Syntheses and structure-activity relationships of taxoids derived from 14β-hydroxy-10-deacetylbaccatin III

Article abstract of DOI:10.1021/jm960563e

A series of new taxoids derived from 14β-hydroxy-10-deacetylbaccatin III was synthesized by means of the β-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A5

Full text of DOI:10.1021/jm960563e

J . Med. Chem. 1997, 40, 267-278
267
Articles
Syn th eses a n d Str u ctu r e-Activity Rela tion sh ip s of Ta xoid s Der ived fr om
14â-Hyd r oxy-10-d ea cetylba cca tin III
Iwao Ojima,*,† J ohn C. Slater,† Scott D. Kuduk,† Craig S. Takeuchi,† Rayomand H. Gimi,† Chung-Ming Sun,†
Young Hoon Park,† Paula Pera,‡ J ean M. Veith,‡ and Ralph J . Bernacki‡
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, and
Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, New York 14263
Received J uly 31, 1996X
A series of new taxoids derived from 14â-hydroxy-10-deacetylbaccatin III was synthesized by
means of the â-lactam synthon method. Most of the new taxoids thus synthesized possess
excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-
29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar
IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and
docetaxel. Modifications at the 3′- and 3′-N-positions exert marked effects on the activity. For
the substituents at C-3′, the cytotoxicity decreases in the order 2-furyl ∼ 2-methyl-1-propenyl
g 2-methylpropyl > (E)-1-propenyl g n-propyl > phenyl . 2,2-dimethylpropyl. For the 3′-N
substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant
increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line
MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper
modification of the substituent at C-10. The observed remarkable effects of the substituents
at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding
of these new taxoids to P-glycoprotein that is responsible for MDR.
In tr od u ction
deacetylbaccatin III (14â-OH-DAB) isolated from the
needles of Taxus wallichiana Zucc.22 The presence of
an additional C-14 hydroxyl group in 14â-OH-DAB was
found to provide much higher water solubility than the
usual 10-deacetylbaccatin III (DAB).22 Therefore, the
new taxoids derived from 14â-OH-DAB might have
substantially improved water solubility, bioavailability,
and hydrophobicity-related drug resistance.13 These
improved pharmacological properties may well be re-
lated to the modification of undesirable toxicity and
activity spectra against various cancer types. With
those possibilities in mind, we decided to develop a new
series of taxoids derived from 14â-OH-DAB. We de-
scribe here the syntheses and structure-activity rela-
tionships of new taxoids bearing a 14â-OH-baccatin III
1,14-carbonate moiety, which have revealed remarkable
effects of substituents at the 3′-, 3′-N-, and 10-positions
on cytotoxicities.
Taxol (paclitaxel)1 and Taxote`re (docetaxel)2 are cur-
rently considered to be two of the most exciting drugs
in cancer chemotherapy.3-7 Both paclitaxel and doce-
taxel8-10 exhibit significant antitumor activity against
various cancers which have not been effectively treated
by existing chemotherapeutic drugs11,12 through their
unique antimitotic mechanism of action.13 Paclitaxel
was approved by the FDA for the treatment of advanced
ovarian cancer in December 1992 and for the treatment
of breast cancer in April 1994. It is also undergoing
clinical trials for other cancers. Docetaxel was approved
by the FDA for the treatment of breast cancer in May
1996 and is currently undergoing phase II and III
clinical trials for breast and lung cancers worldwide.3,12
Although both paclitaxel and docetaxel possess potent
antitumor activity, recent reports have shown that
treatment with these drugs often results in various
undesired side effects as well as multidrug resistance
(MDR).12,14 Therefore, it is important to develop new
taxoid anticancer agents with fewer side effects, supe-
rior pharmacological properties, and improved activity
against various classes of tumors.
Syn th eses of New Ta xoid s
A series of new taxoids were synthesized from 14â-
OH-DAB 1,14-carbonate derivatives using the â-lactam
synthon method.23-27 (3R,4S)-1-Acyl-3-(silyloxy)-4-aryl-
azetidin-2-ones 4 and 5 with extremely high enantio-
meric purity were obtained through a chiral ester
enolate-imine cyclocondensation developed in these
laboratories23,24 in two steps using TMS-aldimine 2A or
three steps using PMP-aldimine 2B in 78-80% overall
yields eqs 1 and 2). Results are summarized in Table
1.
Extensive studies have been performed in different
laboratories on the structure-activity relationships
(SAR) of paclitaxel, docetaxel, and their analogs.3,5,7 As
a part of our continuing SAR study of paclitaxel and
docetaxel analogs,15-21 we have been investigating a
new series of taxoids derived from 14â-hydroxy-10-
† State University of New York at Stony Brook.
‡ Roswell Park Cancer Institute.
7-TES-14â-OH-DAB 1,14-carbonate (8) (TES ) tri-
ethylsilyl) was prepared by reacting 14â-OH-DAB (6)
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
S0022-2623(96)00563-8 CCC: $14.00 © 1997 American Chemical Society

268 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3
Ta ble 1. â-Lactams 4 and 5
Ojima et al.
Sch em e 1a
â-lactam
R1
R2
R3Si
% eea
4a
4b
4c
4d
5a
5b
2-furyl
t-C4H9O
t-C4H9O
t-C4H9O
t-C4H9O
n-C5H11
n-C5H11
i-Pr3Si
i-Pr3Si
i-Pr3Si
Et3Si
t-BuMe2Si
i-Pr3Si
94
94
97
96
94
96
(CH3)2CdCH
(E)-CH3CHdCH
(CH3)3CCH2
phenyl
(CH3)2CdCH
a
Determined by chiral HPLC analysis (see the Experimental
Section).
a
(i) TESCl (9 equiv), pyridine/DMF (1/1), rt; (ii) phosgene,
CH2Cl2.
Sch em e 2a
a
(i) LiHMDS, -40 °C, THF; (ii) R3Cl or TESCl, -40 °C.
Ta ble 2. 7-TES-10-modified-baccatin III 1,14-Carbonates 9
with Et3SiCl in pyridine/DMF at room temperature
followed by treatment with phosgene in dichloromethane
in 64% yield for the two steps (Scheme 1).
7,10-Bis(TES)-14â-OH-DAB 1,14-carbonate (9a ) and
10-acyl-14â-OH-DAB 1,14-carbonates 9b-g were pre-
pared by treating baccatin 8 with 1.1 equiv of LiHMDS
at -40 °C followed by the addition of either TESCl or
an appropriate acyl chloride in freshly distilled THF
(Scheme 2). Results are listed in Table 2.
baccatin
R3
yielda (%)
9a
9b
9c
9d
9e
9f
Et3Si
CH3CO
CH3CH2CO
cyclopropane-CO
(CH3)2N-CO
84
95
74
91
86
54 (79)
65
(E)-CH3CHdCHCO
CH3O-CO
9g
a
Numbers in parentheses indicate conversion yields based on
The reactions of baccatin derivatives 9a -g with 1.2
equiv of â-lactam 4 or 5 in the presence of 1.2 equiv of
LiHMDS at -40 °C for 30 min gave the corresponding
coupling products 10-15 in good yields (Scheme 3). The
coupling products 10-15 were desilylated by treatment
with HF-pyridine (70:30) in pyridine/acetonitrile (1:1)
at room temperature to yield 3′-dephenyl-3′-(2-furyl)-
14â-OH-docetaxel 1,14-carbonates 16a ,b, 3′-dephenyl-
3′-(2-methyl-1-propenyl)-14â-OH-docetaxel 1,14-carbon-
ates 17a -g, 3′-dephenyl-3′-((E)-1-propenyl)-14â-OH-
docetaxel 1,14-carbonates 18a ,b, 3′-dephenyl-3′-(3,3-
dimethylpropyl)-14â-OH-docetaxel 1,14-carbonate 19a ,
3′-N-debenzoyl-3′-N-hexanoyl-14â-OH-paclitaxel 1,14-
carbonate 20a , and 3′-N-debenzoyl-3′-N-hexanoyl-3′-
dephenyl-3′-(2-methyl-1-propenyl)-14â-OH-paclitaxel 1,14-
carbonates 21d -f in good yields. Results are
summarized in Table 3.
the consumed 8.
MCF7-R (doxorubicin-resistant breast). Results are
summarized in Tables 5 and 6. The cytotoxicities of
paclitaxel, docetaxel, SB-T-1001,18 SB-T-1011,19 and SB-
T-101219 are also shown for comparison. As Tables 5
and 6 show, these new taxoids possess, in general,
strong cytotoxicities against human cancer cell lines
with clear SAR.
Table 5 shows the SAR of selected new taxoids,
summarizing the effects of the substituents at the 3′-
and 3′-N-positions, i.e., R1 and R2CO, respectively, on
cytotoxicity. When R1 is phenyl (entries 3-5, 10), a tert-
butoxycarbonyl (t-Boc) group is the best substituent as
R2CO among t-Boc, benzoyl, and n-hexanoyl groups, i.e.,
the cytotoxicity decreases in the order t-Boc . PhCO >
n-C5H11CO. It should be noted that 14â-OH-paclitaxel
1,14-carbonate (SB-T-1012) has at least 1 order of
magnitude weaker activity than paclitaxel, whereas
14â-OH-docetaxel 1,14-carbonate (SB-T-1011) and 14â-
OH-docetaxel (SB-T-1001) possess equivalent or better
activity than paclitaxel. It is very clear that 2-furyl as
well as alkyl and alkenyl groups, i.e., 2-methyl-1-
propenyl, (E)-1-propenyl, 2-methylpropyl, and n-propyl,
substantially increase cytotoxicity (entries 6-8, 12, 13).
It is also clear that a 2,2-dimethylpropyl group at the
3′-position markedly decreases cytotoxicity (19a , entry
9). Among the new taxoids listed in Table 5, 16a and
Several of the 3′-unsaturated analogs (17, 18) were
reduced with Pd/C under 1 atm of H2 to produce the
corresponding 3′-saturated taxanes (22, 23) in high yield
(Scheme 4). Results are listed in Table 4.
Cytotoxicity of New Ta xoid s
Effect of Su bstitu en ts a t 3′- a n d 3′-N-P osition s
on Cytotoxicity. Cytotoxicities of these new taxoids
thus synthesized were evaluated in vitro against several
human cancer cell lines: A121 (ovarian), A549 (non-
small-cell lung), HT-29 (colon), MCF-7 (breast), and

New Taxoids Derived from 14â-OH-DAB
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3 269
Sch em e 3a
values. The taxoids 22b,d ,e also have attractive pro-
files. The observed remarkable activity against the
drug-resistant cancer cells is certainly not restricted to
MCF7-R. The taxoid 17b, for example, shows 1 order
of magnitude better activity (IC50 ) 27 nM) against
A2780-DX5 (doxorubicin-resistant human ovarian can-
cer cell line overexpressing P-glycoprotein) than pacli-
taxel (IC50 ) 203 nM) and docetaxel (IC50 ) 122 nM).
For the observed remarkable effects of the substitu-
ents at C-10 on the activity against the drug-resistant
cell line MCF7-R, we would like to propose the following
hypothesis, although further investigation is necessary
to elucidate it: MDR, i.e., the cross-resistance to various
structurally different cytotoxic agents, has been shown
to be caused by increased outward transport of these
agents through the plasma membrane by the action of
P-glycoprotein.28 The photoaffinity label of P-glycopro-
tein with tritiated photoreactive paclitaxel analog has
recently been performed successfully.29 Thus, it is
reasonable to assume that the observed SAR that is
unique to MCF7-R is related to the binding ability of
these new taxoids to P-glycoprotein. The result that
most of the modifications at C-10 we made are tolerated
for binding to tubulin, whereas the binding of these
taxoids to P-glycoprotein appears to be strongly affected
by the structure of the modifier at C-10, implies that
the 10-position is crucial for P-glycoprotein to recognize
and bind taxoid antitumor agents.21 Accordingly, it
appears that the observed remarkable effects of the
substituents at C-10 on the activity against MCF7-R
could be ascribed to the effective inhibition of the
binding of these new taxoids to P-glycoprotein that is
responsible for MDR.
As we recently published,30 SB-T-1011, developed
earlier in our SAR study on the new series of taxoids
derived from 14â-OH-DAB, possesses high in vivo
antitumor activity against a human ovarian tumor
xenograft in nude athymic mice. As Table 6 shows,
several new taxoids in this series possess 1 order of
magnitude better cytotoxicity than SB-T-1011. There-
fore, the new series of taxoids reported here warrant
further investigation into their in vivo antitumor activi-
ties against different types of tumors, especially drug-
resistant tumors. In fact, several taxoids included here
have already been proved to possess excellent antitumor
activity against human ovarian A121 tumor xenograft
in nude athymic mice. These new taxoids show a clear
dose-response, and a couple of these have a maximum
tolerated dose (MTD) equivalent to that of paclitaxel
(two times as high MTD as that of docetaxel) with much
better cytotoxicity than paclitaxel. Further in vivo
study is actively in progress. These in vivo assay results
will be published elsewhere. Some of these new taxoids
have also been found to cause, indeed, cell cycle arrest
at the G2/M phase and lead to apoptosis (confirmed by
DNA fragmentation). These results will be published
elsewhere.
a
(i) LiHMDS, -40 °C, THF; (ii) HF-pyridine, pyridine/CH3CN,
rt.
17a exhibit excellent overall cytotoxicity, considerably
better than paclitaxel and docetaxel, against different
cancer cell lines.
Table 6 summarizes the effects of the substituent at
the 10-position on cytotoxicity. As Table 6 clearly
shows, the substituent at C-10 exerts a remarkable
effect on the activity against the drug-resistant human
breast cancer cell line, MCF7-R, i.e., the activity in-
creases, dramatically in some cases (16a vs 16b; 18a
vs 18b, 22a vs 22e), by replacing a free hydroxyl group
at C-10 with an acyl group or N,N-dimethylcarbamoyl
group. The activities against normal cancer cell lines
are also somewhat influenced by the substituent at
C-10, but to a much lesser extent. Three taxoids, 16b
and 17c-g, exhibit subnanomolar IC50 values against
all normal cancer cell lines examined as well as 10 nM
level IC50 values against MCF7-R. The taxoid 17f shows
the highest activity against MCF7-R (IC50 ) 17 nM).
This finding is very important since paclitaxel and
docetaxel do not have strong activity against MCF7-R
which expresses MDR phenotype (MDR ) multidrug
resistance). As Table 6 shows, the relative activity
indices, i.e, IC50MCF7-R/IC50MCF-7, of paclitaxel and doce-
taxel against MCF7-R in comparison with MCF-7 are
Con clu sion
A new series of taxoids are derived from 14â-OH-
DAB, and most of these taxoids possess strong cytotox-
icities that are better than that of paclitaxel. Several
of these taxoids show subnanomolar IC50 values against
normal human cancer cell lines, A121 (ovarian), A549
(non-small-cell lung), HT-29 (colon), and MCF-7 (breast).
176 and 235, respectively. With this respect, 17b has
the best relative activity index (IC50MCF7-R/IC50
)
MCF-7
11) while keeping the cytotoxicities against normal
cancer cell lines at the lower nanomolar level IC50

270 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3
Ta ble 3. Syntheses of Taxoids 16-21
Ojima et al.
