Semisynthesis of flexible 5,7-dideoxypaclitaxel derivatives from Taxine B

Article abstract of DOI:10.1002/1099-0690(200105)2001:9<1761::AID-EJOC1761>3.0.CO;2-O

Two new 5,7-dideoxypaclitaxel derivatives with flexible C-rings have been prepared starting from Taxine B, an alkaloid isolated from the leaves of Taxus baccata. Both derivatives lack the oxetane ring present in the antitumor agent paclitaxel, but possess an oxygenated 4β-substituent as a substitute for the oxetane ring oxygen atom. These derivatives provide additional information about the importance of this oxygen atom for cytotoxic activity.

Full text of DOI:10.1002/1099-0690(200105)2001:9<1761::AID-EJOC1761>3.0.CO;2-O

FULL PAPER
Semisynthesis of Flexible 5,7-Dideoxypaclitaxel Derivatives from Taxine B
Patrick H. Beusker,[a] Harald Veldhuis,[a] Bianca A.C. van den Bossche,[a] and
Hans W. Scheeren*[a]
Keywords: Antitumor agents / Natural products / Structure-activity relationships / Synthesis design / Taxine B
Two new 5,7-dideoxypaclitaxel derivatives with flexible C-
rings have been prepared starting from Taxine B, an alkaloid
isolated from the leaves of Taxus baccata. Both derivatives
lack the oxetane ring present in the antitumor agent paclit-
axel, but possess an oxygenated 4β-substituent as a substi-
tute for the oxetane ring oxygen atom. These derivatives
provide additional information about the importance of this
oxygen atom for cytotoxic activity.
Introduction
axel (1b). Derivative 4a showed no inhibitory activity of
microtubule disassembly, whereas 4b showed a 16-fold drop
with respect to docetaxel. Both derivatives were inactive
against a KB cell line. 5(20)-Deoxydocetaxel (5) has recently
been prepared by Dubois and co-workers.[6] Its microtubule
disassembly inhibitory activity was half of that of docetaxel.
No cytotoxicity data were presented.
Paclitaxel (1a), first isolated from the bark of Taxus brevi-
folia in the late 1960s, is considered one of the most promis-
ing chemotherapeutic agents at the moment. It acts by sta-
bilizing microtubules, thereby blocking mitosis, and trig-
gering apoptosis, and has been approved by the American
Food and Drug Administration (FDA) for the treatment of
advanced ovarian cancer, metastatic breast cancer, non-
small cell lung cancer, and Kaposi’s sarcoma.[1]
Thanks to its high cytotoxic activity and unique mechan-
ism of action, and also because of its drawbacks (poor
water solubility and induction of multi-drug resistance), pa-
clitaxel has become the subject of extensive structure-activ-
ity relationship (SAR) studies, in order to obtain better in-
sight into its mechanism of action at the molecular level
and to prepare new, more active analogues with better
pharmacological properties.
The level of importance of the oxetane D-ring for cyto-
toxic activity has not yet been established by SAR studies.
It has been proposed that the ring might serve two func-
tions: (i) the oxygen atom in the oxetane ring may have an
important stabilizing dipolar or hydrogen-bonding interac-
tion with an amino acid residue inside the binding pocket
on polymerized tubulin heterodimers, and (ii) the inflexible
oxetane ring may promote the biologically important con-
formation of paclitaxel because of its rigidifying effect on
the whole taxane skeleton.
Several derivatives with modified D-rings have been syn-
thesized (Figure 1), and all were shown to be less active
than paclitaxel against cancer cell lines. Kingston and col-
leagues[2,3] synthesized -secopaclitaxel 2, which showed
considerably less activity against a KB cell culture assay.
They also prepared thietane analogue 3a, which displayed
a more than 500-fold reduction in activity with respect to
its oxetane ring containing counterpart 3b.[4] Dubois and
co-workers[5] prepared two azetidine derivatives of docet-
Figure 1. Paclitaxel (1a), docetaxel (1b), and D-ring modified deriv-
atives
The low cytotoxic activity of derivatives 3a, 4a, and 4b
does not disallow one of the two alleged functions of the
oxetane ring, as all derivatives are both flexible and without
an oxygen atom. The high microtubule disassembly inhibit-
ory activity of 5, however, seems to imply that rigidity alone
is sufficient for induction of inhibitory activity.
Recent calculations using a minireceptor approach and a
refined model of the paclitaxelϪβ-tubulin binding pocket
have shown that flexible derivatives with oxygenated sub-
stituents at C-4 and C-5 can also be well accommodated
inside the β-tubulin binding pocket.[7] The relatively polar
hydroxy groups at C-4 and C-5 on -secopaclitaxel 2 are
the probable cause of its low tubulin polymerization activ-
ity, due to unfavorable desolvation energies. Conversion of
these alcohol groups to less polar groups, or complete re-
moval of some alcohol groups, reduces the desolvation en-
ergy and should afford flexible derivatives that stabilize mic-
rotubules.[7]
[a]
Department of Organic Chemistry, NSR Center for Molecular
Structure, Design and Synthesis, University of Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, Netherlands
Fax: (internat.) ϩ 31-24/365-2929
Here, we wish to report the synthesis of two flexible C-
ring derivatives that lack a C-5 oxygen substituent, but pos-
E-mail: jsch@sci.kun.nl
Eur. J. Org. Chem. 2001, 1761Ϫ1768
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0509Ϫ1761 $ 17.50ϩ.50/0
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P. H. Beusker, H. Veldhuis, B. A. C. van den Bossche, H. W. Scheeren
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sess an oxygenated 4β-substituent that might substitute for acetylation of the secondary hydroxy group. Allylic substi-
the oxetane ring oxygen atom. Both derivatives also differ tution using bis(dibenzylideneacetone)palladium(0) as the
from paclitaxel at C-7, C-9, and C-10. Modifications at pre-catalyst afforded the desired deoxygenated taxane 9 in
these three positions, however, have been shown to have almost quantitative yield. When the same reaction was car-
only minor effects on biological activity. The derivatives ried out with 7a, taxane 9 was obtained in excellent yield,
have been prepared from taxine (6), an alkaloid mixture the reaction time being almost equal to that for acetate 8.
isolated from the leaves of the European Yew, Taxus bac- This seems understandable, as the palladium catalyst has to
cata.
approach the allylic system from the side opposite to the
allylic ester group in order to be able to expel it.[17] The
bulkiness of the ester group is therefore of minor import-
ance for the reaction rate. Changing the phosphorus ligand
from tri(n-butyl)phosphane to triphenylphosphane induced
a 3-fold reduction in the reaction rate.
We next set out to convert 9 into a 5,7-dideoxypaclitaxel
derivative doubly substituted at C-4, by dihydroxylation of
the exocyclic double bond and acetylation of the two hy-
droxy groups. Dihydroxylation of 9, using a catalytic
amount of osmium tetroxide, proceeded with complete fa-
cial selectivity to afford 10 in moderate yield. The stereo-
chemical outcome of this reaction is the same as for the
5α-hydroxy analogue of 9,[14] which indicates that it is not
determined by the presence and orientation of the 5-hy-
droxy group but solely by the conformation of the molecule,
which causes steric shielding of the β-face of the double
bond by the 8-methyl group.
In order to circumvent concomitant reduction of the
primary acetate group at C-20 when reducing the 13-car-
bonyl group, this reduction was carried out prior to
acetylation. Reduction with DIBALH afforded the desired
α-isomer 11 in good yield (Scheme 2). Acetylation of the
primary hydroxy group at C-20, affording 12, and triethylsi-
lyl protection of the secondary hydroxy group at C-13 gave
taxane 13.
