A new method for synthesis of 7-deoxytaxane analogues by hydrogenation of Δ6,7-taxane derivatives

Article abstract of DOI:10.1248/cpb.50.1398

A new method for the synthesis of 7-deoxytaxane analogues has been established through hydrogenation of Δ^6,7-taxane derivatives. Among several catalysts examined, Pd-C was found to be a most effective catalyst for the preparation of target compound.

Full text of DOI:10.1248/cpb.50.1398

1398
Notes
Chem. Pharm. Bull. 50(10) 1398—1400 (2002)
Vol. 50, No. 10
A New Method for Synthesis of 7-Deoxytaxane Analogues by
Hydrogenation of 6,7-Taxane Derivatives
D
Yasuyuki TAKEDA, Toshiharu YOSHINO, Kouichi UOTO, Hirofumi TERASAWA, and Tsunehiko SOGA*
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center; 1–16–13 Kita-Kasai,
Edogawa-ku, Tokyo 134–8630, Japan. Received May 16, 2002; accepted July 29, 2002
A new method for the synthesis of 7-deoxytaxane analogues has been established through hydrogenation of
6,7-taxane derivatives. Among several catalysts examined, Pd–C was found to be a most effective catalyst for the
preparation of target compound.
D
Key words 7-deoxytaxane analogue; hydrogenation; new efficient method
Paclitaxel (1, Taxol®)1) and docetaxel (2, Taxotere®)2) are
ment of 4 with triflic anhydride in a mixture of pyridine and
currently considered to be some of the most important drugs
used in cancer chemotherapy. Since their discovery, struc-
ture–activity relationships of taxane analogues have been ex-
tensively studied, and these studies have established that the
C-13 side chain, the ester groups at C-2 and C-4, and the
rigid core are essential for biological activity.3,4) In contrast,
it was shown that the C-7 hydroxyl group was not essential
for antitumor activity5) and that modifications of this moiety
could lead to improvements in the cytotoxicity against drug-
resistant cancer cell lines.6,7) On the basis of these findings,
we focused on the 7-deoxytaxane analogues and thus have
established a new method for the synthesis of these com-
pounds.
CH2Cl2 afforded 10-O-formyl-7-O-triflate 5. After removal
of the formyl group at the C-10 position with Me2NH in
THF,13) the resulting compound was treated with DBU to
generate the key intermediate 6,7-dehydro-10-deacetylbac-
catin III 6 (Chart 1).
With this olefin 6, hydrogenation using various catalysts
were carried out (Table 1). With PtO2, both the phenyl ring at
C-2 and 6,7-double bond were smoothly reduced to afford 8
in high yield (entry 1). As with PtO2, the hydrogenation of 6
over Pt–C (100 wt%) generated 8 in good yield (entry 3). By
using Rh–Al2O3 (50 wt%), the target compound 7 was ob-
tained along with unreacted 6 (entry 4). When the amount of
the catalyst was increased, however, hydrogenation of aro-
matic nuclei occurred to provide a mixture of 7 and 8 (entry
5). Therefore, it might be possible to obtain the target com-
pound 7 by controlling the amount of Rh–Al2O3 and the re-
action time. In contrast to the above catalysts, Pd–C was
found effective to produce the target compound 7 selectively
(entry 6). Moreover, the hydrogenation of 6 with this catalyst
proceeded smoothly without reducing the aromatic nuclei
and/or decomposing of starting material, irrespective of an
increase in the amount of catalyst and elongation of the reac-
tion time (entries 7, 8, 9) and was successfully applied to the
direct scale up (entry 10). By the use of Pd(OH)2, the target
compound 7 was obtained as a major product, together with
an unknown byproduct (entry 11).
