Synthetic studies with 13-deoxybaccatin III

Article abstract of DOI:10.1021/jo011183q

An efficient synthesis of 13-epi-7-O-(triethylsilyl)baccatin III from 13-deoxybaccatin III is described. Oxidation of 13-deoxy-7-O-(triethylsilyl)baccatin III with tert-butyl peroxide, followed by reduction with SmI₂, produced 13-epi-7-O-(triethylsilyl)baccatin III in good overall yield. The preparation of 13-oxo-7-O-(triethylsilyl)baccatin III from 13-epi-7-O-(triethylsilyl)baccatin III using tetrapropylammonium perruthenate and N-methylmorpholine N-oxide is also reported.

Full text of DOI:10.1021/jo011183q

Syn th etic Stu d ies w ith
13-Deoxyba cca tin III
Yu Mi Ahn, David G. Vander Velde, and
Gunda I. Georg*
Department of Medicinal Chemistry and the
Drug Discovery Program, Higuchi Biosciences Center,
The University of Kansas, Lawrence, Kansas 66045-7582
F IGURE 1. Structures of paclitaxel (1) and 13-deoxybaccatin
III (2).
georg@ku.edu
Received December 26, 2001
SCHEME 1a
Abstr a ct: An efficient synthesis of 13-epi-7-O-(triethylsilyl)-
baccatin III from 13-deoxybaccatin III is described. Oxida-
tion of 13-deoxy-7-O-(triethylsilyl)baccatin III with tert-butyl
peroxide, followed by reduction with SmI2, produced 13-epi-
7-O-(triethylsilyl)baccatin III in good overall yield. The
preparation of 13-oxo-7-O-(triethylsilyl)baccatin III from 13-
epi-7-O-(triethylsilyl)baccatin III using tetrapropylammo-
nium perruthenate and N-methylmorpholine N-oxide is also
reported.
Paclitaxel (1, Figure 1), a complex diterpene isolated
from the bark of Taxus brevifolia (Pacific Yew),1,2 is a
chemotherapeutic agent with impressive antitumor ac-
tivity.3,4 Paclitaxel is available only in small quantities
from natural sources;1,2 however, semisynthetic ap-
proaches toward paclitaxel synthesis and analogue de-
velopment have been developed, utilizing 10-deacetyl-
baccatin III, a more readily available paclitaxel-related
natural product.5-7 A major advantage of using 10-
deacetylbaccatin III is that it can be obtained from a
regenerable source, the needles of Taxus baccata.8 As
paclitaxel becomes widely used for the treatment of
several types of cancers, plant cell culture represents an
alternative method for paclitaxel production. The major
goal of plant cell culture is to produce paclitaxel in high
yield, minimizing the formation of other taxane diter-
penes.9 However, certain byproducts can become useful
if appropriate synthetic routes can be developed to
convert these intermediates to paclitaxel or its deriva-
tives. We now report on the chemistry of such a byprod-
uct, 13-deoxybaccatin III (2, Figure 1), which is produced
in high quantity from plant cell cultures.9
a
Conditions: (a) NBS, benzoyl peroxide, CCl4, reflux, 8 h, 94%;
(b) NaN3, DMF, 40 °C, 7 h, 79% (5:6 ) 1:1); (c) AgOAc, DMF, 40
°C, 7 h, 85% (5:6 ) 2:1).
The 7-hydroxy group of 13-deoxybaccatin III was
protected with triethylsilyl chloride (TESCl) to provide
13-deoxy-7-O-(triethylsilyl)baccatin III (3)10,11 in 95%
yield. Then, 13-deoxy-7-O-(triethylsilyl)baccatin III (3)
was treated with N-bromosuccinimide (NBS) in the
presence of benzoyl peroxide producing the corresponding
13â-bromo derivative 4 in 94% yield (Scheme 1). Bromo
compound 4 was found to be unstable on silica gel and
was therefore not subjected to purification via column
chromatography. The stereochemistry at C13 of 4 was
determined through NOE experiments. Irradiation of
H16 (δ 1.14) strongly enhanced H2, but not H13, and
irradiation of H17 (δ 1.24) significantly enhanced H14â,
but not H13. Therefore, the stereochemistry of the 13-
bromo group was assigned as 13â. This bromide is
unsuitable for further elaboration into bioactive com-
pounds. When reacted with sodium azide and silver
acetate, the bromide produced a mixture of 10,11-seco
derivative 512 and diene 6 (Scheme 1).13
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J . Am. Chem. Soc. 1971, 93, 2325-2327.