Results and Discussion
Taxine B (6a) and 5 related taxanes 6bϪ6f form the ma-
jor proportion (ca. 40%) of an alkaloid mixture from T.
baccata, easily obtained in 0.5Ϫ1% yield by acid extraction
of dried leaves.[8] Although the structures of taxines 6aϪ6f
are quite distinct from paclitaxel, several groups have used
these alkaloids to prepare 7-deoxypaclitaxel derivatives in a
reasonable number of steps.[9Ϫ14]
The crude alkaloid mixture was purified and converted
into a mixture of compounds 7a and 7b by iodomethyl-
ation, saponification of the acetate groups with concomit-
ant elimination of the trimethylammonium group, protec-
tion of the 9- and 10-hydroxy groups with an isopropylidene
bridge, and protection of the 1- and 2-hydroxy groups with
a benzylidene bridge as previously described (Scheme 1).[14]
Scheme 2. Preparation of taxane 13; reagents and conditions: (a)
OsO4, NMMO, THF/H2O; (b) DIBALH, CH2Cl2, Ϫ20°C; (c)
Ac2O, pyridine, 4°C; (d) TESCl, imidazole, DMF
Scheme 1. Preparation of taxane 9; reagents and conditions: (a)
MeI, Et2O; (b) K2CO3, EtOH/H2O; (c) 2,2-dimethoxypropane,
PTS, CH2Cl2; (d) benzaldehyde dimethyl acetal, PTS, CH2Cl2; (e)
20  NaOH in H2O, THF, ∆; (f) Ac2O, pyridine; (g) Pd(dba)2,
PBu3, HCOOH, NEt3, THF, ∆
Acetylation of the tertiary hydroxy group on 13 proved
troublesome. None of the usual acetylation methods, such
as acetic anhydride/pyridine, acetyl chloride/LDA, acetyl
chloride/LHMDS, afforded the desired product. Treatment
of 13 with methyl chloroformate and lithium hexamethyl-
In order to remove the C-5 ester group, we focused on disilazide, however, afforded carbonate 14, albeit in low
allylic substitution. Mukaiyama and co-workers have been yield.
able to substitute the allylic C-5 acetate group in a related
A similarly low 4-hydroxy group reactivity was encoun-
taxane by hydride, using a palladium-catalyzed substitution tered by Kingston and colleagues in the synthesis of derivat-
reaction with triethylammonium formate as the hydride ive 3a.[4] Possibly, the relatively large thietane ring and the
donor.[15,16] Acetate 8 was therefore prepared by hydrolysis acetoxymethyl group shield the tertiary hydroxy group
of 7a under strongly basic conditions, followed by more effectively than the oxetane ring does. Alternatively, a
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Eur. J. Org. Chem. 2001, 1761Ϫ1768

Semisynthesis of Flexible 5,7-Dideoxypaclitaxel Derivatives from Taxine B
FULL PAPER
different conformation, situating the tertiary hydroxy group ative yield (Scheme 5). Protection of the secondary hydroxy
in a more crowded environment, might be involved. group, affording 23, was followed by reduction of the ke-
The benzylidene bridge of carbonate 14 was oxidatively tone function with sodium borohydride. The reduction
opened with palladium(II) acetate and tert-butyl hydroper- proved completely facial-selective, the hydride approaching
oxide[14] to afford taxane 15 (Scheme 3). Deprotection of the carbonyl group from the α-face to give 24. This reaction
the 13-hydroxy group gave 16, which was then coupled to again demonstrates complete steric blocking of the β-face
β-lactam 21 using standard coupling procedures. Taxane 15 of an exocyclic π-system at C-4 by the 8-methyl group.
was observed as a side product in this reaction, as a con-
sequence of a silyl shift from 21 to 16. Derivative 17 was
obtained upon fluoride-assisted desilylation.
Scheme 3. Preparation of derivative 17; reagents and conditions: (a)
MeOC(O)Cl, LHMDS, CH2Cl2, Ϫ78°C; (b) Pd(OAc)2, tBuOOH,
toluene, 60°C; (c) TBAF, THF; (d) 21, NaHMDS, CH2Cl2, Ϫ78°C;
(e) TBAF, THF
β-Lactam 21 was prepared in 8 steps starting from methyl
(E)-cinnamate, in 27% overall yield. Asymmetric dihy-
Scheme 5. Preparation of derivative 30; reagents and conditions:
droxylation, tosylation, epoxide formation and nucleophilic
epoxide opening afforded 18 as described previously.[18,19]
Following a new route, 18 was converted into β-lactam 21
in 4 steps. Silyl protection of the secondary hydroxy group
gave 19 (Scheme 4). Reduction of the azido group to an
amino group was followed by ring-closure, affording β-lac-
tam 20. N-benzoylation eventually afforded β-lactam 21.
(a) NaIO4, H2O/THF; (b) TESCl, imidazole, DMF; (c) NaBH4,
MeOH, 0°C; (d) MeI, BuLi, THF; (e) tBuOOH, Pd(OAc)2, tolu-
ene, 50°C; (f) TBAF, THF; (g) 28, DCC, DMAP, CH2Cl2; (h)
PTS, MeOH
The 4β-hydroxy group proved to be sterically highly en-
cumbered, as no reaction was observed when 24 was treated
with acetic anhydride/DMAP or acetyl chloride/BuLi.
Methylation of the hydroxy group was accomplished, but
only when large excesses of butyllithium and methyl iodide
were used, the yield being low. The stereochemistry of 4β-
methoxytaxane 25 was confirmed by NOE data. These
showed contacts between 4-H/3-H and 4-H/14α-H, which
clearly proves an α-orientation of 4-H.
Scheme 4. Preparation of β-lactam 21; reagents and conditions: (a)
TESCl, NEt3, THF; (b) H2, Pd/C, EtOAc; (c) TMSCl, Et3N, Et2O,
then tBuMgCl; (d) BzCl, DMAP, NEt3, CH2Cl2
The benzylidene bridge on 25 was oxidatively opened
with tert-butyl hydroperoxide and palladium(II) acetate to
afford 26. Removal of the triethylsilyl protecting group, giv-
In our approaches towards paclitaxel derivatives, this 8- ing 27, was followed by a DCC coupling with 28, which
step preparation of β-lactam 21[20] has been preferred over proceeded in good yield to afford 29.[22] Deprotection of
the Staudinger approach towards β-lactams like 21,[21] as the side chain led to concomitant deprotection of the 9- and
the former method offers intermediates which can easily be 10-hydroxy groups to give D-ring modified derivative 30.
converted into other differently protected side chains such
The biological activities of taxanes 17 and 30 were deter-
as 28 (vide infra). In some cases, these are the reagents of mined in vitro in a range of well defined cancer cell lines.
choice in the coupling step to baccatin III derivatives, as Both derivatives proved virtually inactive against all cell
they provide higher reaction yields.
lines, the IC50 values being 1,000Ϫ10,000 times higher than
The synthesis of a derivative with only an oxygenated 4β- those of paclitaxel. A logical line of reasoning would be to
substituent was envisaged as starting with an oxidative attribute this lack of activity to the flexible C-ring. Altern-
cleavage of the vicinal diol unit on 11. Oxidation with so- atively, the combination of the 4β-acetoxymethyl group and
dium periodate provided 4-oxotaxane 22 in almost quantit- the 4α-methoxycarbonyloxy group may be too bulky to en-
Eur. J. Org. Chem. 2001, 1761Ϫ1768
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P. H. Beusker, H. Veldhuis, B. A. C. van den Bossche, H. W. Scheeren
FULL PAPER
ated aqueous NaHCO3 solution, and brine, dried with anhydrous
Na2SO4, and concentrated in vacuo. The crude product was puri-
fied by column chromatography (EtOAc/heptanes, 8:1), yielding 9
(2.76 g, 5.76 mmol, 90%) as a white, amorphous solid. Ϫ 1H NMR:
δ ϭ 1.14 (s, 3 H, 19-H), 1.36 (s, 3 H, 17-H), 1.46 (s, 3 H, acetonide),
1.52 (s, 3 H, acetonide), 1.68 (s, 3 H, 16-H), 2.03 (s, 3 H, 18-H),
2.47 (d, 1 H, J3Ϫ2 ϭ 5.5 Hz, 3-H), 2.67 (d, 1 H, Jgem ϭ 19.6 Hz,
14-H), 2.74 (d, 1 H, Jgem ϭ 19.6 Hz, 14-H), 4.32 (d, 1 H, 9-H),
4.34 (d, 1 H, 2-H), 4.87 (d, 1 H, J10Ϫ9 ϭ 9.27 Hz, 10-H), 4.98 (br.
s, 1 H, 20-H), 5.47 (br. s, 1 H, 20-H), 5.79 (s, 1 H, Ph-CH),
7.35Ϫ7.46 (m, 5 H, Ph). Ϫ FAB-MS; m/z: 479 [M ϩ H]ϩ. Ϫ
C30H38O5 (478.6): calcd. C 75.28, H 8.00; found C 75.09, H 8.17.
able 17 to fit well inside the binding pocket on polymerized
tubulin heterodimers. The low cytotoxic activity of 30 may
be attributed to the absence of an apolar 4α-substituent on
30, as it has been shown that the 4α-H derivative of paclit-
axel exhibits a greatly reduced tubulin polymerization activ-
ity.[23] New, flexible C-ring derivatives possessing a small,
apolar 4α-substituent and a relatively small, oxygenated 4β-
substituent should divulge the true reason for the low activ-
ity of derivatives 17 and 30. Preparation of such compounds
is currently under investigation.