We recently reported the synthesis of novel 9b-dihydro-
9,10-O-acetal taxane analogues. Potier et al. had already pre-
pared 9a-dihydro-9,10-O-isopropylidene-7-deoxydocetaxel
from natural taxine B and isotaxine B, and its cytotoxicity
was reported to be the same as that of docetaxel.14) On the
other hand, our novel analogues, 9b-isomer, showed stronger
activity against several tumor cell lines than did doc-
etaxel.10,15) Therefore, we applied this newly developed
method to the synthesis of their 7-deoxy analogues. 9,10-O-
Chemistry
Some groups have already reported the synthesis of 7-de-
oxytaxane analogues by employing the Barton deoxygenation
procedure5,8) or the electrochemical reduction of 7a-iodo do-
cetaxel,9) however, those yields were relatively low. In our
previous paper, we achieved the synthesis of 7-deoxytaxane
analogue in satisfactory yield, but still using the organotin
reagent.10) To avoid using the toxic organotin reagent, we
planned to prepare the 7-deoxytaxane analogues by hydro-
genation of D6,7-taxanes. Application of a modified Johnson’s
protocol (Tf2O/DMAP/DMF)11) for the attempted triflation of
10-deacetylbaccatin III (3) was found to provide 10-O-
formyl-10-deacetylbaccatin III (4) unexpectedly.10,12) Treat-
Fig. 1. Structures of Paclitaxel and Docetaxel
Chart 1
* To whom correspondence should be addressed. e-mail: sogatf7t@daiichipharm.co.jp
© 2002 Pharmaceutical Society of Japan

October 2002
1399
Table 1. Hydrogenation of 6 Using Several Catalysts
Entry
Scale (g)
Catalyst (Amount)
Solvent
Time (h)
Product
Yield (%)a)
1
2
3
4
5
6
7
8
9
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
10
PtO2 (50 wt%)
Pt–C (50 wt%)
AcOEt
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
AcOEt
EtOH
EtOH
1.5
14
41
1.5
2
14
14
62
45
24
15
8
89
—
79
—
—
99
99
94
82
99
—
7 and 8 (5 : 6)b)
Pt–C (100 wt%)
Rh–Al2O3 (50 wt%)
Rh–Al2O3 (100 wt%)
Pd–C (50 wt%)
Pd–C (100 wt%)
Pd–C (100 wt%)
Pd–C (100 wt%)
Pd–C (20 wt%)
Pd(OH)2 (50 wt%)
8
6 and 7 (1 : 3)b)
7 and 8 (3 : 2)b)
7
7
7
7
7
7
10
11
c)
0.1
a) Isolated yield. b) Ratios determined by 1H-NMR analysis of the crude mixture. c) 7 was obtained as a mixture of unknown by-product.
Chart 2
Acetonide 910) was treated with triflic anhydride in CH2Cl2 in
the presence of DMAP, elimination of 7-O-triflate occurred
to afford the 6,7-olefin 10. Attempts to reduce the 6,7-double
bond of 10 by using Pd–C or Rh–Al2O3, however, resulted in
the decomposition of the starting material (Chart 2). Highly
strained architecture of 10 in which the cyclic acetal at C-
9/C-10 causes angle distortion may be responsible for this
unfavorable reaction. Though an efficient method to obtain
SEPA-200 polarimeter. Mass spectra were recorded on a JEOL JMS-HX-
100, AX505W, JMS-D300 or JMS-700 spectrometer. Merck Kieselgel 60
(70—230 mesh) was used for column chromatography.
(1S,2S,3R,4S,5R,7S,8S,10R,13S)-4-Acetoxy-2-benzoyloxy-5,20-epoxy-
10-formyloxy-9-oxo-1,7,13-trihydroxytax-11-ene (4) To a solution of
(1S,2S,3R,4S,5R,7S,8S,10R,13S)-4-acetoxy-2-benzoyloxy-5,20-epoxy-9-
oxo-1,7,10,13-tetrahydroxytax-11-ene (10-Deacetylbaccatin III, 3) (10 g,
18.4 mmol) and DMAP (4.5 g, 36.8 mmol) in DMF (100 ml) was added Tf2O
(5.0 ml, 29.7 mmol) dropwise with ice cooling, and the mixture was stirred
at the same temperature for 10 min. The reaction mixture was poured into a
the target compound 11 has not been developed, the hydro- mixture of AcOEt and water, and the layers were separated. The aqueous
genation of other D6,7-taxanes to prepare the various 7-de-
layer was extracted with AcOEt and the combined organic layer was washed
with water, brine, and dried over Na2SO4. The solvent was removed under
reduced pressure, and the residue was triturated with CHCl3–n-hexane. The
resulting precipitate was collected by filtration to give the title compound
oxytaxane analogues are presently under investigation.