(2) Suffness, M.; Wall, M. Discovery and Development of Taxol. In
Taxol Science and Applications; Suffness, M., Ed.; CRC Press: Boca
Raton, FL, 1995; pp 3-25.
(3) The Chemistry and Pharmacology of Taxol and Its Derivatives;
Farina, V., Ed.; Elsevier: Amsterdam, 1995.
(4) Spencer, C. M.; Faulds, D. Drugs 1994, 48, 794-847.
(5) Kingston, D. G. I. J . Chem. Soc., Chem. Commun. 2001, 867-
880.
(6) Taxane Anticancer Agents: Basic Science and Current Status;
Georg, G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; American
Chemical Society: Washington, DC, 1995.
(10) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K. J . Chem.
Soc., Chem. Commun. 1994, 295-296.
(11) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.;
Couladouros, E. A.; Sorensen, E. J . J . Am. Chem. Soc. 1995, 117, 624-
633.
(7) Taxol Science and Applications; Suffness, M., Ed.; CRC Press:
Boca Raton, FL, 1995.
(8) Denis, J . N.; Greene, A. E.; Guenard, D.; Gue´ritte-Voegelein, F.;
Mangatal, L.; Potier, P. J . Am. Chem. Soc. 1988, 110, 5917-5919.
(9) Gi, U.-S.; Min, B.; Hong, S.-S.; Lee, H.-S.; Kim, J .-H. Agric. Chem.
Biotechnol. (Engl. Ed.) 2000, 43, 176-179.
(12) Kingston and co-workers reported compound 5 as the only
product when 13â-chloro-13-deoxy-7-O-(triethylsilyl)baccatin III was
reacted with sodium azide in DMF. The structure of 5 was identical
in all respects to the compound reported in the literature. Chordia,
M. D.; Gharpure, M. M.; Kingston, D. G. I. Tetrahedron 1995, 51,
12963-12970.
10.1021/jo011183q CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002
7140
J . Org. Chem. 2002, 67, 7140-7143

SCHEME 2a
a
Conditions: (a) tert-BuOOH, benzene, 60 °C, 7 h, 78% for product 7; (b) oxidants, tert-BuOOH, benzene, rt, 22-26 h, gave 7 and 8,
0-31% for product 7; (c) PDC, CuBr, or CuCl, tert-BuOOH, benzene, 50-55 °C, 18-23 h; (d) SmI2, THF, rt, 3.5 h, 86%; (e) DEAD, Me3P,
ClCH2CO2H, toluene, from 0 to 90 °C, 24 h, 43% for product 6; (f) TPAP, NMO, CH2Cl2, rt, 2 h, 81%.
TABLE 1. Oxid a tion of 3 w ith Va r iou s Oxid a n ts in th e P r esen ce of ter t-Bu tyl Hyd r op er oxid e in Ben zen e
relative product ratio (%)a
(isolated yield, %)
entry
substrate
reagentsb
time (h)
T (°C)
3
7
8
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
7
7
7
PDC/t-BuOOH
CrO3/t-BuOOH
SeO2/t-BuOOH
PCC/t-BuOOH
CuBr/t-BuOOHc
CuCl/t-BuOOHc
t-BuOOH
20
23
25
23
22
26
22
7
25
25
25
25
55
50
25
60
50
55
55
18
5
100
25
37
0
19
0
0
43(31)
31(14)
0
30(23)
63(43)
100(72)
55(34)
100(78)
100(>95)d
100(>95)d
100(>95)d
37
64
0
45
0
0
26
0
t-BuOOH
PDC/t-BuOOH
CuBr/t-BuOOHc
CuCl/t-BuOOHc
23
18
20
0
0
0
10
11
0
0
a
1
b
Obtained from integration of signals in the H NMR of unpurified reaction products. Ratio of 3:oxidants:t-BuOOH ) 1:10:10. c CuBr
d
and CuCl were used as catalysts. Starting material 7 was recovered quantitatively.
