Semisynthesis of D-ring modified taxoids: Novel thia derivatives of docetaxel

Article abstract of DOI:10.1021/jo015539+

Two novel 5(20)-thia analogues of docetaxel have been synthesized from 10-deacetylbaccatin III or taxine B and isotaxine B. The key step of these syntheses is the concomitant thietane ring formation and acetylation of the tertiary alcohol at C-4. Both compounds are less cytotoxic than docetaxel but have divergent activity on microtubule disassembly.

Full text of DOI:10.1021/jo015539+

5058
J . Org. Chem. 2001, 66, 5058-5065
Sem isyn th esis of D-Rin g Mod ified Ta xoid s: Novel Th ia
Der iva tives of Doceta xel
Ludovic Merckle´, J oe¨lle Dubois,* Estelle Place, Sylviane Thoret, Franc¸oise Gue´ritte,
Daniel Gue´nard, Christiane Poupat, Alain Ahond, and Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS 91198 Gif sur Yvette Cedex, France
joelle.dubois@icsn.cnrs-gif.fr
Received J anuary 23, 2001
Two novel 5(20)-thia analogues of docetaxel have been synthesized from 10-deacetylbaccatin III or
taxine B and isotaxine B. The key step of these syntheses is the concomitant thietane ring formation
and acetylation of the tertiary alcohol at C-4. Both compounds are less cytotoxic than docetaxel
but have divergent activity on microtubule disassembly.
In tr od u ction
information on the presence of such a hydrogen bond
between tubulin and the taxoid and, if it exists, on its
contribution to the binding. While we were preparing the
thietane analogues of docetaxel, the synthesis of a 5(20)-
thiapaclitaxel analogue 2 was published.8 In this case,
formation of the thietane ring led to a C-4 hydroxyl group
that was totally unreactive toward acetylation. The
authors thus introduced a C-4 methoxycarbonyl group
instead of the usual C-4 acetyl moiety. This lack of
reactivity of the C-4 hydroxyl group toward acetylation
was also observed in thia derivatives of 7-deoxybaccatin
III9 in which only the dibenzylidene derivative 3 could
be acetylated (Ac2O, DMAP, pyridine) in moderate yield.
Paclitaxel (Taxol, 1a )1 and docetaxel (Taxotere, 1b)2
are anticancer drugs3 of the taxoid series, which inhibit
cell growth by interacting with microtubules.4 Since their
discovery, structure-activity relationships have been
extensively studied in order to determine the minimal
structural requirements to maintain microtubule bind-
ing.5 These studies have established that the C-13 side
chain, the ester groups at C-2 and C-4, and the rigid core
to which all these moieties are attached are essential for
biological activity.
The role of the oxetane ring, which is still unclear, has
been one of our main interests over the past few years.
Two hypotheses can be proposed to explain the impor-
tance of the D-ring in the interaction with microtubules.
It might either act to rigidify ring C and enforce a
favorable conformation of the side chain at C-13 and acyl
groups at C-2 and C-4 or be directly involved in the
interaction with microtubules via its oxygen atom. In the
paclitaxel-â-tubulin binding site, observed in the electron
crystallographic structure of tubulin,6 the oxygen of the
oxetane ring can be involved in a hydrogen bond with
Thr276.7 Thus, replacement of this atom by sulfur, which
is unable to undergo hydrogen bonding, would give
As part of our studies on the synthesis of D-ring
modified taxoids,9-11 we wish to present here an efficient
method to synthesize the thietane ring with concomitant
C-4 acetylation. Full synthesis of 5(20)-thiadocetaxel (4)
and its 7-deoxy analogue 5 will be described along with
their biological activities.
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J . Am. Chem. Soc. 1971, 93, 2325-2327.
(2) For a review, see: Gue´nard, D.; Gue´ritte-Voegelein, F.; Potier,
P. Acc. Chem. Res. 1993, 26, 160-167.
(3) Gue´nard, D.; Gue´ritte-Voegelein, F.; Lavelle, F. Curr. Pharm.
Design 1995, 1, 95-112.
(4) Schiff, P. B.; Fant, J .; Horwitz, S. B. Nature 1979, 277, 665-
(7) Wang, M.; Cornett, B.; Liotta, D. C.; Snyder, J . P. J . Org. Chem.
2000, 65, 1059-1068.
667.
(5) For general reviews on taxoid chemistry, see: (a) Taxol: Science
and Applications; Suffness, M., Ed.; CRC Press: New York, 1995. (b)
Taxane Anticancer Agents: Basic Science and Current Status; Georg,
I. G., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS Symposium Series
No. 583; American Chemical Society: Washington DC, 1995. (c) The
Chemistry and Pharmacology of Taxol® and its Derivatives; Farina,
V. Ed.; Elsevier: New York, 1995.
(8) Gunatilaka, A. A. L.; Ramdayal, F. D., Sarragiotto, M. H.;
Kingston, D. G. I.; Sackett, D. L.; Hamel, E. J . Org. Chem. 1999, 64,
2694-2703.
(9) Payre´, C.; Al Mourabit, A.; Merckle´, L.; Ahond, A.; Poupat, C.;
Potier, P. Tetrahedron Lett. 2000, 41, 4891-4894.
(10) Marder-Karsenti, R.; Dubois, J .; Bricard, L.; Gue´nard, D.;
Gue´ritte, F. J . Org. Chem. 1997, 62, 6631-6637.
(11) Dubois, J .; Thoret, S.; Gue´ritte, F.; Gue´nard, D. Tetrahedron
Lett. 2000, 41, 3331-3334.
(6) Nogales, E.; Wolf, S.; Downing, K. H. Nature 1998, 391, 199-
203.
10.1021/jo015539+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/22/2001

Semisynthesis of D-Ring Modified Taxoids
J . Org. Chem., Vol. 66, No. 15, 2001 5059
Sch em e 1
Sch em e 2a
a
Reagents: (a) TESCl, imidazole, DMF, rt (69%); (b) Red-Al (4
To synthesize the D-ring modified docetaxel analogues,
two synthetic pathways were considered. In the first, the
oxetane ring of 10-deacetylbaccatin III (6) is opened and
a new ring closure is realized after suitable transforma-
tions. In the second, the C-4 exocyclic double bond of
taxine B (7) and isotaxine B (8) is correctly functionalized
to allow further D-ring formation. The starting materials,
10-deacetylbaccatin III (6), taxine B (7), and isotaxine B
(8), were obtained from the leaves of the European yew
tree Taxus baccata L. in significant yield (up to 1 g/kg
for 6 and commonly 3-5 g/kg for 7 and 8).12 Our approach
to thietane ring formation was identical to the general
strategy we have developed for the construction of the
D-ring in taxoids:13 introduction of a leaving group at C-5
and a sulfur functionality at C-20 allowing ring closure
by intramolecular nucleophilic substitution (Scheme 1).
equiv), THF, 0 °C (59%); (c) (CCl3O)2CO, CH2Cl2-pyridine (85-
15), -15 °C (93%); (d) Et4NBr, BF3‚OEt2, CH2Cl2, rt (63%); (e)
PBu3, DEAD, DMF, rt (72%).
Sch em e 3a
Resu lts a n d Discu ssion
The introduction of the leaving group at C-5 of 10-
deacetylbaccatin III (6) was realized as previously de-
scribed.10 After suitable protection of the various hydroxyl
groups of 13-oxo-10-deacetylbaccatin III (9)14 and oxetane
ring opening with tetraethylammonium bromide, several
attempts were made to introduce a sulfur group on C-20
of compound 10. Classical methods for direct introduction
of sulfur were ineffective, and as for the synthesis of
5(20)-deoxydocetaxel,11 substitution by means of a sul-
fonate using Na2S or a thioacetate only led to C-4,C-20
epoxide formation. Finally, compound 11 was synthesized
directly from 10 as previously described11 (Scheme 2) to
continue the synthesis according to Payre´ et al.9
The mixture of 12-13,15 obtained from taxine B (7) and
isotaxine B (8) by a previously published method,13 was
converted into the single 9-keto compound by J ones
oxidation.16 Because of the presence of the acetyl group
in position 10, solvolysis of the cinnamoyl ester could not
be carried out with 20 N NaOH as had been done in the
first synthesis of D-ring modified taxoids;9 hydroxylamine
sulfate, a reagent reported to produce deacylation of a
a
Reagents: (a) MeI, THF, rt (100%); (b) K2CO3 2%, EtOH, 95%,
rt (91%); (c) (MeO)2CHPh, PTSA, THF, rt (60%); (d) CrO3, H2SO4,
acetone, rt (66%); (e) NH2OH‚H2SO4, Et3N, THF-EtOH-H2O (1:
1:1), 80 °C (50%); (f) m-CPBA, CH2Cl2, 0 °C (94%); (g) MsCl,
pyridine, 0 °C (73%).