In conclusion, we have developed a new method for the
(10.0 g, 95%) as a white powder, mp 250—253 °C. 1H-NMR (CDCl3) d:
1.10 (3H, s), 1.13 (3H, s), 1.68 (3H, s), 1.76 (1H, br s), 1.80—1.93 (1H, m),
2.05 (3H, s), 2.20—2.45 (4H, m), 2.26 (3H, s), 2.56 (1H, ddd, Jϭ6.8, 9.8,
15.1 Hz), 3.88 (1H, d, Jϭ7.1 Hz), 4.15 (1H, d, Jϭ8.3 Hz), 4.31 (1H, d,
Jϭ8.3 Hz), 4.40—4.50 (1H, m), 4.88 (1H, br s), 4.98 (1H, d, Jϭ7.8 Hz),
5.63 (1H, d, Jϭ7.1 Hz), 6.45 (1H, s), 7.48 (2H, t, Jϭ7.4 Hz), 7.61 (1H, t,
Jϭ7.4 Hz), 8.10 (2H, d, Jϭ7.4 Hz), 8.22 (1H, s); FAB-MS (m/z): 573
synthesis of 7-deoxytaxane analogues. Although the applica-
bility might be limited, we believe that this synthetic method
should provide efficient and practical routes to obtain 7-de-
oxytaxane analogues.
Experimental
All chemicals and solvents used in the synthesis were reagent-grade prod- (MϩH)ϩ; Anal. Calcd for C30H36O11·0.75H2O: C, 61.48; H, 6.45. Found: C,
ucts and were used without additional purification. The following abbrevia- 61.52; H, 6.27; IR: 3540, 2940, 2898, 1710, 1452 cmϪ1; [a]D24 Ϫ90.6°
tions are used for the solvent and reagent names: ethyl acetate (AcOEt), 1,8- (cϭ0.54, CHCl3).
diazabicylo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP),
(1S,2S,3R,4S,5R,7S,8S,10R,13S)-4-Acetoxy-2-benzoyloxy-5,20-epoxy-
N,N-dimethylformamide (DMF), tetrahydrofuran (THF), triflic anhydride 10-formyloxy-1,13-dihydroxy-9-oxo-7-trifluoromethanesulfonyloxytax-
(Tf2O). Melting points were obtained on a Yanaco micro melting point appa- 11-ene (5) To a solution of 4 (9.5 g, 16.6 mmol) in a mixture of pyridine
ratus and are uncorrected. NMR spectra were obtained on a JEOL EX-400 (10 ml) and CH2Cl2 (100 ml) was added Tf2O (4.2 ml, 24.9 mmol) with ice
spectrometer, with tetramethylsilane as an internal standard. Chemical shifts cooling, and the mixture was stirred at the same temperature for 1 h. After
are reported in parts per million (ppm, d units). Splitting patterns are desig- adding saturated aqueous NaHCO3 and AcOEt to the reaction mixture, the
nated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. In- layers were separated and the aqueous layer was extracted with AcOEt. The
frared (IR) spectra were obtained on a Hitachi 270-30 spectrometer with combined organic layer was washed with brine, and dried over Na2SO4. The
KBr disks. Elementary analysis was carried out with a Perkin-Elmer Model solvent was removed under reduced pressure and the residue was triturated
240C elemental analyzer. Optical rotations were measured with a Horiba with CHCl3–n-hexane. The resulting precipitate was collected by filtration to

1400
Vol. 50, No. 10
(m/z): 535 (MϩH)ϩ; HR-MS Calcd for C29H43O9: 535.2907. Found,
535.2916; IR: 3442, 2929, 2856, 1720, 1685, 1450 cmϪ1; [a]D23 Ϫ37.3° (cϭ
0.65, CHCl3).
