 142.2, 166.8, 170.0, 173.8, 174.6, 176.1,
203.8. HRMS m/e calcd for C45H61NO14 ·H+: 840.4170. Found:
840.4174 (∆ ) -0.4 ppm). HPLC analysis using a Phenomenex
Curosil-B column: CH3CN/water (2/3) as the solvent system with
a flow rate of 1 mL/min; UV (230 and 254 nm) showed g95%
purity.
3.81 (d, J ) 6.8 Hz, 1 H), 3.87 (s, 3H), 4.20 (m, 2 H), 4.33 (d, J
) 8.4 Hz, 1 H), 4.43 (m, 2H), 4.97 (bd, J ) 9.6 Hz, 1 H), 5.47 (d,
J ) 9.6 Hz, 1H), 5.68 (d, J ) 7.2 Hz, 1H), 6.12 (m, 1 H), 6.30 (s,
1 H), 7.14 (dd, J1 ) 2 Hz, J2 ) 8.4 Hz, 1 H), 7.37 (bt, J ) 8 Hz,
1 H), 7.64 (bs, 1H), 7.70 (bd, J ) 7.6 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ 9.0, 9.5, 14.8, 21.7, 22.0, 22.5, 23.3, 24.8, 25.5,
25.6, 26.7, 27.6, 29.7, 35.6, 35.7, 41.0, 43.2, 45.4, 45.5, 49.2, 55.3,
58.5, 72.2, 72.6, 72.9, 75.1, 75.4, 76.4, 78.8, 81.2, 84.4, 114.2,
120.4, 122.7, 129.6, 130.5, 133.2, 142.1, 159.6, 166.6, 170.0, 173.7,
174.6, 176.1, 203.8. HRMS m/e calcd for C47H65NO15H+: 884.4432.
Found: 884.4413 (∆ ) -2.1 ppm).
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropyl)-3′N-de-tert-butoxycarbonyl-3′N-(cyclopen-
tyloxycarbonyl)docetaxel (18m). White solid; 60% yield (for three
steps from 11b); mp 143-145 °C; [R]20 -70 (c 13.0, CHCl3);
D
10-Propanoyl-3′-dephenyl-3′-(2-methylpropyl)-3′N-debenzoyl-
3′N-cyclopentyloxycarbonyldocetaxel (18f). White solid; 100%;
mp 131-133 °C; [R]20D -67 (c 0.42, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.08 (s, 3 H), 1.13-1.18 (m, 6 H), 1.28 (s, 9 H), 1.60 (s,
3 H), 1.69 (br s, 6 H) 1.72 (m, 1 H), 1.83 (s, 3 H), 2.29 (s, 3 H),
2.31 (s, 2 H), 2.44 (m, 3 H), 3.38 (br s, 1 H), 3.74 (d, J ) 6.9 Hz,
1 H), 4.10 (d, J ) 8.1 Hz, 1 H), 4.13 (br s 1 H), 4.22 (d, J ) 8.1
Hz, 1 H), 4.33 (dd, J ) 10.1, 7.5 Hz, 1 H), 4.67 (m, 2 H), 4.88 (d,
J ) 9.3 Hz, 1 H), 5.23 (d, J ) 8.4 Hz, 1 H), 5.59 (d, J ) 6.9 Hz,
1 H), 6.06 (m, 1 H), 6.24 (s, 1 H), 7.37 (t, 2 H), 7.51 (t, 1 H), 8.01
(d, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.0, 9.5, 14.9, 18.5, 21.9,
22.4, 23.6, 23.6, 25.7, 26.7, 27.5, 29.7, 32.6, 32.6, 35.6, 35.6, 43.2,
45.7, 51.9, 58.5, 72.1, 72.2, 73.7, 75.0, 75.4, 76.4, 77.9, 79.2, 81.1,
84.4, 120.5, 128.6, 129.2, 130.1, 133.0, 133.7, 138.2, 142.3, 156.1,
166.9, 170.2, 172.8, 174.6, 203.8. HRMS: m/e calcd for
C45H61NO15 ·H+: 856.4119. Found: 854.4121 (∆ ) -0.2 ppm).