We also carried out allylic oxidation reactions with
compound 314 using various oxidants (Scheme 2 and
Table 1) in the presence of tert-butyl hydroperoxide. Thus,
7-protected 13-deoxybaccatin III 3 was subjected to
oxidants (PCC, PDC, MnO2, CrO3, and SeO2) in the
presence of tert-butyl hydroperoxide in order to obtain
ketone 8. However, the oxidations gave a mixture of
starting material 3, tert-butylperoxy product 7, and 13-
oxo-7-O-(triethylsilyl)baccatin III (8) (Scheme 2, Table 1,
entries 1-4). When CuCl and CuBr were used as
catalysts in the tert-butyl hydroperoxide oxidation reac-
tions,15,16 none of the ketone 8 was obtained (Table 1,
entries 5 and 6). Furthermore, treatment of 3 with only
tert-butyl hydroperoxide in benzene at 60 °C resulted in
the formation of the tert-butylperoxy derivative 7 in good
yield (78%) as the exclusive product (Scheme 2 and Table
1, entry 8).
The tert-butylperoxy compound 7 could be a potential
intermediate in the pathway leading to the ketone 8.
Thus, the tert-butylperoxy compound 7 was further
reacted with tert-butyl hydroperoxide and PDC,17 CuBr,
and CuCl15,16 in order to produce 13-oxo-7-O-(triethylsi-
lyl)baccatin III (8); however, none of the desired product
was formed, and the tert-butylperoxy compound 7 was
recovered in all cases (Scheme 2 and Table 1, entries
9-11).
(13) The structure of diene 6 was confirmed by HMQC and HMBC
NMR experiments. The protons at C13 and C14 resonate as doublets
at 6.09 and 5.60 ppm, respectively (J 13,14 ) 9.4 Hz). In an HMQC
experiment, H13 and H14 have correlations with carbon signals at
133.6 and 133.0 ppm, respectively. Therefore, we assigned the signal
at 133.6 ppm to C13 and the 133.0 ppm signal to C14. In an HMBC
experiment, we found that the proton at C13 showed three bond
couplings to the carbons at C12 and C14 and a long-range coupling to
C18. The proton at C14 showed three bond couplings to the carbons
The stereochemistry at C13 of the tert-butylperoxy
compound 7 was determined through NOE studies as
described above for bromo compound 4. Since the same
results were obtained, the sterochemistry of the 13-tert-
butylperoxy group was assigned as 13â.
at C1 and C13. The diene
6 was subjected to epoxidation and
dihydroxylation reagents such as mCPBA, oxone, OsO4, and VO(acac)2.
However, starting material was recovered in all cases.
(14) Nicolaou and co-workers reported that compound 3 can also
be converted to enone 8 by oxidation using excess of pyridiniumchlo-
rochromate (30 equiv) in refluxing benzene (75% yield). See also refs
10 and 11.
(15) Salvador, J . A. R.; Sa e´ Melo, M. L.; Campos Neves, A. S.
Tetrahedron Lett. 1997, 38, 119-122.
(16) Schultz, A. G.; Wang, A. J . Am. Chem. Soc. 1998, 120, 8259-
8260.