â-lactam
baccatin
coupling product
yield (%)a
R1
R2
*R3 (R3)b
H (Et3Si)
CH3CO
H (Et3Si)
taxoid
yield (%)a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4c
4c
4d
5a
5b
5b
5b
9a
9b
9a
9b
9c
9d
9e
9f
9g
9a
9a
9a
9a
9d
9e
9f
10a
10b
11a
11b
11c
11d
11e
11f
11g
12a
12b
13a
14a
15d
15e
15f
78
2-furyl
2-furyl
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
t-Boc
n-C5H11
n-C5H11
n-C5H11
n-C5H11
16a
16b
17a
17b
17c
17d
17e
17f
17g
18a
18b
19a
20a
21d
21e
21f
73
78
76
nic
80
(CH3)2CdCH
(CH3)2CdCH
(CH3)2CdCH
(CH3)2CdCH
(CH3)2CdCH
(CH3)2CdCH
(CH3)2CdCH
(E)-CH3CHdCH
(E)-CH3CHdCH
(CH3)3CCH2
phenyl
90d
73
CH3CO
82
87
85
84
CH3CH2-CO
cyclopropane-CO
(CH3)2N-CO
(E)-CH3CHdCH-CO
CH3O-CO
H (Et3Si)
CH3CO
H (Et3Si)
H (Et3Si)
62
84
83
38
55
67
nic
75
52d
80
80
80
nic
72
41 (54)d
82
(CH3)2CdCH
(CH3)2CdCH
(CH3)2CdCH
cyclopropane-CO
(CH3)2N-CO
(E)-CH3CHdCH-CO
55 (76)
50 (65)
54
84
a
b
Numbers in parentheses indicate conversion yield based on the consumed baccatin 9. When *R3 (after deprotection) and R3 (before
deprotection) are different, R3 (protecting group in these cases) is indicated in the parentheses. c ni stands for “not isolated”, i.e., the
coupling products 11a , 12a , and 14a were carried to deprotection without purification. Yield for two steps.
d
Sch em e 4
Exp er im en ta l Section
Gen er a l Meth od . Melting points were determined on a
Thomas-Hoover capillary apparatus and were not corrected.
1H (250 MHz),13C (63 MHz), and 2D NMR spectra were
measured using a Bruker AC-250 spectrometer using tetra-
methylsilane as the internal standard. Infrared spectra were
recorded on a Perkin-Elmer Model 1600 FT-IR spectropho-
tometer with a Hewlett-Packard 7470A plotter using samples
as solutions in a liquid cell, neat oil, or KBr disks. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter.
Thin layer chromatography was performed on Merck DC-
alufolien with Kieselgel 60F-254. Flash column chromatog-
raphy was performed using silica gel 60 (230-400 mesh
ASTM) from E. Merck. Chiral HPLC analysis for the deter-
mination of enantiomeric excess was carried out with a Waters
HPLC assembly consisting of a Waters M45 solvent delivery
system, a Waters Model 680 gradient controller, and a Waters
M440 detector (at 254 nm), equipped with a Spectra Physics
Model SP4270 integrator using a Daicel-Chiracel OD chiral
column (J . T. Baker), employing hexane/2-propanol (13/1) as
the solvent system with a flow rate of 0.2 mL/min. Elemental
analyses were performed at M-H-W Laboratories, Phoenix, AZ,
and Supersun Technology Analytical Laboratory, Stony Brook,
NY. FAB HRMS were performed at UCR Mass Spectrometry
Facility, Riverside, CA.
Ta ble 4. Syntheses of 3′-Alkyl Taxoids 22 and 23
taxoid
R4
R1
*R3
yield (%)
Ma ter ia ls. Chemicals were purchased from Aldrich Chemi-
cal Co. and distilled or recrystallized prior to use. (-)-10-
(Dicyclohexylsulfamoyl)-D-isoborneol was purchased from Al-
drich Chemical Co. (-)-trans-2-Phenylcyclohexyl [(triisopropyl-
silyl)oxy]acetate (1a )24 and (-)-10-(dicyclohexylsulfamoyl)-D-
isobornyl [(triisopropylsilyl)oxy]acetate (1b)31 were prepared
by literature methods. N-TMS-benzaldimine (2f)24 and N-
TMS-furfuraldimine (2b)32 were prepared using methods
previously reported. (3R,4S)-3-[(Triisopropylsilyl)oxy]-4-(2-
furyl)azetidin-2-one (3a ),32 3-[(tert-butyldimethylsilyl)oxy]-4-
phenylazetidin-2-one (3e),24 and (3R,4S)-3-[(triisopropylsilyl)-
oxy]-4-phenylazetidin-2-one (3f)24 were prepared by literature
procedures. 14â-Hydroxy-10-deacetylbaccatin III (14â-OH-
DAB) (7) was a gift from Indena, SpA, Italy.
22a
22b
22d
22e
23a
23b
CH3
CH3
CH3
CH3
H
(CH3)2CHCH2
(CH3)2CHCH2
(CH3)2CHCH2
(CH3)2CHCH2
CH3(CH2)2
H
77
100
91
CH3CO
cyclopropane-CO
(CH3)2N-CO
H
75 (94a)
90
H
CH3(CH2)2
CH3CO
86
a
Conversion yield based on the consumed 17e.
Modifications at the 3′- and 3′-N-positions exert marked
effects on the activity. For the substituents at C-3′, the
cytotoxicity decreases in the order 2-furyl ∼ 2-methyl-
1-propenyl g 2-methylpropyl > (E)-1-propenyl g n-
propyl > phenyl . 2,2-dimethylpropyl. For the 3′-N
substituents, the activity decreases in the order t-
BuOCO > Ph > n-hexanoyl. A significant increase in
the cytotoxicity against the doxorubicin-resistant hu-
man breast cancer cell line MCF7-R is observed with
proper modification of the substituent at C-10. It is
reasonable to interpret the observed remarkable effects
of the substituents at C-10 on the activity against
MCF7-R based on the effective inhibition of the binding
of these new taxoids to P-glycoprotein that is responsible
for MDR. Further investigations into the in vivo
antitumor activities of these new taxoids are actively
underway.
P r ep a r a tion of N-(4-Meth oxyp h en yl)a ld im in es 2.
A
typical procedure is given for the preparation of N-(4-meth-
oxyphenyl)-3-methyl-2-butenaldimine (2b): To a solution of
p-anisidine (1.072 g, 8.7 mmol), recrystallized twice from
EtOH, and anhydrous Na2SO4 in dry CH2Cl2 (20 mL) was
added 3-methyl-2-butenal (1.04 mL, 10.75 mmol). After 1 h,
the Na2SO4 was filtered off and the solvent was removed to
give aldimine 2b in quantitative yield, which was immediately
used in the next step without further purification: 1H NMR
(CDCl3) δ 1.97 (s, 3 H), 1.99 (s, 3 H), 3.78 (s, 3 H), 6.20 (d, J
) 7.2 Hz, 1 H), 6.91 (d, J ) 7.3 Hz, 2 H), 7.12 (d, J ) 7.3 Hz,
2 H), 8.43 (d, J ) 7.2 Hz, 1 H).
In the same manner, N-(4-methoxyphenyl)-(E)-2-butenaldi-

New Taxoids Derived from 14â-OH-DAB
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3 271
Ta ble 5. Effects of Substituents at 3′- and 3′-N-Positions on Cytotoxicity (IC50, nM)a
entry
taxoid
R1
R2
A121
A549
HT-29
MCF-7
MCF7-R
1
2
3
4
5
6
7
8
9
10
11
12
13
paclitaxel
docetaxel
SB-T-1001
SB-T-1011
SB-T-1012
16a
17a
18a
19a
20a
phenyl
phenyl
phenyl
phenyl
phenyl
2-furyl
(CH3)2CdCH
(E)-CH3CHdCH
(CH3)3CCH2
phenyl
phenyl
t-BuO
t-BuO
t-BuO
phenyl
t-BuO
t-BuO
t-BuO
t-BuO
n-C5H11
n-C5H11
t-BuO
t-BuO
6.1
1.2
3.3
6.2
105
0.4
1.7
2.6
106
330
12
3.6
1.0
0.8
2.1
33
0.5
0.2
1.2
51
389
18
1.8
4.4
3.2
1.2
2.1
1.8
24
0.6
0.5
1.9
52
157
16
3.4
3.8
1.7
1.0
1.9
1.8
11
0.5
0.5
1.6
48
299
235
>1000
543
>1000
135
54
762
>1000
>1000
321
13
21d
22a
23a
(CH3)2CdCH
(CH3)2CHCH2
CH3(CH2)2
3.2
2.7
4.2
1.0
2.1
385
265
a
The concentration of compound which inhibits 50% (IC50, nM) of the growth of human tumor cell line: A121 (ovarian carcinoma),
A549 (non-small-cell lung carcinoma), HT-29 (colon carcinoma), MCF-7 (mammary carcinoma), and MCF7-R (mammarian carcinoma
180-fold resistant to doxorubicin) after 72 h drug exposure according to the method developed by Skehan et al.34 (see the Experimental
Section).
Ta ble 6. Effects of the Substituents at C-10 on Cytotoxicity (IC50, nM)a
taxoid
*R3
A121
A549
HT-29
MCF-7
MCF7-R
MCF7-R/MCF-7
paclitaxel
docetaxel
SB-T-1011
SB-T-1012
16a
16b
17a
17b
17c
17d
17e
17f
17g
18a
18b
21d
21e
21f
22a
22b
22d
22e
23a
23b
CH3CO
H
H
H
6.1
1.2
6.2
105
0.4
0.4
1.7
1.5
0.7
0.5
0.7
0.8
0.6
2.6
2.4
12
3.6
1.0
2.1
33
3.2
1.2
1.8
24
1.7
1.0
1.8
11
299
235
543
>1000
135
49
176
235
302
NA
270
96
120
11
130
70
H
0.5
0.5
0.2
1.4
0.5
0.5
0.6
0.5
0.5
1.2
0.4
18
0.6
0.6
0.5
2.4
0.6
1.0
1.2
1.5
0.7
1.9
3.0
16
0.5
0.5
0.5
3.3
0.2
0.4
0.4
0.4
0.3
1.6
1.6
3.2
1.7
2.1
3.0
1.1
0.7
0.6
4.2
4.6
CH3CO
H
CH3CO
CH3CH2CO
cyclopropane-CO
(CH3)2N-CO
(E)-CH3CHdCHCO
CH3O-CO
72
36
26
28
33
17
38
762
72
321
295
137
189
36
22
22
385
201
83
43
127
476
45
100
56
65
63
33
31
H
CH3CO
cyclopropane-CO
(CH3)2N-CO
(E)-CH3CHdCHCO
H
4.8
17
5.5
25
5.1
28
2.5
1.2
1.1
0.6
2.1
2.3
1.4
0.7
1.2
0.6
4.4
4.7
4.2
1.5
3.3
1.3
3.8
4.8
CH3CO
cyclopropane-CO
(CH3)2N-CO
H
37
92
44
CH3CO
a
See the footnote of Table 5.
mine (2c) and N-(4-methoxyphenyl)-3,3-dimethylbutanaldi-
mine (2d ) were prepared and used without further purification.
Asym m et r ic Syn t h esis of 4-Su b st it u t ed (3R,4S)-3-
[(Tr ia lk ylsilyl)oxy]a zetid in -2-on es 3. Meth od A: (3R,4S)-
3-[(Tr iet h ylsilyl)oxy]-4-(2,2-d im et h ylp r op yl)a zet id in -2-
on e (3d ′). To a solution of diisopropylamine (1.16 mL, 8.3
mmol) in THF (15 mL) was added n-BuLi (3.33 mL, 8.3 mmol;
2.5 M in hexanes) at 0 °C. The solution was stirred at 0 °C
for 30 min followed by the addition of 1a (2.5 g, 6.4 mmol) in
THF (20 mL) at -78 °C over a 1 h period via cannula. The
mixture was stirred for 2 h followed by the addition of imine
2d at -85 °C over a period of 1 h. The reaction mixture was
stirred overnight at -85 °C and allowed to slowly warm to
room temperature. The reaction was quenched by the addition
of aqueous saturated NH4Cl. The aqueous layer was extracted
with ether (2 × 30 mL). The combined organic layers were
washed with 3% HCl and brine, dried over anhydrous MgSO4,
and concentrated in vacuo. The residue was subjected to
column chromatography on silica gel (hexanes/EtOAc ) 5/1)
to give an inseparable mixture of (3R,4S)-3-[(triisopropylsilyl)-
oxy]-4-(2,2-dimethylpropyl)azetidin-2-one (3d ) and (-)-10-(di-
cyclohexylsulfamoyl)-D-isoborneol, which was used in the next
step without further purification. The chiral HPLC analysis
of this mixture showed that the enantiomeric purity of 3d was
96% ee.
20 min, the solvent was evaporated and the resulting crude
oil was purified by column chromatography on silica gel
(hexanes/EtOAc ) 5/1) to afford 3-hydroxy-4-(2,2-dimethyl-
propyl)azetidin-2-one (936 mg, 94% yield for two steps) as a
white solid: mp 185-186 °C; [R]20 +51.81° (c 8.3, CH3OH);
D
1H NMR (CD3OD) δ 0.89 (s, 3 H), 1.28 (dd, J ) 14.6, 8.0 Hz,
1 H), 1.62 (dd, J ) 14.5, 4.0 Hz, 1 H), 3.23 (bs, 1 H), 3.73 (m,
1 H), 4.72 (d, J ) 4.7 Hz, 1 H); 13C NMR (CD3OD) δ 28.75,
29.35, 42.82, 52.72, 76.54, 173.2. Anal. (C8H15NO2) C, H, N.
To a solution of (3R,4S)-3-hydroxy-4-(2,2-dimethylpropyl)-
azetidin-2-one (600 mg, 3.87 mmol) in DMF (5 mL) and
imidazole (0.66 g, 2.5 equiv) was added Et3SiCl (0.68 mL, 4.06
mmol) with stirring. The mixture was stirred overnight at
room temperature, and then additional Et3SiCl (0.07 mL) was
added to complete the reaction. The reaction mixture was
diluted with ether and washed with water and 3% HCl. The
combined organic layers were dried over anhydrous MgSO4
and concentrated in vacuo. Purification of the crude product
by flash chromatography on silica gel (hexanes/EtOAc ) 2/1)
provided 3d ′ (888 mg, 88% yield) as a colorless oil: [R]20
D
+36.7° (c 2.4, CHCl3); 1H NMR (CHCl3) δ 0.65 (bq, J ) 7.9
Hz, 6 H), 0.92 (s, 9 H), 0.96 (t, J ) 7.9 Hz, 9 H), 1.37 (dd, J )
14.7, 8.4 Hz, 1 H), 1.66 (dd, J ) 14.7, 3.5 Hz, 1 H), 3.76 (ddd,
J ) 8.4, 4.7, 3.5 Hz, 1 H), 4.82 (dd, J ) 4.7, 2.8 Hz, 1 H), 6.7
(bs, 1 H); 13C NMR (CDCl3) δ 4.67, 6.59, 29.81, 43.35, 52.89,
77.76, 170.13. Anal. (C14H29NO2Si) C, H, N.
To a solution of a mixture of 3d and (-)-10-(dicyclohexyl-
sulfamoyl)-D-isoborneol, thus obtained, in THF (23 mL) was
added n-Bu4NF (7 mL, 7.03 mmol; 1.0 M in THF) at 0 °C. After
Meth od B: (3R,4S)-3-[(Tr iisopr opylsilyl)oxy]-4-(2-m eth -
yl-1-p r op en yl)a zetid in -2-on e (3b). To a solution of i-Pr2NH

272 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3
Ojima et al.
(0.93 mL, 6.64 mmol) in dry THF (10 mL) was added n-BuLi
(2.66 mL, 6.64 mmol; 2.5 M in hexanes) at 0 °C. After stirring
chloride with 3-[(tert-butyldimethylsilyl)oxy]-4-phenylazetidin-
2-one (3g)24 and 3-[(triisopropylsilyl)oxy]-4-(2-methyl-1-prope-
nyl)azetidin-2-one (3b), respectively, in the presence of trieth-
ylamine and DMAP in dichloromethane.
for 10 min, the reaction mixture was cooled to -84 °C.
