Synthesis of novel thiol taxoids based on the 7,10-di-(2,2,2- trichloroethyloxycarbonyl)-10-deacetylbaccatin III: Both the syn and anti 10-deacetyl-2′-deoxy-2′-mercaptopaclitaxels

Article abstract of DOI:10.1016/j.tet.2004.03.064

Two new kinds of docetaxel compound, with a mercapto group instead of the hydroxyl on the C13 side chain (both syn and anti), via the 7,10-di-(2,2,2- trichloroethyloxycarbonyl)-10-deacetylbaccatin III route, were synthesized. The uses of trans and cis oxazoline compounds, and their stereoselective ring-opening reactions with thiolacetic acid, were proved to be key steps.

Full text of DOI:10.1016/j.tet.2004.03.064

Tetrahedron 60 (2004) 4133–4138
Synthesis of novel thiol taxoids based on the
7,10-di-(2,2,2-trichloroethyloxycarbonyl)-10-deacetylbaccatin III:
both the syn and anti 10-deacetyl-20-deoxy-20-mercaptopaclitaxels
c
Xin Qi,a,b Sang-Hyeup Lee,c Juyoung Yoond and Yoon-Sik Lee
,
,
*
*
aSchool of Chemical Engineering, Dalian University of Technology, Dalian 116012, People’s Republic of China
bSchool of Electrical Engineering & Computer Science, Seoul National University, Seoul 151-742, South Korea
cSchool of Chemical Engineering, Seoul National University, Seoul 151-742, South Korea
dDepartment of Chemistry, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemun-Ku, Seoul 120-750, South Korea
Received 6 March 2004; revised 22 March 2004; accepted 24 March 2004
Abstract—Two new kinds of docetaxel compound, with a mercapto group instead of the hydroxyl on the C13 side chain (both syn and anti),
via the 7,10-di-(2,2,2-trichloroethyloxycarbonyl)-10-deacetylbaccatin III route, were synthesized. The uses of trans and cis oxazoline
compounds, and their stereoselective ring-opening reactions with thiolacetic acid, were proved to be key steps.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
previous report,6 the syntheses of new kinds of thiol
surroga0tes of paclitaxel on the C-13 side chain instead of
the C-2 hydroxyl group 3a/3b were demonstrated by means
of 7-triethylsilyl baccatin III. Here, another kind of 20
mercapto taxoids is reported, with a free hydroxyl on the C-
10 position 4a/4b, utilizing the 7,10-di-(2,2,2-
trichloroethyloxycarbonyl)-10-deacetylbaccatin III (7,10-
diTroc DAB) 5 approach. As a matter of fact, the 7,10-
diTroc DAB proved to be another important synthetic
intermediate for the semi-synthesis of many taxoids
compounds,7 as did the 7-TES-baccatin III. One example
is the docetaxel 2, a semisynthetic analog of paclitaxel.
Meanwhile, simultaneous modification methods, on differ-
ent positions in the taxoids structure, recently emerged4a,8
and have begun to appear as an important tool in the search
for new taxoid analogues bearing better physical, chemical
and biological properties, especially when parallel9 and
The complex natural product paclitaxel (Taxolw) 1, first
isolated from Taxus brevifolia,1 is a member of a large
family of taxane diterpenoids.2 Paclitaxel has excellent
clinical activity against ovarian and breast cancers, and also
shows promising results in the treatment of other cancers.3
Extensive studies on the structure activity relationship
(SAR) have been explored. It is already well known that a
free hydroxyl group at the C-20 position on the C-13 side
chain is crucial for microtubule binding4 and may play as a
hydrogen bond donor.5 In light of this hypothesis, the
introduction of thiol functionality, which is more acidic
instead of hydroxyl onto the C-13 side chain, would be of
great interest for the study about the taxoid binding site on
microtubules and for the development of new compounds
bearing more desirable properties than paclitaxel. In our
Keywords: Taxol; Oxazoline; Mercapto taxoid.
*
Corresponding authors. Tel.: þ82-2-3277-2400; fax: þ82-2-3277-2384 (J.Y.); tel.: þ82-2-880-7073; fax: þ82-2-888-1604 (Y.-S.L.); e-mail addresses:
jyoon@ewha.ac.kr; yslee@snu.ac.kr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.064

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X. Qi et al. / Tetrahedron 60 (2004) 4133–4138
Scheme 1. (i) DCC, 4-Pyrrolidinopyridine, toluene, rt, 2 h, 92%. (ii) Thiolacetic acid, dioxane, 70 8C, 12 h, 72%. (iii) Zn dust, MeOH/HAc (1:1), 60 8C, 2 h,
77%. (iv) LiOH, MeOH/H2O, rt, 2 h, 68%.
combinatorial synthesis10 were used for quick and con-
venient scans. In these cases, the thiol taxoid analogues,
bearing two free hydroxyl groups at the 7 and 10 sites,
would be interesting precursors for this kind of application,
as the different reactivity of the two hydroxy groups are well
known.
A ring-opening reaction, with thiolacetic acid in a dilute 1,4-
dioxane solution, was performed at 70 8C for 12 h to give
the anti C-13 side chain product of 8b. The disappearance of
the two oxazoline ring proton peaks, and the appearance of
the amide peak at 8.07 ppm (doublet, J¼7.9 Hz), the H30 at
5.71 ppm (doublet–doublet, J¼4.07, 9.26 Hz), the H20 at
4.82 ppm (doublet, J¼4.10 Hz) and the C20 thioacetyl group
1
at 2.44 ppm, in the H NMR spectrum demonstrated the
2. Results and discussion
formation of the anti C-13 side chain.