5-O-cinnamoyl moiety in the presence of acetate groups,17
was thus used successfully. The resulting compound 14
was then epoxidized and a leaving group was introduced
by mesylating the C-5 hydroxyl function to afford com-
pound 15 (Scheme 3).
F or m a tion of th e Th ieta n e Rin g. When an attempt
was made to open the 4(20)-epoxide of 11 with sodium
thioacetate according to the described conditions,9 the
expected C-20 thioacetate was not obtained. Instead, a
new compound 16 was formed, but in very low yield
(17%). To simplify the procedure, potassium thioacetate
was used instead of sodium thioacetate which must be
generated in situ by the action of NaH on thioacetic acid.
The new product 16 was then obtained in higher yield
(76%), again without formation of the C-20 thioacetyl
derivative. The same reaction conditions applied to 15
also led to a new compound 17 in an acceptable yield
(55%) (Scheme 4).
(12) Poupat, C.; Hook, I.; Gue´ritte, F.; Ahond, A.; Gue´nard, D.;
Adeline, M.-T.; Wang, X.-P.; Dempsey, D.; Breuillet, S.; Potier, P.
Planta Med. 2000, 66, 580-584.
(13) Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991,
47, 9823-9838.
(14) Marder, R.; Dubois, J .; Gue´nard, D.; Gue´ritte-Voegelein, F.;
Potier, P. Tetrahedron 1995, 51, 1985-1994.
(15) Poujol, H. Ph.D. Thesis, Paris XI-Orsay University, 1996.
(16) Poujol, H.; Ahond, A.; Al Mourabit, A.; Chiaroni, A.; Poupat,
C.; Riche, C.; Potier, P. Tetrahedron 1997, 53, 5169-5184.
(17) (a) Bathini, Y.; Micetich, R. G.; Daneshtalab, M. Synth. Com-
mun. 1994, 24, 1513-1517. (b) Fenoglio, I.; Nano, G. M.; Vander Velde,
D. G.; Appendino, G. Tetrahedron Lett. 1996, 37, 3203-3206.

5060 J . Org. Chem., Vol. 66, No. 15, 2001
Merckle´ et al.
Sch em e 4
Sch em e 6a
Sch em e 5
a
Reagents: (a) PhLi, THF, -72 °C (74%); (b) NaBH4, EtOH/
THF (20:80), rt (21%); (c) 21, DCC, DMAP, toluene, rt (85%); (d)
PTSA, MeOH, rt (52%).
The new derivatives of 10-deacetylbaccatin III and
taxine B-isotaxine B, 16 and 17, respectively, showed
similar NMR spectra indicating the formation of the
thietane ring together with the presence of an acetyl
group at C-4. This was further proved by mass spectro-
metric analysis. The formation of these compounds may
be explained by the following sequence of reactions:
epoxide opening by nucleophilic attack of thioacetate at
C-20, transacetylation from the C-20 to the C-4 position
and nucleophilic substitution of the C-5 bromide or
mesylate by the C-20 thiolate thus formed (Scheme 5).
This method afforded directly the expected thietane
ring together with the acetyl group at C-4 previously
shown to be difficult to obtain.8,9 This intramolecular
approach proved to be very efficient and could be applied
to the formation of other heterocycles.
In the 10-deacetylbaccatin III series, an additional
product (compound 18) was also obtained whose propor-
tion increased with the quantity of potassium thioacetate
used while 16 became the minor product of the reaction.
Spectroscopic data (NMR and mass spectrometry) were
in agreement with the structure depicted for 18. The
formation of this compound may be explained by inter-
molecular nucleophilic attack of thioacetate at C-5.
However, it must be noted that intermolecular substitu-
tion at C-5 has never been observed during the course of
our studies on the modification of the oxetane ring,
probably because of the steric hindrance caused by the
C-19 methyl and the C-20 methylene groups in an axial
position. The formation of a cyclic disulfide derivative
together with a thietane ring has already been observed
by Gunatilaka et al.8 in the taxoid series and also by
Hirota et al.18 in nucleosides. The mechanism proposed
by the latter for the formation of the disulfide goes
through a nucleophilic attack of the thietane ring by
another thiolate followed by oxidative coupling of the
resulting dithiol. This mechanism may also provide a
plausible explanation for the formation of 18.
Syn th esis of 5(20)-Th ia d oceta xel a n d Its 7-Deoxy
An a logu e. The synthesis of 5(20)-thiadocetaxel 4 was
then completed using the following steps (Scheme 6).
First, the C-1,C-2 carbonate of 16 was readily opened by
phenyllithium in acceptable yield (19, 74%) without
affecting the C-13 ketone. Reduction of the latter with
NaBH4 then afforded the C-13R isomer 20, but in poor
yield compared to that obtained with the parent com-
pounds bearing an oxetane, an azetidine, or a cyclopropyl
D-ring. Modifications of the reaction conditions (reagents:
boranes or aluminum hydrides, solvent, temperature) did
not lead to any improvement. The best conditions were
those employed for the syntheses of aza-10 and deoxydoc-
etaxel11 and which afforded the desired compound 20 in
21% along with 44% of unreacted 19. The great difference
in reactivity toward reducing agents between 13-oxo-10-
deacetylbaccatin III and 13-oxo-5(20)thia-10-deacetyl-
baccatin III is difficult to explain since no modifications
were observed in the environment of the ketone at
position 13 in the crystal structure of 19 (unpublished
data). The main difference between these two compounds
was the decreased solubility of 19 in protic solvents.
Esterification at C-13 of 20 was then realized with the
2-(4-OMe)phenyl-1,3-oxazolidine derivative of N-Boc-
phenylisoserine 21, DCC and DMAP in toluene at room
temperature leading to compound 22 in good yield (85%).
Finally, deprotection of 22 with p-toluenesulfonic acid in
methanol afforded the desired compound 4 (52% yield).
To complete the synthesis of 7-deoxy-10-acetyl-5(20)-
thiadocetaxel 5 (Scheme 7), the first step was the
transformation of the 1,2-benzylidene acetal of 17 into a
2-benzoyl group. Unfortunately, the hydroxyl functions
in positions 1 and 2 of 17 could not be deprotected with
tBuOOH and CuCl2 without concomitant oxidation of the
(18) Hirota, K.; Kitade, Y.; Tomishi, M.; De Clerk, E. J . Chem. Soc.,
Perkin Trans. 1 1988, 2233-2241.

Semisynthesis of D-Ring Modified Taxoids
J . Org. Chem., Vol. 66, No. 15, 2001 5061
Sch em e 7a
Ta ble 1. Resu lts of Biologica l Eva lu a tion of
5(20)-Th ia d oceta xel An a logu es
microtubule disassembly
inhibitory activitya
IC50/IC50(paclitaxel)
cytotoxicity against
compd
KB cell lineb IC50 (nM)
1a
1b
4
5
27
1
0.5
2
1.2
0.6
650
200
0.2
not significant
0.8
a
IC50 is the concentration that inhibits 50% of the rate of
microtubule disassembly. The ratio IC50/IC50(paclitaxel) gives the
b
activity with respect to paclitaxel. IC50 measures the drug
concentration required for the inhibition of 50% cell proliferation
after 72 h incubation.
5 were still active on KB cells but showed a much lower
cytotoxicity than their parent compounds 1b and 27,
respectively. In the taxoid series, a few derivatives have
already been reported to be inactive on tubulin but still
cytotoxic.22,23 In the case of the 7- and 10-O-acyl deriva-
tives,23 this lack of reactivity toward tubulin was hypoth-
esized to be due to increased hydrophobicity. For this
reason, the chromatographic hydrophobic index æ0 of both
compounds 4 and 5 was calculated as previously de-
scribed;23 the resulting values, æ0 ) 70.5 and 83, respec-
tively, could not account for their contrasting activities.24
Suspecting a different cellular mode of action of com-
pound 5, its effect on the cell cycle, studied by flow
cytometry, turned out to be similar to paclitaxel (arrest
in G2/M stage) but to a very much lower extent. The
reasons for these divergent activities on microtubule
disassembly between 4 and 5 are as yet unclear.