give the title compound (11.5 g) as a white solid, which contained a small
amount of pyridine and was used for the next reaction without further purifi-
cation. 1H-NMR (CDCl3) d: 1.06 (3H, s), 1.20 (3H, s), 1.61 (1H, br s), 1.88
(3H, s), 2.05—2.40 (4H, m), 2.25 (3H, s), 2.31 (3H, s), 2.80—2.95 (1H, m),
4.01 (1H, d, Jϭ7.1 Hz), 4.16 (1H, d, Jϭ8.5 Hz), 4.35 (1H, d, Jϭ8.5 Hz),
4.80—4.90 (1H, br s), 4.95 (1H, d, Jϭ8.8 Hz), 5.53 (1H, dd, Jϭ7.8,
10.3 Hz), 5.69 (1H, d, Jϭ7.1 Hz), 6.73 (1H, s), 7.50 (2H, t, Jϭ7.8 Hz), 7.63
(1H, t, Jϭ7.8 Hz), 8.10 (2H, d, Jϭ7.8 Hz), 8.20 (1H, s); FAB-MS (m/z): 705
(MϩH)ϩ.
(1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-1,13-dihy-
droxy-5,20-epoxy-9,10-(isopropylidenedioxy)tax-6,11-diene (10) To
a
solution of 9 (1.0 g, 1.71 mmol) and DMAP (2.1 g, 17.1 mmol) in CH2Cl2
(30 ml) was added Tf2O (1.15 ml, 6.83 mmol) with ice cooling, and the mix-
ture was stirred at the same temperature for 6 h. The reaction mixture was
poured into a mixture of AcOEt and saturated aqueous NaHCO3. The layers
were separated, and the aqueous layer was extracted with AcOEt. The com-
bined organic layer was washed with water, brine, and dried over Na2SO4.
The solvent was removed under reduced pressure, and the residue was chro-
matographed on silica gel eluted with CHCl3–acetone (50 : 1 (v/v)). The elu-
ate was concentrated under reduced pressure, and the residue was triturated
with CHCl3–n-hexane. The resulting powder was collected by filtration to
give the title compound (0.42 g, 43%) as a white powder, mp 143—144 °C.
1H-NMR (CDCl3) d: 1.14 (3H, s), 1.42 (3H, s), 1.53 (3H, s), 1.54 (3H, s),
1.59 (3H, s), 1.73 (1H, s), 1.91 (3H, s), 2.09 (1H, dd, Jϭ7.3, 15.1 Hz), 2.16
(1H, d, Jϭ8.1 Hz), 2.32—2.39 (1H, m), 2.34 (3H, s), 3.22 (1H, d,
Jϭ5.8 Hz), 4.03 (1H, d, Jϭ7.3 Hz), 4.26 (1H, d, Jϭ8.0 Hz), 4.34 (1H, d,
Jϭ8.1 Hz), 4.78—4.81 (1H, m), 4.82 (1H, d, Jϭ4.1 Hz), 5.53 (1H, d,
Jϭ7.5 Hz), 5.67 (1H, dd, Jϭ3.2, 10.2 Hz), 5.92 (1H, d, Jϭ6.0 Hz), 6.10 (1H,
d, Jϭ10.2 Hz), 7.48 (2H, t, Jϭ7.8 Hz), 7.60 (1H, t, Jϭ7.8 Hz), 8.15 (2H, d,
Jϭ7.8 Hz); FAB-MS (m/z): 569 (MϩH)ϩ; HR-MS Calcd for C32H41O9:
569.2751. Found, 569.2764; IR: 3507, 2975, 1725, 1689, 1482 cmϪ1; [a]D24
Ϫ12.9° (cϭ1.04, CHCl3).