J . Org. Chem, Vol. 67, No. 20, 2002 7141

To effect the reductive cleavage of the oxygen-oxygen
bond in tert-butylperoxy compound 7 to form 13-epi-
baccatin III 9, a variety of hydride delivering reagents
were used, including LiAlH4, NaBH4, LiBH4, and L-
Selectride. However, none of these reagents provided the
desired product. The results of these reactions included
multiple ester cleavage products or recovery of the
starting taxane diterpene. Dimethyl sulfide, triphenyl-
phosphine, and trimethoxyphosphine were also unsuc-
cessfully employed in the attempted reductive cleavage
of the oxygen-oxygen bond of peroxide 7.18 Therefore,
we turned our attention to SmI2,19 as a reducing reagent,
which cleanly reacted with 7 to generate the desired
product, 13-epi-7-O-(triethylsilyl)baccatin III (9) in excel-
lent yield (86%, Scheme 2). The coupling constants
between H13 and both H14R and H14â of 13-epi-7-O-
(triethylsilyl)baccatin III (9) show 9.7 and 3.5 Hz, re-
spectively, which are similar to those reported before for
13-epi-paclitaxel.20
In 1995, the syntheses of 13-epi-paclitaxel and 4-de-
acetyl-13-epi-baccatin III via removal of the 4-acetyl
group of a 13-ketobaccatin III derivative were pub-
lished.20 The free 4-hydroxy group assisted in the trans-
annular delivery of a hydride [Me4NBH(OAc)3] to the 13-
ketone moiety yielding the corresponding 4-deacetyl-13-
epi-baccatin III. The new two-step preparation of 13-epi-
baccatin III from 13-deoxy-7-O-(triethylsilyl)baccatin III
by tert-butyl hydroperoxide oxidation followed by SmI2
reduction avoids the deacetylation and reacetylation at
C4.
Mitsunobu conditions were then utilized in an attempt
to invert the C13 stereochemistry of 13-epi-baccatin III
9; however, starting material was recovered in all cases
investigated.21 These results are in agreement with the
observation that the cup-shaped conformation of the
taxane diterpene ring disfavors reactions at C13 from the
concave side of the molecule.10,11
13-epi-7-O-(Triethylsilyl)baccatin III (9) was treated
with tetrapropylammonium perruthenate (TPAP) and
N-methylmorpholine N-oxide (NMO) to obtain 13-oxo-7-
O-(triethylsilyl)baccatin III (8) in 81% yield (Scheme 2).
The structure of 8 was identical in all respects to the
compound described in the literature.10,11 Compound 8
can be converted regio- and stereoselectively to 7-O-
(triethylsilyl)baccatin III by reduction with NaBH4.10,11
(Triethylsilyl)baccatin III (9) was oxidized to 13-oxo-7-
O-(triethylsilyl)baccatin III (8) using TPAP/NMO condi-
tions.
Exp er im en ta l Section
Gen er a l. 1H NMR and 13C NMR spectra were recorded in
CDCl3 on a Bruker DRX-400 spectrometer operating at 400
MHz, and 100 MHz, respectively. High-resolution mass spec-
trometry (HRMS) spectra were obtained on a VG instrument
ZAB double-focusing mass spectrometer. Column chromatogra-
phy was carried out employing silica gel (EM-9385-9, 230-400
mesh). Analytical thin-layer chromatography (TLC) was per-
formed on a silica gel 60F254 plate (EM-5717, Merck). SmI2 was
freshly prepared from samarium metal and 1,2-diiodoethane
using the procedure described by Kagan.22 THF and CH2Cl2 were
distilled before use, and anhydrous solvents were purchased
commercially.
13-Deoxy-7-O-(tr ieth ylsilyl)ba cca tin III (3). To a solution
of 13-deoxybaccatin III (2, 102 mg, 0.18 mmol) in DMF (3 mL)
were added TESCl (300 µL, 10 equiv) and 4-(dimethylamino)-
pyridine (catalytic amount). The reaction mixture was stirred
at room temperature for 17 h and then poured into ice water
(10 mL) and extracted with CH2Cl2. The organic phase was
washed with 10% HCl, saturated NaHCO3, and brine solution.
The organic phase was dried over anhydrous Na2SO4, and the
solvent was removed under reduced pressure. The residue was
purified by flash silica gel column chromatography (2:1 EtOAc/
hexane) to give 3 (117 mg, 95%) as a white solid: mp 208-209
°C; Rf 0.74 (1:1 EtOAc/hexane); [R]20 -6.32 (c 0.590, CHCl3).