Molecular modeling of thiadocetaxel 4 showed that,
while the elongated C-S bond (vs C-O) leads to a
slightly more strained D-ring, there are no dramatic
changes in the overall conformation of the molecule
compared to docetaxel. The main differences reside on
the charge on the heteroatom of the D-ring (+0.05 on the
sulfur of compound 4 and -0.265 on the oxygen of
docetaxel) and the bulkiness of sulfur. The docking of the
structures of docetaxel and thiadocetaxel onto the pacli-
taxel binding site of tubulin was also realized, showing
that the distances between the hydroxyl group of Thr276
and oxygen or sulfur of the D-ring are 2.76 and 2.24 Å,
respectively, while the more bulky sulfur atom creates a
steric hindrance at that position. Thus, in the case of the
thia derivatives, there would be no possibility of hydrogen
bonding between the hydroxyl group of Thr276 on â-tu-
bulin and the heteroatom of the D-ring as previously
proposed.7 The tubulin-taxoid complex would then be
less stabilized, thereby explaining the activity decrease
which was observed.
a
Reagents: (a) CH3COSK, DMF, 60 °C (55%); (b) tBuOOH,
CuCl2, toluene, rt (56%); (c) CH3COSK, DMF, 60 °C (12%); (d)
NaBH4, THF-MeOH (6:1), 0 °C (60%); (e) 21, DCC, DMAP,
toluene, rt (78%); (f) PTSA, MeOH, rt (97%).
sulfur atom. The reaction was thus performed on 15
before thietane ring formation. Treatment of this new
derivative 23 with potassium thioacetate provided the
thietane 24 in poor yield (12%) but the following steps of
reduction, esterification, and final deprotection led to the
final compound 5 with satisfactory yields.
Biologica l Activities. Compounds 4 and 5 were
evaluated for their effects in vitro on the cold-induced
disassembly process of microtubules into tubulin19 and
on the growth of KB cells.20 The activity of 7-deoxy-10-
acetyl-5(20)-thiadocetaxel 5 was compared to its parent
compound 7-deoxy-10-acetyl-docetaxel 27.21
In conclusion, the syntheses of 5,20-thiadocetaxel 4 and
of its 7-deoxy analogue 5 confirm the prediction of an
activity decrease when the oxygen of the D-ring is
replaced by a sulfur atom. Though the difference in
activity between docetaxel and compound 4 on microtu-
bule disassembly is weak (only 4×), supporting the
hypothesis of the loss of a hydrogen bond, the lack of
activity of 5 on microtubule disassembly does not allow
Though less active than docetaxel, its thia analogue 4
retained good activity on microtubule disassembly whereas
the 7-deoxy thia analogue 5 showed no significant inhibi-
tion (Table 1). On the other hand, both compounds 4 and
(19) Lataste, H.; Se´nihl, V.; Wright, M.; Gue´nard, D.; Potier, P. Proc.
Natl. Acad. Sci. U.S.A. 1984, 81, 4090-4094.
(22) Cheng, Q.; Oritani, T.; Horiguchi, T.; Yamada, T.; Mong, Y.
Bioorg. Med. Chem. Lett. 2000, 10, 517-521.
(20) Da Silva, A. D.; Machado, A. S.; Tempeˆte, C.; Robert-Gero, M.
Eur. J . Med. Chem. 1994, 29, 149-152.
(23) Gue´nard, D.; Thoret, S.; Dubois, J .; Adeline, M.-T.; Wang, Q.;
Gue´ritte, F. Bioorg. Med. Chem. 2000, 8, 145-156.
(21) Poujol, H.; Al Mourabit, A.; Ahond, A.; Poupat, C.; Potier, P.
Tetrahedron 1997, 53, 12575-12594.
(24) æ0 (docetaxel) ) 64, æ0 (27) ) 76.6, and for the cytotoxic 7- or
10-O-acyl derivatives23 inactive on microtubule disassembly, æ0 > 100.

5062 J . Org. Chem., Vol. 66, No. 15, 2001
Merckle´ et al.
bon a te (348 mg, 93%) as an amorphous white solid: IR
(CHCl3) 1806, 1720, 1688 cm-1; 1H NMR (300 MHz, CDCl3) δ
0.62 (12H, m), 0.98 (18H, m), 1.27 (3H, s), 1.32 (3H, s), 1.67
(3H, s), 1.95 (1H, m), 2.06 (3H, s), 2.52 (1H, m), 2.74 (1H, d, J
) 5.2 Hz), 2.80 (1H, d, J ) 19.1 Hz), 3.66 (1H, d, J ) 19.1 Hz),
4.10 (1H, dd, J ) 10.3 Hz, J ′ ) 7.4 Hz), 4.46 (1H, d, J ) 8.1
Hz), 4.49 (1H, d, J ) 5.2 Hz), 4.62 (1H, d, J ) 8.1 Hz), 4.80
(1H, dd, J ) 9.6 Hz, J ′ ) 2.9 Hz), 5.31 (1H, s); 13C NMR (75
MHz, CDCl3) δ 5.2, 6.0, 6.8, 7.0, 10.3, 14.2, 18.7, 31.6, 38.0,
40.5, 41.9, 47.6, 60.6, 72.9, 73.3, 78.0, 80.1, 80.5, 87.5, 88.9,
137.9, 153.1, 155.0, 197.9, 204.7; MS (FAB+) m/z 657 (MLi+).
(d) Et4NBr (362 mg, 1.72 mmol, 3.5 equiv) and BF3‚OEt2
(0.91 mL, 0.74 mmol, 1.5 equiv) were added to a solution of
2-d e b e n zoyl-4-d e a ce t yl-7,10-d i(t r ie t h ylsilyl)-13-oxo-
DAB 1, 2 ca r bon a te (320 mg, 0.49 mmol) in 300 mL dry CH2-
Cl2. The solution was stirred at room temperature for 45 min
and then hydrolyzed. After standard workup, the residue was
purified on silica gel (CH2Cl2/Et2O 80:20) to yield pure 10 (226
mg, 63%) as a white amorphous solid: IR (CHCl3) 3510, 1805,
1717, 1686 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.64 (12H, m),
0.99 (18H, m), 1.23 (3H, s), 1.32 (3H, s), 1.79 (3H, s), 2.23 (1H,
m), 2.28 (3H, s), 2.38 (1H, m), 2.88 (1H, d, J ) 19.1 Hz), 3.02
(1H, sl), 3.56 (1H, s), 3.72 (1H, dl, J ) 9.4 Hz), 3.62 (1H, d, J
) 4.4 Hz), 3.97 (1H, d, J ) 19.1 Hz), 4.09 (1H, d, J ) 9.4 Hz),
4.35 (1H, d, J ) 4.4 Hz), 4.48 (1H, dd, J ) 10.3 Hz, J ′ ) 4.4
Hz), 4.68 (1H, t, J ) 2.2 Hz), 5.47 (1H, s); 13C NMR (75 MHz,
CDCl3) δ 5.2, 5.9, 6.9, 13.3, 15.0, 18.7, 31.9, 37.3, 41.0, 42.1,
44.6, 60.7, 62.6, 62.7, 70.2, 73.8, 77.6, 81.0, 89.2, 139.1, 153.0,
154.8, 197.5, 204.1; MS (FAB+) m/z 753-755 (MNa+).