1,2-Benzylidene-4α,20-dihydroxy-9,10-isopropylidene-5-deoxyta-
xicin-I (10): NMMO (1.40 g, 10.4 mmol) and OsO4 (7.6 mL,
0.61 mmol; 2.5 wt-% in tert-butyl alcohol) were added to a solution
of 9 (2.91 g, 6.08 mmol) in THF (78 mL) and water (18 mL). The
reaction mixture was stirred for 6 d at room temperature, with 2
mL of water being added every day. The reaction was quenched by
addition of Na2S2O4 (320 mg, 1.84 mmol) and Florisil (2.5 g). After
20 min, the reaction mixture was filtered through Celite and diluted
with ethyl acetate (100 mL) and water (30 mL). The aqueous layer
was separated from the organic layer and washed with ethyl acetate
(50 mL). The combined organic fractions were washed with brine,
dried with anhydrous Na2SO4, and concentrated in vacuo. The
crude product was purified by column chromatography (EtOAc/
heptanes, 3:2), yielding 10 (2.08 g, 4.06 mmol, 67%) as a glassy
solid. Ϫ 1H NMR: δ ϭ 1.16 (s, 3 H, 19-H), 1.40 (s, 3 H, 17-H),
1.44 (s, 3 H, acetonide), 1.49 (s, 3 H, acetonide), 1.67 (s, 3 H, 16-
H), 2.00 (s, 3 H, 18-H), 2.10 (d, 1 H, J3Ϫ2 ϭ 5.1 Hz, 3-H), 2.31
(dd, 1 H, JOH-20 ϭ 2.2 Hz, JOH-20Ј ϭ 9.4 Hz, 20-OH), 2.79 (d, 1 H,
Experimental Section
General Remarks: All solvents were, if necessary, distilled and dried
prior to use, following standard procedures.
Ϫ
1H NMR
(300 MHz), 13C NMR (75 MHz) and 2D NMR experiments were
performed with a Bruker AC300 spectrometer in CDCl3, using
TMS as the internal standard unless otherwise stated. Chemical
shifts are reported in parts per million (ppm) and coupling con-
stants (J) are given in Hertz (Hz). Ϫ Mass spectra were recorded
with an MAT 9005, using FAB and EI modes. Ϫ Elemental ana-
lyses were carried out with a Carlo Erba Instruments CHNSO EA
1108 element analyzer. Ϫ Thin layer chromatography was carried
out on Merck precoated 60 F-254 silica gel plates (thickness:
0.25 mm). Ϫ Column chromatography was carried out using Baker
silica gel (63Ϫ200 mesh).
1,2-Benzylidene-9,10-isopropylidene-5α-acetyltaxicin-I (8): Aqueous
NaOH (20 , 25 mL) was added to a solution of 7a (5.00 g,
8.00 mmol) in THF (60 mL). The reaction mixture was stirred at
reflux temperature for 2 d, diluted with water (50 mL), and ex-
tracted twice with dichloromethane (150 mL). The combined or-
ganic fractions were washed with brine, dried with anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography (EtOAc/heptanes, 1:1), yielding the sa-
ponified product (3.00 g, 6.07 mmol, 76%). This was dissolved in
dry pyridine (25 mL), and acetic anhydride (8 mL) was added. The
reaction mixture was stirred for 4 d at room temperature. The mix-
ture was then diluted with ethyl acetate (75 mL), washed with a 0.5
 aqueous KHSO4 solution, a saturated aqueous Na2CO3 solution,
and brine, dried with anhydrous Na2SO4, and concentrated in va-
cuo. The crude product was purified by column chromatography
(EtOAc/heptanes, 1:3), yielding 8 (4.00 g, 7.45 mmol, 93%) as a
white, amorphous solid. Ϫ 1H NMR: δ ϭ 1.13 (s, 3 H, 19-H), 1.37
(s, 3 H, 17-H), 1.47 (s, 3 H, acetonide), 1.54 (s, 3 H, acetonide),
1.57 (s, 3 H, 16-H), 1.94 (s, 3 H, 18-H), 2.10 [s, 3 H, CH3C(O)],
2.65 (d, 1 H, Jgem ϭ 19.6 Hz, 14-H), 2.72 (d, 1 H, Jgem ϭ 19.6 Hz,
Jgem ϭ 19.3 Hz, 14-H), 3.29 (s, 1 H, 4-OH), 3.34 (d, 1 H, Jgem
ϭ
19.3 Hz, 14-OH), 3.71 (pseudo-t, 1 H, J ϭ 10.2 Hz, 20Ј-H), 3.96
(br. d, 1 H, Jgem ϭ 10.8 Hz, 20-H), 4.24 (d, 1 H, J9Ϫ10 ϭ 9.3 Hz,
9-H), 4.35 (d, 1 H, J2Ϫ3 ϭ 5.1 Hz, 2-H), 4.77 (d, 1 H, J10Ϫ9
ϭ
9.3 Hz, 10-H), 5.87 (s, 1 H, Ph-CH), 7.41 (m, 5 H, Ph). Ϫ FAB-
MS; m/z: 513 [M ϩ H]ϩ, 535 [M ϩ Na]ϩ. Ϫ C30H40O7 (512.6):
calcd. C 70.29, H 7.86; found C 69.90, H 7.82.
Reduction of Diol 10 to Triol 11: DIBALH (5.9 mL, 8.8 mmol; 25
wt-% solution in toluene) was added slowly at Ϫ20°C to a solution
of 10 (1.00 g, 1.95 mmol) in dichloromethane (30 mL). After 30
min, a 10% aqueous solution of citric acid (30 mL) was added. The
two layers were separated and the aqueous layer was extracted
twice with dichloromethane (20 mL). The combined organic frac-
tions were washed with a saturated aqueous NaHCO3 solution and
brine, dried with anhydrous Na2SO4, and concentrated in vacuo.
The crude product was purified by column chromatography
(EtOAc/heptanes, 3:2), yielding 11 (612 mg, 1.19 mmol, 61%) as a
1
white solid. Ϫ H NMR: δ ϭ 1.12 (s, 3 H, 19-H), 1.20 (s, 3 H, 17-
14-H), 3.05 (d, 1 H, J3Ϫ2 ϭ 5.3 Hz, 3-H), 4.32 (d, 1 H, J9Ϫ10
ϭ
H), 1.42 (s, 3 H, acetonide), 1.46 (s, 3 H, acetonide), 1.58 (s, 3 H,
16-H), 2.01 (s, 3 H, 18-H), 2.28 (dd, 1 H, Jgem ϭ 16.0 Hz, J14Ϫ13 ϭ
2.4 Hz, 14-H), 2.37 (br. d, 1 H, JOH-20 ϭ 7.0 Hz, 20-OH), 2.52 (d,
9.2 Hz, 9-H), 4.37 (d, 1 H, J2Ϫ3 ϭ 5.3 Hz, 2-H), 4.91 (d, 1 H,
J10Ϫ9 ϭ 9.2 Hz, 10-H), 5.27 (m, 2 H, 20-H ϩ 5-H), 5.66 (br. s, 1
H, 20-H), 5.78 (s, 1 H, Ph-CH), 7.36Ϫ7.44 (m, 5 H, Ph). Ϫ FAB-
MS; m/z: 559 [M ϩ Na]ϩ. Ϫ C32H40O7 (536.7): calcd. C 71.62, H
7.51; found C 71.34, H 7.63.
1 H, J3Ϫ2 ϭ 4.5 Hz, 3-H), 2.65 (dd, 1 H, Jgem ϭ 15.9 Hz, J14Ϫ13
ϭ
10.0 Hz, 14-H), 2.92 (br. d, JOH-13 ϭ 8.0 Hz, 13-OH), 3.56 (s, 1 H,
4-OH), 3.63 (pseudo-t, 1 H, J ϭ 9.7 Hz, 20Ј-H), 4.07 (br. d, 1 H,
20-H), 4.08 (d, 1 H, J9Ϫ10 ϭ 9.3 Hz, 9-H), 4.18 (d, 1 H, J2Ϫ3
ϭ
1,2-Benzylidene-9,10-isopropylidene-5-deoxytaxicin-I (9): Tri(n-bu-
tyl)phosphane (80 µL, 0.32 mmol) was added to a solution of
bis(dibenzylideneacetone)palladium(0) (36.8 mg, 0.0640 mmol) in
dry THF (50 mL). Triethylamine (1.78 mL, 12.8 mmol), formic
acid (491 µL, 12.8 mmol), and 7a (3.99 g, 6.38 mmol) were added
successively at 0°C. The reaction mixture was stirred at reflux tem-
perature for 3 d. It was then diluted with ethyl acetate (80 mL),
washed with a saturated aqueous NH4Cl solution, water, a satur-
4.5 Hz, 2-H), 4.47 (pseudo-t, J ϭ 9.2 Hz, 13-H), 4.74 (d, 1 H,
J10Ϫ9 ϭ 9.3 Hz, 10-H), 5.81 (s, 1 H, Ph-CH), 7.37Ϫ7.48 (m, 5 H,
Ph). Ϫ FAB-MS; m/z: 537 [M ϩ Na]ϩ. Ϫ C30H42O7·0.5 H2O
(523.7): calcd. C 68.80, H 8.27; found C 68.53, H 8.04.