(1S,2S,3R,4S,5R,7S,8R,10R,13S)-4-Acetoxy-2-benzoyloxy-5,20-epoxy-
9-oxo-1,10,13-trihydroxytax-6,11-diene (6) To a solution of 5 (11.5 g) in
THF (115 ml) was added Me2NH (2.0 M in THF, 12.3 ml, 24.5 mmol), and
the mixture was stirred at room temperature for 1.5 h. After adding ethyl for-
mate (2.0 ml, 24.5 mmol) to the reaction mixture, the resulting mixture was
stirred at the same temperature for further 15 min. The reaction mixture was
concentrated under reduced pressure and the residue was suspended in a
mixture of THF (5 ml) and 1,4-dioxane (50 ml). To this suspension was
added DBU (5 ml), and the mixture was stirred at 100 °C for 30 min. The re-
action mixture was poured into a cold mixture of 1 N HCl and AcOEt. The
layers were separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was washed with saturated aqueous NaHCO3, brine
and dried over Na2SO4. The solvent was removed under reduced pressure,
and the residue was chromatographed on silica gel eluted with CHCl3–
AcOEt (1 : 1 (v/v)). The eluate was concentrated under reduced pressure,
and the residue was triturated with n-hexane–AcOEt. The resulting precipi-
tate was collected by filtration to give the title compound (6.8 g, 79%) as a
1
white solid, mp 160—162 °C. H-NMR (CDCl3) d: 1.07 (3H, s), 1.13 (3H,
s), 1.66 (1H, br s), 1.92 (3H, s), 1.95—2.35 (3H, m), 2.00 (3H, d, Jϭ1.0 Hz),
2.31 (3H, s), 4.18 (1H, d, Jϭ6.5 Hz), 4.23 (1H, d, Jϭ1.5 Hz), 4.30 (1H, d,
Jϭ8.3 Hz), 4.43 (1H, d, Jϭ8.3 Hz), 4.82—4.93 (1H, br s), 5.02 (1H, s), 5.10
(1H, d, Jϭ5.4 Hz), 5.76 (1H, d, Jϭ9.8 Hz), 5.81 (1H, d, Jϭ6.5 Hz), 6.04
(1H, dd, Jϭ5.4, 9.8 Hz), 7.49 (2H, t, Jϭ7.8 Hz), 7.62 (1H, t, Jϭ7.8 Hz),
8.14 (2H, d, Jϭ7.8 Hz); FAB-MS (m/z): 527 (MϩH)ϩ; Anal. Calcd for
C29H34O9·0.5H2O: C, 65.03; H, 6.59. Found: C, 65.07; H, 6.64; IR: 3461,
2991, 2898, 1710, 1488 cmϪ1; [a]D24 Ϫ89.4° (cϭ0.17, CHCl3).
References and Notes
1) Wani M. C., Taylor H. L., Wall M. E., Coggon P., McPhali A. T., J.
Am. Chem. Soc., 93, 2325—2327 (1971).
2) Guéritte-Voegelein F., Guénard D., Lavelle F., Le Goff M.-T., Mangatal
L., Potier P., J. Med. Chem., 34, 992—998 (1991).
3) For review see: Suffness M., Annu. Rep. Med. Chem., 28, 305—314
(1993).
4) For review see: Guénard D., Guéritte-Voegelein F., Potier P., Acc.
Chem. Res., 26, 160—167 (1993).
5) Chen S.-H., Huang S., Kant J., Fairchild C., Wei J., Farina V. J., Org.
Chem., 58, 5028—5029 (1993).
6) Iimura S., Uoto K., Ohsuki S., Chiba J., Yoshino T., Iwahana M.,
Jimbo T., Terasawa H., Soga T., Bioorg. Med. Chem. Lett., 11, 407—
410 (2001)
7) Altstadt T. J., Fairchild C. R., Golik J., Johnston K. A., Kadow J. F.,
Lee F. Y., Long B. H., Rose W. C., Vyas D. M., Wong H., Wu M.-J.,
Wittman M. D., J. Med. Chem., 44, 4577—4583 (2001).
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3798—3799 (1993).