2-Deben zoyl-4-d ea cetyl-4(20)-ep oxy-5r-br om o-7,10-d i-
(tr ieth ylsilyl)-13-oxo-D-seco-DAB 1,2 car bon ate (11). Tribu-
tylphosphine (140 µL, 0.57 mmol, 2 equiv) and diethyl azodi-
carboxylate (89 µL, 0.57 mmol, 2 equiv) were added to a
solution of 10 (209 mg, 0.29 mmol) in 2 mL of dry DMF. The
solution was stirred at room temperature for 44 h. After
removal of the solvent and standard workup, the residue was
purified on silica gel (heptane/AcOEt 80:20) to yield pure 11
(147 mg, 72%) as a white amorphous solid along with starting
material 10 (25 mg, 12%). Compound 11: IR (CHCl3) 3029,
1809, 1720, 1689 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.67 (12H,
m), 1.03 (18H, m), 1.26 (3H, s), 1.27 (3H, s), 1.36 (3H, s), 2.38
(3H, s), 2.45 (2H, m), 2.90 (1H, d, J ) 5.2 Hz), 2.92 (1H, d, J
) 19.9 Hz), 3.20 (1H, d, J ) 19.9 Hz), 3.60 (1H, d, J ) 5.2 Hz),
3.89 (1H, t, J ) 3.7 Hz), 3.95 (1H, d, J ) 4.4 Hz), 4.19 (1H, d,
J ) 4.4 Hz), 4.55 (1H, dd, J ) 11.0 Hz, J ′ ) 5.2 Hz), 5.50 (1H,
s); 13C NMR (75 MHz, CDCl3) δ 5.1, 6.0, 7.0, 11.8, 15.3, 18.8,
31.8, 38.7, 39.6, 41.2, 42.1, 56.4, 58.6, 60.5, 63.2, 70.2, 77.6,
79.7, 88.2, 139.2, 152.9, 154.3, 196.6, 204.2; MS (FAB+) m/z
719-721 (MLi+).
us a definite conclusion as to the reality of such an
interaction.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were purchased from
Fluka or Aldrich and were used without further purification
unless indicated otherwise. Solvents were purchased from
SDS. Toluene was distilled before use. General methods were
the same as previously described.25 Standard workup means
extraction with a suitable solvent (CH2Cl2 unless otherwise
specified), washing the extract with H2O or brine, drying over
Na2SO4 or MgSO4, and evaporation under reduced pressure.
10-Deacetylbaccatin III (DAB) (6), taxine B (7), and isotaxine
B (8) were extracted from Taxus baccata needles, and the acid
side chain of docetaxel 21 was a gift from Alain Commerc¸on
(Aventis Pharma). Microtubular proteins were purified from
bovine brain as previously described.26 Molecular modeling
studies were realized using Sybyl software from Tripos with
the MMFF94 force field.
2-Deben zoyl-4-deacetyl-5r-br om o-7,10-di(tr ieth ylsilyl)-
20-h yd r oxy-13-oxo-D-seco-DAB 1,2 ca r bon a te (10). (a) To
a solution of 13-oxo-10-d ea cetylba cca tin III (9) (1.7 g, 3.16
mmol) in 130 mL of dry DMF was added imidazole (1.72 mg,
25.2 mmol, 8 equiv). Then triethylsilyl chloride (3.18 mL, 18.9
mmol, 6 equiv) was added dropwise at room temperature. The
solution was stirred for 15 h. After removal of the solvent, 100
mL of AcOEt and 70 mL of water were added. After standard
workup, the residue was purified on silica gel (heptane/AcOEt
80:20) to yield pure 7,10-d i(tr ieth ylsilyl)-13-oxo-DAB (1.67
g, 69%) as an amorphous solid: IR (CHCl3) 1725, 1671, 1601,
1
1200 cm-1; H NMR (300 MHz, CDCl3) δ 0.66 (12H, m), 1.00
(18H, m), 1.21 (3H, s), 1.29 (3H, s), 1.58 (3H, s), 1.92 (1H, m),
2.05 (3H, s), 2.20 (3H, s), 2.56 (1H, m), 2.64 (1H, d, J ) 19.6
Hz), 2.93 (1H, d, J ) 19.6 Hz), 3.94 (1H, d, J ) 6.6 Hz), 4.13
(1H, d, J ) 8.8 Hz), 4.33 (1H, d, J ) 8.8 Hz), 4.43 (1H, dd, J
) 10.3 Hz, J ′ ) 7.4 Hz), 4.90 (1H, bd, J ) 8.1 Hz), 5.38 (1H,
s), 5.69 (1H, d, J ) 6.6 Hz), 7.48, 7.63, 8.08 (5H, m); 13C NMR
(75 MHz, CDCl3) δ 5.3, 6.2, 6.9, 7.1, 10.0, 13.5, 17.8, 21.9, 33.1,
37.5, 42.5, 43.6, 46.3, 59.6, 73.0, 73.2, 76.5, 77.0, 78.7, 80.7,
83.9, 128.8, 129.1, 130.2, 134.0, 136.1, 158.5, 167.0, 170.3,
199.0, 204.0; MS (FAB+) m/z 793 (MNa+).
(b) Red-Al (3.5 M in toluene, 2.1 mL, 7.2 mmol, 4 equiv)
was added at 0 °C to a THF solution (11.6 mL) of 7,10-d i-
(tr ieth ylsilyl)-13-oxo-DAB (1.38 g, 1.8 mmol). The solution
was stirred at 0 °C for 20 min, and the reaction was stopped
by careful addition of 4 mL of a saturated K+,Na+ tartrate
solution. After standard workup with AcOEt, the residue was
purified by silica gel chromatography (heptane/AcOEt 60:40)
to afford 2-d eben zoyl-4-d ea cetyl-7,10-d i(tr ieth ylsilyl)-13-
oxo-DAB (666 mg, 59%) as an amorphous solid: IR (CHCl3)
3592, 1721, 1687 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.62 (12H,
m), 0.99 (18H, m), 1.26 (3H,s), 1.27 (3H, s), 1.73 (3H, s), 1.95
(1H, m), 2.06 (3H, s), 2.52 (1H, m), 2.74 (1H, d, J ) 5.2 Hz),
2.80 (1H, d, J ) 19.1 Hz), 3.66 (1H, d, J ) 19.1 Hz), 4.10 (1H,
dd, J ) 7.4 Hz, J ′ ) 10.3 Hz), 4.46 (1H, d, J ) 8.1 Hz), 4.49
(1H, d, J ) 5.2 Hz), 4.62 (1H, d, J ) 8.1 Hz), 4.80 (1H, dd, J
) 2.9 Hz, J ′ ) 9.6 Hz), 5.31 (1H, s); 13C NMR (62.5 MHz,
CDCl3) δ 5.3, 6.2, 6.9, 7.0, 10.3, 13.4, 18.0, 32.6, 37.6, 43.1,
43.4, 51.2, 59.1, 73.2, 73.8, 75.1, 76.8, 78.1, 82.0, 85.3, 134.4,
135.1, 158.2, 200.5, 205.0; MS (FAB+) m/z 647 (MNa+).
(c) A solution of 2-d eben zoyl-4-d ea cetyl-7,10-d i(tr ieth -
ylsilyl)-13-oxo-DAB (360 mg, 0.58 mmol) in 8.4 mL of a
mixture CH2Cl2/pyridine (85/15) was cooled to -18 °C. Triph-
osgene (274 mg, 0.92 mmol, 1.6 equiv) was then added, and
the solution was stirred for 20 min at -18 °C. The reaction
was stopped by addition of a saturated sodium bicarbonate
solution. After standard workup, the residue was purified on
silica gel (heptane/AcOEt 75:25) to yield pure 2-d eben zoyl-
The compounds 12 and 13 were prepared from taxine B (7)
and isotaxine B (8) according to the described procedure13,15
(a -c).
1,2-O-Ben zylid en e-9-oxo-10-a cetylta xicin e I (14). (d) To
a dry acetone solution (10 mL) of compounds 12 and 13 (112
mg, 1.79 mmol) was added J ones reagent (1 equiv of CrO3).
The solution was stirred for 10 min at room temperature and
quenched with water. After standard workup, the residue was
purified by preparative TLC (heptane/AcOEt 5:5) to afford 1,2-
O-ben zylid en e-9-oxo-10-a cetyl-5-cin n a m oylta xicin e I (74
mg, 66%) as an amorphous solid: [R]20D +74.5 (c 1.01, CHCl3);
1
IR (CHCl3) 1745, 1711, 1678, 1638 cm-1; H NMR (250 MHz,
CDCl3) δ 1.31 (6H, s), 1.33 (3H, s), 1.46-2.24 (4H, m), 2.26
(3H, s), 2.31 (3H, s), 2.86 (2H, s), 3.83 (1H, d, J ) 5.0 Hz),
3.96 (1H, d, J ) 5.1 Hz), 5.30 (1H, s), 5.42 (1H, bs), 5.72 (1H,
s), 5.75 (1H, bs), 6.41 (1H, d, J ) 15.9 Hz), 6.75 (1H, s), 7.35-
7.49 (8H, m), 7.68 (1H, d, J ) 16.0 Hz), 7.72-7.76 (2H, m);
13C NMR (75 MHz, CDCl3) δ 14.7, 15.7, 18.6, 21.0, 27.8, 31.7,
32.6, 42.5, 45.0, 45.3, 57.2, 76.7, 77.2, 81.6, 83.8, 103.2, 117.7,
118.7, 126.8, 128.1, 128.5, 128.6, 128.7, 129.1, 129.6, 130.6,
134.5, 137.3, 140.4, 140.5, 146.0, 151.0, 166.1, 169.5, 199.7,
204.3; MS (CI+) m/z 625 (MH+).