The methodology applied to the synthesis of 4b involved in
a similar pathway, as described in our previous paper,6a with
the trans-oxazoline carboxylic acids, 6b, and 7,10-diTroc
DAB, 5,7f serving as starting materials, as shown in Scheme 1.
The two Troc groups, at the 7 and 10 positions, were then
simultaneously removed by means of the zinc dust method
in a mixture of methanol and acetic acid (1:1) at 60 8C to
give 9b.7e The 1H NMR spectrum clearly showed the loss of
the two Troc groups. Also, the H10 shifted from 6.07 ppm
to, a relatively high field, 5.03 ppm due to the loss of the
strong electron-withdrawing neighboring group, as did the
H7 proton from 5.43 to 4.12 ppm. The HRMS spectrum
further confirmed the removal of Troc groups as shown by a
molecular ion peak of 870 ([MþH]þ).
Thus, the excess (3.5 equiv.) trans- (4S, 5R)-2,4-diphenyl-
oxazoline-5-carboxylic acid 6b, which was generated by
hydrolysis from the corresponding methyl ester,11 was
coupled with 5 in the presence of DCC and 4-pyrrolidino-
pyridine to afford a new kind of oxazoline intermediate 7b,
which was fully characterized with a yield of 92%. First, the
HRMS spectrum revealed a characteristic [MþHþ4]
molecular ion peak, showing the existence of six chlorine
atoms. With the aid of 2D NMR experiments, the complete
assignments of 7 could be made. First, the 1H–13C HMQC
2D NMR clearly showed the positions of the pairs of
H20a,b, H6a,b and H14a,b, and the four alkyl methyl
groups, at 1.20, 1.25, 1.85 and 2.02 ppm, respectively. Then,
the two doublet peaks, at 4.94 and 5.60 ppm with a coupling
Finally, the selective removal of the S-acetyl group from the
side chain of 9b was achieved under aqueous basic
conditions. However, potassium bicarbonate, which was
used in the paclitaxel case, was obviously not enough to
completely cleave the S-acetyl group this time. Even with
the excess amount of base used, there will always be some
un-reacted starting material as with the use of potassium
carbonate. Maybe the free C10 hydroxyl group accounted
for the phenomenon of the increased acidity. Then, an
equivalent amount of lithium hydroxide was used to afford
4b. Surprisingly, no epimerization appeared to happen at the
C20 position, namely, no syn amide peak was found at
around 7.0 ppm, which always accompanied the main
product in the paclitaxel case.
1
constant of 7.0 Hz in H NMR spectrum, were consistent
with a trans oxazoline structure,12 and correlated only with
each other. As proved previously,6a the small amount of cis
oxazoline ester mixed with the trans isomer did not affect
1
the purity of the coupling product. The H–1H COSY 2D
NMR revealed two correlated 7-Troc methylene protons, at
4.60 and 4.90 ppm, doublet (J¼11.8 Hz) and the two
correlated 10-Troc methylene protons, at 4.76 ppm, triplet
(J¼12.2 Hz). Other protons, such as H2 and H3 at 5.70 and
3.93 ppm, respectively, both doublet, J¼7.0 Hz, correlated
with each other, H7, at 5.58 ppm, multiplet, and correlated
with the H6a and H6b, at 2.62 and 2.06 ppm, respectively
and H5, at 4.93 ppm, multiplet, and correlated with the H6a
only, were consistent with the desired structure.
Unlike the straightforward process for the trans isomer, with
the synthesis of the cis oxazoline, 6a, the problem of
epimerization was again encountered, as in the case with
7-TES-baccatin III6b (Scheme 2). That is, when 3.5 equiv.
of 6a were coupled to 5, only 38% of the cis oxazoline
derivative 7a was obtained, with more than half undergoing
the C-50 configuration inversion pathway to afford 7b, with a

X. Qi et al. / Tetrahedron 60 (2004) 4133–4138
4135
Scheme 2. (i) DCC, 4-Pyrrolidinopyridine, toluene, rt, 2 h, 7a (38%), 7b (52%). (ii) Thiolacetic acid, dioxane, 70 8C, 12 h, 80 8C, 12 h, 95 8C, 12 h, 8a/8b,
72%. (iii) Zn dust, MeOH/HAc (1:1), 60 8C, 2 h, 9a (52.2%), 9b (18%). (iv) LiOH, MeOH/H2O, rt, 2 h, 58%.
yield of 52%, which was even worse than in the case
employing 7-TES-baccatin III. Maybe this could be
attributed to the more bulky Troc groups, which might
further compress the space around the C-13 hydroxyl group.