A
solution of 1a (2.00 g, 5.12 mmol) in dry THF (5 mL) was added
via cannula. After the mixture stirred for an additional 2 h,
a solution of imine 2b (1.65 g, 8.70 mmol) in dry THF (5 mL)
was added via cannula. The reaction mixture was stirred for
2 h and then allowed to warm to room temperature overnight
with stirring. The reaction was quenched with aqueous
saturated NH4Cl (50 mL), and the mixture was extracted with
ethyl acetate (3 × 100 mL). The combined organic layers were
washed with 10% aqueous NaHCO3 (100 mL) and brine and
then dried over anhydrous MgSO4. The solvent was removed
under reduced pressure to give the crude product, which was
purified by column chromatography (hexanes/EtOAc ) 15/1,
then 6/1) to give (3R,4S)-1-(4-methoxyphenyl)-3-[(triisopropyl-
silyl)oxy]-4-(2-methyl-1-propenyl)azetidin-2-one (1.24 g, 60%
yield) as a light yellow oil. The enantiomeric excess of this
â-lactam was 94% ee. based on the chiral HPLC analysis: 1H
NMR (CDCl3) δ 0.95-1.18 (m, 21 H), 1.64 (s, 3 H), 1.75 (s, 3
H), 4.43 (dd, J ) 9.5, 4.7 Hz, 1 H), 4.98 (dd, J ) 4.7, 2.3 Hz,
4a : 98% yield; pale yellow oil; 1H NMR (CDCl3) δ 0.87-1.09
(m, 21 H), 1.43 (s, 9 H), 5.10 (d, J ) 5.6 Hz, 1 H), 5.14 (d, J )
5.6, 1 H), 6.34-6.38 (m, 2 H), 7.40 (s, 1 H); 13C NMR (CDCl3)
δ 11.68, 17.39, 17.45, 27.87, 56.17, 77.83, 83.47, 109.75, 110.47,
142.75, 147.76, 147.96, 165.80. Anal. (C21H35O5NSi) C, H, N.
4c: 91% yield; slightly yellow oil; 1H NMR (CDCl3) δ 1.02-
1.08 (m, 21 H), 1.48 (s, 9 H), 1.74 (dd, J ) 6.4, 1.2 Hz, 3 H),
4.44 (dd, J ) 8.6, 5.8 Hz, 1 H), 4.95 (d, J ) 5.8 Hz, 1 H), 5.54
(ddd, J ) 15.4, 8.6, 1.2 Hz, 1 H), 5.84 (dq, J ) 15.4, 6.4 Hz, 1
H); 13C NMR (CDCl3) δ 11.76, 17.52, 17.95, 27.97, 61.06, 83.06,
124.80, 132.72, 148.22, 166.07. Anal. (C20H31NO4Si) C, H, N.
4d : 98% yield; colorless oil: [R]20 +112.4° (c 1.14, CHCl3);
D
1H NMR (250 MHz, CHCl3) δ 0.55 (m, 6 H), 0.80 (s, 9 H), 0.84
(t, J ) 8.0 Hz, 9 H), 1.37 (s, 9 H), 1.48 (d, J ) 13.5 Hz, 1 H),
1.83 (dd, J ) 13.5, 9.4 Hz, 1 H), 3.93 (dd, J ) 9.4, 5.8 Hz, 1
H), 4.80 (d, J ) 5.8 Hz, 1 H); 13C NMR (63 MHz, CDCl3) δ
4.67, 6.59, 28.03, 29.48, 29.66, 38.15, 56.11, 75.82, 83.02, 148.0,
166.2. Anal. Calcd. for C19H37NO4Si: C, 61.41; H, 10.09; N,
1 H), 5.31 (bd, J ) 9.5 Hz, 1 H), 6.25 (bs, 1 H). Anal. (C23H37
NO3Si) C, H, N.
-
3.77. Found: C, 61.65; H, 9.94; N, 3.84.
1
5a : 72% yield; yellow oil; [R]20 +87.5° (c 0.24, CHCl3); H
To a solution of (3R,4S)-1-(4-methoxyphenyl)-3-[(triisopro-
pylsilyl)oxy]-4-(2-methyl-2-propenyl)azetidin-2-one (1.01 g, 5.19
mmol) in acetonitrile (90 mL) were added dropwise ammonium
cerium(IV) nitrate (10.15 g, 18.5 mmol) in water (135 mL) and
additional water (210 mL) over a period of 1.5 h at -5 °C. The
mixture was diluted with water (200 mL) and extracted with
ethyl acetate (200 mL). The organic layer was washed
successively with saturated NaHCO3 (100 mL), saturated
NaHSO3 (100 mL), and again with saturated NaHCO3 (100
mL). The organic layer was then dried over anhydrous MgSO4
and concentrated in vacuo. The residue was submitted to
column chromatography on silica gel (hexane/EtOAc ) 3:1,
then 2:1) affording 3b (663 mg, 90% yield) as a light yellow
D
NMR (CDCl3) δ 0.17 (s, 3 H), 0.46 (s, 3 H), 0.65 (s, 9 H), 0.88
(bt, 3 H), 1.29-1.35 (m, 4 H), 1.61-1.69 (m, 2 H), 2.65-2.86
(m, 2 H), 5.06 (d, J ) 5.8 Hz, 1 H), 5.13 (d, J ) 5.8 Hz, 1 H),
7.19-7.33 (m, 5 H). Anal. (C21H33NO3Si) C, H, N.
5b: 89% yield; yellow oil; 1H NMR (CDCl3) δ 0.85-0.92 (m,
3 H), 1.00-1.16 (m, 21 H), 1.25-1.33 (m, 4 H), 1.54-1.68 (m,
2 H), 1.76 (d, J ) 0.9 Hz, 3 H), 1.79 (d, J ) 0.9 Hz, 3 H), 2.66
(t, J ) 7.5 Hz, 2 H), 4.80 (dd, J ) 9.6, 6.0 Hz, 1 H), 4.99 (d, J
) 6.0 Hz, 1 H), 5.21 (dd, J ) 9.6, 0.9 Hz, 1 H).
7-(Tr ieth ylsilyl)-14â-h yd r oxy-10-d ea cetylba cca tin III
(7).33 To a solution of 14â-OH-DAB (6) (800 mg, 1.47 mmol)
in pyridine (60 mL) and N,N-dimethylformamide (60 mL) was
added Et3SiCl (2.50 mL, 14.7 mmol) dropwise via syringe at
room temperature. After 4 h, the reaction was quenched by
adding ethyl acetate (200 mL) and pyridine was removed by
successive washing with aqueous saturated CuSO4 until no
color change was observed. The organic layer was washed
with water, dried over MgSO4 and concentrated. Silica gel
chromatography (hexane/ethyl acetate ) 1/1) afforded 7-TES-
14â-OH-DAB (7) (928 mg, 96% yield) as a white solid: 1H NMR
(CDCl3) δ 0.50 (m, 6 H), 0.97 (m, 9 H), 1.21 (s, 3 H), 1.58 (s, 3
H), 1.58 (s, 3 H), 1.73 (s, 3 H), 1.85 (dt, 1 H), 1.99 (s, 3 H), 2.23
(s, 3 H), 2.24 (s, 2 H), 2.47 (ddd, 1 H), 3.94 (d, J ) 7.2 Hz, 1
H), 4.14 (d, J ) 8.4 Hz, 1 H), 4.32 (d, J ) 8.1 Hz, 1 H), 4.41 (d,
J ) 6.3 Hz, 1 H), 4.84 (t, 1 H), 4.94 (d, J ) 8.4 Hz, 1 H), 5.14
(s, 1 H), 5.19 (s, 1 H), 5.58 (d, J ) 7.2 Hz, 1 H), 7.40 (t, 2 H),
7.54 (t, 1 H), 8.10 (d, 2 H); 13C NMR (CDCl3) δ 5.1, 6.7, 9.9,
15.1, 19.5, 22.6, 26.8, 37.2, 38.6, 42.7, 47.0, 57.9, 67.9, 72.9,
74.7, 74.8, 76.5, 78.8, 80.7, 84.2, 128.6, 129.4, 130.0, 133.6,
135.1, 141.9, 167.0, 170.7, 210.3; IR (CDCl3) 3465, 2952, 2884,
1725, 1702, 1602, 1443, 1361, 1273, 1237, 1173, 1138, 1102,
1
solid: mp 85-86 °C; H NMR (CDCl3) δ 0.97-1.21 (m, 21 H),
1.68 (d, J ) 2.3 Hz, 3 H), 1.19 (d, J ) 2.3 Hz, 3 H), 4.43 (dd,
J ) 9.5, 4.7 Hz, 1 H), 4.98 (dd, J ) 4.7, 2.3 Hz, 1 H), 5.31 (d,
J ) 9.5 Hz, 1 H). Anal. (C16H31NO2Si) C, H, N.
In the same manner, (3R,4S)-3-[(triisopropylsilyl)oxy]-4-((E)-
1-propenyl)azetidin-2-one (3c) was prepared. 3c: 72% yield;
light yellow oil; 1H NMR (CDCl3) δ 1.01-1.14 (m, 21 H), 1.76
(d, J ) 6.4 Hz, 3 H), 4.13 (dd, J ) 8.0, 4.7 Hz, 1 H), 4.97 (dd,
J ) 4.7, 2.3 Hz, 1 H), 5.56 (dd, J ) 15.5, 8.0 Hz, 1 H), 5.70
(dq, J ) 15.8, 6.4 Hz, 1 H), 5.89 (bs, 1 H). The enantiomeric
excess was 97% ee. based on the chiral HPLC analysis.
P r ep a r a tion of (3R,4S)-1-(ter t-Bu toxyca r bon yl)-3-[(tr i-
a lk ylsilyl)oxy]-4-su bstitu ted -a zetid in -2-on es 4 a n d 5. A
typical procedure is described for the preparation of (3R,4S)-
1-(tert-butoxycarbonyl)-3-[(triisopropylsilyl)oxy]-4-(2-methyl-1-
propenyl)azetidin-2-one (4b). To a solution of â-lactam 3b (503
mg, 1.69 mmol), (N,N-dimethylamino)pyridine (DMAP) (20
mg), and triethylamine (0.71 mL, 5.07 mmol) in dichloro-
methane (20 mL) at 0 °C was added a solution of di-tert-butyl
dicarbonate (922 mg, 4.23 mmol) in dichloromethane (5 mL).
The reaction mixture was stirred at room temperature for 2
h, and the reaction was quenched with saturated NH4Cl. The
mixture was extracted with ethyl acetate and the organic layer
washed with brine, dried over magnesium sulfate, and con-
centrated in vacuo. Purification of the crude product by
column chromatography on silica gel (hexanes/EtOAc ) 5/1)
afforded the N-t-Boc-â-lactam 4b (659 mg, 98% yield) as a pale
yellow oil: 1H NMR (CDCl3) δ 1.02-1.20 (m, 21 H), 1.48 (s, 9
H), 1.77 (d, J ) 1.0 Hz, 3 H), 1.79 (d, J ) 1.0 Hz, 3 H), 4.75
(dd, J ) 9.8, 5.6 Hz, 1 H), 4.98 (d, J ) 5.6 Hz, 1 H), 5.28 (dd,
J ) 9.8, 1.0 Hz, 1 H).
1067, 1020, 997, 820, 738, 709 cm-1
.
7-(Tr ieth ylsilyl)-14â-h yd r oxy-10-d ea cetylba cca tin III
1,14-Ca r bon a te (8). To a solution of 7-TES-14â-OH-DAB (7)-
(600 mg, 0.888 mmol) in dry dichloromethane (100 mL) were
added pyridine (1.44 mL, 17.8 mmol) and phosgene (1.01 mL,
1.95 mmol) dropwise via a syringe at 0 °C. After 10 min, the
reaction was quenched with aqueous saturated NH4Cl (20 mL)
at 0 °C and the mixture allowed to warm to room temperature.
The reaction mixture was extracted with ethyl acetate (200
mL), and the organic layer was washed with water, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. Pu-
rification of the crude product by flash chromatography on
silica gel (hexanes/EtOAc ) 1/1) afforded 8 (498 mg, 80% yield)
as a white solid: mp 139-142 °C; 1H NMR (CDCl3) δ 0.54 (m,
12 H), 0.96 (m, 18 H), 1.04 (s, 3 H), 1.19 (s, 3 H), 1.66 (s, 3 H),
1.84 (dt, 1 H), 2.02 (s, 3 H), 2.24 (s, 2 H), 2.27 (s, 3 H), 2.48
(m, 1 H), 3.90 (d, J ) 7.2 Hz, 1 H), 4.13 (d, J ) 8.4 Hz, 1 H),
4.27 (d, J ) 8.1 Hz, 1 H), 4.41 (dd, J ) 6.6 Hz, 1 H), 4.80 (t, 1
H), 4.92 (d, J ) 8.4 Hz, 1 H), 5.21 (s, 1 H), 5.60 (d, J ) 6.9 Hz,
1 H), 7.43 (t, 2 H), 7.56 (t, 1 H), 8.08 (d, 2 H); 13C NMR (CDCl3)
δ 5.2, 5.9, 6.8, 6.9, 10.3, 14.6, 19.4, 22.7, 26.6, 37.3, 38.4, 42.7,
In the same manner, (3R,4S)-1-(tert-butoxycarbonyl)-3-
[(triisopropylsilyl)oxy]-4-(2-furyl)azetidin-2-one (4a ), (3R,4S)-
1-(tert-butoxycarbonyl)-3-[(triisopropylsilyl)oxy]-4-((E)-1-pro-
penyl)azetidin-2-one (4c), and (3R,4S)-1-(tert-butoxycarbonyl)-
3-[(triethysilyl)oxy]-4-(2,2-dimethylpropyl)azetidin-2-one (4d )
were prepared. (3R,4S)-1-n-Hexanoyl-3-[(tert-butyldimethyl-
silyl)oxy]-4-phenylazetidin-2-one (5a ) and (3R,4S)-1-n-hex-
anoyl-3-[(triisopropylsilyl)oxy]-4-(2-methyl-1-propenyl)azetidin-
2-one (5b) were prepared by the reactions of n-hexanoyl

New Taxoids Derived from 14â-OH-DAB
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3 273
47.2, 58.6, 67.8, 72.8, 74.9, 75.9, 76.7, 78.7, 80.9, 84.0, 128.5,
129.5, 130.0, 133.4, 136.8, 137.9, 167.1, 170.7, 205.8; IR
(CDCl3) 3516, 2952, 2876, 1716, 1452, 1367, 1271, 1239, 1143,
(79% based on the consumed 8); white solid; 1H NMR (CDCl3)
δ 0.55 (t, J ) 7.6 Hz, 6 H), 0.89 (t, J ) 7.6 Hz, 9 H), 1.09 (s, 3
H), 1.32 (s, 3 H), 1.70 (s, 3 H), 1.74-1.81 (m, 1 H), 1.91 (dd, J
) 6.7, 1.3 Hz, 3 H), 2.19 (s, 3 H), 2.27 (s, 3 H), 2.44-2.57 (m,
1 H), 3.53 (d, J ) 5.5 Hz, 1 H), 3.71 (d, J ) 7.1 Hz, 1 H), 4.16
(d, J ) 8.4 Hz, 1 H), 4.29 (d, J ) 8.4 Hz, 1 H), 4.45 (dd, J )
10.3, 6.6 Hz, 1 H), 4.77 (d, J ) 5.6 Hz, 1 H), 4.94 (m, 2 H),
5.96 (dd, J ) 15.4, 1.3 Hz, 1 H), 6.07 (d, J ) 7.1 Hz, 1 H), 6.44
(s, 1 H), 7.09 (dq, J ) 15.4, 6.8 Hz, 1 H), 7.46 (t, J ) 7.4 Hz,
2 H), 7.60 (t, J ) 7.4 Hz, 1 H), 8.01 (d, J ) 7.4 Hz, 2 H).
7-(Tr iet h ylsilyl)-10-(m et h oxyca r b on yl)-14â-h yd r oxy-
10-d ea cetylba cca tin III 1,14-ca r bon a te (9g): 65% yield;
1106, 1069, 1003, 985, 866, 820, 738, 709 cm-1
.
Gen er a l P r oced u r e for Mod ifica tion a t th e C-10 P osi-
tion of 7-TES-14â-OH-DAB 1,14-Ca r bon a te (8). A typical
procedure is described for the preparation of 7-(triethylsilyl)-
10-acetyl-14â-hydroxybaccatin 1,14-carbonate (9b): To a solu-
tion of 8 (120 mg, 0.17 mmol) in THF (5 mL) was added 1.0 M
LiHMDS in hexane (0.20 mL, 0.20 mmol) at -40 °C. After
the reaction mixture stirred for 10 min, freshly distilled acetyl
chloride (15 µL, 0.30 mmol) was added dropwise at -40 °C.