4-d ea cet yl-7,10-d i(t r iet h ylsilyl)-13-oxo-DAB 1,
2 ca r -
(e) To a solution of 1,2-O-ben zylid en e-9-oxo-10-a cetyl-5-
cin n a m oylta xicin e I (662 mg, 1.06 mmol) in 30 mL of dry
THF was added NH2OH-H2SO4 (347 mg, 2.11 mmol, 2 equiv)
in 30 mL of EtOH and 30 mL of H2O. The solution was stirred,
(25) Marder-Karsenti, R.; Dubois, J .; Chiaroni, A.; Riche, C.; Gue´-
nard, D.; Gue´ritte, F.; Potier, P. Tetrahedron 1998, 54, 15833-15844.
(26) Dubois, J .; Le Goff, M. T.; Gue´ritte-Voegelein, F.; Gue´nard, D.;
Tollon, Y.; Wright, M. Bioorg. Med. Chem. 1995, 3, 1357-1368.

Semisynthesis of D-Ring Modified Taxoids
J . Org. Chem., Vol. 66, No. 15, 2001 5063
and Et3N (0.295 mL, 2.11 mmol, 2 equiv) was added. The
solution was heated for 8 h at 80 °C, and 8 equiv of NH2OH-
H2SO4, and Et3N were added. The solution was stirred for an
additional 12 h. After standard workup, the residue was
purified by flash chromatography on silica gel (heptane/AcOEt
8:2) to afford 14 (260 mg, 50%) as an amorphous solid along
with starting material 1,2-O-ben zylid en e-9-oxo-10-a cetyl-
Hz), 3.58 (1H, d, J ) 12.5 Hz), 3.62 (1H, d, J ) 5.2 Hz), 3.98
(1H, dd, J ) 5.2 Hz, J ′ ) 10.3 Hz), 4.34 (1H, dd, J ) 5.9 Hz,
J ′ ) 10.3 Hz), 4.42 (1H, d, J ) 5.2 Hz), 5.34 (1H, s); 13C NMR
(75 MHz, CDCl3) δ 5.15, 6.02, 6.83, 7.03, 12.08, 14.29, 18.48,
22.65, 31.82, 35.35, 40.62, 41.58, 42.03, 45.29, 61.14, 72.55,
77.91, 80.38, 87.17, 88.79, 138.18, 152.31, 154.74, 171.04,
196.08, 204.38; MS (FAB+) m/z 715 (MLi+); HRMS (CI+) calcd
for C35H57O9Si2S(MH+) m/z 709.3262, found 709.3234. Com-
5-cin n a m oylta xicin e I (36 mg, 6%). Compound 14: [R]20
D
-51.0 (c 0.88, CHCl3); IR (CHCl3) 3594, 1749, 1710, 1683 cm-1
;
pound 18: IR (CHCl3) 1811, 1720, 1687 cm-1; H NMR (300
1
1H NMR (300 MHz, CDCl3) δ 1.25 (3H, s), 1.28 (3H, s), 1.29
(3H, s), 1.32-1.41 (2H, m), 1.82 (2H, m), 2.25 (6H, s), 2.71 (2H,
d, J ) 19 Hz), 2.79 (1H, d, J ) 19 Hz), 3.92 (1H, d, J ) 5 Hz),
4.03 (1H, d, J ) 4.9 Hz), 4.21 (1H, bs), 5.09 (1H, bs), 5.61 (1H,
bs), 5.70 (1H, s), 6.77 (1H, s), 7.35-7.44 (5H, m); 13C NMR (75
MHz, CDCl3) δ 14.7, 15.5, 18.7, 21.0, 29.8, 31.1, 32.3, 42.5,
42.6, 45.4, 57.7, 75.1, 76.6, 82.3, 84.6, 103.1, 115.3, 126.8, 128.6,
129.6, 137.6, 141.1, 145.6, 149.8, 169.7, 200.2, 205.1; MS(CI+)
m/z 495 (MH+); HRMS (CI+) calcd for C29H35O7 (MH+) m/z
495.2382, found 495.2393.
MHz, CDCl3) δ 0.61 (12H, m), 0.96 (18H, m), 1.25 (3H, s), 1.29
(3H, s), 1.32 (3H, s), 2.08 (3H, s), 2.14 (1H,m), 2.36 (1H, m),
2.80 (1H, d, J ) 19.4 Hz), 3.14 (1H, dd, J ) 5.9 Hz, J ′ ) 12.8
Hz), 3.19 (1H, d, J ) 4.7 Hz), 3.32 (2H, qAB, J ) 13.9 Hz),
3.85 (1H, d, J ) 19.4 Hz), 4.07 (1H, dd, J ) 4.5 Hz, J ′ ) 11.3
Hz), 4.36 (1H, d, J ) 4.5 Hz), 5.39 (1H, s); 13C NMR (75 MHz,
CDCl3) δ 5.0, 5.9, 6.8, 7.0, 11.4, 14.3, 18.5, 31.6, 34.9, 40.5,
42.1, 47.9, 48.3, 62.1, 64.4, 73.3, 77.5, 80.5, 85.3, 88.7, 137.8,
152.4, 154.2, 197.8, 204.2; MS (FAB+) m/z 705 (MLi+); HRMS
(FAB+) calcd for C33H54O8LiSi2S2 (MLi+) m/z 705.2958, found
705.2960.
1,2-O-Be n zylid e n e -9-oxo-10-a ce t yl-4r(20)-e p oxy-5-
m esylta xicin e I (15). (f) To a dry CH2Cl2 solution (100 mL)
of compound 14 (5.23 g, 10.6 mmol) cooled to 0 °C was added
m-CPBA (2.74 g, 15.9 mmol, 1.5 equiv). The solution was
stirred for 30 min at 0 °C and quenched by a 10% solution of
Na2SO3. After standard workup, the residue was purified by
flash chromatography on silica gel (heptane/AcOEt 7:3) to
afford 1,2-O-b en zylid en e-9-oxo-10-a cet yl-4r(20)-ep oxy-
2-Deb en zoyl-1,2-O-b en zylid en e-7-d eoxy-5(20)-d eoxy-
5(20)-su lfa n yl-13-oxoba cca tin III (17). To a dry DMF
solution (10 mL) of 15 (33 mg, 56.1 µmol) was added potassium
thioacetate (64 mg, 561 µmol, 10 equiv). The solution was
stirred at 60 °C for 1 week, and the DMF was evaporated
under reduced pressure. After standard workup, the residue
was purified on preparative TLC (CH2Cl2/MeOH 98:2) to afford
17 (17 mg, 55%) as an amorphous solid along with starting
ta xicin e I (5.10 g, 94%) as an amorphous solid: [R]20 -23.0
D
(c 1.79, CHCl3); IR (CHCl3) 3589, 1748, 1712, and 1683 cm-1
;
material 15 (6 mg, 20%). Compound 17: [R]20 -13.0 (c 0.43,
D
1H NMR (300 MHz, CDCl3) δ 1.24 (3H, s), 1.26 (3H, s), 1.35
(3H, s), 1.37-1.45 (2H, m), 1.92 (2H, m), 2.25 (3H, s), 2.26 (3H,
s), 2.56 (1H, d, J ) 4.8 Hz), 2.70 (1H, d, J ) 19.8 Hz), 3.10
(1H, d, J ) 19.7 Hz), 3.23 (1H, t, J ) 2.8 Hz), 3.57 (1H, d, J )
5 Hz), 3.74 (1H, d, J ) 3.9 Hz), 3.9 (1H, d, J ) 4 Hz), 5.61
(1H, s), 6.75 (1H, s), 7.33-7.47 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 14.7, 16.0, 18.8, 21.0, 27.1, 30.0, 32.1, 38.3, 42.9, 45.0,
52.9, 57.5, 62.7, 74.4, 76.6, 82.0, 103.6, 127.1, 128.6, 129.6,
137.6, 141.9, 149.9, 169.7, 200.5, 204.7; MS (FAB+) m/z 533
(MNa+); HRMS (CI+) calcd for C29H35O8 (MH+) m/z 511.2331,
found 511.2304.