D
The structure of 3 was identical in all respects to the compound
described in the literature.10,11
13-Deoxy-13â-ter t-bu tylp er oxy-7-O-(tr ieth ylsilyl)ba cca -
tin III (7). To a solution of 13-deoxy-7-O-(triethylsilyl)baccatin
III (3, 80 mg, 0.12 mmol) in benzene (5 mL) in an ice-water
bath was added tert-butyl hydroperoxide (400 µL, 70 wt % in
water). The reaction mixture was heated at 60 °C for 7 h; the
reaction was quenched with water (5 mL), and the mixture was
and extracted with EtOAc. The organic layer was dried over
anhydrous Na2SO4, and then the solvent was evaporated. The
residue was purified by flash silica gel column chromatography
(1:4 EtOAc/hexane) to give 7 (72 mg, 78%) as a white solid: mp
169-170 °C; Rf 0.54 (1:2 EtOAc/hexane); IR (KBr) υ 3500 (br),
1
2960, 2875, 1745, 1724, 1716, 1370, 1238, 1102 cm-1; H NMR
δ 8.13 (d, J ) 7.1 Hz, 2H), 7.62 (t, J ) 7.4 Hz, 1H), 7.51 (t, J )
7.5 Hz, 2H), 6.49 (s, 1H), 5.65 (d, J ) 6.8 Hz, 1H), 4.99 (d, J )
8.0 Hz, 1H), 4.47 (dd, J ) 6.9 10.0 Hz, 1H), 4.34 (A of AB, d,
J ) 8.4 Hz, 1H), 4.29 (dd, J ) 3.0, 9.0 Hz, 1H), 4.18 (B of AB, d,
J ) 8.4 Hz, 1H), 3.60 (d, J ) 6.8 Hz, 1H), 2.63 (dd, J ) 9.6, 16.0
Hz, 1H), 2.56 (m, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H),
2.16 (dd, J ) 2.5, 16.0 Hz, 1H), 1.89 (m, 1H), 1.69 (s, 3H), 1.28
(s, 9H), 1.25 (s, 3H), 1.19 (s, 3H), 0.94 (t, J ) 7.8 Hz, 9H), 0.59
(dq, J ) 2.2, 7.9 Hz, 6H); 13C NMR δ 202.0, 170.6, 169.9, 167.2,
140.5, 138.2, 134.0, 130.5, 129.7, 129.0, 84.3, 83.6, 81.7, 81.0,
80.6, 76.7, 76.4, 73.4, 72.8, 59.5, 47.3, 42.6, 37.8, 33.9, 32.0, 27.1,
22.5, 21.4, 19.4, 10.1, 7.2, 5.7; HRMS (FAB) m/z calcd for
In conclusion, an efficient synthetic pathway has been
developed to prepare 13-epi-baccatin III by oxidation of
13-deoxy-7-O-(triethylsilyl)baccatin III (3) with tert-butyl
peroxide, followed by reduction with SmI2. 13-epi-7-O-
C41H64O12SiN [M + NH4]+ 790.4198, found 790.4215; [R]20
-3.64 (c 0.560, CHCl3).
D
(17) Chidambaram, N.; Chandrasekaran, S. J . Org. Chem. 1987, 52,
5048-5051.
13-Oxo-7-O-(tr ieth ylsilyl)ba cca tin III (8). To a solution of
13-epi-7-O-(triethylsilyl)baccatin III (9, 1 mg, 0.0014 mmol) in
CH2Cl2 (0.3 mL) were added TPAP (catalytic amount) and NMO
(2 mg). The reaction mixture was stirred at room temperature
for 2 h. The solution was purified by filtration over silica gel
(1:3 EtOAc/hexane) to give 8 (0.8 mg, 81%) as a white solid: Rf
0.36 (1: EtOAc/hexane). The structure of 8 was identical in all
respects to the compound described in the literature.10,11
(18) Matsusita, Y.; Sugamoto, K.; Matsui, T. Chem. Lett. 1993, 925-
928.
(19) Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett.
1995, 36, 7419-7422.
(20) Hoemann, M. Z.; Vander Velde, D. G.; Aube´, J .; Georg, G. I.;
J ayasinghe, L. R. J . Org. Chem. 1995, 60, 2918-2921.