10-Propanoyl-3′-dephenyl-3′-(2-methylpropyl)-3′N-debenzoyl-
3′N-cyclohexyloxycarbonyldocetaxel (18g). White solid; 100%;
mp 142-144 °C; [R]20D -60 (c 1.28, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.08 (s, 3 H), 1.13-1.18 (m, 6 H), 1.28 (s, 9 H), 1.60 (s,
3 H), 1.69 (br, s, 6 H), 1.72 (m, 1 H), 1.83 (s, 3 H), 2.29 (s, 3 H),
2.31 (s, 2 H), 2.44 (m, 3 H), 3.38 (br s, 1 H), 3.74 (d, J ) 6.9 Hz,
1 H), 4.10 (d, J ) 8.1 Hz, 1 H), 4.13 (br s 1 H), 4.22 (d, J ) 8.1
Hz, 1 H), 4.33 (dd, J ) 10.1, 7.5 Hz, 1 H), 4.67 (m, 2 H), 4.88 (d,
J ) 9.3 Hz, 1 H), 5.23 (d, J ) 8.4 Hz, 1 H), 5.64 (d, J ) 7.0 Hz,
1 H), 6.18 (m, 1 H), 6.30 (s, 1 H), 7.46 (t, 2 H), 7.59 (t, 1 H), 8.09
(d, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.0, 9.5, 14.9, 18.5, 21.9,
22.4, 23.6, 23.7, 25.3, 25.7, 26.7, 27.5, 31.8, 35.6, 35.6, 43.2, 45.7,
51.8, 58.5, 72.1, 72.2, 73.7, 75.0, 75.4, 76.4, 79.2, 81.0, 84.4, 120.6,
128.6, 129.2, 130.1, 133.0, 133.7, 138.1, 142.3, 155.8, 166.9, 170.2,
172.8, 174.6, 203.8. HRMS m/e calcd for C46H63NO15H+: 870.4273.
Found: 870.4276 (∆ ) +0.3 ppm).
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropyl)-3′N-de-tert-butoxycarbonyl-3′N-(cyclopro-
panecarbonyl)docetaxel (18h). White solid; 100%; mp 139-141
°C; [R]20D -74.5 (c 14.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
0.71 (m, 2H), 0.86 (m, 2H), 0.95 (dd, J1 ) 6.4 Hz, J2 ) 16.4 Hz,
6 H), 1.15 (s, 3H), 1.21-1.41 (m, 8 H), 1.62-1.78 (m, 5 H), 1.88
(m, 3H), 2.38 (m, 4H), 2.54 (m, 4H), 3.66 (bs, 1H), 3.79 (d, J )
7.2 Hz, 1 H), 3.87 (s, 1H), 4.20 (m, 2 H), 4.32 (d, J ) 8.4 Hz, 1
H), 4.42 (m, 2 H), 4.96 (dd, J1 ) 2 Hz, J2 ) 9.6 Hz, 1 H), 5.67 (d,
J ) 7.2 Hz, 1H), 5.78 (d, J ) 9.2 Hz, 1H), 6.14 (m, 1 H), 6.30 (s,
1 H), 7.14 (bdd, 1 H), 7.37 (bt, J ) 8 Hz, 1 H), 7.63 (bs, 1H), 7.70
(bd, J ) 7.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 7.3, 7.5,
9.0, 9.6, 14.5, 14.8, 21.8, 22.0, 22.5, 23.2, 24.7, 26.7, 27.6, 35.6,
35.7, 40.9, 43.2, 45.5, 50.0, 55.3, 58.5, 72.1, 72.4, 73.0, 75.1, 75.4,
76.4, 78.9, 81.1, 84.4, 114.3, 120.4, 122.6, 129.6, 130.5, 133.0,
142.2, 159.6, 166.7, 170.0, 173.7, 173.8, 174.6, 203.8. HRMS m/e
calcd for C44H59O15N·H+: 842.3963. Found: 842.3941 (∆ ) -2.6
ppm).
1H NMR (400 MHz, CDCl3) δ 0.95 (dd, J1 ) 6.4 Hz, J2 ) 10 Hz,
6 H), 1.14 (s, 3 H), 1.25 (m, 7 H), 1.35-1.72 (m, 15 H), 1.85 (s,
3H), 2.36 (m, 5H), 2.54 (m, 4H), 3.81 (d, J ) 8 Hz, 1 H), 3.87 (s,
1H), 4.12-4.20 (m, 3 H), 4.33 (d, J ) 8.4 Hz, 1 H), 4.42 (m, 1
H), 4.69 (d, J ) 9.6 Hz, 1 H), 4.89 (m, 1 H), 4.98 (d, J1 ) 8 Hz,
1 H), 5.66 (d, J ) 7.2 Hz, 1H), 6.20 (m, 1 H), 6.30 (s, 1 H), 7.13
(dd, J1 ) 2.8 Hz, J2 ) 8.4 Hz, 1 H), 7.37 (bt, J ) 8 Hz, 1 H), 7.64
(bs, 1H), 7.70 (bd, J ) 7.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 9.0, 9.5, 14.8, 21.7, 22.0, 22.5, 23.2, 23.5, 23.6, 24.6, 26.7, 27.5,
32.5, 32.6, 35.5, 41.2, 43.2, 45.6, 51.6, 55.3, 58.5, 72.1, 72.5, 73.0,
75.1, 75.4, 76.4, 77.8, 79.1, 81.1, 84.4, 114.2, 120.5, 122.7, 129.6,
130.4, 133.0, 142.3, 156.1, 159.7, 166.8, 170.0, 173.7, 174.6, 203.8.