From a chemical point of view, the formation of an enol
should be the intermediate process of the configuration
inversion.6b However, the separation of 7a and 7b was
easier than that of their TES counterparts, as the abundance
of the cis derivative was clearly lower than that of 7b on the
TLC plate. The two peaks at 5.8 and 5.41 ppm, with a
coupling constant of 10.6 Hz in the 1H NMR spectrum of 7a
confirmed the cis structure,12 while 7b was identical in
every respect with the trans sample. One of the obvious
differences in the 1H NMR spectrum of 7a was that the H13
occurred at 5.56 ppm, compared to 6.24 ppm with 7b, which
proved by the correlation with the H14a and H14b in the
1H–1H COSY 2D NMR analysis. Another difference was
the exchange of the chemical shifts between the protons on
the C4 acetyl group (2.04–2.24 ppm) and the two C14
protons (2.25–2.42 to 1.92–2.02 ppm).
with another enolation process occurring in the reaction
procedure. Therefore, it would be easier for the activated
molecular species to carry sufficient energy to overcome the
energy barrier to directly undergo the C50 configuration
inversion pathway.6b In that case, the temperature used for
the 7-TES-baccatin model seemed to be not suitable for the
di-Troc conditions. No further optimization of the process
has been made in this paper.
The two isomers could be separated after removing of the
Troc groups using zinc dust to obtain both 9a and 9b, which
could be distinguished by the chemical shift features of the
amides at 6.84 and 8.17 ppm for 9a and 9b, respectively.
Removal of the S-acetyl group by an equivalent amount of
lithium hydroxide in aqueous methanol solution of 9a
afforded 4a, with the evidence of the disappearance of the
doublet peak at 4.8 ppm on the 1H NMR and HRMS. On this
occasion, a small amount of 4b accompanied the 4a.
3. Conclusions
The ring-opening reaction with thiol acetic acid inherited
the bad configuration inversion behavior of the cis oxazoline
structure. Even though the temperature applied to the
reaction vial was carefully controlled, the product was a
mixture with the 8a:8b ratio 3.2:1 (confirmed by 1H NMR),
while the amide peak at 6.87 ppm revealed the syn side
chain. Again, the pressure from the two bulky Troc groups
has caused greater instability of 8a than in the TES
counterpart (in which a cis/trans ratio of 35:1 was received),
In conclusion, two new kinds of docetaxel compound with a
mercapto group instead of a hydroxyl on the C13 side chain
(both syn and anti), via the 7,10-di-(2,2,2-trichloroethyl-
oxycarbonyl)-10-deacetylbaccatin III route, were syn-
thesized. The uses of trans and cis oxazoline compounds,
and their stereoselective ring-opening reactions with
thiolacetic acid, were proved to be key steps. This kind of
thiol taxoids, bearing two free hydroxyl functional groups,

4136
X. Qi et al. / Tetrahedron 60 (2004) 4133–4138
will be useful in the search for new taxoid analogues, with
better physical, chemical and biological properties, using
combinatorial or parallel syntheses.
1H), 4.59 (d, J¼11.8 Hz, 1H), 4.76 (t, J¼12.1 Hz, 2H), 4.86
(d, J¼11.8 Hz, 1H), 4.94 (m, 2H), 5.56 (m, 2H), 5.60 (d,
J¼7.3 Hz, 1H), 5.69 (d, J¼7.0 Hz,1H), 6.24–6.28 (m, 2H),
7.37–7.65(m, 11H), 8.06 (d, J¼7.9 Hz, 2H), 8.18 (d,
J¼7.7 Hz, 2H); 13C NMR (CDCl3, 150 MHz) d 11.00,
14.94, 21.18, 21.84, 26.63, 33.47, 35.87, 43.35, 47.23,
56.46, 71.95, 74.54, 75.11, 76.50, 76.63, 77.38, 77.68,
79.25, 79.30, 80.82, 83.74, 83.94, 94.45, 126.66, 127.05,
128.59, 128.96, 129.07, 129.31, 130.33, 132.50, 132.57,
134.16, 141.04, 142.60, 153.38, 153.48, 164.00, 167.16,
170.24, 170.32, 200.87; HRMS (FAB) m/z¼1144.1240
[MþHþ2]þ, Calcd for C51H50Cl6NO16(1142.1244. Anal.
Calcd for C51H49Cl6NO16: C, 53.51; H, 4.32; N, 1.22;
Found: C, 53.59; H, 4.44; N, 1.20.
4. Experimental
4.1. General methods
Unless otherwise noted, materials were obtained from
commercial suppliers and were used without further
purification. (4S,5R) and (4S,5S) 2,4-diphenyloxazoline-5-
carboxylic acids were synthesized by the literature
procedure.11 7,10-Di-(2,2,2-trichloroethyloxycarbonyl)-10-
deacetylbaccatin III 5 was prepared by the literature method
from 10-deacetylbaccatin III.7f Toluene and dioxane were
freshly distilled over sodium-benzophenone ketyl. Solvents
for re-crystallization were purified by standard methods
before use. Flash chromatography was carried out on silica
gel 60 (230–400 mesh ASTM; Merck). Thin layer
chromatography (TLC) was carried out using Merck 60
F254 plates with a 0.25 mm thickness. Preparative TLC
was performed with Merck 60 F254 plates with a 1 mm
thickness.