The mixture was allowed to warm to 0 °C over a period of 30
min. The reaction mixture was then concentrated in vacuo.
Purification by flash chromatography on silica gel (hexanes/
EtOAc ) 1/1) afforded 9b (124 mg, 95% yield) as a white
solid: 1H NMR (CDCl3) δ 0.51-0.62 (m, 6 H), 0.92 (t, J ) 7.9
Hz, 9 H), 1.13 (s, 3 H), 1.31 (s, 3 H), 1.71 (s, 3 H), 1.88 (m, 1
H), 2.19 (s, 6 H), 2.30 (s, 3 H), 2.53 (m, 1 H), 2.98 (bs, 1 H),
3.71 (d, J ) 7.3 Hz, 1 H), 4.19 (d, J ) 8.3 Hz, 1 H), 4.30 (d, J
) 8.3 Hz, 1 H), 4.46 (dd, J ) 10.6, 6.5 Hz, 1 H), 4.79 (d, J )
5.7 Hz, 1 H), 4.94 (d, J ) 8.5 Hz, 1 H), 4.98 (bt, 1 H), 6.08 (d,
J ) 7.3 Hz, 1 H), 6.43 (s, 1 H), 7.47 (t, J ) 7.6 Hz, 2 H), 7.61
(t, J ) 7.4 Hz, 1 H), 8.02 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3)
δ 5.25, 6.71, 10.07, 14.77, 20.79, 21.63, 22.32, 25.90, 31.57,
36.98, 41.46, 46.61, 58.79, 69.41, 71.97, 72.03, 74.99, 75.98,
80.37, 83.95, 84.00, 88.34, 128.16, 128.89, 129.83, 133.04,
134.14, 141.78, 152.76, 164.78, 169.16, 170.41, 200.70.
In the same manner, 9a ,c-g were prepared.
1
white solid; H NMR (CDCl3) δ 0.58 (m, 6 H), 0.92 (m, 9 H),
1.14 (s, 3 H), 1.29 (s, 3 H), 1.65 (s, 1 H), 1.71 (s, 3 H), 1.90 (m,
1 H), 2.20 (s, 3 H), 2.29 (s, 3 H), 2.53 (m, 1 H), 3.09 (bs, 1 H),
3.67 (d, J ) 7.1 Hz, 1 H), 3.82 (s, 3 H), 4.17 (d, J ) 8.5 Hz, 1
H), 4.29 (d, J ) 8.5 Hz, 1 H), 4.44 (dd, J ) 10.5, 6.6 Hz, 1 H),
4.78 (d, J ) 5.6 Hz, 1 H), 4.93 (d, J ) 8.3 Hz, 1 H), 5.00 (bs,
1 H), 6.07 (d, J ) 7.2 Hz, 1 H), 6.23 (s, 1 H), 7.46 (t, J ) 7.4
Hz, 2 H), 7.61 (t, J ) 7.4 Hz, 1 H), 8.01 (d, J ) 7.4 Hz, 2 H);
13C NMR (CDCl3) δ 5.3, 6.7, 10.0, 14.2, 14.9, 21.1, 21.4, 22.3,
25.7, 30.9, 36.9, 41.3, 46.6, 55.2, 58.6, 60.5, 69.4, 71.7, 72.0,
76.0, 78.4, 80.2, 83.9, 84.1, 88.4, 128.1, 128.9, 129.8, 132.2,
134.2, 143.3, 152.9, 154.7, 164.8, 170.4, 200.5.
Gen er a l P r oced u r e for th e Syn th eses of P r otected
Ta xoid s 10-15 th r ou gh th e Cou p lin g of â-La cta m s 4 a n d
5 w ith a P r otected Ba cca tin (9). A typical procedure is
described for the preparation of 2′-(triisopropylsilyl)-3′-dephen-
yl-3′-(2-furyl)-7,10-bis(triethylsilyl)-14â-hydroxydocetaxel 1,14-
carbonate (10a ): 7,10-Bis(TES)-14â-OH-DAB 1,14-carbonate
(9a ) (100 mg, 0.123 mmol) was dissolved in dry THF (8 mL)
under nitrogen. The solution was cooled to -45 °C. LiHMDS
(0.15 mL; 1.0 M solution in THF) was added dropwise, and
the solution was stirred for 2 min. â-Lactam 4a (75 mg, 0.184
mmol) was then added dropwise, and the mixture was stirred
at -45 °C for 7-10 min. The reaction was quenched with
7,10-Bis(tr ieth ylsilyl)-14â-h yd r oxy-10-d ea cetylba cca -
tin III 1,14-ca r bon a te (9a ): Et3SiCl (0.10 mL, 0.60 mmol)
was used instead of an acyl chloride; 84% yield; white solid;
mp 145-148 °C; [R]20 -54.5° (c 0.11, CHCl3); 1H NMR
D
(CDCl3); δ 0.49-0.62 (m, 12 H), 0.91-1.05 (m, 18 H), 1.19 (s,
3 H), 1.22 (s, 3 H), 1.79 (s, 3 H), 1.82 (dt, J ) 9.3 Hz, 1 H),
2.10 (s, 3 H), 2.31 (s, 3 H), 2.49 (m, 1 H), 3.74 (d, J ) 7.2 Hz,
1 H), 4.19 (d, J ) 8.4 Hz, 1 H), 4.34 (d, J ) 8.4 Hz, 1 H), 4.74
(d, J ) 5.7 Hz, 1 H), 4.95 (d, J ) 9.3 Hz, 1 H), 5.11 (s, 1 H),
6.02 (d, J ) 7.2 Hz, 1 H), 7.47 (t, 2 H), 7.60 (t, 1 H), 8.02 (d, 2
H); 13C NMR (CDCl3) δ 5.6, 6.3, 7.2, 7.3, 10.8, 14.7, 21.5, 22.6,
26.1, 37.4, 41.8, 59.1, 70.1, 71.9, 72.8, 76.0, 77.4, 80.7, 84.2,
84.8, 89.1, 128.7, 129.2, 130.2, 134.4, 136.6, 137.3, 153.6, 165.2,
170.7, 205.2. Anal. (C42H62O12Si2) C, H, N.
saturated NH4
Cl (2 mL); the mixture was extracted with ethyl
acetate (2 × 15 mL) and dried over anhydrous MgSO4. After
evaporation of the solvent, the residue was purified by column
chromatography on silica gel using hexane/EtOAc (4/1) as the
eluant to afford the coupling product 10a (117 mg, 78%) as a
white solid: 1H NMR (CDCl3) δ 0.54-0.73 (m, 12 H), 0.93-
1.05 (m, 39 H), 1.27 (s, 3 H), 1.32 (s, 3 H), 1.37 (s, 9 H), 1.71
(s, 3 H), 1.86 (s, 3 H), 1.91 (m, 1 H), 2.49 (s, 3 H), 2.53 (m, 1
H), 3.76 (d, J ) 7.4 Hz, 1 H), 4.21 (d, J ) 8.5 Hz, 1 H), 4.26 (d,
J ) 8.5 Hz, 1 H), 4.38 (dd, J ) 6.5, 10.5 Hz, 1 H), 4.82-4.91
(m, 2 H), 5.06 (bs, 1 H), 5.12 (s, 1 H), 5.25 (bd, J ) 9.5 Hz, 1
H), 5.42 (bd, J ) 9.5 Hz, 1 H), 6.09 (d, J ) 7.4 Hz, 1 H), 6.26
(bs, 1 H), 6.35 (bs, 1 H), 6.41 (d, J ) 6.4 Hz, 1 H), 7.37 (bs, 1
H), 7.46 (t, J ) 7.4 Hz, 2 H), 7.57 (t, J ) 7.2 Hz, 1 H), 8.03 (d,
J ) 7.5 Hz, 2 H); 13C NMR (CDCl3) δ 5.19, 5.92, 6.81, 6.92,
10.52, 12.39, 13.76, 17.76, 17.79, 21.90, 22.75, 25.63, 28.17,
29.68, 37.11, 41.80, 46.28, 52.80, 58.68, 69.53, 72.39, 73.29,
74.21, 75.09, 76.19, 79.82, 80.49, 80.58, 83.85, 88.07, 107.67,
110.83, 128.14, 128.90, 129.95, 131.33, 133.85, 138.50, 141.92,
151.89, 155.06, 164.85, 170.65, 170.83, 203.96; IR (KBr disk)
3448, 2954, 2872, 1825, 1772, 1731, 1490, 1366, 1243, 1143,
1084 cm-1. Anal. (C63H97NO17NSi3) C, H, N.
7-(Tr ieth ylsilyl)-10-pr opan oyl-14â-h ydr oxy-10-deacetyl-
ba cca tin III 1,14-ca r bon a te (9c): 74% yield; white solid; 1H
NMR (CDCl3) δ 0.58 (m, 6 H), 0.91 (m, 9 H), 1.12 (s, 3 H), 1.19
(t, J ) 7.45 Hz, 3 H), 1.22 (s, 3 H), 1.69 (s, 3 H), 1.86 (t, J )
12.0 Hz, 1 H), 2.17 (s, 3 H), 2.27 (s, 3 H), 2.47 (m, 3 H), 3.32
(d, J ) 5.3 Hz, 1 H), 3.69 (d, J ) 7.2 Hz, 1 H), 4.17 (d, J ) 8.4
Hz, 1 H), 4.28 (d, J ) 8.4 Hz, 1 H), 4.45 (dd, J ) 10.5, 6.6 Hz,
1 H), 4.77 (d, J ) 5.7 Hz, 1 H), 4.93 (m, 2 H), 6.05 (d, J ) 7.2
Hz, 1 H), 6.42 (s, 1 H), 7.45 (t, J ) 7.9 Hz, 2 H), 7.61 (t, J )
7.2 Hz, 1 H), 8.01 (d, J ) 7.5 Hz, 2 H).
7-(Tr ieth ylsilyl)-10-(cyclopr opylcar bon yl)-14â-h ydr oxy-
10-d ea cetylba cca tin III 1,14-ca r bon a te (9d ): 91% yield;
white solid; 1H NMR (CDCl3) δ 0.56 (q, J ) 8.1 Hz, 6 H), 0.85-
1.01 (m, 13 H), 1.12 (s, 3 H), 1.30 (s, 3 H), 1.68-1.83 (m, 4 H),
1.85-1.93 (m, 1 H), 2.18 (s, 3 H), 2.27 (s, 3 H), 2.40-2.56 (m,
1 H), 3.30 (d, J ) 5.5 Hz, 1 H), 3.69 (d, J ) 7.1 Hz, 1 H), 4.16
(d, J ) 8.3 Hz, 1 H), 4.29 (d, J ) 8.3 Hz, 1 H), 4.43 (dd, J )
10.4, 6.5 Hz, 1 H), 4.78 (d, J ) 5.6 Hz, 1 H), 4.90-4.98 (m, 2
H), 6.06 (d, J ) 7.2 Hz, 1 H), 6.41 (s, 1 H), 7.46 (t, J ) 7.4 Hz,
2 H), 7.60 (t, J ) 7.4 Hz, 1 H), 8.01 (d, J ) 7.4 Hz, 2 H).
7-(Tr ieth ylsilyl)-10-(N,N-d im eth ylca r ba m oyl)-14â-h y-
d r oxy-10-d ea cetylba cca tin III 1,14-ca r bon a te (9e): 86%
In the same manner, 10b-15 were prepared. The protected
taxoids 11a , 12a , and 14a were used in the next step
(deprotection) without spectroscopic characterization.
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-fu r yl)-7-(tr ieth -
ylsilyl)-14â-h yd r oxy-10-d ea cetylba cca tin III 1,14-ca r bon -
1
a te (10b): 78% yield; white solid; H NMR (CDCl3) δ 0.52-
0.63 (m, 12 H), 0.85-1.10 (m, 30 H), 1.28 (s, 3 H), 1.34 (s, 3
H), 1.36 (s, 9 H), 1.73 (s, 3 H), 1.90 (m, 1 H), 2.02 (s, 3 H), 2.19
(s, 3 H), 2.49 (s, 3 H), 2.54 (m, 1 H), 3.73 (d, J ) 7.4 Hz, 1 H),
4.21 (d, J ) 8.4 Hz, 1 H), 4.27 (d, J ) 8.4 Hz, 1 H), 4.45 (dd,
J ) 10.4, 6.5 Hz, 1 H), 4.80-4.90 (m, 2 H), 5.07 (bs, 1 H), 5.23
(bd, J ) 9.6 Hz, 1 H), 5.42 (bd, J ) 9.6 Hz, 1 H), 6.10 (d, J )
7.4 Hz, 1 H), 6.25 (bs, 1 H), 6.34 (bs, 1 H), 6.43 (m, 2 H), 7.37
(bs, 1 H), 7.47 (t, J ) 7.3 Hz, 2 H), 7.57 (t, J ) 7.2 Hz, 1 H),
8.03 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3) δ 5.22, 6.68, 10.12,
12.42, 14.35, 17.78, 20.69, 22.44, 22.69, 25.65, 28.16, 36.99,
41.82, 46.25, 52.78, 58.68, 69.27, 71.92, 73.24, 74.03, 74.24,
76.03, 79.73, 80.52, 80.54, 84.03, 87.84, 107.63, 110.84, 128.01,
1
yield; white solid; H NMR (CDCl3) δ 0.55 (q, J ) 7.6 Hz, 6
H), 0.90 (t, J ) 7.6 Hz, 9 H), 1.12 (s, 3 H), 1.30 (s, 3 H), 1.70
(s, 3 H), 1.81-1.91 (m, 1 H), 2.23 (s, 3 H), 2.28 (s, 3 H), 2.44-
2.56 (m, 1 H), 2.93 (s, 3 H), 3.06 (s, 3 H), 3.45 (d, J ) 5.6 Hz,
1 H), 3.70 (d, J ) 7.2 Hz, 1 H), 4.16 (d, J ) 8.4 Hz, 1 H), 4.29
(d, J ) 8.4 Hz, 1 H), 4.44 (dd, J ) 10.4, 6.5 Hz, 1 H), 4.77 (d,
J ) 5.7 Hz, 1 H), 4.91-4.99 (m, 2 H), 6.06 (d, J ) 7.2 Hz, 1
H), 6.31 (s, 1 H), 7.46 (t, J ) 7.4 Hz, 2 H), 7.60 (t, J ) 7.4 Hz,
1 H), 8.01 (d, J ) 7.4 Hz, 2 H).
7-(Tr iet h ylsilyl)-10-((E)-2-b u t en oyl)-14â-h yd r oxy-10-
d ea cetylba cca tin III 1,14-ca r bon a te (9f): 54% isolated yield

274 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3
Ojima et al.
128.94, 129.97, 133.92, 134.19, 137.62, 141.93, 151.76, 151.91,
155.09, 164.80, 169.07, 170.52, 170.84, 200.11; IR (KBr disk)
3348, 2954, 2872, 1825, 1731, 1490, 1366, 1237, 1149, 1084
cm-1. Anal. (C59H85O18NSi2) C, H, N.
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-((E)-1-p r op en yl)-
7-(t r iet h ylsilyl)-10-a cet yl-14â-h yd r oxyd ocet a xel 1,14-
1
ca r bon a te (12b): 75% yield; white solid; H NMR (CDCl3) δ
0.58 (q, J ) 7.9 Hz, 6 H), 0.90 (t, J ) 7.9 Hz, 9 H), 1.04-1.14
(m, 27 H), 1.40 (s, 9 H), 1.71 (s, 3 H), 1.77-1.81 (m, 1 H), 1.98
(s, 3 H), 2.17 (s, 3 H), 2.38-2.49 (m, 4 H), 3.70 (d, J ) 7.2 H,
1 H), 4.21 (d, J ) 8.4 Hz, 1 H), 4.29 (d, J ) 8.4 Hz, 1 H), 4.39-
4.52 (m, 1 H), 4.62 (bs, 1 H), 4.80-4.93 (m, 2 H), 5.44-5.62
(m, 1 H), 5.64-5.83 (m, 1 H), 6.10 (d, J ) 7.2 Hz, 1 H), 6.29-
6.38 (bs, 1 H), 6.41 (s, 1 H), 7.48 (t, J ) 7.3 Hz, 2 H), 7.59 (t,
J ) 7.3 Hz, 1 H), 8.03 (d, J ) 7.3 Hz, 2 H).