(21) Treatment of 9 with diethyl azodicarboxylate (DEAD), trimeth-
ylphosphine, and chloroacetic acid (or p-nitrobenzoic acid) in toluene
at 90 °C resulted in the formation of elimination product 6 instead of
providing baccatin III 10 (Scheme 2). Other conditions for the Mit-
sunobu reaction of 9 were investigated ((a) triphenylphosphine, p-
nitrobenzoic acid, DEAD, at room temperature in THF; (b) triphen-
ylphosphine, p-nitrobenzoic acid, DEAD, at 90 °C in toluene; (c)
trimethylphosphine, p-nitrobenzoic acid, DEAD, at room temperature
in THF).
13-epi-7-O-(Tr ieth ylsilyl)ba cca tin III (9). To a solution of
7 (20 mg, 0.026 mmol) in dry THF (2 mL) under argon was added
SmI2 (0.1 M solution in THF) until the color of the reaction
(22) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693-2698.
7142 J . Org. Chem., Vol. 67, No. 20, 2002

became dark blue. The reaction mixture was stirred at room
temperature for 3.5 h. The reaction solution was diluted with
methylene chloride (10 mL), and the solution was washed with
10% Na2S2O3. The organic layer was dried over MgSO4, and the
solvent was removed under reduced pressure. The residue was
purified by filtration over silica gel (5:1 EtOAc/hexane) to give
9 (15.5 mg, 86%) as a white solid: mp 201-202 °C dec; Rf 0.15
(1:2 EtOAc/hexane); IR (KBr) υ 3491 (br), 2956, 2877, 1723, 1371,
m/z calcd for C37H53O11Si [M + H]+ 701.3357, found 701.3383;
[R]20 -3.61 (c 0.815, CHCl3).
D
Ack n ow led gm en t. This work was generously sup-
ported by the Samyang Genex Corporation in Korea.
The starting material 13-deoxybaccatin III (2) was
provided to us for this study by the Samyang Genex
Corporation. This work was supported in part by the
Kansas Technology Enterprise Corporation through the
Centers of Excellence Programs and the National
Institutes of Health.
1248, 1108 cm-1 1H NMR δ 8.11 (d, J ) 7.2 Hz, 2H), 7.62 (t,
;
J ) 7.4 Hz, 1H), 7.49 (t, J ) 7.5 Hz, 2H), 6.46 (s, 1H), 5.66 (d,
J ) 7.0 Hz, 1H), 4.96 (d, J ) 8.3 Hz, 1H), 4.46 (dd, J ) 6.8, 10.4
Hz, 1H), 4.32 (A of AB, d, J ) 8.4 Hz, 1H), 4.17 (B of AB, d, J )
8.4 Hz, 1H), 3.97 (dd, J ) 3.5, 9.7 Hz, 1H), 3.76 (s, 1H), 3.62 (d,
J ) 7.1 Hz, 1H), 2.73 (dd, J ) 9.8, 15.7 Hz, H), 2.54 (m, 1H),
2.33 (s, 3H), 2.21 (s, 3H), 2.16 (dd, J ) 3.4, 8.4 Hz, 1H), 1.89 (m,
1H), 1.69 (s, 3H), 1.29 (s, 9H), 1.27 (s, 3H), 1.19 (s, 3H), 0.94 (t,
J ) 7.8 Hz, 9H), 0.59 (dq, J ) 2.2, 7.9 Hz, 6H); 13C NMR δ 202.0,
170.5, 169.7, 167.3, 140.8, 138.2, 134.1, 130.4, 129.7, 129.0, 84.4,
83.8, 81.7, 76.7, 76.6, 73.4, 72.7, 70.0, 68.4, 59.4, 47.4, 42.5, 37.7,
36.8, 32.0, 30.1, 22.6, 21.4, 19.6, 18.7, 10.1, 7.1, 5.7; HRMS (FAB)
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for formation of compounds 4-6, reaction of 4 with
sodium azide or silver acetate, and attempted Mitsunobu
reactions with compound 9 and 1H and 13C NMR spectra for
compounds 3-7 and 9. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O011183Q
J . Org. Chem, Vol. 67, No. 20, 2002 7143