(1S,2S,3R,4S,5R,7S,8R,10R,13S)-4-Acetoxy-2-benzoyloxy-5,20-epoxy-
9-oxo-1,10,13-trihydroxytax-11-ene (7) (General Procedure, Entry 7)
6
(100 mg, 190 mmol) was hydrogenated (balloon) in EtOH (3 ml) over 10%
Pd–C (100 mg) for 14 h. After removal of the catalyst by filtration, the fil-
trate was concentrated under reduced pressure and the residue was chro-
matographed on silica gel eluted with CHCl3–MeOH (50 : 1 (v/v)). The elu-
ate was concentrated under reduced pressure to give the title compound
(100 mg, 99%) as a white amorphous powder. 1H-NMR (CDCl3) d: 1.06
(3H, s), 1.09 (3H, s), 1.50—1.55 (1H, m), 1.61 (1H, br s), 1.80 (3H, s),
1.90—2.41 (6H, m), 2.06 (3H, s), 2.29 (3H, s), 3.92 (1H, d, Jϭ7.3 Hz), 4.17
(1H, d, Jϭ1.5 Hz), 4.22 (1H, d, Jϭ8.3 Hz), 4.33 (1H, d, Jϭ8.3 Hz), 4.82—
4.92 (1H, m), 4.96 (1H, dd, Jϭ3.2, 9.6 Hz), 5.24 (1H, d, Jϭ1.5 Hz), 5.62
(1H, d, Jϭ7.3 Hz), 7.48 (2H, t, Jϭ7.3 Hz), 7.61 (1H, t, Jϭ7.3 Hz), 8.12 (2H,
d, Jϭ7.3 Hz); FAB-MS (m/z): 529 (MϩH)ϩ; HR-MS Cacld for C29H37O9:
529.2438. Found, 529.2448; IR: 3451, 2956, 1714, 1600, 1488 cmϪ1; [a]D25
Ϫ25.2° (cϭ1.04, CHCl3).
(1S,2S,3R,4S,5R,7S,8R,10R,13S)-4-Acetoxy-2-cyclohexanecarbony-
loxy-5,20-epoxy-9-oxo-1,10,13-trihydroxytax-11-ene (8) (General Proce-
dure, Entry 1) 6 (100 mg, 190 mmol) was hydrogenated (balloon) in
AcOEt (3 ml) over PtO2 (50 mg) for 1.5 h. After removal of the catalyst by
filtration, the filtrate was concentrated under reduced pressure and the
residue was triturated with CHCl3. The resulting powder was collected by
filtration to give the title compound (90 mg, 89%) as a white powder, mp
127—128 °C. 1H-NMR (CDCl3) d: 0.98 (3H, s), 1.07 (3H, s), 1.21—1.56
(7H, m), 1.64 (1H, m), 1.74 (3H, s), 1.78—1.80 (1H, m), 1.93—2.32 (8H,
m), 2.02 (3H, m), 2.18 (3H, s), 3.78 (1H, d, Jϭ7.1 Hz), 4.12 (1H, d,
Jϭ1.5 Hz), 4.19 (1H, d, Jϭ8.0 Hz), 4.47 (1H, d, Jϭ7.3 Hz), 4.84 (1H, m),
4.97 (1H, d, Jϭ9.5 Hz), 5.19 (1H, s), 5.38 (1H, d, Jϭ7.0 Hz); FAB-MS
9) Pulicani J.-P., Bouchard H., Bourzat J.-D., Commerçon A., Tetrahedron
Lett., 35, 9709—9712 (1994).
10) Ishiyama T., Iimura S., Yoshino T., Chiba J., Uoto K., Terasawa H.,
Soga T., Bioorg. Med. Chem. Lett. accepted.
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Wicnienski N. A., Kelly R. C., Tetrahedorn Lett., 35, 7893—7896
(1994).
12) A related O-formylation reaction; Barluenga J., Campos P. J., Gonza-
les-Nuñez E., Asensio G., Synthesis, 1985, 426—428 (1985).
13) After removal of the formyl group at the C-10 position with Me2NH,
the excess amount of Me2NH was treated with HCO2Me to afford
DMF and MeOH, which were easily removed by evaporation.
14) Poujol H., Mourabit A. A., Ahond A., Poupat C., Potier P.,
Tetrahedron, 53, 12575—12594 (1997).
15) Ishiyama T., Iimura S., Ohsuki S., Uoto K., Terasawa H., Soga T.,
Bioorg. Med. Chem. Lett., 12, 1083—1086 (2002).