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-m et h yl-1-p r o-
p en yl)-7-(t r iet h ylsilyl)-10-a cet yl-14â-h yd r oxyd ocet a xel
1,14-ca r bon a te (11b): 80% yield; white solid; 1H NMR
(CDCl3) δ 0.52-0.61 (m, 6 H), 0.88-0.94 (m, 9 H), 1.03-1.21
(m, 21 H), 1.27 (s, 3 H), 1.33 (s, 3 H), 1.41 (s, 9 H), 1.72 (s, 3
H), 1.74 (s, 3 H), 1.77 (s, 3 H), 1.83-1.94 (m, 1 H), 1.99 (s, 3
H), 2.18 (s, 3 H), 2.50 (m, 1 H), 3.72 (d, J ) 7.4 Hz, 1 H), 4.20
(d, J ) 8.4 Hz, 1 H), 4.29 (d, J ) 8.4 Hz, 1 H), 4.45 (dd, J )
10.2, 6.5 Hz, 1 H), 4.56-4.70 (m, 3 H), 4.86-4.92 (m, 2 H),
5.29 (d, J ) 7.8 Hz, 1 H), 6.11 (d, J ) 7.4 Hz, 1 H), 6.28 (d, J
) 6.6 Hz, 1 H), 6.42 (s, 1 H), 7.45 (m, 2 H), 7.60 (m, 1 H), 8.01
(m, 2 H).
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-m et h yl-1-p r o-
p en yl)-7-(t r iet h ylsilyl)-10-p r op a n oyl-14â-h yd r oxyd oce-
ta xel 1,14-ca r bon a te (11c): 82% yield; white solid; 1H NMR
(CDCl3) δ 0.55 (m, 6 H), 0.91 (m, 9 H), 1.11 (m, 24 H), 1.19 (m,
4 H), 1.22 (s, 3 H), 1.30 (s, 3 H), 1.41 (s, 9 H), 1.69 (s, 3 H),
1.75 (s, 3 H), 1.75 (s, 3 H), 1.77 (s, 3 H), 1.87 (m, 1 H), 2.03 (s,
3 H), 2.47 (m, 5 H), 3.70 (d, J ) 7.2 Hz, 1 H), 4.17 (d, J ) 9.0
Hz, 1 H), 4.29 (d, J ) 9.0 Hz, 1 H), 4.45 (dd, J ) 10.5, 6.5 Hz,
1 H), 4.62 (m, 2 H), 4.78 (d, J ) 5.7 Hz, 1 H), 4.93 (m, 2 H),
5.25 (d, J ) 8.9 Hz, 1 H), 6.09 (d, J ) 7.3 Hz, 1 H), 6.27 (d, J
) 6.1 Hz, 1 H), 6.43 (s, 1 H), 7.46 (t, J ) 7.7 Hz, 2 H), 7.61 (t,
J ) 7.3 Hz, 1 H), 8.01 (d, J ) 7.2 Hz, 2 H).
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2,2-d im eth ylp r o-
p yl)-7,10-b is(t r iet h ylsilyl)-14â-h yd r oxyd ocet a xel 1,14-
1
ca r bon a te (13a ): 80% yield; white solid; H NMR (CDCl3) δ
0.53-0.77 (m, 12 H), 0.93-1.03 (m, 18 H), 0.96 (s, 9 H), 1.14
(m, 21 H), 1.25-1.35 (m, 2 H), 1.28 (s, 3 H), 1.43 (s, 9 H), 1.54
(s, 3 H), 1.69 (s, 3 H), 1.87 (m, 1 H), 1.88 (s, 3 H), 2.33 (s, 1 H),
2.39 (s, 3 H), 2.54 (m, 1 H), 3.71 (d, J ) 6.9 Hz, 1 H), 3.74 (m,
1H), 3.96-4.55 (m, 8 H), 4.84-4.99 (m, 3 H), 5.11 (s, 1 H),
5.13 (s, 1 H), 6.06-6.13 (m, 2 H), 6.14 (d, J ) 6.8 Hz, 1 H),
7.43 (m, 2 H), 7.57 (m, 2 H), 8.02 (m, 2 H), 8.10 (d, J ) 7.0 Hz,
1 H); 13C NMR (CDCl3) δ 5.2, 5.9, 6.8, 6.9, 10.4, 12.2, 12.4,
14.1, 17.9, 18.0, 22.0, 22.6, 25.7, 28.5, 29.8, 30.3, 37.1, 41.9,
42.5, 43.1, 46.2, 52.0, 53.6, 58.8, 69.6, 72.4, 75.0, 75.1, 75.2,
75.4, 75.7, 76.2, 79.4, 79.5, 80.6, 83.8, 87.9, 128.2, 128.8, 129.2,
129.8, 130.3, 131.3, 131.8, 134.0, 134.2, 138.4, 152.2, 153.9,
154.9, 164.8, 170.2, 204.0.
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-m et h yl-1-p r o-
p en yl)-3′-N-h exa n oyl-7-(t r iet h ylsilyl)-10-(cyclop r op yl-
ca r bon yl)-14â-h yd r oxyd oceta xel 1,14-ca r bon a te (15d ):
72% yield; white solid; 1H NMR (CDCl3) δ 0.55 (q, J ) 7.8 Hz,
6 H), 0.80 (t, J ) 6.7 Hz, 3 H), 0.90 (t, J ) 7.8 Hz, 9 H), 1.04-
1.25 (m, 25 H), 1.29 (s, 3 H), 1.34 (s, 3 H), 1.50-1.58 (m, 2 H),
1.70-1.77 (m, 9 H), 1.84-1.93 (m, 1 H), 2.01 (s, 3 H), 2.04-
2.28 (m, 2 H), 2.42-2.55 (m, 4 H), 3.69 (d, J ) 7.5 Hz, 1 H),
4.20 (d, J ) 8.4 Hz, 1 H), 4.28 (d, J ) 8.4 Hz, 1 H), 4.44 (dd,
J ) 10.6, 6.4 Hz, 1 H), 4.72 (d, J ) 4.9 Hz, 1 H), 4.82 (d, J )
7.1 Hz, 1 H), 4.88 (d, J ) 8.3 Hz, 1 H), 5.01-5.10 (m, 1 H),
5.37 (d, J ) 8.3 Hz, 1 H), 5.51 (d, J ) 8.2 Hz, 1 H), 6.09 (d, J
) 7.5 Hz, 1 H), 6.31 (d, J ) 6.5 Hz, 1 H), 6.42 (s, 1 H), 7.47 (t,
J ) 7.5 Hz, 2 H), 7.60 (t, J ) 7.5 Hz, 1 H), 8.05 (d, J ) 7.5 Hz,
2 H).
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-m et h yl-1-p r o-
p en yl)-3′-N-h exa n oyl-7-(tr ieth ylsilyl)-10-(N,N-d im eth yl-
ca r ba m oyl)-14â-h yd r oxyd oceta xel 1,14-ca r bon a te (15e):
55% yield; white solid; 1H NMR (CDCl3) δ 0.55 (q, J ) 7.6 Hz,
6 H), 0.80 (t, J ) 6.7 Hz, 3 H), 0.90 (t, J ) 7.6 Hz, 9 H), 1.10
(bs, 25 H), 1.29 (s, 3 H), 1.33 (s, 3 H), 1.43-1.59 (m, 2 H), 1.65-
1.76 (m, 9 H), 1.81-1.98 (m, 1 H), 2.00-2.21 (m, 5 H), 2.48
(bs, 4 H), 2.93 (s, 3 H), 3.06 (s, 3 H), 3.71 (d, J ) 7.4 Hz, 1 H),
4.20 (d, J ) 8.3 Hz, 1 H), 4.28 (d, J ) 8.3 Hz, 1 H), 4.45 (dd,
J ) 10.6, 6.6 Hz, 1 H), 4.72 (d, J ) 4.9 Hz, 1 H), 4.82 (d, J )
7.1 Hz, 1 H), 4.90 (d, J ) 8.3 Hz, 1 H), 5.00-5.10 (m, 1 H),
5.37 (d, J ) 8.1 Hz, 1 H), 5.51 (d, J ) 8.2 Hz, 1 H), 6.09 (d, J
) 7.4 Hz, 1 H), 6.34 (bs, 2 H), 7.47 (t, J ) 7.4 Hz, 2 H), 7.60
(t, J ) 7.4 Hz, 1 H), 8.05 (d, J ) 7.4 Hz, 2 H).
2′-[(Tr iisop r op ylsilyl)oxy]-3′-d ep h en yl-3′-(2-m eth yl-1-
p r o p e n y l)-3′-N -h e x a n o y l-7-(t r ie t h y ls ily l)-10-((E )-2-
bu t en oyl)-14â-h yd r oxyd ocet a xel 1,14-ca r b on a t e (15f):
50% yield (65% conversion yield); white solid; 1H NMR (CDCl3)
δ 0.56 (q, J ) 7.6 Hz, 6 H), 0.80 (t, J ) 6.7 Hz, 3 H), 0.89 (t,
J ) 7.6 Hz, 9 H), 1.04-1.22 (m, 25 H), 1.27 (s, 3 H), 1.40 (s, 3
H), 1.68-1.76 (m, 11 H), 1.92 (dd, J ) 6.9, 1.4 Hz, 3 H), 2.04
(s, 3 H), 2.35-2.56 (m, 6 H), 3.71 (d, J ) 7.4 Hz, 1 H), 4.20 (d,
J ) 8.3 Hz, 1 H), 4.28 (d, J ) 8.3 Hz, 1 H), 4.46 (dd, J ) 10.4,
6.4 Hz, 1 H), 4.69-4.96 (m, 4 H), 4.98-5.11 (m, 1 H), 5.36 (d,
J ) 8.2 Hz, 1 H), 5.53 (d, J ) 8.1 Hz, 1 H), 5.96 (dd, J ) 15.7,
1.4 Hz, 1 H), 6.09 (d, J ) 7.4 Hz, 1 H), 6.32 (d, J ) 7.2 Hz, 1
H), 6.46 (s, 1 H), 7.08 (dq, J ) 15.7, 6.9 Hz, 1 H), 7.46 (t, J )
7.5 Hz, 2 H), 7.59 (t, J ) 7.5 Hz, 1 H), 8.04 (d, J ) 7.5 Hz, 2
H).
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-m et h yl-1-p r o-
p en yl)-7-(tr ieth ylsilyl)-10-(cyclop r op ylca r bon yl)-14â-h y-
d r oxyd oceta xel 1,14-ca r bon a te (11d ): 87% yield; white
solid; 1H NMR (CDCl3) δ 0.55 (q, J ) 7.9 Hz, 6 H), 0.86-0.92
(m, 11 H), 0.98-1.16 (m, 29 H), 1.40 (s, 9 H), 1.68-1.77 (m,
10 H), 1.82-1.92 (m, 1 H), 1.99 (s, 3 H), 2.49 (bs, 4 H), 3.70 (d,
J ) 7.3 Hz, 1 H), 4.19 (d, J ) 8.3 Hz, 1 H), 4.27 (d, J ) 8.3 Hz,
1 H), 4.43 (dd, J ) 10.5, 6.4 Hz, 1 H), 4.54-4.78 (m, 3 H),
4.84-4.92 (m, 1 H), 5.26-5.30 (m, 1 H), 6.09 (d, J ) 7.3 Hz, 1
H), 6.27 (d, J ) 6.6 Hz, 1 H), 6.42 (s, 1 H), 7.44 (t, J ) 7.4 Hz,
2 H), 7.59 (t, J ) 7.4 Hz, 1 H), 7.99 (d, J ) 7.4 Hz, 2 H).
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-m et h yl-1-p r o-
p en yl)-7-(tr ieth ylsilyl)-10-(N,N-d im eth ylca r ba m oyl)-14â-
h yd r oxyd oceta xel 1,14-ca r bon a te (11e): 85% yield; white
1
solid; H NMR (CDCl3) δ 0.58 (q, J ) 7.6 Hz, 6 H), 0.94 (t, J
) 7.6 Hz, 9 H), 1.03 (bs, 21 H), 1.24 (s, 3 H), 1.34 (s, 3 H), 1.41
(s, 9 H), 1.65-1.81 (m, 9 H), 1.83-1.92 (m, 1 H), 2.02 (s, 3 H),
2.42 (bs, 4 H), 2.96 (s, 3 H), 3.02 (s, 3 H), 3.71 (d, J ) 7.4 Hz,
1 H), 4.20 (d, J ) 8.4 Hz, 1 H), 4.27 (d, J ) 8.4 Hz, 1 H), 4.44
(dd, J ) 10.4, 6.5 Hz, 1 H), 4.53-4.77 (m, 3 H), 4.84-4.96 (m,
2 H), 5.29 (d, J ) 7.5 Hz, 1 H), 6.10 (d, J ) 7.4 Hz, 1 H), 6.29
(d, J ) 6.5 Hz, 1 H), 6.35 (s, 1 H), 7.44 (t, J ) 7.4 Hz, 2 H),
7.59 (t, J ) 7.4 Hz, 1 H), 8.01 (d, J ) 7.4 Hz, 2 H).
2′-[(Tr iisop r op ylsilyl)oxy]-3′-d ep h en yl-3′-(2-m eth yl-1-
p r op en yl)-7-[(tr ieth ylsilyl)oxy]-10-((E)-2-bu ten oyl)-14â-
h yd r oxyd oceta xel 1,14-ca r bon a te (11f): 84% yield; white
1
solid; H NMR (CDCl3) δ 0.56 (q, J ) 7.6 Hz, 6 H), 0.90 (t, J
) 7.6 Hz, 9 H), 1.10 (s, 21 H), 1.26 (s, 3 H), 1.36 (s, 3 H), 1.40
(s, 9 H), 1.70-1.78 (m, 9 H), 1.92 (dd, J ) 6.8, 1.3 Hz, 3 H),
2.02 (bs, 4 H), 2.44-2.58 (m, 4 H), 3.73 (d, J ) 7.3 Hz, 1 H),
4.21 (d, J ) 8.4 Hz, 1 H), 4.28 (d, J ) 8.4 Hz, 1 H), 4.46 (dd,
J ) 10.4, 6.5 Hz, 1 H), 4.53-4.76 (m, 3 H), 4.84-4.94 (m, 2
H), 5.29 (d, J ) 7.9 Hz, 1 H), 5.93 (dd, J ) 15.6, 1.3 Hz, 1 H),
6.11 (d, J ) 7.4 Hz, 1 H), 6.28 (d, J ) 6.5 Hz, 1 H), 6.46 (s, 1
H), 7.09 (dq, J ) 15.6, 6.8 Hz, 1 H), 7.49 (t, J ) 7.4 Hz, 2 H),
7.60 (t, J ) 7.4 Hz, 1 H), 8.01 (d, J ) 7.4 Hz, 2 H).
2′-(Tr iisop r op ylsilyl)-3′-d ep h en yl-3′-(2-m et h yl-1-p r o-
pen yl)-7-(tr ieth ylsilyl)-10-(m eth oxycar bon yl)-14â-h ydr ox-
yd oceta xel 1,14-ca r bon a te (11g): 55% yield; white solid; 1H
NMR (CDCl3) δ 0.53 (m, 6 H), 0.86 (m, 9 H), 1.09 (s, 21 H),
1.15 (s, 3 H), 1.19 (m, 6 H), 1.31 (s, 9 H), 1.66 (s, 3 H), 1.73 (s,
3 H), 1.77 (s, 3 H), 1.86 (m, 1 H), 1.91 (s, 3 H), 2.34 (s, 3 H),
2.38 (s, 2 H), 2.41 (m, 1 H), 3.81 (d, J ) 6.6 Hz, 1 H), 4.15 (d,
J ) 8.2 Hz, 1 H), 4.26 (d, J ) 8.2 Hz, 1 H), 4.41 (s, 1 H), 4.45
(dd, J ) 10.6, 6.5 Hz, 1 H), 4.79 (m, 1 H), 4.89 (d, J ) 8.9 Hz,
1 H), 5.30 (d, J ) 7.7 Hz, 1 H), 5.65 (d, J ) 6.6 Hz, 1 H), 6.06
(t, J ) 7.2 Hz, 1 H), 6.47 (s, 1 H), 7.40 (t, J ) 7.3 Hz, 2 H),
7.54 (t, J ) 7.3 Hz, 1 H), 8.01 (d, J ) 7.2 Hz, 2 H).