4.1.2. (20S,30S) 30-N-Benzoylamino-20-deoxy-20-thio-
acetyl-7,10-di-(2,2,2-trichloroethyloxycarbonyl)pacli-
taxel 8b. Compound 7b (100 mg, 0.087 mmol), thiolacetic
acid (1.0 mL) and dioxane (3.0 mL) were added in an 8 mL
pressure vial at room temperature. The vial was then closed
tightly with a Teflon disk lid, and was heated at 70 8C for
12 h. After concentration under reduced pressure, the sticky
yellowish oil was purified by flash chromatography (EtOAc/
hexane, 1:3) to get 8b (76.8 mg, 0.063 mmol, 72%) as a
white solid. An analytical sample was obtained by re-
crystallization (EtOAc/hexane) as white crystals: mp 173–
5 8C; [a]1D6¼271.28 (c¼0.506, CHCl3); IR (KBr) 3417,
3019, 2955, 1767, 1738, 1663, 1259 cm21 1H NMR
;
(CDCl3, 600 MHz) d 1.13 (s, 3H), 1.19 (s, 3H), 1.24 (s,
3H), 1.76 (s, 1H), 1.80 (s, 3H), 2.00–2.04 (m, 1H), 2.12–
2.21 (m, 2H), 2.32 (s, 3H), 2.44 (s, 3H), 2.59–2.64 (m, 1H),
3.78 (d, J¼7.0 Hz, 1H), 4.11 (d, J¼8.6 Hz, 1H), 4.31 (d,
J¼8.6 Hz, 1H), 4.59 (d, J¼11.8 Hz, 1H), 4.75 (t,
J¼12.0 Hz, 2H), 4.82 (d, J¼4.1 Hz, 1H), 4.88 (d,
J¼11.8 Hz, 1H), 4.93 (d, J¼8.9 Hz, 1H), 5.43–5.46 (dd,
J¼7.2, 10.6 Hz, 1H), 5.62 (d, J¼7.0 Hz, 1H), 5.71 (dd,
J¼4.1, 9.3 Hz, 1H), 6.07 (m, 2H), 7.36–7.63 (m, 11H), 7.89
(m, 2H), 8.06 (m, 2H); 13C NMR (CDCl3, 150 MHz) d
10.73, 13.59, 21.03, 21.93, 26.24, 30.40, 33.18, 35.08,
43.06, 50.04, 54.42, 56.09, 71.78, 74.25, 76.21, 76.25,
77.12, 77.38, 78.82, 78.94, 80.46, 83.69, 126.12, 127.12,
128.66, 128.70, 128.77, 128.95, 129.27, 130.15, 131.81,
131.97, 133.89, 137.78, 142.13, 153.00, 153.15, 166.90,
170.09, 171.21, 192.41, 200.62; HRMS (FAB) m/z¼
1220.1223 [MþHþ2]þ, Calcd for C53H54Cl6NO17S¼
1218.1231. Anal. Calcd for C53H53Cl6NO17S: C, 52.14; H,
4.38; N, 1.15; S, 2.63; Found: C, 52.16; H, 4.46; N, 1.12; S,
2.42.
Melting points were measured with Bu¨chi 530 melting point
apparatus, and are uncorrected. 1H NMR spectra were
recorded using Bruker Avance 500 or 600 spectrometers
with TMS as internal standard. Chemical shifts were
expressed in ppm and coupling constants (J) in Hz. 13C
NMR were recorded using Bruker Avance 300 or 600
spectrometers. Infrared spectra were recorded on JASCO
FTIR-200 Spectrometer. Mass spectra were obtained using
JEOL JMS AX505WA or JMS-600 Mstation spectrometers.
Elemental analyses were performed using EA 1110 (CHNS-
O) (Thermo Finnigan, Italy). Optical rotations were
measured using JASCO 3100 polarimeter.
4.1.1. Compound 7b. A solution of DCC (130 mg,
0.63 mmol) in dry toluene (10 mL) was added to a
suspension of 7,10-diTroc-10-deacetylbaccatin III
5
(187 mg, 0.21 mmol), trans-carboxylic acid 6b (168 mg,
0.63 mmol) and catalytic amount of 4-pyrrolidinopyridine
in 10 mL of dry toluene at 0 8C under N2 while stirring.
After 10 min at 0 8C, the reaction mixture was stirred for
another 2 h at room temperature (the reaction was
monitored by TLC, EtOAc/hexane¼1:2), then passed
through a short silica gel plug (,5 g) and further eluted
with 50 mL of EtOAc. The combined eluent was concen-
trated to dry under reduced pressure. A mixture of EtOAc
and hexane (20:20 mL) was added to the residue and the
suspension was filtered through a cotton plug. The filtration
was concentrated again. Careful purification of the residue
by flash chromatography twice (EtOAc/hexane, 1:3)
afforded the desired product 7b (220 mg, 0.19 mmol,
92%) as a white solid. An analytical sample was obtained
by re-crystallization (EtOAc/hexane) as white fluffy