CHCl3); IR (CHCl3) 1747, 1729, 1717, and 1682 cm-1; 1H NMR
(250 MHz, CDCl3) δ 1.22 (3H, s), 1.26 (3H, s), 1.65 (2H, m),
1.85 (3H, s), 2.08 (3H, s), 2.09 (3H, s), 2.24 (3H, s), 2.57 (2H,
s), 3.43 (1H, d, J ) 12 Hz), 3.61 (1H, d, J ) 5 Hz), 3.75 (1H,
d, J ) 12 Hz), 3.95 (1H, d, J ) 5 Hz), 4.02 (1H, dd, J ) 3.5 Hz,
J ′ ) 6 Hz), 5.83 (1H, s), 6.53 (1H, s), 7.35-7.50 (5H, m); 13C
NMR (62.5 MHz, CDCl3) δ 14.3, 16.4, 18.5, 20.9, 22.7, 31, 32.2,
33.8, 36.4, 41.9, 42.7, 44.1, 44.5, 55.3, 76.6, 81.2, 83.5, 89.3,
102.8, 126.2, 128.5, 129.3, 138.2, 141.5, 150.9, 169.4, 170.8,
198.7, 204.8; MS (CI+) m/z 569 (MH+).
7,10-Di(tr ieth ylsilyl)-5(20)-d eoxy-5(20)-su lfa n yl-13-oxo-
DAB (19). To a dry THF solution (3 mL) of 16 (73 mg, 0.10
mmol) cooled to -72 °C was added under argon a hexane
solution of phenyllithium (2 M, 0.36 mL, 0.72 mmol, 7 equiv).
The solution was stirred for 1 h at -72 °C and then poured
into a mixture of CH2Cl2 and of saturated NH4Cl solution and
stirred for 1 min at room temperature. After standard workup,
the residue was purified on preparative TLC (heptane/AcOEt
75:25) to yield 19 (59 mg, 74%) as a white crystalline solid:
(g) To a solution of 1,2-O-ben zylid en e-9-oxo-10-a cetyl-
4r(20)-ep oxyta xicin e I (242 mg, 47.4 mmol) in dry pyridine
cooled at 0 °C was added dropwise mesyl chloride (0.550 mL,
7.15 mmol, 15 equiv). The solution was stirred for 30 min at
0 °C. After standard workup, the residue was purified by
preparative TLC (CH2Cl2/MeOH 98:2) to yield 15 (204 mg,
73%) as an amorphous solid: [R]20 -15.5 (c 0.23, CHCl3); IR
D
(CHCl3) 1749, 1715, 1679 cm-1; 1H NMR (300 MHz, CDCl3) δ
1.23 (3H, s), 1.27 (3H, s), 1.35 (3H, s), 1.51-2.19 (4H, m), 2.23
(3H, s), 2.27 (3H, s), 2.62 (1H, d, J ) 4.9 Hz), 2.74 (1H, d, J )
19.8 Hz), 2.98 (1H, d, J ) 19.8 Hz), 3.08 (3H, s), 3.57 (1H, d,
J ) 4.85 Hz), 3.71 (1H, bs), 4.23 (1H, bs), 5.59 (1H, s), 6.71
(1H, s), 7.35-7.42 (5H, m); 13C NMR (62.5 MHz, CDCl3) δ 14.6,
16.1, 18.6, 20.9, 27.9, 29.9, 32.3, 39.1, 39.5, 42.9, 44.7, 52.2,
57.0, 59.6, 76.6, 81.5, 84.1, 86.1, 103.7, 126.9, 128.6, 129.7,
137.1, 142.2, 151.2, 169.4, 199.6, 203.6; MS (CI+) m/z 589
(MH+).
1
mp 196-198d °C; IR (CHCl3) 1723, 1673 cm-1; H NMR (300
MHz, CDCl3) δ 0.63 (12H, m), 0.98 (18H, m), 1.20 (3H, s), 1.26
(3H, s), 1.80 (3H, s), 2.02 (3H, s), 2.07 (1H,m), 2.11 (3H, s),
2.42 (1H, m), 2.49 (1H, d, J ) 19.9 Hz), 2.74 (1H, d, J ) 19.9
Hz), 3.00 (1H, d, J ) 11.8 Hz), 3.23 (1H, d, J ) 11.8 Hz), 3.34
(1H, s), 3.67 (1H, d, J ) 6.6 Hz), 3.87 (1H, dd, J ) 5.9 Hz, J ′
) 10.3 Hz), 4.18 (1H, dd, J ) 5.9 Hz, J ′ ) 11.8 Hz), 5.31 (1H,
s), 5.67 (1H, d, J ) 6.6 Hz), 7.50 (2H, t, J ) 7.4 Hz), 7.62 (1H,
t, J ) 7.4 Hz), 8.08 (2H, d, J ) 7.4 Hz); 13C NMR (75 MHz,
CDCl3) δ 5.3, 6.2, 6.9, 7.1, 11.7, 13.5, 17.9, 22.8, 33.2, 36.2,
40.5, 42.5, 42.7, 43.3, 47.9, 59.9, 73.0, 73.5, 77.0, 79.6, 88.5,
128.9, 129.4, 130.2, 133.9, 136.2, 153.6, 166.9, 170.6, 198.6,
204.1; MS (L-SIMS+) m/z 793 (MLi+).
2-Deb en zoyl-7,10-d i(t r iet h ylsilyl)-5(20)-d eoxy-5(20)-
su lfa n yl-13-oxo-DAB 1,2-Ca r bon a te (16) a n d 2-Deben -
zoyl-7,10-di(tr ieth ylsilyl)-5(20)-d eoxy-5(20)-d ith ia -13-oxo-
DAB 1,2 Ca r bon a te (18). To a solution of 11 (103 mg, 0.14
mmol) in 4 mL of dry DMF was added potassium thioacetate
(33 mg, 0.29 mmol, 2 equiv). The solution was stirred at 60 °C
for 8 h. After removal of the solvent and standard workup in
ethyl acetate, the residue was purified by preparative TLC
(heptane/AcOEt 70:30) to yield pure 16 (78 mg, 76%) along
with compound 18 (9.8 mg, 10%) as white amorphous solids.
With a large excess of potassium thioacetate (321 mg, 28 mmol,
20 equiv) and 11 (102 mg, 0.14 mmol) in 5 mL of dry DMF
over 4 h at 65 °C, the major product was 18 (53.1 mg, 54%)
and the minor was 16 (22 mg, 22%). Compound 16: IR (CHCl3)
1811, 1720, 1686 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.63 (12H,
m), 0.98 (18H, m), 1.26 (3H, s), 1.30 (3H, s), 1.83 (3H, s), 2.10
(3H, s), 2.13 (3H, s), 2.16 (1H,m), 2.62 (1H, m), 2.65 (1H, d, J
) 19.9 Hz), 2.90 (1H, d, J ) 19.9 Hz), 3.42 (1H, d, J ) 12.5
7,10-Di(t r iet h ylsilyl)-5(20)-d eoxy-5(20)-su lfa n yl-DAB
(20). To a THF solution (2 mL) of 19 (53 mg, 68 µmol) was
added NaBH4 (18 mg, 475 µmol, 7 equiv) in 0.44 mL of EtOH.
The solution was stirred at room temperature for 4 h. After
standard workup with ethyl acetate, the residue was purified
on preparative TLC (heptane/AcOEt 60:40) to yield 20 (11.2
mg, 21%) as a white amorphous solid along with starting
material 19 (23.2 mg, 44%). Compound 20: IR (CHCl3) 3577,
1
1720 cm-1; H NMR (300 MHz, CDCl3) δ 0.62 (12H, m), 0.99
(18H, m), 1.20 (3H, s), 1.26 (3H, s), 1.78 (3H, s), 2.10 (3H, s),
2.23(1H, m), 2.29 (2H, m), 2.37 (3H, s), 2.46 (1H,m), 3.11 (1H,
d, J ) 11.8 Hz), 3.41 (1H, d, J ) 11.8 Hz), 3.93 (1H, d, J ) 7.4
Hz), 4.00 (1H, dd, J ) 5.9 Hz, J ′ ) 10.3 Hz), 4.29 (1H, dd, J )
5.9 Hz, J ′ ) 11.8 Hz), 4.81 (1H, dd, J ) 8.8 Hz, J ′ ) 15.4 Hz),

5064 J . Org. Chem., Vol. 66, No. 15, 2001
Merckle´ et al.