HRMS m/e calcd for C46H63O16NH+: 886.4225. Found: 886.4211
(∆ ) -1.6 ppm).
In Vitro Cell Growth Inhibition Assay. (a) Tumor cell growth
inhibition was determined according to the method established by
Skehan et al.51 Human cancer cells LCC6-WT (Pgp-), MCF-7
(Pgp-), LCC6-MDR (Pgp+), and NCI/ADR (Pgp+) were plated
at a density of 400-2000 cells/well in 96-well plates and allowed
to attach overnight. These cell lines were maintained in RPMI-
1640 medium (Roswell Park Memorial Institute growth medium)
supplemented with 5% fetal bovine serum and 5% Nu serum
(Collaborative Biomedical Product, MA). Taxoids were dissolved
in DMSO and further diluted with RPMI-1640 medium. Triplicate
wells were exposed to various treatments. After 72 h of incubation,
100 µL of ice-cold 50% trichloroacetic acid (TCA) was added to
each well, and the samples were incubated for 1 h at 4 °C. Plates
were then washed five times with water to remove TCA and serum
proteins, and 50 µL of 0.4% sulforhodamine B (SRB) was added
to each well. Following a 5 min incubation, plates were rinsed five
times with 0.1% acetic acid and air-dried. The dye was then
solubilized with 10 mM Tris base (pH 10.5) for 5 min on a gyratory
shaker. Optical density was measured at 570 nm. The IC50 values
were then calculated by fitting the concentration-effect curve data
with the sigmoid-Emax model using nonlinear regression, weighted
by the reciprocal of the square of the predicted effect.52
(b) Human pancreatic cancer cell lines MIA PaCa-2, CFPAC-1,
BxPC-3, and PANC-1 were cultured as specified by ATCC
(Manassas, VA). For cytotoxicity assays the cells were plated at a
density of 2.5 × 104 cells/well in 24-well plates and allowed to
adhere overnight. The medium was changed the following morning
and replaced with medium containing taxane derivatives or vehicle
control. Taxoids were dissolved in DMSO to 10 mM and were
further diluted in appropriate medium prior to addition to cells.
Each dose of drug or vehicle was tested in triplicate, and the
experiment is representative of at least three independent trials. After
72 h of treatment, the medium was aspirated and the cells were
washed in warm PBS. MTT reagent (Sigma) was diluted in RPMI-
1640 medium without phenol red (Invitrogen) and added to the
cells at 0.5 mg/mL. After 3 h of incubation, the reagent was
aspirated, the plate was washed with PBS, and MTT formazan
crystals were dissolved in 500 µL of acidified isopropanol (0.1 N
hydrochloric acid). Subsequently, 100 µL of the solution was
transferred to a microtiter plate. Absorbance at 570 nM was
measured on a ThermoMax plate reader (Molecular Devices). The
2-Debenzoyl-2-(3-methoxybenzoyl)-10-propanoyl-3′-dephenyl-
3′-(2-methylpropan-1-yl)-3′N-de-tert-butoxycarbonyl-3′N-(cyclo-
hexanecarbonyl)docetaxel (18k). White solid; 100%; mp 143-145
1
°C; [R]20 -85 (c 14.0, CHCl3); H NMR (400 MHz, CDCl3) δ
D
0.95 (dd, J1 ) 6.4 Hz, J2 ) 16.4 Hz, 6 H), 1.15-1.37 (m, 16 H),
1.57-1.40 (m, 10 H), 1.87 (m, 5H), 2.38 (m, 5H), 2.54 (m, 4H),

3220 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Ojima et al.
IC50 values were obtained by using the same method as that
described for (a).
stock solution was further diluted by PBS prior to administration
so that the appropriate concentration of each drug could be injected
in a final volume of 0.2 mL. The taxoid was administered iv using
tail vein injection three times at 3-day intervals on days 19, 22,
and 25 (20 mg/kg × 3, total dose of 60 mg/kg). The tumor size
was measured and the volume calculated in the same manner as
that described above.
Tubulin Polymerization Assay. Assembly and disassembly of
calf brain microtubule protein (MTP) were monitored spectropho-
tometrically (Beckman Coulter DU 640, Fullerton, CA) by recording
changes in turbidity at 350 nm at 37 °C.53,54 MTP was diluted to
1 mg/mL in MES buffer containing 3 M glycerol. The concentration
of tubulin in MTP is 85%, and that is taken into consideration when
the ratios of tubulin to drug are presented in Figures 1 and 2.