needles: mp 214–6 8C (dec.); [a]1D0¼241.18 (c¼0.50,
CHCl3); IR (KBr) 3573, 3016, 2958, 1764, 1732,
4.1.3. (20S,30S) 10-Deacetyl-20-deoxy-20-epi-acetyl-
mercaptopaclitaxel 9b. Zinc dust (100 mg) was added in
one portion to a vigorously stirred solution of 8b (75 mg,
0.0615 mmol) in a mixture of 2 mL MeOH and 2 mL acetic
acid at 60 8C under N2. After 2 h, the reaction mixture was
cooled down, then passed through a cotton plug and eluted
with EtOAc (20 mL). The eluent was concentrated to dry
and the residue was re-dissolved in a mixture of EtOAc and
brine (45 mL:15 mL). The organic layer was then dried over
anhydrous sodium sulfate. After concentration in vacuo, the
crude product was purified by flash chromatography
(EtOAc/hexane¼1:1) to afford product 9b (41 mg,
0.047 mmol, 77%) as a white solid: mp 164–6 8C;
[a]1D1¼285.18 (c¼0.77, CHCl3); IR (KBr) 3368, 2941,
1
1658 cm21; H NMR (CDCl3, 600 MHz) d 1.20 (s, 3H),
1.74 (s, 1H), 1.85 (s, 3H), 2.02–2.08 (m, 8H), 2.25–2.29
(m, 1H), 2.38–2.42 (m, 1H), 2.62–2.68 (m, 1H), 3.93 (d,
J¼7.0 Hz, 1H), 4.15 (d, J¼8.5 Hz, 1H), 4.30 (d, J¼8.6 Hz,

X. Qi et al. / Tetrahedron 60 (2004) 4133–4138
4137
2833, 1732, 1646, 1548 cm 21; 1H NMR (CDCl3, 600 MHz)
d 1.06 (s, 3H), 1.08 (s, 3H), 1.15 (s, 3H), 1.68 (s, 1H), 1.69
(s, 3H), 1.78–1.85 (m, 1H), 2.08–2.20 (m, 2H), 2.28 (s,
3H), 2.43 (s, 3H), 2.53–2.59 (m, 1H), 3.77 (d, J¼7.1 Hz,
1H), 4.11–4.15 (m, 3H), 4.29 (d, J¼8.5 Hz, 1H), 4.78 (d,
J¼4.0 Hz, 1H), 4.92 (d, J¼8.2 Hz, 1H), 5.0 (s, 1H), 5.60 (d,
J¼7.1 Hz, 1H), 5.69 (dd, J¼3.9, 9.3 Hz, 1H), 6.05 (t,
J¼8.6 Hz, 1H), 7.29–7.62 (m, 11H), 7.90 (d, J¼7.4 Hz,
2H), 8.06 (d, J¼7.5 Hz, 2H), 8.16 (d, J¼9.3 Hz, 1H); 13C
NMR (CDCl3, 150 MHz) d 10.11, 13.57, 20.87, 22.23,
26.58, 30.67, 35.66, 37.13, 43.23, 46.65, 50.29, 54.80,
57.75, 72.11, 72.29, 74.62, 75.13, 76.77, 79.22, 81.02,
84.40, 126.46, 127.40, 128.75, 128.92, 129.03, 129.41,
129.44, 130.40, 132.21, 134.03, 134.05, 135.92, 138.16,
138.42, 167.23, 167.27, 170.16, 171.45, 192.73, 211.54;
HRMS (FAB) m/z¼870.3159 [MþH]þ, Calcd for
C47H52NO13S¼870.3145.
EtOAc and hexane (40 mL) was added to the residue and the
suspension was filtered through a cotton plug. The filtration
was concentrated again. Careful purification of the residue
by flash chromatography twice (EtOAc/hexane, 1:3)
afforded 7b (378 mg, 0.33 mmol, 52%) as a white solid
(proved by 1H NMR) and 7a (276 mg, 0.24 mmol, 38%) as a
white solid: mp 174–6 8C; [a]1D6¼253.48 (c¼1.14, CHCl3);
1
IR (KBr) 3526, 3043, 2974, 1759, 1728, 1663 cm21; H
NMR (CDCl3, 600 MHz) d 1.09 (s, 3H), 1.11 (s, 3H), 1.58
(s, 1H), 1.59 (s, 3H), 1.81 (s, 3H), 1.92 (m, 1H), 2.01 (m,
1H), 2.04 (m, 1H), 2.24 (s, 3H), 2.59–2.64 (m, 1H), 3.75 (d,
J¼6.9 Hz, 1H), 4.13 (d, J¼8.5 Hz, 1H), 4.27 (d, J¼8.5 Hz,
1H), 4.60 (d, J¼11.8 Hz, 1H), 4.74–4.79 (dd, J¼15.1, 11.8
Hz, 2H), 4.90 (d, J¼11.8 Hz, 1H), 4.92–4.94 (m, 1H), 5.43
(d, J¼10.5 Hz, 1H), 5.48–5.51 (dd, J¼10.7, 7.2 Hz, 1H),
5.60 (t, J¼8.1 Hz, 1H), 5.61 (d, J¼7.0 Hz, 1H), 5.79 (d,
J¼10.5 Hz, 1H), 6.13 (s, 1H), 7.25–7.65 (m, 11H), 8.04 (d,
J¼7.3 Hz, 2H), 8.11 (d, J¼7.3 Hz, 2H); 13C NMR (CDCl3,
150 MHz) d 10.95, 14.57, 21.23, 22.59, 26.51, 33.48, 36.12,
43.15, 47.07, 56.36, 71.86, 73.97, 74.40, 76.47, 76.60,
77.40, 77.68, 79.10, 79.29, 80.94, 81.62, 83.84, 94.46,
126.76, 128.46, 128.89, 128.95, 129.05, 129.13, 129.30,
130.30, 131.84, 132.53, 134.13, 136.59, 142.50, 153.40,
153.46, 164.78, 167.02, 168.25, 169.90, 200.87; HRMS
4.1.4. (20S,30S) 10-Deacetyl-20-deoxy-20-epi-mercapto-
paclitaxel 4b.