Acetylation of Triol 11 To Give Acetate 12: Acetic anhydride (600
µL, 6.40 mmol) was added at 0°C to a solution of 11 (2.02 g,
3.92 mmol) in dry pyridine (80 mL). The reaction mixture was
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Eur. J. Org. Chem. 2001, 1761Ϫ1768

Semisynthesis of Flexible 5,7-Dideoxypaclitaxel Derivatives from Taxine B
FULL PAPER
stirred overnight at 4°C. The reaction was quenched with a 1 
aqueous HCl solution (100 mL) and the resulting mixture was ex-
tracted twice with ethyl acetate (100 mL). The combined organic
fractions were washed with brine, dried with anhydrous Na2SO4,
and concentrated in vacuo. Purification by column chromatography
(EtOAc/heptanes, 1:1) yielded 12 (1.54 g, 2.78 mmol, 70%) as a
Ϫ C40H60O10Si·0.25 H2O (733.5): calcd. C 65.50, H 8.31; found C
65.27, H 7.81.
Oxidative Opening of the Benzylidene Acetal on 14 To Give Benzo-
ate 15: Palladium(II) acetate (17 mg, 0.076 mmol) and tert-butyl
hydroperoxide (84 µL, 5.0Ϫ6.0  solution in decane) were added
to a solution of 14 (300 mg, 0.412 mmol) in toluene (10 mL). The
reaction mixture was stirred at 60 °C for 24 h and then filtered
through Celite, which was rinsed afterwards with ethyl acetate (25
mL). The combined organic fractions were washed with brine,
dried with anhydrous Na2SO4, and concentrated in vacuo. Column
chromatography (CH2Cl2/heptanes/EtOAc, 10:5:2) yielded 15
(132 mg, 0.177 mmol, 43%) as a white solid. Ϫ 1H NMR: δ ϭ
0.67 [q, 6 H, J ϭ 7.8 Hz, Si(CH2CH3)3], 1.00 [t, 9 H, J ϭ 7.8 Hz,
Si(CH2CH3)3], 1.22, (s, 3 H, 19-H), 1.24 (s, 3 H, 17-H), 1.42 (s, 3
H, acetonide), 1.49 (s, 3 H, acetonide), 1.77 (s, 3 H, 16-H), 1.98 (s,
3 H, 18-H), 2.21 [s, 3 H, C(O)CH3], 2.64 (d, 1 H, J3Ϫ2 ϭ 4.8 Hz,
3-H), 3.14 (dd, 1 H, Jgem ϭ 14.8 Hz, J14Ϫ13 ϭ 6.0 Hz, 14-H), 3.64
(s, 3 H, OCH3), 4.21 (d, 1 H, Jgem ϭ 13.5 Hz, 20-H), 4.33 (d, 1 H,
1
white solid. Ϫ H NMR: δ ϭ 1.19 (s, 3 H, 19-H), 1.20 (s, 3 H, 17-
H), 1.42 (s, 3 H, acetonide), 1.47 (s, 3 H, acetonide), 1.59 (s, 3 H,
16-H), 2.01 (s, 3 H, 18-H), 2.06 [s, 3 H, C(O)CH3], 2.23 (br. d, 1
H, J ϭ 16.2 Hz, 14-H), 2.53 (d, 1 H, J3Ϫ2 ϭ 4.5 Hz, 3-H), 2.61 (dd,
1 H, Jgem ϭ 16.3 Hz, J14Ϫ13 ϭ 10.2 Hz, 14-H), 4.10 (d, 1 H, J9Ϫ10 ϭ
9.4 Hz, 9-H), 4.14 (d, 1 H, J2Ϫ3 ϭ 4.4 Hz, 2-H), 4.42 (br. d, 1 H,
J ϭ 9 Hz, 13-H), 4.44 (d, 1 H, Jgem ϭ 13 Hz, 20-H), 4.74 (d, 1 H,
J10Ϫ9 ϭ 9 Hz, 10-H), 4.78 (d, 1 H, Jgem ϭ 13 Hz, 20-H), 5.84 (s, 1
H, Ph-CH), 7.37Ϫ7.52 (m, 5 H, Ph). Ϫ FAB-MS; m/z: 579 [M ϩ
Na]ϩ. Ϫ C32H42O8·0.25 H2O (561.2): calcd. C 68.49, H 7.99; found
C 68.25, H 7.54.
Protection of Acetate 12 To Give Silyl Ether 13: Chlorotriethylsilane
(2.10 mL, 12.5 mmol) was added to a solution of imidazole (2.21 g,
32.5 mmol) in DMF (10 mL). The mixture was stirred for 20 min
at room temperature, after which a solution of 12 (1.39 g,
2.49 mmol) in DMF (10 mL) was added. After 1.5 h, the reaction
mixture was diluted with ethyl acetate (100 mL) and water (100
mL). The layers were separated and the aqueous layer was washed
three times with ethyl acetate. The combined organic fractions were
washed with brine, dried with anhydrous Na2SO4, and concen-
trated in vacuo. Column chromatography (EtOAc/heptanes, 1:2)
J9Ϫ10 ϭ 9.6 Hz, 9-H), 4.55 (d, 1 H, Jgem ϭ 13.5 Hz, 20-H), 4.82 (d,
1 H, J10Ϫ9 ϭ 9.6 Hz, 10-H), 4.99 (m, 1 H, 13-H), 5.75 (d, 1 H,
J2Ϫ3 ϭ 4.7 Hz, 2-H), 7.46 (pseudo-t, 2 H, J ϭ 7.4 Hz, Ph), 7.58
(pseudo-t, 1 H, J ϭ 7 Hz, Ph), 7.98 (d, 2 H, J ϭ 7.3 Hz, Ph). Ϫ
FAB-MS; m/z: 1512 [2
M ϩ ϩ Ϫ
Na]ϩ, 767 [M Na]ϩ.
C40H60O11Si·2H2O (781.0): calcd. C 61.51, H 8.26; found C 61.87,
H 7.76.
Desilylation of Carbonate 15 To Give Alcohol 16: Tetrabutylammo-
nium fluoride (300 µL, 0.3 mmol; 1  solution in THF) was added
to a solution of 15 (185 mg, 0.248 mmol) in THF (10 mL). The
reaction mixture was stirred at room temperature for 10 min and
the reaction was quenched by addition of a saturated aqueous
NaHCO3 solution (20 mL) and ethyl acetate (20 mL). The layers
were separated and the aqueous layer was extracted twice with ethyl
acetate (15 mL). The combined organic fractions were washed with
brine, dried with anhydrous Na2SO4, and concentrated in vacuo.