Microtubule assembly was carried out with 10 µM taxoid (19, 14g,
or 14i). Paclitaxel (10 µM) was also used for comparison purpose.
Calcium chloride (6 mM) was added to the assembly reaction after
50 min to follow the calcium-induced microtubule depolymeriza-
tion. For the experiments shown in Figure 1, tubulin stored in liquid
nitrogen was centrifuged just before use and protein concentration
adjusted to 1 mg/mL, while the experiments in Figure 2 used tubulin
stored in liquid nitrogen as it was at 1 mg/mL concentration.
Electron Microscopy. Aliquots (50 µL) were taken from in vitro
polymerization assays at the end of the reaction and placed onto
300-mesh carbon-coated, Formvar treated copper grids. Samples
were then stained with 20 µL of 2% uranyl acetate and viewed
with a JEOL model 100CX electron microscope.
Animals and Tumor Xenografts. Female severe combined
immune deficient (SCID) mice aged 6-8 weeks were obtained from
the National Cancer Institute (Frederick, Maryland) and were housed
and monitored at the Medical Research Complex at Roswell Park
Cancer Institute. All experimental procedures and protocols were
approved by the Institutional Animal Care and Use Committee.
The human colon tumor DLD-1, which expresses Pgp, was initiated
by implantation of approximately 50 mg of non-necrotic tumor
fragments on the right flank using a 12-gauge trocar needle.
Chemotherapy was started when the tumor was established as a
palpable mass, (approximately 50-100 mm3 size), 5 days after
implantation and continued either every 3 days or weekly. Each
drug treatment group or drug-free vehicle consisted of 5 mice per
group; untreated controls contained 10 mice per group.
Drug Preparation for in Vivo Experiments. Taxoid 19 was
prepared as a 30 mg/mL stock solution in equal parts of Tween-80
(polyoxyethylene-sorbitan monooleate, purchased from Sigma
Chemical Company) and absolute ethanol. Each stock solution was
further diluted before use in 0.9% NaCl (saline) so that the
appropriate concentration of each drug could be injected iv via the
tail vein, in a volume of approximately 0.4 mL for a 20 g mouse.
In Vivo Tumor Growth Inhibition Assay against DLD-1
Tumor Xenograft. For each animal, the tumor length (l) and width
(w), each in mm, were measured using electronic calipers and
recorded every 3-4 days. Tumor volume (V), in mm3, was
calculated using the formula V ) 0.4(l)(w2). The time in days to
the predetermined target tumor volume of 600 mm3 was linearly
interpolated from a plot of log(volume) versus time. Statistically
significant differences in tumor volumes between control and drug-
treated mice were determined by the Cox-Mantel test. For the
Cox-Mantel test, the time-to-event data for animals that did not
reach the target tumor volume, either because of long-term cure
(defined as those animals that were still alive at the conclusion of
the experiment whose tumors either completely regressed or did
not reach the preset target volume) or early death due to drug
toxicity, were treated as censored data. All statistical tests were
two-sided.
In Vivo Efficacy Assay of Taxoid 19 against CFPAC-1
Tumor Xenograft. A preliminary in vivo efficacy evaluation of
taxoid 19 was also performed against human pancreatic cancer
xenograft in male Swiss nude mice aged 6-8 weeks obtained from
Taconic Farms (Hudson, New York). The human pancreatic cancer
cell line CFPAC-1, which expresses high levels of mdr1, was used
for the experiments. CFPAC-1 cancer cells (1 × 106) were
resuspended in 200 µL of PBS and injected bilaterally into the flanks
of mice using a 26 gauge needle. Treatment started when the tumor
was established as a palpable mass (approximately 100 mm3 in
size) 19 days after the injection. Taxoid 19 was prepared as a 30
mg/mL stock solution in Tween-80 and absolute ethanol (1:1). Each
Acknowledgment. This work was supported by the National
Institutes of Health (Grants CA103314 and GM42798 to I.O.,
Grants CA083185 and CA077263 to S.B.H., Grants CA55360
to D.B.-S, and Grant CA73872 to R.J.B.), a Targeted Research
Opportunities grant from School of Medicine, State University
of New York at Stony Brook, and the Lustgarten Foundation
(support to D.B.-S.). Generous support from Indena SpA is also
gratefully acknowledged. The authors (I.O. and J.C.) are grateful
to Dr. Marianne Poruchynsky and Dr. Tito Fojo, National
Cancer Institute, for providing us with paclitaxel-resistant
ovarian cancer cell lines, 1A9PTX10 and 1A9PTX22. The
authors (I.O., J.C., and L.S.) also thank Rebbeca Rowehl, the
Cell Culture and Hybridoma Core Facility, Stony Brook
University, for technical service and advice.
Supporting Information Available: 1H and 13C NMR spectra
of new taxoids and characterization data for synthetic intermediates.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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