A solution of LiOH·H2O (1.56 mg,
0.037 mmol) in 0.2 mL water (degassed before used) was
added dropwise to a stirred solution of 9b (32 mg
0.037 mmol) in 2 mL MeOH at room temperature during
30 min under N2. After addition, the reaction was continued
for another 1.5 h. A mixture of CHCl3 and water
(15 mL:15 mL) was added. The mixture was acidified by
2 or 3 drops of 1 N HCl to pH 1–2. The aqueous layer was
extracted with CHCl3 (3£15 mL) and the combined organic
layer was washed with brine (10 mL) and then dried over
anhydrous sodium sulfate. After concentration in vacuo, the
crude product was purified by preparative TLC (CHCl3/
MeOH¼20:1) in dark place to afford final product 4b
(20.8 mg, 0.025 mmol, 68%) as a white solid: mp 206–8 8C
(dec.); [a]1D3¼þ11.78 (c¼0.40, MeOH); IR (KBr) 3465,
(FAB)
C51H50Cl6NO16¼1142.1244.
m/z¼1144.1240
[MþHþ2]þ,
Calcd
Calcd
for
for
Anal.
C51H49Cl6NO16: C, 53.51; H, 4.32; N, 1.22; Found: C,
53.93; H, 4.40; N, 1.02.
4.1.6. (20R,30S) 30-N-Benzolamino-20-deoxy-20-thiolacetyl-
7,10-di-(2,2,2-trichloroethyloxycarbonyl)paclitaxel 8a.
Compound 7a (270 mg, 0.236 mmol), thiolacetic acid
(1.3 mL) and dioxane (4.0 mL) were added in an 8 mL
pressure vial at room temperature. The vial was then closed
tightly with a Teflon disk lid, and was heated stepwise at
70 8C for 12 h, 80 8C 12 h and 95 8C 12 h. After concen-
tration under reduced pressure, the sticky oil was purified by
flash chromatography (EtOAc/hexane, 1:3) to get 8a
(207 mg, 0.17 mmol, 72() as a white solid, which mixtured
with trans- diastereoisomer 8b (the ratio of cis/trans is 3.2:1
as shown by 1H NMR): mp 181–3 8C; [a]1D6¼þ6.38
(c¼1.77, CHCl3); IR (KBr) 3415, 3010, 2953, 1768, 1732,
2986, 2927, 1726, 1663, 1601 cm21 1H NMR (CDCl3,
;
600 MHz) d 1.08 (s, 3H), 1.11 (s, 3H), 1.16 (s, 3H), 1.63 (s,
1H), 1.72 (s, 3H), 1.79–1.84 (m, 1H), 2.00–2.04 (m, 2H),
2.2–2.22 (m, 2H), 2.36 (s, 3H), 2.53–2.59 (m, 2H), 3.80 (d,
J¼8.3 Hz, 1H), 3.85 (dd, J¼4.3, 13.1 Hz, 1H), 4.13–4.15
(m, 3H), 4.30 (d, J¼10.1 Hz, 1H), 4.93 (d, J¼7.1 Hz, 1H),
5.05 (s, 1H), 5.63 (d, J¼8.5 Hz, 1H), 5.77 (dd, J¼4.2,
11.3 Hz, 1H), 6.05 (m, 1H), 7.29–7.63 (m, 11H), 7.94 (d,
J¼8.8 Hz, 2H), 8.06 (d, J¼8.8 Hz, 2H), 8.18 (d, J¼11.3 Hz,
1H); 13C NMR (CDCl3, 150 MHz) d 10.17, 14.02, 14.51,
23.08, 23.21, 26.76, 29.63, 30.09, 35.72, 43.34, 45.06,
46.90, 57.99, 71.73, 72.39, 74.85, 75.08, 76.49, 76.98,
79.19, 81.37, 84.43, 126.52, 127.51, 128.88, 129.11, 129.21,
129.48, 129.56, 130.45, 132.45, 167.40, 170.02, 173.32,
211.61; HRMS (FAB) m/z¼828.3065 [MþH]þ, Calcd for
C45H50NO12S¼828.3196.
1
1679, 1610 cm21; H NMR (CDCl3, 600 MHz) d 1.14 (s,
3H), 1.18 (s, 3H), 1.58 (s, 1H), 1.80 (s, 3H), 1.89 (s, 3H),
2.00–2.06 (m, 1H), 2.13–2.44 (m, 2H), 2.31 (s, 3H), 2.46
(s, 3H), 2.59–2.62 (m, 1H), 3.82 (d, J¼6.9 Hz, 1H), 4.12
(m, 1H), 4.28 (d, J¼8.5 Hz, 1H), 4.57 (d, J¼11.7 Hz, 1H),
4.74 (m, 3H), 4.89 (d, J¼11.8 Hz, 1H), 4.93 (d, J¼9.3 Hz,
1H), 5.52 (d, J¼8.1 Hz, 1H), 5.60 (d, J¼7.0 Hz, 1H), 5.72
(m, 1H), 6.05 (m, 1H), 6.20 (s, 1H), 6.87 (d, J¼8.7 Hz, 1H),
7.31–8.10 (m, 15H); 13C NMR (CDCl3, 150 MHz) d 10.68,
14.48, 20.84, 22.25, 26.23, 30.49, 33.13, 34.91, 42.97,
46.80, 49.04, 55.77, 56.10, 70.90, 74.10, 76.07, 77.21,
78.78, 78.87, 80.29, 83.66, 94.15, 126.50, 127.21, 128.63,
129.28, 130.04, 131.94, 132.08, 133.54, 134.84, 139.13,
142.04, 153.05, 166.46, 166.75, 168.40, 169.97, 195.50,
200.56; HRMS (FAB) m/z¼1220.1223 [MþHþ2]þ, Calcd
for C53H54Cl6NO17S¼1218.1231.