Column chromatography (EtOAc/heptanes, 2:1) yielded 16
(114 mg, 0.181 mmol, 73%) as a white solid. Ϫ 1H NMR: δ ϭ 1.14,
(s, 3 H, 19-H), 1.24 (s, 3 H, 17-H), 1.43 (s, 3 H, acetonide), 1.50 (s,
3 H, acetonide), 1.65 (s, 3 H, 16-H), 2.03 (s, 3 H, 18-H), 2.25 [s, 3
H, C(O)CH3], 2.48 (dd, 1 H, Jgem ϭ 15.1 Hz, J14Ϫ13 ϭ 10.1 Hz,
14-H), 2.77 (dd, 1 H, Jgem ϭ 15 Hz, J14Ϫ13 ϭ 3.4 Hz, 14-H), 2.82
(d, 1 H, J3Ϫ2 ϭ 4.9 Hz, 3-H), 3.65 (s, 3 H, OCH3), 4.22 (d, 1 H,
1
yielded 13 (1.33 g, 1.97 mmol, 79%) as a white solid. Ϫ H NMR:
δ ϭ 0.62 [q, 6 H, J ϭ 7.9 Hz, Si(CH2CH3)3], 0.96 [t, 9 H, J ϭ
7.8 Hz, Si(CH2CH3)3], 1.22 (s, 6 H, 17-H ϩ 19-H), 1.41 (s, 3 H,
acetonide), 1.45 (s, 3 H, acetonide), 1.59 (s, 3 H, 16-H), 1.94 (s, 3
H, 18-H), 2.05 [s, 3 H, C(O)CH3], 2.29 (m, 2 H, 3-H ϩ 14-H), 2.73
(dd, 1 H, Jgem ϭ 15.2 Hz, J14Ϫ13 ϭ 4.2 Hz, 14-H), 4.11 (d, 1 H,
J9Ϫ10 ϭ 10 Hz, 9-H), 4.46 (d, 1 H, Jgem ϭ 11.9 Hz, 20-H), 4.67 (d,
1 H, Jgem ϭ 12.0 Hz, 20-H), 4.73 (m, 2 H, 10-H ϩ 13-H), 5.77 (s,
1 H, Ph-CH), 7.35Ϫ7.39 (m, 3 H, Ph), 7.46Ϫ7.51 (m, 2 H, Ph). Ϫ
FAB-MS; m/z: 693 [M ϩ Na]ϩ. Ϫ C38H58O8Si·0.25 H2O (675.5):
calcd. C 67.57, H 8.73; found C 67.41, H 8.26.
Methoxycarbonylation of Silyl Ether 13 To Give Carbonate 14: A
solution of lithium bis(trimethylsilyl)amide (3.4 mmol) [prepared
from butyllithium (2.1 mL, 3.4 mmol; 1.6  solution in n-hexane)
and hexamethyldisilazane (789 µL, 3.74 mmol) in THF (2 mL) at
0°C] was added at Ϫ78 °C to a solution of 13 (765 mg, 1.14 mmol)
in THF (10 mL). After 10 min, methyl chloroformate (885 µL,
11.4 mmol) was added, and the reaction mixture was then stirred
for 15 min at Ϫ78 °C. The reaction mixture was diluted with ethyl
acetate (50 mL) and washed successively with a saturated aqueous
NH4Cl solution and brine. The organic layer was dried with anhyd-
rous Na2SO4 and concentrated in vacuo. Column chromatography
Jgem ϭ 13.6 Hz, 20-H), 4.30 (d, 1 H, J9Ϫ10 ϭ 9.5 Hz, 9-H), 4.57 (d,
1 H, Jgem ϭ 13.6 Hz, 20-H), 4.68 (m, 1 H, 13-H), 4.81 (d, 1 H,
J10Ϫ9 ϭ 9.5 Hz, 10-H), 5.77 (d, 1 H, J2Ϫ3 ϭ 4.7 Hz, 2-H), 7.47
(pseudo-t, 2 H, J ϭ 7.6 Hz, Ph), 7.60 (pseudo-t, 1 H, J ϭ 7.4 Hz,
Ph), 7.98 (d, 2 H, J ϭ 7.2 Hz, Ph). Ϫ FAB-MS; m/z: 1284 [2 M ϩ
Na]ϩ, 653 [M ϩ Na]ϩ. Ϫ C34H46O11 (630.7): calcd. C 64.75, H
7.35; found C 64.66, H 7.34.
Coupling of Alcohol 16 with β-Lactam 21 and Desilylation To Give
(EtOAc/heptanes, 1:7) yielded 14 (325 mg, 0.446 mmol, 39%) as a Derivative 17: β-Lactam 21 (18.1 mg, 0.0495 mmol) was added to
white solid, together with recovered 13 (110 mg, 0.164 mmol, 14%).
Ϫ H NMR: δ ϭ 0.60 [q, 6 H, J ϭ 7.8 Hz, Si(CH2CH3)3], 0.94 [t,
9 H, J ϭ 7.8 Hz, Si(CH2CH3)3], 1.26, (s, 3 H, 19-H), 1.29 (s, 3 H,
17-H), 1.41 (s, 3 H, acetonide), 1.46 (s, 3 H, acetonide), 1.63 (s, 3
a solution of 16 (20.9 mg, 0.0331 mmol) in THF (2 mL). The reac-
tion mixture was cooled to Ϫ78 °C, after which sodium bis(trime-
thylsilyl)amide (79 µL, 0.079 mmol; 1  solution in THF) was ad-
ded. The reaction mixture was stirred for 3 h at Ϫ78 °C. The reac-
1
H, 16-H), 1.90 [s, 3 H, C(O)CH3], 1.94 (s, 3 H, 18-H), 2.25 (dd, 1 tion was quenched by addition of a saturated aqueous NH4Cl solu-
H, Jgem ϭ 15 Hz, J14Ϫ13 ϭ 9.7 Hz, 14-H), 2.28 (d, 1 H, J3Ϫ2
4.7 Hz, 3-H), 2.84 (dd, 1 H, Jgem ϭ 15.0 Hz, J14Ϫ13 ϭ 5.7 Hz, 14-
ϭ
tion (5 mL), and the mixture was diluted with ethyl acetate (5 mL).
The layers were separated and the aqueous fraction was extracted
H), 3.75 (s, 3 H, OCH3), 4.10 (d, 1 H, J2Ϫ3 ϭ 4.7 Hz, 2-H), 4.19 twice with ethyl acetate (5 mL). The combined organic fractions
(d, 1 H, J9Ϫ10 ϭ 9.4 Hz, 9-H), 4.64 (d, 1 H, Jgem ϭ 14.1 Hz, 20- were washed with brine, dried with anhydrous Na2SO4, and con-
H), 4.74 (d, 1 H, Jgem ϭ 14 Hz, 20-H), 4.75 (d, 1 H, J10Ϫ9 ϭ 9 Hz, centrated in vacuo. This afforded crude 2Ј-TES-protected 17
10-H), 4.88 (m, 1 H, 13-H), 5.76 (s, 1 H, Ph-CH), 7.31Ϫ7.35 (m, 3
(23 mg, 0.023 mmol, 70%), which was deprotected without prior
H, Ph), 7.41Ϫ7.45 (m, 2 H, Ph). Ϫ FAB-MS; m/z: 751 [M ϩ Na]ϩ. purification as follows. Tetrabutylammonium fluoride (28 µL,
Eur. J. Org. Chem. 2001, 1761Ϫ1768
1765

P. H. Beusker, H. Veldhuis, B. A. C. van den Bossche, H. W. Scheeren
FULL PAPER
0.028 mmol; 1  solution in THF) was added to a solution of 2Ј-
TES-protected 17 (23 mg, 0.023 mmol) in THF (1.5 mL). The reac-
tion mixture was stirred at room temperature for 10 min. The reac-
tion was quenched by addition of a saturated aqueous NaHCO3
solution (5 mL) and ethyl acetate (5 mL). The layers were separated
and the aqueous fraction was extracted twice with ethyl acetate (5
mL). The combined organic fractions were washed with brine,
dried with anhydrous Na2SO4, and concentrated in vacuo. Purifica-
tion by means of PLC (preparative layer chromatography) on alu-
mina (EtOAc/heptanes, 2:1) yielded 17 (15 mg, 0.017 mmol, 72%)
9 H, J ϭ 7.88 Hz, Si(CH2CH3)3], 4.79 (d, 1 H, J2Ϫ3 ϭ 4.7 Hz, 2-
H), 5.08 (dd, 1 H, J3Ϫ2 ϭ 4.7 Hz, J3-NH ϭ 2.68 Hz, 3-H), 6.17 (br.
s, 1 H, NH), 7.28Ϫ7.38 (m, 5 H, Ph). Ϫ EI-MS; m/z: 277 [M]ϩ. Ϫ
C15H23NO2Si (277.4): calcd. C 64.94, H 8.36, N 5.05; found C
65.17, H 8.43, N 5.08.