5.31 (1H, s), 5.59 (1H, d, J ) 7.4 Hz), 7.47 (2H, t, J ) 7.4 Hz),
7.58 (1H, t, J ) 7.4 Hz), 8.09 (2H, d, J ) 7.4 Hz); 13C NMR (75
MHz, CDCl3) δ 5.4, 6.2, 7.0, 7.1, 12.2, 14.7, 19.7, 23.8, 26.7,
36.5, 39.6, 40.6, 42.8, 42.9, 49.0, 59.2, 68.3, 73.2, 75.2, 76.1,
79.0, 89.9, 128.8, 129.9, 130.2, 133.6, 136.4, 138.1, 167.1, 172.7,
205.8; MS (L-SIMS+) m/z 811 (MNa+).
workup, the residue was purified by preparative TLC (CH2-
Cl2/MeOH 98:2) to afford 24 (15 mg, 12%) as an amorphous
solid: [R]20D -6.5 (c 0.43, CHCl3); IR (CHCl3) 3413, 1747, 1718,
and 1677 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.17 (3H, s), 1.21
(3H, s), 1.80 (3H, s), 2.10 (3H, s), 2.23 (3H, s), 2.27 (3H, s),
2.65 (1H, d, J ) 19.95 Hz), 2.97 (1H, d, J ) 19.9 Hz), 3.17
(1H, d, J ) 11.6 Hz), 3.40 (1H, d, J ) 11.7 Hz), 4.04 (1H, t, J
) 7.8 Hz), 4.06 (1H, d, J ) 6.85 Hz), 5.72 (1H, d, J ) 6.85 Hz),
6.51 (1H, s), 7.50 (2H, bt, J ) 7.45 Hz), 7.63 (1H, bt, J ) 7.35
Hz), 8.09 (2H, bd, J ) 7.15 Hz); 13C NMR (75 MHz, CDCl3) δ
13.8, 17.4, 19.0, 20.9, 22.8, 29.8, 32.9, 35.1, 36.3, 43.0, 43.2,
44.9, 45.0, 53.7, 74.3, 75.4, 78.9, 89.0, 128.9, 129.3, 130.2, 134.0,
140.9, 152.1, 167.0, 169.4, 170.4, 197.8, 204.3; MS (CI+) m/z
585 (MH+).
5(20)-De oxy-5(20)-su lfa n yl-7,10-d i(t r ie t h ylsilyl)-13-
[[(4S,5R)-2-(4-m eth oxyp h en yl)-3-(ter t-bu tyloxyca r bon yl)-
4-p h en yl-1,3-oxa zolid in -5yl]ca r bon yl]-DAB (22). To a tolu-
ene solution (3 mL) of 20 (30 mg, 38 µmol) were added 4-DMAP
(7.8 mg, 63 µmol, 1.7 equiv), DCC (23.6 mg, 110 µmol, 3 equiv),
and 21 (47.9 mg, 120 µmol, 3.2 equiv). The solution was stirred
for 1.5 h at room temperature. After standard workup, the
residue was purified on preparative TLC (heptane/AcOEt 70:
30) to yield 22 (38 mg, 85%) as a white amorphous solid: IR
(CHCl3) 1704, 1613, 1515, 1456, 1248 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.59 (12H, m), 0.96 (18H, m), 1.00 (9H, s) 1.17 (3H,
s), 1.19 (3H, s), 1.53 (3H, s), 1.73 (6H, s), 2.06 (3H, m), 2.49
(1H, m), 3.04 (1H, d, J ) 11.8 Hz), 3.29 (1H, d, J ) 11.8 Hz),
3.75 (1H, d, J ) 7.4 Hz), 3.81 (3H, s), 3.98 (1H, dd, J ) 5.9
Hz, J ′ ) 10.3 Hz), 4.23 (1H, dd, J ) 5.9 Hz, J ′ ) 11.8 Hz),
4.61 (1H, d, J ) 4.4 Hz), 5.09 (1H, s), 5.32 (1H, bd, J ) 4.4
Hz), 5.58 (1H, d, J ) 7.4 Hz), 6.10 (1H, m), 6.66 (1H, bs), 6.93
(2H, d, J ) 7.4 Hz), 7.43 (11H, m), 8.02 (2H, d, J ) 7.4 Hz);
13C NMR (50 MHz, CDCl3) δ 5.4, 6.2, 7.0, 7.1, 12.3, 13.7, 20.6,
22.4, 26.7, 28.0, 35.7 36.2, 40.3, 42.9, 43.0, 48.9, 55.3, 64.0,
71.8, 73.0, 75.4, 75.5, 79.5, 80.9, 83.6, 88.5, 92.7, 113.9, 126.7,
128.3, 128.7, 128.9, 129.1, 130.2, 133.7, 134.7, 136.9, 151.8,
160.5, 167.2, 169.7, 169.9, 205.3; MS (L-SIMS+) m/z 1176
(MLi+).
7-Deoxy-5(20)-d eoxy-5(20)-su lfa n ylba cca tin III (25). To
a solution of 24 (43 mg, 74 µmol) in dry THF (0.6 mL) and dry
MeOH (0.1 mL) cooled at 0 °C was added NaBH4 (15 mg, 400
µmol, 5 equiv). The solution was stirred at 0 °C for 2 h. After
standard workup, the residue was purified by preparative TLC
(heptane/AcOEt 3:7) to afford 25 (28 mg, 60%) as an amor-
phous solid along with starting material 24 (10 mg, 21%).
Compound 25: [R]20 -45.5 (c 0.89, CHCl3); IR (CHCl3) 1734,
D
1711 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.09 (3H, s), 1.10 (3H,
s), 1.83 (3H, s), 2.11 (3H, d, J ) 1.25 Hz), 2.22 (3H, s), 2.37
(3H, s), 3.15 (1H, d, J ) 11.55 Hz), 3.44 (1H, d, J ) 11.6 Hz),
3.99 (1H, d, J ) 7 Hz), 4.02 (1H, t, J ) 8.1 Hz), 4.82 (1H, m),
5.63 (1H, d, J ) 7 Hz), 6.42(1H, s), 7.51 (2H, bt, J ) 7.35 Hz),
7.61 (1H, bt, J ) 7.45 Hz), 8.11 (2H, bd, J ) 7.25 Hz); 13C
NMR (75 MHz, CDCl3) δ 15.1, 17.5, 21.0, 23.7, 26.5, 30.0, 35.7,
36.6, 40.0, 42.6, 45.4, 46.0, 53.2, 68.3, 75.0, 76.1, 79.1, 90.3,
128.8, 129.8, 130.2, 132.0, 133.7, 145.1, 167.1, 170.0, 172.4,
206.3; MS (CI+) m/z 509 (MH+ - AcOH - H2O).
5(20)-Deoxy-5(20)-su lfa n yld oceta xel (4). To a MeOH
solution (3 mL) of 22 (38 mg, 32 µmol) was added PTSA (18.6
mg, 98 µmol, 3.1 equiv). The solution was stirred at room
temperature for 2.5 h and quenched by an excess ethyl acetate.