4.1.5. Compound 7a. A solution of DCC (464 mg,
2.25 mmol) in dry toluene (20 mL) was added to a
suspension of 7,10-diTroc-10-deacetylbaccatin III
5
(570 mg, 0.636 mmol), cis-carboxylic acid 6a (600 mg,
2.25 mmol) and catalytic amount of 4-pyrrolidinopyridine
in 30 mL of dry toluene at 0 8C under N2 while stirring.
After 10 min at 0 8C, the reaction mixture was stirred for
another 3 h at room temperature (the reaction was
monitored by TLC, EtOAc/hexane¼1:2), then passed
through a short silica gel plug (,5 g) and further eluted
with 50 mL of EtOAc. The combined eluent was concen-
trated to dry under reduced pressure. A 1:1 mixture of
4.1.7. (20R,30S) 10-Deacetyl-20-deoxy-20-acetylmercapto-
paclitaxel 9a. Zinc dust (250 mg) was added in one portion
to a vigorously stirred solution of 8a/8b (195 mg,
0.16 mmol) in a mixture of 3 mL MeOH and 3 mL acetic

4138
X. Qi et al. / Tetrahedron 60 (2004) 4133–4138
acid at 62 8C under N2. After 2 h, the reaction mixture was
cooled down, then passed through a cotton plug and eluted
with EtOAc (20 mL). The eluent was concentrated to dry
and the residue was re-dissolved in a mixture of EtOAc and
brine (60:15 mL). The organic layer was then dried over
anhydrous sodium sulfate. After concentration in vacuo, the
crude product was purified by preparative TLC (EtOAc/
hexane¼1:1) to afford trans product 9a (24 mg,
0.028 mmol, 18%) and cis-product 9a (73 mg,
0.084 mmol, 52.5%) as a white solid: mp 168–70 8C;
[a]1D4¼þ9.628 (c¼0.21, CHCl3); IR (KBr) 3374, 2942,
2832, 1726, 1647, 1458 cm21; 1H NMR (CDCl3, 600 MHz)
d 1.07 (s, 3H), 1.13 (s, 3H), 1.54 (br, 2H), 1.72 (s, 3H), 1.79
(s, 3H), 1.88–1.92 (m, 2H), 2.10–2.47 (m, 1H), 2.30 (s,
3H), 2.44 (s, 3H), 2.55 (m, 1H), 3.83 (d, J¼7.1 Hz, 1H),
4.13 (s, 1H), 4.17 (d, J¼8.5 Hz, 1H), 4.19 (br, 1H), 4.26 (d,
J¼8.5 Hz, 1H), 4.75 (d, J¼10.5 Hz, 1H), 4.92 (d, J¼8.2 Hz,
1H), 5.13 (s, 1H), 5.60 (d, J¼7.1 Hz, 1H), 5.73 (t, J¼9.7 Hz,
1H), 6.03 (t, J¼8.8 Hz, 1H), 6.85 (t J¼8.7 Hz, 1H), 7.33–
7.72 (m, 11H), 7.72 (d, J¼7.5 Hz, 2H), 8.02 (d, J¼7.5 Hz,
1H); 13C NMR (DMSO, 150 MHz) d 9.81, 13.56, 20.81,
22.37, 26.51, 30.20, 42.85, 45.91, 52.56, 70.73, 70.76,
73.57, 74.81, 75.34, 76.87, 80.15, 83.79, 127.45, 127.74,
128.09, 128.35, 128.50, 128.67, 129.47, 130.06, 131.54,
134.15, 135.57, 136.83, 139.27, 165.21, 166.23, 166.31,
169.49, 170.69, 192.56, 209.28; HRMS (FAB) m/
z¼870.3150 [MþH]þ, Calcd for C47H52NO13S¼870.3145.
Anal. Calcd for C47H51NO13S: C, 64.90; H, 5.91; N, 1.61; S,
3.68; Found: C, 64.60; H, 6.40; N, 1.46; S, 3.20.
Acknowledgements
We thank Hanmi Pharmaceutical Co., Ltd for the generous
donation of 10-deacetylbaccatin III. This work was
supported by Korea Science and Engineering Foundation
(R14-2003-014-01001-0) and the Brain Korea 21 Program.
References and notes
1. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail,
A. T. J. Am. Chem. Soc. 1971, 93, 2325.
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Rev. Med. 1997, 48, 353. (b) In Progress in the chemistry of
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4. (a) Baloglu, E.; Hoch, J. M.; Chatterjee, S. K.; Ravindra, R.;
Bane, S.; Kingston, D. G. I. Bioorg. Med. Chem. 2003, 11,
´ ´
1557. (b) Lozynski, M.; Rusinska-Roszak, D. Tetrahedron
´
Lett. 1995, 36, 8849. (c) Jimenez-Barbero, J.; Souto, A. A.;
Abal, M.; Barasoain, I.; Evangelio, J. A.; Acun˜a, A. U.;
Andreu, J. M.; Amat-Guerri, F. Bioorg. Med. Chem. 1998, 6,
1857. (d) Kant, J.; Huang, S.; Wong, H.; Fairchild, C.; Vyas,
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(e) Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Acc. Chem.