Benzoylation of 20 To Give β-Lactam 21: Triethylamine (1.04 mL,
7.49 mmol), 4-(dimethylamino)pyridine (9.2 mg, 0.075 mmol), and
freshly distilled benzoyl chloride (655 µL, 5.64 mmol) were added
at 0°C to a solution of 20 (1.04 g, 3.75 mmol) in dichloromethane
(40 mL). The reaction mixture was stirred for 20 h at room temper-
ature, diluted with dichloromethane (30 mL), and then washed with
a saturated aqueous NH4Cl solution and brine, dried with anhyd-
rous Na2SO4, filtered, and concentrated in vacuo. Column chroma-
tography (EtOAc/heptanes, 2:5) yielded 21 (1.24 g, 3.27 mmol,
1
as a white solid. Ϫ H NMR: δ ϭ 1.22, (s, 3 H, 19-H), 1.24 (s, 3
H, 17-H), 1.40 (s, 3 H, 16-H), 1.49 (s, 3 H, acetonide), 1.53 (s, 3
H, acetonide), 1.68 (s, 3 H, 18-H), 2.19 [s, 3 H, C(O)CH3], 2.45
(dd, 1 H, Jgem ϭ 15.3 Hz, J14Ϫ13 ϭ 10.2 Hz, 14-H), 2.60 (d, 1 H,
J3Ϫ2 ϭ 4.8 Hz, 3-H), 3.10 (dd, 1 H, Jgem ϭ 15.3 Hz, J14Ϫ13
ϭ
87%) as an oil. Ϫ 1H NMR: δ ϭ 0.48 [m, 6 H, Si(CH2CH3)3], 0.80
[t, 9 H, J ϭ 7.88 Hz, Si(CH2CH3)3], 5.15 (d, 1 H, J2Ϫ3 ϭ 6.12 Hz,
2-H), 5.41 (d, 1 H, J3Ϫ2 ϭ 6.12 Hz, 3-H), 7.29Ϫ7.38 (m, 5 H, Ph),
7.48 (t, 2 H, J ϭ 7.9 Hz, Bz), 7.60 (m, 1 H, Bz), 8.03 (m, 2 H, Bz).
Ϫ EI-MS; m/z: 496 [M ϩ TES]ϩ, 382 [M ϩ 1]ϩ; peak match: calcd.
for C22H27NO3Si: 381.17602; found 381.17584.
5.4 Hz, 14-H), 3.42 (d, 1 H, JOH-2Ј ϭ 6.5 Hz, 2Ј-OH), 3.64 (s, 3 H,
OCH3), 4.24 (d, 1 H, Jgem ϭ 13.4 Hz, 20-H), 4.32 (d, 1 H, J9Ϫ10
ϭ
9.5 Hz, 9-H), 4.48 (d, 1 H, Jgem ϭ 13.4 Hz, 20-H), 4.69 (d, 1 H,
J10Ϫ9 ϭ 9.5 Hz, 10-H), 4.71 (dd, 1 H, 2Ј-H), 5.70 (dd, 1 H, J ϭ
8.8 Hz, J ϭ 3.1 Hz, 3Ј-H), 5.78 (d, 1 H, J2Ϫ3 ϭ 4.8 Hz, 2-H), 6.05
(m, 1 H, 13-H), 7.33Ϫ7.59 (m, 11 H, Ph), 7.82 (d, 2 H, J ϭ 7.0 Hz,
Ph), 7.97 (d, 2 H, J ϭ 7.2 Hz, Ph). Ϫ FAB-MS; m/z: 1818 [2 M ϩ
Na]ϩ, 920 [M ϩ Na]ϩ. Ϫ C50H59NO14·2H2O (934.0): calcd. C
64.30, H 6.80, N 1.50; found C 64.42, H 6.56, N 1.64.
Oxidative Cleavage of Triol 11 To Give Ketone 22: A solution of 11
(809 mg, 1.57 mmol) and sodium periodate (1.34 g, 6.28 mmol) in
THF/water (40 mL, 11:9 v/v) was stirred for 72 h at room temper-
ature. The reaction mixture was then diluted with ethyl acetate (25
mL) and water (25 mL). The layers were separated and the aqueous
layer washed with ethyl acetate (25 mL). The combined organic
fractions were washed with brine, dried with anhydrous Na2SO4,
and concentrated in vacuo. Column chromatography (CH2Cl2/
EtOAc, 10:1) afforded 22 (748 mg, 1.55 mmol, 99%) as a white
solid. Ϫ 1H NMR: δ ϭ 1.11 (s, 3 H, 19-H), 1.16 (s, 3 H, 17-H),
1.45 (s, 3 H, acetonide), 1.48 (s, 3 H, acetonide), 1.57 (s, 3 H, 16-
H), 1.91 (dd, 1 H, Jgem ϭ 15.8 Hz, J14Ϫ13 ϭ 4.1 Hz, 14-H), 2.06 (s,
3 H, 18-H), 2.26Ϫ2.42 (m, 3 H, 14-H ϩ 2 ϫ 6-H/7-H/8-H), 3.34
(d, 1 H, J3Ϫ2 ϭ 5.8 Hz, 3-H), 4.10 (d, 1 H, J9Ϫ10 ϭ 9 Hz, 9-H),
4.11 (d, 1 H, J2Ϫ3 ϭ 6 Hz, 2-H), 4.71 (m, 1 H, 13-H), 4.88 (d, 1 H,
J10Ϫ9 ϭ 9.4 Hz, 10-H), 5.85 (s, 1 H, Ph-CH), 7.30Ϫ7.37 (m, 3 H,
Ph), 7.48Ϫ7.51 (m, 2 H, Ph). Ϫ FAB-MS; m/z: 505 [M ϩ Na]ϩ,
987 [2 M ϩ Na]ϩ. Ϫ C29H38O6·0.5 H2O (491.6): calcd. C 70.85, H
7.99; found C 71.14, H 7.86.
Silylation of Alcohol 18 To Give Silyl Ether 19: Triethylamine (7.75
mL, 55.3 mmol) and chlorotriethylsilane (4.65 mL, 27.7 mmol)
were added to a solution of methyl (2R,3S)-3-azido-2-hydroxy-3-
phenylpropanoate (18) (2.04 g, 9.22 mmol) in THF (60 mL). The
resulting suspension was stirred overnight. It was diluted with ethyl
acetate (150 mL) and then washed with water and brine, dried with
anhydrous Na2SO4, filtered, and concentrated in vacuo. Column
chromatography (EtOAc/heptanes, 1:8) yielded 19 (2.96 g,
8.82 mmol, 96%) as an oil. Ϫ 1H NMR: δ ϭ 0.55 [m, 6 H,
Si(CH2CH3)3], 0.90 [t, 9 H, J ϭ 7.89 Hz, Si(CH2CH3)3], 3.61 (s, 3
H, OCH3), 4.32 (d, 1 H, J2Ϫ3 ϭ 5.93 Hz, 2-H), 4.80 (d, 1 H, J3Ϫ2 ϭ
5.93 Hz, 3-H), 7.29Ϫ7.37 (m, 5 H, Ph). Ϫ FAB-MS; m/z: 306 [M
Ϫ N2 Ϫ H]ϩ, 293 [M Ϫ N3]ϩ. Ϫ C16H25N3O3 (335.5): calcd. C
57.28, H 7.51, N12.53; found C 56.87, H 7.66, N12.27.
Reduction of 19 and Ring-Closure To Give β-Lactam 20: Pd/C (10%
Pd on C, 150 mg) was added to a solution of 19 (2.90 g, 8.64 mmol)
in ethyl acetate (30 mL). The resulting suspension was hydrogen-
ated for 20 h using a Parr apparatus. The reaction mixture was
filtered through Celite, which was thoroughly rinsed with ethyl
acetate. The combined organic fractions were concentrated in va-
cuo, affording methyl (2R,3S)-3-amino-3-phenyl-2-(triethylsilyl-
oxy)propanoate (2.58 g, 8.34 mmol) as an oil. Ϫ 1H NMR: δ ϭ
Silylation of 22 To Give Silyl Ether 23: A solution of imidazole
(368 mg, 5.41 mmol) and chlorotriethylsilane (349 µL, 2.08 mmol)
in DMF (15 mL) was stirred for 15 min at room temperature, after
which 22 (200 mg, 0.414 mmol) was added. The mixture was stirred
for 5 h at room temperature, diluted with ethyl acetate (40 mL),
and extracted with water (40 mL). The water/DMF layer was
washed with ethyl acetate (40 mL). The combined organic fractions
were washed with brine, dried with anhydrous Na2SO4, and con-
centrated in vacuo. Column chromatography (EtOAc/hexanes, 1:5)
afforded 23 (227 mg, 0.380 mmol, 92%) as a white solid. Ϫ 1H
NMR: δ ϭ 0.55 [q, 6 H, J ϭ 7.9 Hz, Si(CH2CH3)3], 0.92 [t, 9 H,
J ϭ 7.9 Hz, Si(CH2CH3)3], 1.12 (s, 3 H, 19-H), 1.15 (s, 3 H, 17-H),
1.44 (s, 3 H, acetonide), 1.47 (s, 3 H, acetonide), 1.56 (s, 3 H, 16-
H), 1.88 (dd, 1 H, Jgem ϭ 15.6 Hz, J14Ϫ13 ϭ 3.9 Hz, 14-H), 2.01 (s,
3 H, 18-H), 2.22Ϫ2.38 (m, 3 H, 14-H ϩ 2 ϫ 6-H/7-H/8-H), 3.36
(d, 1 H, J3Ϫ2 ϭ 5.8 Hz, 3-H), 4.07 (m, 2 H, 2-H ϩ 9-H), 4.60 (m,
1 H, 13-H), 4.88 (d, 1 H, J10Ϫ9 ϭ 9.4 Hz, 10-H), 5.86 (s, 1 H, Ph-
CH), 7.30Ϫ7.36 (m, 3 H, Ph), 7.45Ϫ7.49 (m, 2 H, Ph). Ϫ FAB-
MS; m/z: 596 [M]ϩ, 619 [M ϩ Na]ϩ, 711 [M ϩ TES]ϩ. Ϫ
C35H52O6Si (596.9): calcd. C 70.43, H 8.78; found C 70.43, H 8.73.