Gen er a l P r oced u r e for th e Syn th eses of Ta xoid s 16-
21 by th e Dep r otection of Silyl-P r otected Ta xoid s 10-
15. A typical procedure is described for the preparation of 3′-
d e p h e n y l -3 ′-(2 -m e t h y l -1 -p r op e n y l )-1 0 -a ce t y l -1 4 â-
hydroxydocetaxel 1,14-carbonate (17b): The protected coupling

New Taxoids Derived from 14â-OH-DAB
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3 275
product 11b (170 mg, 0.15 mmol) was dissolved in acetonitrile/
pyridine (1/1, 10 mL) and cooled to 0 °C. HF/pyridine (70/30)
was added dropwise (0.1 mL/10 mg of reactant). The mixture
was stirred at 0 °C for 1 h and then at room temperature
overnight. After the disappearance of 11b on TLC analysis,
the reaction was quenched with saturated CuSO4. The reac-
tion mixture was extracted with EtOAc, and the extracts were
washed with saturated CuSO4 (2 × 15 mL) and water (2 × 15
mL) and dried over anhydrous MgSO4. Evaporation of the
solvent followed by purification of the crude product by flash
chromatography (silica gel; hexane/EtOAc ) 1/2) afforded
taxoid 17b (128 mg, 73% yield) as a white solid: mp 165-170
3′-Dep h en yl-3′-(2-m et h yl-1-p r op en yl)-10-p r op a n oyl-
14â-h yd r oxyd oceta xel 1,14-ca r bon a te (17c): 62% yield;
white solid; mp 165-168 °C; [R]20 -48.2° (c 0.125, CHCl3);
D
1H NMR (CDCl3) δ 1.30 (m, 8 H), 1.35 (s, 3 H), 1.42 (s, 9 H),
1.71 (s, 3 H), 1.75 (s, 3 H), 1.77 (s, 3 H), 1.85 (m, 1 H), 1.90 (s,
3 H), 2.44 (s, 3 H), 2.53 (m, 3 H), 3.69 (d, J ) 7.3 Hz, 1 H),
4.22 (d, J ) 8.3 Hz, 1 H), 4.28 (d, J ) 8.3 Hz, 1 H), 4.33 (s, 1
H), 4.39 (dd, J ) 10.5, 6.5 Hz, 1 H), 4.70 (m, 1 H), 4.82 (d, J
) 6.9 Hz, 2 H), 4.93 (d, J ) 8.3 Hz, 1 H), 5.23 (d, J ) 8.2 Hz,
1 H), 6.10 (d, J ) 7.3 Hz, 1 H), 6.27 (s, 1 H), 6.38 (d, J ) 6.9
Hz, 1 H), 7.45 (t, J ) 7.9 Hz, 2 H), 7.61 (t, J ) 7.2 Hz, 1 H),
8.01 (d, J ) 7.3 Hz, 2 H); 13C NMR (CDCl3) δ 9.0, 9.7, 14.2,
15.0, 18.7, 22.4, 23.1, 25.9, 26.0, 27.5, 28.3, 35.4, 41.7, 45.1,
52.2, 58.7, 60.4, 69.5, 71.8, 74.3, 74.6, 75.1, 75.9, 79.7, 80.5,
84.2, 88.2, 119.3, 127.9, 128.9, 129.9, 133.6, 134.2, 139.9, 151.9,
164.7, 170.5, 172.0, 174.3, 202.3. Anal. (C45H59NO16) C, H,
N.
°C; [R]20 -52.6° (c 0.038, CHCl3); 1H NMR (CDCl3) δ 1.26 (s,
D
3 H), 1.32 (s, 3 H), 1.40 (s, 9 H), 1.70 (s, 3 H), 1.73 (s, 3 H),
1.75 (s, 3 H), 1.88 (s, 3 H), 1.93 (m, 1 H), 2.22 (s, 3 H), 2.43 (s,
3 H), 2.47 (d, J ) 4.5 Hz, 1 H), 2.55 (m, 1 H), 3.68 (d, J ) 7.3
Hz, 1 H), 4.19-4.37 (m, 5 H), 4.69 (m, 1 H), 4.80 (d, J ) 6.9
Hz, 1 H), 4.92 (m, 2 H), 5.22 (d, J ) 8.7 Hz, 1 H), 6.09 (d, J )
7.3 Hz, 1 H), 6.26 (s, 1 H), 6.37 (d, J ) 6.2 Hz, 1 H), 7.45 (t, 2
H), 7.60 (t, 1 H), 8.00 (d, 2 H); 13C NMR (CDCl3) δ 9.6, 14.9,
18.6, 20.7, 22.3, 22.9, 25.8, 26.0, 28.2, 35.5, 41.7, 45.1, 52.1,
58.7, 69.5, 71.65, 74.2, 74.8, 75.9, 79.7, 80.5, 84.2, 88.1, 119.5,
127.9, 128.9, 129.8, 133.5, 134.2, 139.4, 139.9, 151.9, 156.3,
164.7, 170.4, 170.8, 172.0, 202.1; IR (KBr disk) 3421, 2979,
3′-De p h e n yl-3′-(2-m e t h yl-1-p r op e n yl)-10-(cyclop r o-
pylcar bon yl)-14â-h ydr oxydocetaxel 1,14-car bon ate (17d):
84% yield; white solid; mp 137-140 °C; [R]20 -40.0° (c 0.30,
D
1
CHCl3); H NMR (CDCl3) δ 1.00-1.13 (m, 4 H), 1.28 (s, 3 H),
1.34 (s, 3 H), 1.42 (s, 9 H), 1.70 (s, 3 H), 1.74-1.77 (m, 8 H),
1.89 (s, 3 H), 2.44 (s, 3 H), 2.50-2.57 (m, 1 H), 3.67 (d, J ) 7.3
Hz, 1 H), 4.04 (bs, 1 H), 4.20-4.42 (m, 4 H), 4.66-4.76 (m, 1
H), 4.82 (d, J ) 7.0 Hz, 1 H), 4.92 (d, J ) 9.1 Hz, 1 H), 5.22
(m, 1 H), 6.09 (d, J ) 7.3 Hz, 1 H), 6.25 (s, 1 H), 6.38 (d, J )
5.9 Hz, 1 H), 7.46 (t, J ) 7.5 Hz, 2 H), 7.61 (t, J ) 7.5 Hz, 1
H), 8.01 (d, J ) 7.5 Hz, 2 H); 13C NMR (CDCl3) δ 9.41, 9.62,
12.95, 14.19, 15.01, 18.68, 22.38, 23.11, 25.87, 26.09, 28.03,
28.27, 35.37, 41.70, 45.04, 52.15, 58.71, 60.41, 69.54, 71.81,
74.28, 74.63, 75.03, 75.93, 76.21, 79.75, 80.52, 80.67, 84.25,
88.16, 116.49, 119.33, 127.92, 128.95, 129.88, 133.59, 134.24,
140.05, 151.93, 164.71, 170.46, 172.04, 174.89, 202.40. Anal.
(C46H59NO16) C, H, N.
1824, 1734, 1685, 1508, 1458, 1239, 1165 cm-1. Anal. (C44H56
NO16) C, H, N.
-
In the same manner, taxoids 16-21 were prepared using
the method shown above.
3′-Dep h en yl-3′-(2-fu r yl)-14â-h yd r oxyd ocet a xel 1,14-
1
ca r bon a te (16a ): 73% yield; white solid; H NMR (CDCl3) δ
1.24 (s, 3 H), 1.31 (s, 3 H), 1.37 (s, 9 H), 1.77 (s, 3 H), 1.86 (m,
1 H), 1.91 (s, 3 H), 2.46 (s, 3 H), 2.56 (m, 1 H), 3.80 (d, J ) 7.4
Hz, 1 H), 4.22 (d, J ) 8.5 Hz, 1 H), 4.29 (d, J ) 8.5 Hz, 1 H),
4.29 (m, 2 H), 4.75-4.84 (m, 2 H), 4.92 (bd, J ) 8.9 Hz, 1 H),
5.22 (s, 1 H), 5.40 (bd, J ) 9.4 Hz, 1 H), 5.58 (bd, J ) 9.4 Hz,
1 H), 6.09 (d, J ) 7.4 Hz, 1 H), 6.34 (bs, 1 H), 6.38 (bs, 1 H),
6.44 (d, J ) 6.1 Hz, 1 H), 7.42 (bs, 1 H), 7.49 (t, J ) 7.4 Hz, 2
H), 7.61 (t, J ) 7.3 Hz, 1 H), 8.03 (d, J ) 7.6 Hz, 2 H); 13C
NMR (CDCl3) δ 10.00, 14.45, 21.96, 22.47, 25.55, 28.19, 36.58,
41.67, 45.98, 51.45, 57.91, 69.31, 71.56, 72.22, 74.08, 74.84,
76.10, 79.64, 80.47, 80.83, 84.09, 88.18, 107.76, 110.81, 127.89,
129.03, 129.98, 134.20, 135.90, 136.43, 142.47, 151.26, 151.99,
155.62, 164.84, 170.77, 171.75, 209.78. Anal. (C42H49O17N)
C, H, N.
3′-Dep h en yl-3′-(2-m eth yl-1-p r op en yl)-10-(N,N-d im eth -
ylcar bam oyl)-14â-h ydr oxydocetaxel 1,14-car bon ate (17e):
83% yield; white solid; mp 168-171 °C; [R]20 -63.0° (c 0.27,
D
1
CHCl3); H NMR (250 MHz, CDCl3) δ 1.24 (s, 3 H), 1.32 (s, 3
H), 1.41 (s, 9 H), 1.67-1.78 (m, 10 H), 1.91 (s, 3 H), 2.44 (s, 3
H), 2.48-2.59 (m, 1 H), 2.95 (s, 3 H), 3.03 (s, 3 H), 3.13 (bs,
1H), 3.68 (d, J ) 7.4 Hz, 1 H), 4.21 (d, J ) 8.4 Hz, 1 H), 4.27-
4.35 (m, 2 H), 4.41 (bt, 1 H), 4.64-4.77 (m, 1 H), 4.79-4.89
(m, 2 H), 4.95 (d, J ) 7.9 Hz, 1 H), 5.23 (d, J ) 8.7 Hz, 1 H),
6.09 (d, J ) 7.4 Hz, 1 H), 6.21 (s, 1 H), 6.39 (d, J ) 6.7 Hz, 1
H), 7.46 (t, J ) 7.5 Hz, 2 H), 7.61 (t, J ) 7.5 Hz, 1 H), 8.01 (d,
J ) 7.5 Hz, 2 H); 13C NMR (63 MHz, CDCl3) δ 9.47, 15.05,
18.68, 22.38, 23.41, 25.85, 26.24, 28.28, 35.24, 36.06, 36.73,
41.71, 44.98, 52.14, 58.66, 69.63, 72.05, 74.33, 75.03, 75.45,
75.92, 79.82, 80.57, 80.64, 84.43, 88.25, 119.39, 127.95, 128.95,
129.88, 133.83, 134.22, 139.62, 140.41, 151.98, 155.76, 164.71,
170.41, 172.07, 204.19. Anal. (C45H60N2O16) C, H, N.
3′-Dep h en yl-3′-fu r yl-10-a cet yl-14â-h yd r oxyd ocet a xel
1,14-ca r bon a te (16b): 76% yield; white solid; 1H NMR
(CDCl3) δ 1.28 (s, 3 H), 1.33 (s, 3 H), 1.38 (s, 9 H), 1.72 (s, 3
H), 1.89 (m, 4 H), 2.25 (s, 3 H), 2.46 (s, 3 H), 2.56 (m, 1 H),
3.71 (d, J ) 7.4 Hz, 1 H), 4.25 (d, J ) 8.5 Hz, 1 H), 4.29 (d, J
) 8.5 Hz, 1 H), 4.39 (dd, J ) 10.7, 6.5 Hz, 1 H), 4.79 (bs, 1 H),
4.84 (d, J ) 6.8 Hz, 1 H), 4.92 (bd, J ) 8.5 Hz, 1 H), 5.29-5.50
(m, 2 H), 6.10 (d, J ) 7.4 Hz, 1 H), 6.27 (s, 1 H), 6.34 (bs, 1 H),
6.38 (bs, 1 H), 6.44 (d, J ) 6.4 Hz, 1 H), 7.42 (bs, 1 H), 7.49 (t,
J ) 7.5 Hz, 2 H), 7.61 (t, J ) 7.2 Hz, 1 H), 8.04 (d, J ) 7.6 Hz,
2 H); 13C NMR (CDCl3) δ 9.65, 14.92, 20.75, 22.45, 22.97, 25.90,
28.17, 29.66, 35.46, 41.73, 45.13, 51.48, 58.68, 69.33, 71.70,
72.34, 74.75, 74.82, 75.94, 79.58, 80.52, 80.92, 84.22, 88.07,
107.81, 110.78, 127.89, 128.98, 129.95, 133.67, 134.13, 139.44,
142.48, 151.00, 164.70, 170.73, 170.89, 171.67, 202.07. Anal.
(C44H51O18N) C, H, N.
3′-D e p h e n y l-3′-(2-m e t h y l-1-p r o p e n y l)-10-((E )-2-
bu t en oyl)-14â-h yd r oxyd ocet a xel 1,14-ca r b on a t e (17f):
38% yield; white solid; mp 147-151 °C; [R]20 -70.0° (c 0.20,
D
CHCl3); 1H NMR (CDCl3) δ 1.29 (s, 3 H), 1.35 (s, 3 H), 1.42 (s,
9 H), 1.71 (s, 3 H), 1.75 (s, 3 H), 1.77 (s, 3 H), 1.90 (s, 3 H),
1.94 (dd, J ) 6.8, 1.3 Hz, 3 H), 2.11-2.18 (m, 1 H), 2.45 (s, 3
H), 2.49-2.62 (m, 1 H), 3.71 (d, J ) 7.3 Hz, 1 H), 4.22 (d, J )
8.4 Hz, 1 H), 4.27-4.30 (bs, 1 H), 4.32 (d, J ) 8.4 Hz, 1 H),
4.41 (m, 1 H), 4.67-4.85 (m, 3 H), 4.95 (d, J ) 7.8 Hz, 1 H),
5.24 (d, J ) 8.5 Hz, 1 H), 5.98 (dd, J ) 15.6, 1.3 Hz, 1 H), 6.11
(d, J ) 7.3 Hz, 1 H), 6.32 (s, 1 H), 6.39 (d, J ) 7.3 Hz, 1 H),
7.10 (dq, J ) 15.6, 7.1 Hz, 1 H), 7.46 (t, J ) 7.4 Hz, 2 H), 7.61
(t, J ) 7.4 Hz, 1 H), 8.01 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3)
δ 9.65, 14.99, 18.35, 18.69, 22.39, 23.14, 25.87, 26.11, 28.28,
30.15, 35.40, 41.71, 45.04, 52.15, 58.74, 69.56, 71.85, 74.27,
74.55, 75.94, 79.76, 84.26, 88.19, 119.28, 121.22, 128.95,
129.89, 134.25, 140.11, 147.96, 153.85, 164.51, 166.03, 170.22,
171.91, 202.33.