After standard workup, the residue was purified on prepara-
tive TLC (CH2Cl2/MeOH 95:5) to yield 4 (13.9 mg, 52%) as a
white amorphous solid: IR (CHCl3) 3440, 1715, 1494, 1453
5(20)-Deoxy-5(20)-su lfa n yl-7-d eoxy-13-[[(4S,5R)-2-(4-
m eth oxyp h en yl)-3-(ter t-bu tyloxyca r bon yl)-4-p h en yl-1,3-
oxa zolid in -5yl]ca r bon yl]ba cca tin III (26). To a solution of
25 (10 mg, 17 µmol), compound 21 (14 mg, 34 µmol, 2 equiv),
and DCC (16 mg, 77 µmol, 4.5 equiv) in dry toluene (1 mL)
was added 4-DMAP (3 mg, 26 µmol, 1.5 equiv). The solution
was stirred at 80 °C for 3 h. After standard workup, the residue
was purified by preparative TLC (heptane/AcOEt 1:1) to afford
1
cm-1; H NMR (250 MHz, CDCl3) δ 1.13 (3H, s), 1.21 (3H, s),
1.37 (9H, s), 1.78 (1H, m), 1.85 (3H, s), 1.86 (3H, s), 2.17 (1H,
m), 2.30 (1H, m), 2.39 (3H, s), 2.33 (1H, m), 3.12 (1H, d, J )
11.6 Hz), 3.41 (1H, d, J ) 11.6 Hz), 3.94 (1H, d, J ) 6.9 Hz),
4.07 (2H, m), 4.66 (1H, bs), 5.23 (1H, s), 5.31 (1H, bd, J ) 9.2
Hz), 5.59 (1H, d, J ) 9.2 Hz), 5.64 (1H, d, J ) 6.9 Hz), 6.16
(1H, t, J ) 6.9 Hz), 7.33, 7.40, 7.41 (5H, m), 7.50 (2H, t, J )
26 (13 mg, 78%) as an amorphous solid: [R]20 -44.5 (c 0.48,
D
CHCl3); IR (CHCl3) 3405, 1734, 1710 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.04 (9H, s), 1.09 (3H, s), 1.20 (3H, s), 1.64 (3H, s),
1.76 (6H, s), 2.01-2.16 (3H, m), 2.21 (3H, s), 3.09 (1H, d, J )
11.55 Hz), 3.38 (1H, d, J ) 11.6 Hz), 3.77 (1H, d, J ) 7.3 Hz),
3.81 (3H,s), 3.97 (1H, t, J ) 8.65 Hz), 4.61 (1H, d, J ) 5.65
Hz), 5.35 (1H, bs), 5.6 (1H, d, J ) 7.3 Hz), 6.11(1H, bt, J )
7.35 Hz), 6.33 (1H, s), 6.35 (1H, br s), 6.92 (2H, d, J ) 8.7 Hz),
7.42 (5H, m), 7.43 (2H, d, J ) 8.95 Hz), 7.50 (2H, bt, J ) 7.45
Hz), 7.63 (1H, bt, J ) 7.45 Hz), 8.03 (2H, br d, J ) 8.45 Hz);
13C NMR (62.5 MHz, CDCl3) δ 14.2, 17.2, 20.9, 21.8, 22.4, 26.4,
27.9, 30.3, 36.2, 36.4, 37.5, 42.8, 44.9, 45.8, 52.9, 55.5, 64.1,
71.6, 74.3, 76.2, 79.6, 80.9, 89.1, 92.7, 114.0, 126.7, 128.3, 128.8,
129.1, 129.7, 130.2, 132.6, 133.8, 141.4, 151.6, 160.5, 167.2,
169.5, 169.7, 170.0, 206.4; MS (ESI+) m/z 990 (MNa+).
7.9 Hz), 7.62 (1H, t, J ) 7.9 Hz), 8.09 (2H, d, J ) 7.9 Hz); 13
C
NMR (75 MHz, CDCl3) δ 11.4, 14.1, 20.5, 23.2, 26.4, 28.1, 35.9,
36.2, 39.6, 42.9, 43.0, 48.5, 58.1, 71.7, 71.7, 73.9, 74.4, 75.3,
78.5, 89.0, 126.7, 127.8, 128.6, 129.8, 130.1, 133.5, 135.3, 138.5,
155.8, 166.9, 170.8, 172.4, 210.9; MS (L-SIMS+) m/z 846
(MNa+); HRMS (FAB+) calcd for C43H53NO13SNa (MNa+) m/z
846.3149, found 846.3135.
2-B e n zo y l-9-o x o -10-a c e t y l-4r(20)-e p o x y -5-m e s y l-
ta xicin e I (23). To a solution of 15 (2.05 g, 3.49 mmol) in dry
toluene were added over a period of 3 weeks CuCl2 (4.69 g,
34.9 mmol, 10 equiv) and tBuOOH (15.1 mL, 157 mmol, 45
equiv). The reaction was quenched with water, and copper
salts were filtered. After standard workup, the residue was
purified by flash chromatography on silica gel (heptane/AcOEt
9:1, 8:2, and 7:3) to afford 23 (1.19 g, 56%) as an amorphous
solid: [R]20D -23.0 (c 0.10, CHCl3); IR (CHCl3) 3337, 1749, 1719,
and 1676 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.23 (3H, s), 1.26
(3H, s), 1.35 (3H, s), 2.26 (3H, s), 2.29 (3H, s), 2.52 (1H, d, J )
4 Hz), 2.75 (1H, d, J ) 19.6 Hz), 2.94 (1H, d, J ) 4 Hz), 3.13
(3H, s), 3.19 (1H, d, J ) 19.5 Hz), 4.03 (1H, d, J ) 4.5 Hz),
4.15 (1H, bs), 5.46 (1H, d, J ) 4.6 Hz), 6.78 (1H, s), 7.47 (2H,
t, J ) 7.8 Hz), 7.62 (1H, bt, J ) 7.35 Hz), 8.06 (2H, dd, J ) 1.2
Hz, J ′ ) 7.2 Hz); 13C NMR (62.5 MHz, CDCl3) δ 14.3, 15.9,
17.9, 20.9, 27.5, 30.9, 32.9, 39.1, 40.9, 43.7, 44.0, 51.6, 56.5,
60.4, 74.3, 75.9, 77.4, 86.9, 128.8, 128.9, 130.3, 134.1, 141.8,
152.1, 166.7, 169.4, 198.7, 202.8; MS (CI+) m/z 605 (MH+).
7-Deoxy-5(20)-d eoxy-5(20)-su lfa n yl-13-oxoba cca tin III
(24). To a solution of 23 (135 mg, 2.24 mmol) in 20 mL of dry
DMF was added potassium thioacetate (52 mg, 0.46 mmol, 2
equiv). The solution was stirred at 60 °C for 17 h, and the DMF
was evaporated under reduced pressure. After standard
7-Deoxy-10-a cetyl-5(20)-d eoxy-5(20)-su lfa n yld oceta x-
el (5). To a dry MeOH solution (0.1 mL) of 26 (10 mg, 10 µmol)
cooled to 0 °C was added a 0.012 M solution of PTSA (0.88
mL, 10 µmol, 1 equiv) in MeOH. The solution was stirred at 0
°C for 10 min and at room temperature for 3 h. The residue
was purified by preparative TLC (heptane/AcOEt 1:1) to afford
5 (9 mg, 97%) as an amorphous solid: [R]20 -41.5 (c 0.36,
D
CHCl3); IR (CHCl3) 3438, 1733, 1713, 1647 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.13 (3H, s), 1.22 (3H, s), 1.35 (9H, s), 1.84
(6H, s), 2.22 (3H, s), 2.40 (3H, s), 3.14 (1H, d, J ) 11.55 Hz),
3.43 (1H, d, J ) 11.55 Hz), 3.53 (1H, bs), 3.86 (1H, d, J ) 7.1
Hz), 4.04 (1H, t, J ) 8.1 Hz), 4.66 (1H, bs), 5.32 (1H, bs), 5.47
(1H, d, J ) 9.55 Hz), 5.66 (1H, d, J ) 7.2 Hz), 6.18 (1H, bt, J
) 8.25 Hz), 6.41 (1H, s), 7.39 (5H, m), 7.5 (2H, bt, J ) 7.3 Hz),
7.61 (1H, bt, J ) 7.35 Hz), 8.11 (2H, bd, J ) 7.2 Hz); 13C NMR
(62.5 MHz, CDCl3) δ 14.7, 17.4, 20,1, 21.6, 23.5, 26.5, 28.3,
29.8, 30.1, 36.1, 36.1, 36.7, 42.9, 45.0, 46.0, 53.1, 56.1, 72.1,
74.0, 74.4, 76.1, 79.3, 80.2, 89.7, 126.9, 128.1, 128.9, 129.4,
130.3, 133.0, 133.8, 138.7, 141.0, 155.3, 167.2, 169.8, 170.7,

Semisynthesis of D-Ring Modified Taxoids
J . Org. Chem., Vol. 66, No. 15, 2001 5065
172.5, 206.1; MS (ESI+) m/z 872 (MNa+); HRMS (FAB+) calcd
for C45H56NO13S (MH+) m/z 850.3431, found 850.3472.
of 19. C. Gaspard is also acknowledged for cytotoxicity
evaluations and Drs. G. Atassi and A. Pierre´ (Servier
Research Institute) for the cell cycle studies performed
on compound 5.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The authors gratefully acknowl-
edge financial support from the European Community
(AIR3-CT94-1979). We thank Dr. A. Commerc¸on (Aven-
tis-Pharma) for a gift of the docetaxel acid side chain,
J .-F. Gallard for performing NMR spectra, and A.
Chiaroni for the X-ray analysis of the crystal structure
J O015539+