0.46 [m,
6 H, Si(CH2CH3)3], 0.82 [t, 9 H, J ϭ 7.9 Hz,
Si(CH2CH3)3], 3.68 (s, 3 H, OCH3), 4.28 (d, 1 H, J2Ϫ3 ϭ 4.1 Hz,
2-H), 4.30 (d, 1 H, J3Ϫ2 ϭ 4.1 Hz, 3-H), 7.22Ϫ7.35 (m, 5 H, Ph).
Ϫ Triethylamine (1.51 mL, 10.8 mmol) and trimethylsilyl chloride
(1.27 mL, 10.0 mmol) were added at 0°C to a solution of the crude
product in diethyl ether (100 mL). The solution was stirred at room
temperature for 1 h and then cooled to 0°C. A solution of tert-
butylmagnesium chloride (12.5 mL, 25.0 mmol; 2.0  solution in
diethyl ether) was added slowly. The reaction mixture was stirred
at room temperature for 3 h, diluted with ether (100 mL), and ex-
tracted with a saturated aqueous NH4Cl solution. The aqueous
fraction was extracted with diethyl ether and the combined organic
fractions were washed with brine, dried with anhydrous Na2SO4,
filtered, and concentrated in vacuo. Column chromatography
(EtOAc/heptanes, 1:1) yielded 20 (1.43 g, 5.17 mmol, 62%) as a
white solid. Ϫ H NMR: δ ϭ 0.44 [m, 6 H, Si(CH2CH3)3], 0.76 [t, was added in small portions at 0°C to a solution of 23 (300 mg,
Reduction of 23 To Give Alcohol 24: NaBH4 (57.9 mg, 1.53 mmol)
1
1766
Eur. J. Org. Chem. 2001, 1761Ϫ1768

Semisynthesis of Flexible 5,7-Dideoxypaclitaxel Derivatives from Taxine B
FULL PAPER
0.503 mmol) in methanol (10 mL). After stirring for 20 min at 0°C,
the reaction was quenched by slow addition of a saturated aqueous
afforded 28 mg (0.078 mmol, 91%) of 27 after column chromato-
graphy (EtOAc/heptanes, 1:2). Ϫ H NMR: δ ϭ 1.16 (s, 3 H, 17-
1
NH4Cl solution (5 mL). Next, ethyl acetate (10 mL) and water (10 H), 1.36 (s, 3 H, 19-H), 1.42 (s, 3 H, acetonide), 1.49 (s, 3 H, aceton-
mL) were added and the layers were separated. The aqueous layer
was washed twice with ethyl acetate (10 mL). The combined or-
ganic fractions were washed with a saturated aqueous NaHCO3
solution and brine, dried with anhydrous Na2SO4, and concen-
trated in vacuo. Column chromatography (EtOAc/heptanes, 2:3) af-
forded 24 (265 mg, 0.442 mmol, 88%) as a white solid. Ϫ 1H NMR:
ide), 1.62 (s, 3 H, 16-H), 1.99 (s, 3 H, 18-H), 2.32 (dd, 1 H, Jgem
15.3 Hz, J14Ϫ13 ϭ 4.2 Hz, 14-H), 2.44 (dd, 1 H, J3Ϫ2 ϭ 5.4 Hz,
J3Ϫ4 ϭ 1.0 Hz, 3-H), 2.53 (dd, 1 H, Jgem ϭ 15.3 Hz, J14Ϫ13
9.7 Hz, 14-H), 2.62 (s, 3 H, OCH3), 3.68 (br. s, 1 H, 4-H), 4.27 (d,
1 H, J9Ϫ10 ϭ 9.5 Hz, 9-H), 4.74 (d, 1 H, J10Ϫ9 ϭ 9.5 Hz, 10-H), 4.84
(m, 1 H, 13-H), 5.59 (d, 1 H, J2Ϫ3 ϭ 5.4 Hz, 2-H), 7.46 (pseudo-t,
ϭ
ϭ
δ ϭ 0.59 [q, 6 H, J ϭ 7.9 Hz, Si(CH2CH3)3], 0.95 [t, 9 H, J ϭ 2 H, J ϭ 7.7 Hz, Ph), 7.52 (t, 1 H, J ϭ 7.3, Ph), 8.10 (d, 2 H, J ϭ
7.9 Hz, Si(CH2CH3)3], 1.17 (s, 3 H, 17-H), 1.41 (s, 3 H, 19-H), 1.42
7.3 Hz, Ph). Ϫ FAB-MS; m/z: 537 [M ϩ Na]ϩ, 1051 [2M ϩ Na]ϩ.
(s, 3 H, acetonide), 1.45 (s, 3 H, acetonide), 1.57 (s, 3 H, 16-H), Ϫ C30H42O7·2H2O (550.7): calcd. C 65.43, H 8.42; found C 65.32,
1.90 (s, 3 H, 18-H), 2.02 (dd, 1 H, Jgem ϭ 15.2 Hz, J14Ϫ13 ϭ 4.2 Hz,
14-H), 2.09 (m, 1 H, 3-H), 2.38 (dd, 1 H, Jgem ϭ 15.2 Hz, J14Ϫ13 ϭ
9.3 Hz, 14-H), 2.69 (br. s, 1 H, 4-OH), 4.07 (d, 1 H, J9Ϫ10 ϭ 9.5 Hz,
9-H), 4.13 (d, 1 H, J2Ϫ3 ϭ 4.4 Hz, 2-H), 4.34 (br. s, 1 H, 4-H), 4.68
(m, 1 H, 13-H), 4.69 (d, 1 H, J10Ϫ9 ϭ 9.5 Hz, 10-H), 5.82 (s, 1 H,
Ph-CH), 7.35Ϫ7.40 (m, 3 H, Ph), 7.45Ϫ7.49 (m, 2 H, Ph). Ϫ FAB-
MS; m/z: 598 [M]ϩ, 621 [M ϩ Na]ϩ. Ϫ C35H54O6Si·H2O (616.9):
calcd. C 68.14, H 9.15; found C 68.41, H 9.00.
H 8.72.