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4.1.8. (20R,30S) 10-Deacetyl-20-deoxy-20-mercapto-
6. (a) Qi, X.; Lee, S.-H.; Yoon, J.; Lee, Y.-S. Tetrahedron 2003,
59, 7409. (b) Qi, X.; Lee, S.-H.; Yoon, J.; Lee, Y.-S.
Tetrahedron 2004, 60, 3599.
paclitaxel 4a.
A solution of LiOH·H2O (2.69 mg,
0.064 mmol) in 0.2 mL water (degassed before used) was
added dropwise to a stirred solution of 9a (55.6 mg
0.064 mmol) in 2 mL MeOH at room temperature under
N2. After addition, the reaction was continued for another
1.5 h. A mixture of CHCl3 and water (15 mL:15 mL) was
added. The mixture was acidified by 2 or 3 drops of 1 N HCl
to pH 1–2. The aqueous layer was extracted with CHCl3
(3£15 mL) and the combined organic layer was washed
with brine (10 mL) and then dried over anhydrous sodium
sulfate. After concentration in vacuum, the crude product
was purified by preparative TLC (CHCl3/MeOH¼20:1) in
dark place to afford final product 4a (31 mg, 0.037 mmol,
57.8%) as a white solid: mp 198–200 8C; [a]1D2¼23.388
(c¼0.308, MeOH); IR (KBr) 3417, 2947, 2854, 1731, 1633,
7. (a) Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.;
Kuduk, S. Tetrahedron Lett. 1993, 34, 4149. (b) Ojima, I.;
Habus, I.; Zhao, M. Z.; Zucco, M.; Park, Y. H.; Sun, C. M.;
Brigaud, T. Tetrahedron 1992, 48, 6985. (c) Wahl, A.;
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Gueritte-Voegelein, F.; Guenard, D.; Le Goff, M.-T.; Potier, P.
´
Tetrahedron 1992, 48, 6965. (d) Commercon, A.; Bezard, D.;
Bernard, F.; Bourzat, J. D. Tetrahedron Lett. 1992, 33, 5185.
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(e) Mangatal, L.; Adeline, M.-T.; Guenard, D.; Gueritte-
Voegelein, F.; Potier, P. Tetrahedron 1989, 45, 4177.
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(f) Gueritte-Voegelein, F.; Senilh, V.; David, B.; Guenard,
D.; Potier, P. Tetrahedron 1986, 42, 4451.
8. (a) Jagtap, P. G.; Baloglu, E.; Barron, D. M.; Bane, S.;
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M. D.; Yuan, H.; Jagtap, P. G.; Kadow, J. F.; Long, B. H.;
Fairchild, C. R.; Johnston, K. A.; Kingston, D. G. I. Bioorg.
Med. Chem. 2001, 9, 171. (c) Ojima, I.; Lin, S.; Slater, J. C.;
Wang, T.; Pera, P.; Bernacki, R. J.; Ferlini, C.; Scambia, G.
Bioorg. Med. Chem. 2000, 8, 1619.
1
1528 cm21; H NMR (CDCl3, 600 MHz) d 1.08 (s, 3H),
1.14 (s, 3H), 1.24–1.31 (m, 2H), 1.52 (s, 3H), 1.70 (s, 1H),
1.73 (s, 3H), 1.82 (m, 1H), 2.04 (m, 1H), 2.21 (m, 1H), 2.27
(d, J¼5.8 Hz, 1H), 2.56–2.60 (m, 1H), 3.86 (d, J¼7.0 Hz,
1H), 4.02 (t, J¼8.6 Hz, 1H), 4.16 (d, J¼8.5 Hz, 1H), 4.20
(m, 2H), 4.29 (d, J¼8.5 Hz, 1H), 4.95 (d, J¼9.4 Hz, 1H),
5.19 (s, 1H), 5.64 (d, J¼7.0 Hz, 1H), 5.66 (t, J¼8.0 Hz, 1H),
6.04 (t, J¼8.6 Hz, 1H), 7.05 (m, 1H), 7.28–7.62 (m, 11H),
7.80 (d, J¼7.4 Hz, 2H), 8.06 (d, J¼7.4 Hz, 2H); 13C NMR
(CDCl3, 150 MHz) d 10.15, 14.71, 20.94, 22.80, 26.68,
29.46, 31.18, 36.00, 37.22, 43.24, 46.66, 47.28, 56.01,
57.82, 71.87, 72.22, 74.67, 75.08, 76.78, 79.21, 81.20,
84.34, 127.30, 127.40, 128.70, 128.93, 129.02, 129.22,
129.47, 130.36, 132.23, 124.02, 134.22, 136.01, 138.74,
138.95, 167.20, 167.41, 170.13, 171.10, 211.68; HRMS
9. (a) Bhat, L.; Liu, Y.; Victory, S. F.; Himes, R. H.; Georg, G. I.
Bioorg. Med. Chem. Lett. 1998, 8, 3181. (b) Liu, Y.; Ali, S. M.;
Boge, T. C.; Georg, G. I.; Victory, S.; Zygmunt, J.; Marquez,
R. T.; Himes, R. H. Comb. Chem. High Throughput Screen.
2002, 5, 39.
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62, 6029.
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Tetrahedron 2002, 58, 2777.
[MþH]þ,
Calcd
for
12. Lee, S.-H.; Yoon, J.; Nakamura, K.; Lee, Y.-S. Org. Lett.
2000, 2, 1243.
(FAB) m/z¼828.3008
C45H50NO12S¼828.3196.