3′-De p h e n yl-3′-(2-m e t h yl-1-p r op e n yl)-14â-h yd r oxy-
d oceta xel 1,14-ca r bon a te (17a ): 90% yield; colorless film;
mp 167-169 °C; [R]20D -44.4° (c 0.45, CHCl3); 1H NMR (CDCl3)
δ 1.26 (s, 3 H), 1.32 (s, 3 H), 1.40 (s, 9 H), 1.70 (s, 3 H), 1.73
(s, 3 H), 1.75 (s, 3 H), 1.88 (s, 3 H), 1.93 (m, 1 H), 2.22 (s, 3 H),
2.43 (s, 3 H), 2.47 (d, J ) 4.5 Hz, 1 H), 2.55 (m, 1 H), 3.68 (d,
J ) 7.3 Hz, 1 H), 4.19-4.37 (m, 5 H), 4.69 (m, 1 H), 4.80 (d, J
) 6.9 Hz, 1 H), 4.92 (m, 2 H), 5.12 (s, 1 H), 5.22 (d, J ) 8.7 Hz,
1 H), 6.09 (d, J ) 7.3 Hz, 1 H), 6.37 (d, J ) 6.2 Hz, 1 H), 7.45
(t, 2 H), 7.60 (t, 1 H), 8.00 (d, 2 H); 13C NMR (CDCl3) δ 9.6,
14.9, 18.6, 20.7, 22.3, 22.9, 25.8, 26.0, 28.2, 35.5, 41.7, 45.1,
52.1, 58.7, 69.5, 71.65, 74.2, 74.8, 75.9, 79.7, 80.5, 84.2, 88.1,
119.5, 127.9, 128.9, 129.8, 133.5, 134.2, 139.4, 139.9, 151.9,
156.3, 164.7, 170.8, 172.0, 202.1; IR (KBr disk) 3421, 2979,
3′-Dep h en yl-3′-(2-m eth yl-1-p r op en yl)-10-(m eth oxyca r -
bon yl)-14â-h yd r oxyd oceta xel 1,14-ca r bon a te (17g): 67%
yield; white solid; mp 163-165 °C; [R]20 -53.9° (c 0.168,
D
CHCl3); 1H NMR (CDCl3) δ 1.25 (s, 3 H), 1.32 (s, 3 H), 1.42 (s,
9 H), 1.75 (m, 6 H), 1.85 (m, 1 H), 1.93 (s, 3 H), 2.45 (s, 3 H),
2.56 (m, 1 H), 3.67 (d, J ) 7.3 Hz, 1 H), 3.87 (s, 3 H), 4.22 (d,
J ) 8.5 Hz, 1 H), 4.29 (d, J ) 8.5 Hz, 1 H), 4.32 (d, J ) 4.8 Hz,
1824, 1734, 1685, 1508, 1458, 1239, 1165 cm-1. Anal. (C42H53
NO16) C, H, N.
-

276 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3
Ojima et al.
1 H), 4.36 (dd, J ) 6.5, 10.9 Hz, 1 H), 4.72 (m, 1 H), 4.83 (m,
2 H), 4.93 (d, J ) 8.0 Hz, 1 H), 5.24 (d, J ) 8.2 Hz, 1 H), 6.07
(s, 1 H), 6.11 (d, J ) 7.5 Hz, 1 H), 6.39 (d, J ) 6.1 Hz, 1 H),
7.46 (t, J ) 7.3 Hz, 2 H), 7.61 (t, J ) 7.2 Hz, 1 H), 8.01 (d, J
) 7.3 Hz, 2 H); 13C NMR (CDCl3) δ 9.6, 14.2, 18.7, 22.4, 22.9,
25.9, 28.3, 29.7, 35.5, 41.6, 45.0, 52.2, 55.8, 58.7, 69.5, 71.7,
74.2, 75.0, 75.9, 77.5, 79.7, 80.5, 80.7, 84.2, 88.1, 119.3, 127.9,
129.0, 129.9, 133.1, 134.3, 139.7, 140.8, 151.9, 155.5, 164.7,
170.5, 172.0, 202.5. Anal. (C44H57NO17) C, H, N.
3′-Dep h en yl-3′-(2-m eth yl-1-p r op en yl)-3′-N-d eben zoyl-
3′-N-h exa n oyl-10-d ea cetyl-10-cyclop r op yl-14â-h yd r oxy-
p a clita xel 1,14-ca r bon a te (21d ): 81.6% yield; white solid;
mp 157-161 °C; [R]20D -33.3° (c 0.36, CHCl3); 1H NMR (CDCl3)
δ 0.84 (t, J ) 6.6 Hz, 3 H), 1.00-1.13 (m, 4 H), 1.19-1.29 (m,
7 H), 1.34 (s, 3 H), 1.52-1.63 (m, 2 H), 1.70 (s, 3 H), 1.74-
1.78 (m, 7 H), 1.89 (bs, 4 H), 2.12-2.21 (m, 2 H), 2.45-2.59
(m, 4 H), 3.69 (d, J ) 7.5 Hz, 1 H), 4.14-4.28 (m, 2 H), 4.36-
4.42 (m, 2 H), 4.83 (d, J ) 6.9 Hz, 1 H), 4.92 (d, J ) 8.2 Hz, 1
H), 5.00-5.09 (m, 1 H), 5.30 (d, J ) 7.3 Hz, 1 H), 5.77 (d, J )
7.7 Hz, 1 H), 6.09 (d, J ) 7.5 Hz, 1 H), 6.25 (s, 1 H), 6.41 (d,
J ) 6.7 Hz, 1 H), 7.48 (t, J ) 7.4 Hz, 2 H), 7.61 (t, J ) 7.4 Hz,
1 H), 8.06 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3) δ 9.41, 9.68,
12.92, 13.92, 14.92, 18.75, 22.32, 22.47, 23.28, 25.29, 25.87,
26.03, 31.30, 35.34, 36.57, 41.73, 45.04, 50.87, 58.68, 69.54,
71.76, 74.29, 74.58, 75.94, 76.51, 79.71, 80.42, 84.28, 88.37,
118.97, 127.86, 128.97, 130.04, 133.57, 134.23, 139.81, 139.99,
151.93, 164.76, 170.74, 172.13, 174.25, 174.92, 202.36. Anal.
(C47H61NO15) C, H, N.
3′-De p h e n yl-3′-((E )-1-p r o p e n yl)-14â-h y d r ox yd o c e -
ta xel 1,14-ca r bon a te (18a ): 52% yield (for two steps); white
solid; mp 168-172 °C; [R]20D -42.1° (c 0.095, CHCl3); 1H NMR
(CDCl3) δ 1.20 (s, 3 H), 1.29 (s, 3 H), 1.36 (s, 9 H), 1.71-1.74
(m, 6 H), 1.88 (s, 3 H), 2.01 (s, 3 H), 2.43 (s, 3 H), 2.52 (m, 1
H), 3.77 (d, J ) 7.2 Hz, 1 H), 4.18-4.42 (m, 4 H), 4.59 (bs, 1
H), 4.79 (d, J ) 6.8 Hz, 1 H), 4.91 (d, J ) 8.8 Hz, 1 H), 5.16-
5.22 (m, 2 H), 5.54 (dd, J ) 15.4, 5.7 Hz, 1 H), 5.74 (dq, J )
15.4, 6.5 Hz, 1 H), 6.07 (d, J ) 7.2 Hz, 1 H), 6.39 (d, J ) 5.8
Hz, 1 H), 7.46 (t, J ) 7.4 Hz, 2 H), 7.59 (t, J ) 7.4 Hz, 1 H),
8.00 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3) δ 9.98, 14.17, 14.47,
17.89, 21.89, 22.00, 22.45, 25.60, 28.26, 29.69, 36.55, 41.67,
45.96, 55.10, 57.93, 61.03, 69.36, 71.57, 73.58, 74.10, 74.58,
76.06, 79.64, 80.51, 84.06, 88.16, 126.93, 127.89, 129.00,
129.23, 129.93, 134.19, 136.01, 136.39, 152.25, 155.82, 164.82,
170.53, 172.31, 209.76. Anal. (C41H51NO16) C, H, N.
3′-Dep h en yl-3′-(2-m eth yl-1-p r op en yl)-3′-N-d eben zoyl-
3′-N-h exa n oyl-10-d ea cetyl-10-(N,N-d im eth ylca r ba m oyl)-
14â-h yd r oxyp a clita xel 1,14-ca r bon a te (21e): 54% yield;
1
white solid; mp 152-156 °C; [R]20 -45.0° (c 0.2, CHCl3); H
D
NMR (CDCl3) δ 0.84 (t, J ) 6.7 Hz, 3 H), 1.20-1.27 (m, 7 H),
1.33 (s, 3 H), 1.53-1.63 (m, 5 H), 1.70 (s, 3 H), 1.75 (s, 3 H),
1.77 (s, 3 H), 1.91 (bs, 4 H), 2.12-2.21 (m, 2 H), 2.50 (bs, 4 H),
2.96 (s, 3 H), 3.03 (s, 3 H), 3.10 (bs, 1 H), 3.69 (d, J ) 7.5 Hz,
1 H), 4.23 (d, J ) 8.3 Hz, 1 H), 4.29 (d, J ) 8.3 Hz, 1 H), 4.38-
4.49 (m, 2 H), 4.83 (d, J ) 6.9 Hz, 1 H), 4.95 (d, J ) 7.8 Hz, 1
H), 5.00-5.09 (m, 1 H), 5.30 (d, J ) 9.0 Hz, 1 H), 5.75 (d, J )
7.7 Hz, 1 H), 6.08 (d, J ) 7.5 Hz, 1 H), 6.20 (s, 1 H), 6.42 (d,
J ) 5.6 Hz, 1 H), 7.48 (t, J ) 7.4 Hz, 2 H), 7.61 (t, J ) 7.4 Hz,
1 H), 8.06 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3) δ 9.50, 13.94,
15.01, 18.75, 22.32, 22.47, 23.59, 25.30, 25.88, 26.20, 31.33,
35.18, 36.07, 36.58, 36.75, 41.73, 44.95, 50.88, 58.63, 69.61,
72.04, 74.36, 74.71, 75.38, 75.93, 79.79, 80.46, 84.49, 119.00,
128.97, 130.04, 133.80, 134.23, 140.02, 140.22, 151.76, 155.88,
3′-Dep h en yl-3′-((E)-1-p r op en yl)-10-a cetyl-14â-h yd r oxy-
d oceta xel 1,14-ca r bon a te (18b): 80% yield; white solid; mp
1
171-175 °C; H NMR (CDCl3) δ 1.18 (s, 3 H), 1.20 (s, 3 H),
1.28 (s, 9 H), 1.60 (s, 3 H), 1.63 (d, J ) 6.4 Hz, 3 H), 1.70-1.78
(m, 1 H), 1.82 (s, 3 H), 2.11 (s, 3 H), 2.35 (s, 3 H), 2.37-2.48
(m, 1 H), 3.60 (d, J ) 7.4 Hz, 1 H), 4.09 (d, J ) 8.5 Hz, 1 H),
4.18 (d, J ) 8.5 Hz, 1 H), 4.16-4.25 (m, 1 H), 4.28 (d, J ) 3.5
Hz, 1 H), 4.42 (bm, 1 H), 4.73 (d, J ) 6.8 Hz, 1 H), 4.84 (d, J
) 8.3 Hz, 1 H), 5.43 (dd, J ) 15.5, 5.7 Hz, 1 H), 5.62 (dq, J )
15.5, 6.4 Hz, 1 H), 5.98 (d, J ) 7.4 Hz, 1 H), 6.24 (s, 1 H), 6.25
(bd, 1 H), 7.38 (t, J ) 7.5 Hz, 2 H), 7.52 (t, J ) 7.5 Hz, 1 H),
7.90 (d, J ) 7.5 Hz, 2 H); 13C NMR (CDCl3) δ 13.59, 18.53,
21.57, 24.50, 26.09, 26.54, 29.57, 32.03, 39.70, 45.59, 49.67,
51.74, 52.07, 52.76, 53.10, 53.44, 53.78, 57.32, 58.88, 62.37,
73.34, 74.82, 77.24, 77.91, 78.73, 79.89, 83.74, 84.43, 88.29,
92.15, 131.05, 131.73, 132.62, 132.88, 133.74, 137.38, 138.20,
143.17, 159.80, 168.83, 174.31, 174.71, 176.04, 178.83, 188.72,
191.84, 205.96. Anal. (C43H53NO17) C, H, N.
165.02, 170.68, 172.16, 174.19, 204.22. Anal. (C46H62N2O15
C, H, N.
)
3′-Dep h en yl-3′-(2-m et h yl-1-p r op en yl)-3′-N-h exa n oyl-
10-((E)-2-bu ten oyl)-14â-h yd r oxyd oceta xel 1,14-ca r bon a te
(21f): 83.8% yield; white solid; [R]20 -57.7° (c 0.26, CHCl3);
D
1H NMR (CDCl3) δ 0.84 (t, J ) 6.7 Hz, 3 H), 1.20-1.28 (m, 7
H), 1.34 (s, 3 H), 1.50-1.63 (m, 2 H), 1.71 (s, 3 H), 1.74 (s, 3
H), 1.77 (s, 3 H), 1.89 (bs, 4 H), 1.94 (dd, J ) 7.1, 1.6 Hz, 3 H),
2.13-2.21 (m, 2 H), 2.50-2.62 (m, 4 H), 3.71 (d, J ) 7.5 Hz, 1
H), 4.20-4.31 (m, 2 H), 4.36-4.44 (m, 2 H), 4.84 (d, J ) 6.9
Hz, 1 H), 4.92-5.08 (m, 2 H), 5.30 (d, J ) 8.8 Hz, 1 H), 5.75
(d, J ) 7.5 Hz, 1 H), 5.98 (dd, J ) 15.6, 1.6 Hz, 1 H), 6.09 (d,
J ) 7.5 Hz, 1 H), 6.31 (s, 1 H), 6.41 (d, J ) 5.7 Hz, 1 H), 7.11
(dq, J ) 15.6, 6.9 Hz, 1 H), 7.48 (t, J ) 7.4 Hz, 2 H), 7.61 (t,
J ) 7.4 Hz, 1 H), 8.06 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3)
δ 9.69, 13.93, 14.93, 18.35, 18.76, 22.33, 22.48, 23.31, 25.30,
25.88, 26.06, 31.33, 35.39, 36.58, 41.73, 45.04, 50.89, 58.72,
69.55, 71.81, 74.29, 74.48, 74.67, 75.98, 79.73, 80.43, 84.31,
88.37, 119.00, 121.22, 127.86, 128.98, 130.04, 133.62, 134.26,
139.84, 139.99, 147.99, 164.77, 165.95, 170.77, 172.13, 174.22,
202.33.
3′-D e p h e n y l-3′-(2,2-d im e t h y lp r o p y l)-14â-h y d r o x y -
d oceta xel 1,14-ca r bon a te (19a ): 80% yield; white solid; mp
158-161 °C; [R]20 -38.2° (c 0.34, CHCl3); 1H NMR (CDCl3) δ
D
0.99 (s, 9 H), 1.29 (s, 3 H), 1.33 (s, 3 H), 1.40 (s, 9 H), 1.56 (bd,
J ) 14.5 Hz, 1 H), 1.70 (m, 1 H), 1.80 (s, 3 H), 1.86 (m, 1 H),
1.94 (s, 3 H), 2.48 (s, 3 H), 2.59 (ddd, J ) 14.1, 8.0, 3.0 Hz, 1
H), 3.81 (d, J ) 7.5 Hz, 1 H), 4.08 (m, 1 H), 4.27 (m, 6 H), 4.80
(m, 1 H), 4.83 (d, J ) 6.9 Hz, 1 H), 4.94 (d, J ) 7.9 Hz, 1 H),
5.18 (s, 1 H), 6.11 (d, J ) 7.4 Hz, 1 H), 6.45 (d, J ) 6.5 Hz, 1
H), 7.48 (t, 2 H), 7.62 (t, 1 H), 8.03 (d, 2 H); 13C NMR (CDCl3)
δ 9.96, 14.5, 22.0, 25.7, 28.3, 29.8, 30.3, 36.7, 41.6, 44.3, 45.8,
51.2, 57.8, 69.4, 71.6, 74.1, 74.4, 75.6, 76.5, 77.2, 79.7, 80.4,
80.5, 83.9, 88.2, 127.9, 128.9, 129.9, 134.2, 136.1, 136.3, 152.0,
156.2, 164.8, 170.6, 172.4, 209.8. Anal. (C43H58NO15) C, H,
N.