Coupling of Alcohol 27 with Oxazolidine 28 To Give the Protected
Derivative 29: 4-Pyrrolidinopyridine (7.3 mg, 0.049 mmol), 28
(24 mg, 0.060 mmol), and dicyclohexyl carbodiimide (13 mg,
0.063 mmol) were added at 0°C to a solution of 27 (23 mg,
0.045 mmol) in toluene/CH2Cl2 (1.5 mL, 30:1 v/v). The reaction
mixture was allowed to warm to room temperature and was stirred
for 45 min. Diethyl ether (5 mL) was added and the resulting sus-
pension was filtered through Celite. The filtrate was washed with
water and brine, dried with anhydrous Na2SO4, and concentrated
in vacuo. Column chromatography (EtOAc/heptanes, 1:2) afforded
29 (29 mg, 0.032 mmol, 71%) as a white solid. Ϫ 1H NMR: δ ϭ
1.23 (s, 3 H, 19-H), 1.34 (s, 3 H, 17-H), 1.43 (s, 3 H, acetonide),
1.49 (s, 3 H, acetonide), 1.65 (s, 3 H, 16-H), 1.92 (s, 3 H, 18-H),
2.24 (dd, 1 H, Jgem ϭ 15.5 Hz, 14-H), 2.37 (dd, 1 H, J3Ϫ2 ϭ 5.4 Hz,
Methylation of Alcohol 24 To Give Methyl Ether 25: n-Butyllithium
(3.4 mL, 5.4 mmol; 1.6  solution in n-hexane) was added to a
solution of 24 (218 mg, 0.364 mmol) in THF (10 mL). The solution
was stirred for 30 min at 0°C, after which methyl iodide (454 µL,
7.3 mmol) was added carefully. The mixture was allowed to warm
to room temperature and was stirred for 20 h. The reaction was
quenched by addition of a saturated aqueous NH4Cl solution (5
mL) and the mixture was then diluted with ethyl acetate (20 mL)
and water (10 mL). The layers were separated and the combined
organic fractions were washed with a saturated aqueous NaHCO3
solution and brine, dried with anhydrous Na2SO4, and concen-
trated in vacuo. Column chromatography (EtOAc/heptanes, 1:4) af-
forded 25 (127 mg, 0.207 mmol, 57%) as a white solid. Ϫ 1H NMR:
δ ϭ 0.57 [q, 6 H, J ϭ 7.9 Hz, Si(CH2CH3)3], 0.94 [t, 9 H, J ϭ
7.9 Hz, Si(CH2CH3)3], 1.16 (s, 3 H, 17-H), 1.35 (s, 3 H, 19-H), 1.41
(s, 3 H, acetonide), 1.45 (s, 3 H, acetonide), 1.56 (s, 3 H, 16-H),
1.90 (s, 3 H, 18-H), 1.93 (dd, 1 H, J14Ϫ13 ϭ 4.5 Hz, 14-H), 2.07 (m,
1 H, 3-H), 2.28 (dd, 1 H, Jgem ϭ 15.3 Hz, J14Ϫ13 ϭ 9.7 Hz, 14-H),
3.21 (s, 3 H, OCH3), 3.67 (br. s, 1 H, 4-H), 4.08 (m, 2 H, 9-H ϩ 2-
H), 4.64 (m, 1 H, 13-H), 4.71 (d, 1 H, J10Ϫ9 ϭ 9.4 Hz, 10-H), 5.89
(s, 1 H, Ph-CH), 7.33Ϫ7.37 (m, 3 H, Ph), 7.50Ϫ7.52 (m, 2 H, Ph).
Ϫ FAB-MS; m/z: 635 [M ϩ Na]ϩ. Ϫ C36H56O6Si (612.9): calcd. C
70.55, H 9.21; found C 70.38, H 9.07.
J3Ϫ4 ϭ 3.4 Hz, 3-H), 2.57 (s, 3 H, OCH3), 2.66 (dd, 1 H, Jgem
ϭ
15.5 Hz, 14-H), 3.62 (m, 1 H, 4-H), 3.80 (s, 3 H, C6H4OCH3), 4.29
(d, 1 H, J9Ϫ10 ϭ 9.4 Hz, 9-H), 4.74 (d, 1 H, J10Ϫ9 ϭ 9.4 Hz, 10-
H), 5.02 (d, 1 H, 2Ј-H), 5.60 (d, 1 H, J2Ϫ3 ϭ 5.4 Hz, 2-H), 5.72 (br.
s, 1 H, 3Ј-H), 6.06 (br. d, 1 H, 13-H), 6.73 (br. s, 1 H, p-Me-
OC6H4CH), 6.80 (d, 2 H, J ϭ 8.3 Hz, Ph), 7.22Ϫ7.39 (m, 14 H,
Ph), 7.50 (t, 1 H, J ϭ 7.4 Hz, Ph), 8.10 (d, 2 H, J ϭ 7.1 Hz, Ph).
Ϫ FAB-MS; m/z: 900 [M]ϩ, 922 [M ϩ Na]ϩ.
Deprotection of 29 To Give Derivative 30: A solution of 29 (26 mg,
0.029 mmol) and p-toluenesulfonic acid (4.4 mg, 0.025 mmol) in
methanol (10 mL) was stirred for 5 d at room temperature. The
reaction mixture was diluted with ethyl acetate (15 mL) and the
resulting solution was washed with a saturated aqueous NaHCO3
solution and brine, dried with anhydrous Na2SO4, and concen-
trated in vacuo. Column chromatography (EtOAc/heptanes, 1:1) af-
forded 30 (18 mg, 0.023 mmol, 81%) as a white solid. Ϫ 1H NMR:
δ ϭ 1.10 (s, 3 H, 19-H), 1.16 (s, 3 H, 17-H), 1.45 (s, 3 H, 16-H),
1.86 (s, 3 H, 18-H), 2.01 (dd, 1 H, J3Ϫ4 ϭ 2.4 Hz, J3Ϫ2 ϭ 7.5 Hz,
3-H), 2.14 (dd, 1 H, Jgem ϭ 14.8 Hz, J14Ϫ13 ϭ 7.0 Hz, 14-H), 2.42
(dd, 1 H, Jgem ϭ 14.8 Hz, J14Ϫ13 ϭ 7.0 Hz, 14-H), 2.58 (s, 3 H,
Oxidative Opening of the Benzylidene Acetal on 25 To Give Benzo-
ate 26: The same procedure was followed as for 15, except that the
reaction mixture was stirred at 50°C for 3 d. In this way, 100 mg
(0.163 mmol) of taxane 25 afforded 49 mg (0.078 mmol, 48%) of
26 after column chromatography (EtOAc/heptanes, 1:5). Ϫ 1H
NMR: δ ϭ 0.70 [q, 6 H, J ϭ 7.9 Hz, Si(CH2CH3)3], 1.05 [t, 9 H,
J ϭ 7.9 Hz, Si(CH2CH3)3], 1.14 (s, 3 H, 17-H), 1.34 (s, 3 H, 19-H),
1.41 (s, 3 H, acetonide), 1.48 (s, 3 H, acetonide), 1.60 (s, 3 H, 16-
OCH3), 3.60 (br. d, 1 H, J ϭ 2.3 Hz, 4-H), 4.08 (d, 1 H, J9Ϫ10
9.6 Hz, 9-H), 4.35 (d, 1 H, J10Ϫ9 ϭ 9.6 Hz, 10-H), 4.74 (d, 1 H, J2Ј-
ϭ
ϭ 2.0 Hz, 2Ј-H), 5.70 (pseudo-t, 1 H, J ϭ 7.0 Hz, 13-H), 5.83
3Ј
(dd, 1 H, J3Ј-NH ϭ 9.3 Hz, J3Ј-2Ј ϭ 2.0 Hz, 3Ј-H), 5.92 (d, 1 H,
J
2Ϫ3 ϭ 7.5 Hz, 2-H), 7.01 (d, 1 H, JNH-3Ј ϭ 9.3 Hz, NH), 7.21Ϫ7.49
(m, 11 H, Ph), 7.78 (d, 2 H, J ϭ 7.2 Hz, Ph), 7.98 (d, 2 H, J ϭ
7.2 Hz, Ph). FAB-MS; m/z: 764 [M
Na]ϩ.
H), 1.92 (s, 3 H, 18-H), 2.32 (dd, 1 H, Jgem ϭ 15.3 Hz, J14Ϫ13
ϭ
4.0 Hz, 14-H), 2.46 (dd, 1 H, J14Ϫ13 ϭ 9.2 Hz, 14-H), 2.48 (m, 1
H, 3-H), 2.61 (s, 3 H, OCH3), 3.62 (br. s, 1 H, 4-H), 4.24 (d, 1 H,
J9Ϫ10 ϭ 9.5 Hz, 9-H), 4.75 (d, 1 H, J10Ϫ9 ϭ 9.5 Hz, 10-H), 5.56 (d,
1 H, J2Ϫ3 ϭ 5.3 Hz, 2-H), 7.44 (pseudo-t, 2 H, J ϭ 7.5 Hz, Ph),
7.55 (t, 1 H, J ϭ 7.3 Hz, Ph), 8.06 (d, 2 H, J ϭ 7.1 Hz, Ph). Ϫ
FAB-MS; m/z: 652 [M ϩ Na ϩ H]ϩ. Ϫ C36H56O7Si·H2O (646.9):
calcd. C 66.84, H 9.04; found C 66.91, H 8.87.
Ϫ
ϩ
Ϫ
C43H51NO10·1.5H2O (768.9): calcd. C 67.17, H 7.08, N 1.82; found
C 67.03, H 6.97, N 1.99.
Acknowledgments
Desilylation of 26 To Give Alcohol 27: The same procedure was
followed as for 16. In this way, 38 mg (0.060 mmol) of taxane 26
Financial support from the European Commission (FAIR
CT96Ϫ1781) is gratefully acknowledged.
Eur. J. Org. Chem. 2001, 1761Ϫ1768
1767

P. H. Beusker, H. Veldhuis, B. A. C. van den Bossche, H. W. Scheeren
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1768
Eur. J. Org. Chem. 2001, 1761Ϫ1768