Syn th eses of Ta xoid s 22 a n d 23 th r ou gh Hyd r ogen a -
tion of Ta xoid s 17 a n d 18. A typical procedure is described
for the preparation of 3′-dephenyl-3′-propyl-14â-hydroxydoce-
taxel 1,14-carbonate (23a ): A solution 18a (40 mg, 0.049 mmol)
in ethyl acetate (3 mL) was added to 10% PdC (20 mg) under
1 atm of H2. The mixture was stirred at 40 °C for 36 h.
Removal of the catalyst by filtration and removal of the solvent
3′-N-Deb en zoyl-3′-N-n -h exa n oyl-10-d ea cet yl-14â-h y-
d r oxyp a clita xel 1,14-ca r bon a te (20a ): 41% yield; white
1
solid; mp 159-163 °C; [R]20 -9.1° (c 0.11, CHCl3); H NMR
D
(CDCl3) δ 0.81 (t, J ) 6.7 Hz, 3 H), 1.20-1.28 (m, 7 H), 1.32
(s, 3 H), 1.55 (bt, J ) 6.5 Hz, 2 H), 1.79 (s, 3 H), 1.85 (bs, 1 H),
1.90 (s, 3 H), 2.18-2.29 (m, 2 H), 2.55 (s, 3 H), 2.58-2.62 (m,
1 H), 3.81 (d, J ) 7.7 Hz, 1 H), 4.21-4.27 (m, 3 H), 4.78-4.81
(m, 2 H), 4.89 (d, J ) 8.2 Hz, 1 H), 5.15 (s, 1 H), 5.73 (dd, J )
9.2, 2.7 Hz, 1 H), 6.08 (d, J ) 7.7 Hz, 1 H), 6.37 (d, J ) 9.2 Hz,
1 H), 6.52 (d, J ) 6.3 Hz, 1 H), 7.33-7.44 (m, 5 H), 7.50 (t, J
) 6.9 Hz, 2 H), 7.60 (t, J ) 7.1 Hz, 1 H), 8.12 (d, J ) 7.4 Hz,
2 H); 13C NMR (CDCl3) δ 10.10, 13.89, 14.31, 22.29, 22.63,
25.25, 25.60, 31.36, 36.52, 36.71, 41.67, 45.95, 54.09, 57.84,
69.36, 71.63, 73.78, 73.93, 74.75, 76.15, 77.21, 79.69, 80.40,
84.07, 88.36, 126.62, 127.79, 128.13, 128.95, 129.01, 130.29,
134.17, 135.49, 136.41, 137.70, 151.91, 165.01, 171.16, 172.20,
173.58, 209.76. Anal. (C45H53NO15) C, H, N.
1
gave 23a (36 mg, 90%) as a white solid: mp 164-168 °C; H
NMR (CDCl3) δ 0.98 (t, J ) 7.2 Hz, 3 H), 1.25 (s, 3 H), 1.28-
1.46 (m, 11 H), 1.62-1.91 (m, 9 H), 2.48-2.60 (m, 4 H), 3.80
(d, J ) 7.5 Hz, 1 H), 4.04-4.16 (m, 1 H), 4.21-4.32 (m, 3 H),
4.38 (bs, 1 H), 4.82 (m, 2 H), 4.93 (d, J ) 8.3 Hz, 1 H), 5.19 (s,
1 H), 6.10 (d, J ) 7.5 Hz, 1 H), 6.45 (d, J ) 6.2 Hz, 1 H), 7.48
(t, J ) 7.4 Hz, 2 H), 7.61 (d, J ) 7.4 Hz, 1 H), 8.03 (d, J ) 7.4
Hz, 2 H); 13C NMR (CDCl3) δ 9.97, 13.99, 14.47, 19.47, 22.05,
22.05, 25.63, 28.24, 33.91, 36.73, 41.70, 45.93, 53.01, 57.87,
69.35, 71.67, 73.09, 74.10, 74.63, 76.09, 79.65, 80.46, 84.01,

New Taxoids Derived from 14â-OH-DAB
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3 277
88.14, 127.95, 129.01, 129.99, 134.15, 136.04, 136.49, 152.40,
156.95, 165.10, 171.15, 173.88, 209.83.
In the same manner, 22b,d ,e and 23b were prepared using
the method described above.
2.35 (bs, 1 H), 2.49 (s, 3 H), 2.50-2.62 (m, 2 H), 3.71 (d, J )
7.4 Hz, 1 H), 3.83 (bs, 1 H), 4.00-4.10 (m, 1 H), 4.22 (d, J )
8.4 Hz, 1 H), 4.29 (d, J ) 8.4 Hz, 1 H), 4.35-4.44 (m, 2 H),
4.76 (d, J ) 8.9 Hz, 1 H), 4.86 (d, J ) 6.6 Hz, 1 H), 4.93 (d, J
) 7.7 Hz, 1 H), 6.11 (d, J ) 7.4 Hz, 1 H), 6.27 (s, 1 H), 6.44 (d,
J ) 6.6 Hz, 1 H), 7.49 (t, J ) 7.5 Hz, 2 H), 7.61 (t, J ) 7.3 Hz,
1 H), 8.03 (d, J ) 7.3 Hz, 2 H); 13C NMR (CDCl3) δ 9.68 13.95,
14.20, 14.98, 19.44, 20.75, 22.51, 23.11, 25.96, 28.23, 29.69,
33.94, 35.45, 41.79, 45.07, 53.05, 58.74, 60.38, 69.40, 71.75,
73.12, 74.64, 74.78, 75.96, 79.60, 80.34, 80.53, 84.24, 88.12,
127.95, 129.00, 129.98, 133.56, 134.10, 139.72, 151.82, 156.20,
164.76, 170.64, 170.91, 173.06, 202.15.
Cytotoxicity Assa y in Vitr o.30 Tumor cell growth inhibi-
tion was determined according to the method established by
Skehan et al.34 Human tumor cells (A121 ovarian carcinoma,
HT-29 colon carcinoma, A549 non-small-cell lung carcinoma,
MCF-7 breast carcinoma, and MCF7-R doxorubicin-resistant
breast carcinoma) were plated at a density of 400 cells/well in
96-well plates and allowed to attached 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 Biomedi-
cal Product, MA). Taxanes were solubilized in DMSO and
further diluted with RPMI-1640 medium. Triplicate wells
were exposed to various treatments. After 72 h 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.35
3′-De p h e n yl-3′-(2-m e t h ylp r op yl)-14â-h yd r oxyd oce -
ta xel 1,14-ca r bon a te (22a ): 77% yield; white solid; mp 161-
1
162 °C; [R]20 -37.8° (c 1.1, CH2Cl2); H NMR (CDCl3) δ 0.97
D
(d, J ) 6.0 Hz, 3 H), 0.99 (d, J ) 6.0 Hz, 3 H), 1.25 (s, 3 H),
1.33 (s, 3 H), 1.38 (s, 9 H), 1.66-1.98 (m, 3 H), 1.79 (s, 3 H),
1.93 (s, 3 H), 2.49 (s, 3 H), 2.57 (m, 1 H), 3.81 (d, J ) 7.4 Hz,
1 H), 4.05 (m, 1 H), 4.25 (bs, 1 H), 4.23-4.31 (m, 3 H), 4.77
(bd, J ) 8.9 Hz, 1 H), 4.83 (d, J ) 6.8 Hz, 1 H), 4.94 (d, J )
8.1 Hz, 1 H), 5.18 (s, 1 H), 6.11 (d, J ) 7.4 Hz, 1 H), 6.47 (bd,
J ) 6.2 Hz, 1 H), 7.48 (m, 2 H), 7.62 (m, 1 H), 8.04 (d, J ) 7.7
Hz, 2 H); 13C NMR (CDCl3) δ 10.01, 14.47, 22.07, 22.17, 22.45,
23.23, 24.86, 25.66, 28.24, 29.85, 36.78, 40.35, 41.67, 45.88,
51.87, 57.83, 69.39, 71.68, 73.86, 74.09, 74.59, 76.08, 77.21,
79.67, 80.39, 83.95, 88.16, 127.95, 128.97, 129.95, 134.16,
136.04, 136.37, 151.94, 156.27, 164.85, 170.66, 172.86, 209.84;
IR (KBr disk) 3434, 2954, 2930, 1821, 1734, 1713, 1363, 1237,
1088 cm-1. Anal. (C42H55NO16) C, H, N.
3′-Dep h en yl-3′-(2-m eth ylp r op yl)-10-a cetyl-14â-h yd r ox-
yd oceta xel 1,14-ca r bon a te (22b): 100% yield; white solid;
mp 158-162 °C; [R]20D -57.1° (c 0.56, CHCl3); 1H NMR (CDCl3)
δ 0.99 (m, 6 H), 1.29 (s, 3 H), 1.35 (s, 3 H), 1.38 (s, 9 H), 1.72
(m, 6 H), 1.91 (bm, 4 H), 2.26 (s, 3 H), 2.48 (bs, 1 H), 2.56 (s,
3 H), 2.58 (m, 1 H), 3.71 (d, J ) 7.4 Hz, 1 H), 4.01 (m, 1 H),
4.10 (m, 1 H), 4.24 and 4.30 (AB quartet, J ) 8.7 Hz, 2 H),
4.40 (m, 2 H), 4.75 (d, J ) 8.8 Hz, 1 H), 4.87 (d, J ) 6.9 Hz, 1
H), 4.94 (d, J ) 8.3 Hz, 1 H), 6.09 (d, J ) 7.5 Hz, 1 H), 6.26 (s,
1 H), 6.44 (d, J ) 6.0 Hz, 1 H), 7.45 (t, 2 H), 7.60 (t, 1 H), 8.00
(d, 2 H); 13C NMR (CDCl3) δ 9.7, 15.0, 20.8, 22.1, 22.5, 23.2,
24.8, 26.0, 28.2, 35.5, 40.4, 41.8, 45.1, 51.7, 58.7, 69.4, 71.7,
73.8, 74.5, 74.8, 75.9, 79.6, 80.4, 84.2, 88.2, 127.9, 129.0, 130.0,
133.5, 134.1, 139.8, 151.8, 156.2, 164.7, 170.6, 170.9, 171.3,
172.9, 202.2; IR (CDCl3) 3422, 2983, 1824, 1732, 1508, 1465,
1243 cm-1. Anal. (C44H58NO16) C, H, N.
3′-Dep h en yl-3′-(2-m eth ylp r op yl)-10-(cyclop r op ylca r bo-
n yl)-14â-h ydr oxydocetaxel 1,14-car bon ate (22d): 91% yield;
white solid; mp 129-133 °C; [R]20 -40.9° (c 0.22, CHCl3); 1H
D
Ack n ow led gm en t. This research was supported by
grants from the National Institutes of Health (GM427980
to I.O.), the Center for Biotechnology at Stony Brook
which is sponsored by the New York State Science &
Technology Foundation (to I.O.), and the National
Cancer Institute (13038 to R.J .B.). General support
from Indena, SpA (to I.O. and R.J .B), is also gratefully
acknowledged. Two of the authors (J .C.S. and S.D.K.)
thank the U.S. Department of Education for GAANN
fellowships.
NMR (CDCl3) δ 0.88 (dd, J ) 6.6, 1.2 Hz, 2 H), 0.95-1.01 (m,
6 H), 1.07-1.12 (m, 2 H), 1.28 (s, 3 H), 1.33-1.43 (m, 14 H),
1.63 (s, 3 H), 1.68-1.83 (m, 5 H), 1.89 (s, 3 H), 2.44-2.60 (m,
4 H), 3.69 (d, J ) 7.4 Hz, 1 H), 3.98 (d, J ) 6.1 Hz, 1 H), 4.22
(d, J ) 8.4 Hz, 1 H), 4.26-4.43 (m, 4 H), 4.72 (d, J ) 8.9 Hz,
1 H), 4.85 (d, J ) 7.0 Hz, 1 H), 4.93 (d, J ) 8.0 Hz, 1 H), 6.09
(d, J ) 7.4 Hz, 1 H), 6.25 (s, 1 H), 6.46 (d, J ) 6.1 Hz, 1 H),
7.47 (t, J ) 7.5 Hz, 2 H), 7.61 (t, J ) 7.5 Hz, 1 H), 8.03 (d, J
) 7.5 Hz, 2 H); 13C NMR (CDCl3) δ 9.44, 9.70, 12.95, 14.21,
15.08, 22.15, 22.51, 23.26, 24.94, 26.02, 27.96, 28.23, 32.48,
33.97, 35.37, 40.40, 41.76, 45.01, 51.63, 58.68, 69.44, 71.79,
73.85, 74.60, 75.93, 79.64, 80.43, 84.27, 88.22, 127.90, 129.01,
133.55, 134.16, 139.86, 151.91, 156.25, 164.76, 170.63, 172.99,
174.94, 202.38.
Refer en ces
3′-Dep h en yl-3′-(2-m eth ylp r op yl)-10-(N,N-d im eth ylca r -
ba m oyl)-14â-h yd r oxyd oceta xel 1,14-ca r bon a te (22e): 75%
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. Plant Antitumor Agents. VI. The Isolation and Structure of
Taxol, a Novel Antileukemic and Antitumor Agent from Taxus
brevifolia. J . Am. Chem. Soc. 1971, 93, 2325-2327.
(2) Gue´ritte-Voegelein, F.; Mangatal, L.; Gue´nard, D.; Potier, P.;
Guilhem, J .; Cesario, M.; Pascard, C. Structure of a Synthetic
Taxol Precursor: N-tert-Butoxycarbonyl-10-deacetyl-N-deben-
zoyltaxol. Acta Crystallogr. 1990, C46, 781-784.
(3) Taxane Anticancer Agents: Basic Science and Current Status;
Georg, G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; American
Chemical Society: Washington, DC, 1995.
(4) Suffness, M. Taxol: From Discovery to Therapeutic Use. In
Annual Reports in Medicinal Chemistry; Bristol, J . A., Ed.;
Academic Press: San Diego, 1993; Vol. 28, Chapter 32, pp 305-
314.
yield (94% conversion yield); white solid; mp 166-170 °C; [R]20
D
-40.5° (c 0.37, CHCl3); 1H NMR (CDCl3) δ 0.97 (t, J ) 5.4 Hz,
6 H), 1.27 (s, 3 H), 1.33 (s, 3 H), 1.39 (bs, 10 H), 1.62-1.72 (m,
5 H), 1.91 (bs, 4 H), 2.47 (s, 3 H), 2.49-2.61 (m, 1 H), 2.96 (s,
3 H), 3.03 (s, 3 H), 3.10 (bs, 1 H), 3.69 (d, J ) 7.4 Hz, 1 H),
4.22 (d, J ) 8.4 Hz, 1 H), 4.26-4.35 (m, 2 H), 4.36-4.46 (m, 1
H), 4.73 (d, J ) 9.0 Hz, 1 H), 4.86 (d, J ) 6.9 Hz, 1 H), 4.94 (d,
J ) 7.7 Hz, 1 H), 6.09 (d, J ) 7.5 Hz, 1 H), 6.20 (s, 1 H), 6.46
(d, J ) 6.3 Hz, 1 H), 7.47 (t, J ) 7.4 Hz, 2 H), 7.60 (t, J ) 7.4
Hz, 1 H), 8.02 (d, J ) 7.4 Hz, 2 H); 13C NMR (CDCl3) δ 9.48,
14.20, 15.13, 22.16, 22.51, 23.26, 23.58, 24.85, 26.21, 28.24,
35.21, 36.07, 36.75, 40.43, 41.79, 44.95, 51.62, 58.66, 69.54,
72.07, 73.86, 74.70, 75.41, 75.92, 79.71, 80.49, 84.47, 88.32,
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