Synthesis and biological evaluation of 2-epi-paclitaxel

Full text of DOI:10.1021/jo951530u

J . Org. Chem. 1996, 61, 799-801
799
thenate(VII)/N-methylmorpholine N-oxide (TPAP/NMO)
in CH2Cl2 at room temperature then gave a good yield of
the 2-oxo compound 4 (Scheme 1). Compound 4 was
characterized primarily on the basis of its 1H and 13C-
Syn th esis a n d Biologica l Eva lu a tion of
2-epi-P a clita xel
Mahendra D. Chordia and David G. I. Kingston*
1
NMR spectra; in its H-NMR spectrum the signal for H-2
was missing and H-3 appeared as a singlet at 4.12 ppm,
while in its 13C-NMR spectrum the resonance for C-2
appeared at 199.9 ppm.
Department of Chemistry, Virginia Polytechnic Institute and
State University, Blacksburg, Virginia 24061-0212
Received August 18, 1995
Reduction of 4 with NaBH4 in THF/MeOH at room
temperature gave exclusive formation of a single new
compound 5 more polar than the 2-debenzoyl compound
Studies both in our laboratories1 and in those of others2
have demonstrated convincingly that the presence of an
aroyl substituent at the C-2 position of paclitaxel (1) is
necessary for full biological activity and that the nature
of the aroyl substituent can cause profound changes (both
positive and negative) in the extent of this activity. The
reasons for this requirement of a 2-aroyl group are not
fully understood, although one intriguing hypothesis is
based on the observation that a “hydrophobic collapse”
of the C-3′ phenyl, the C-2 benzoyl, and the C-4 acetate
occurs in polar solvents.3 It is proposed that the occur-
rence of this collapse is related to the bioactivity of
paclitaxel, but it is not clear why there is an apparent
linkage between bioactivity and hydrophobic collapse.
Although a number of different aroyl groups have been
substituted for the benzoyl group at the C-2 position of
paclitaxel,1,2 all the substitutions to date have retained
the original 2R stereochemistry of paclitaxel. The syn-
thesis of 2-epi-paclitaxel would provide further insight
into the structural and stereochemical requirements for
activity, and we herein report such a synthesis.
The synthesis of 2-epi-paclitaxel proceeded through the
key 2-debenzoylpaclitaxel intermediate 3. Various meth-
ods for the preparation of 2-debenzoylpaclitaxels have
been reported,1b,2 including reduction with Red-Al,2e
electroreduction,2g and treatment with potassium tert-
butoxide.2h In our original report,1b we described the use
of phase transfer catalysis, but we have subsequently
developed a more convenient procedure involving the
reaction of 2′-(tert-butyldimethylsilyl)-7-(triethylsilyl)-
paclitaxel (2) with Triton B (40% trimethylbenzylammo-
nium hydroxide in MeOH) in CH2Cl2 at -78 to -10 °C.
This procedure gave the 2-debenzoyl derivative 3 in 75%
yield. Oxidation of 3 with tetrapropylammonium perru-
1
3. The H-NMR spectrum of 5 showed the resonance of
H-2R as a doublet (J ) 2.4Hz; coupling to the OH proton)
at 3.62 ppm and that of H-3R as a singlet at 3.41 ppm,
consistent with a dihedral angle of approximately 90°
between H-2R and H-3R. The 13C-NMR spectrum of 5
included a resonance for C-2 at 83.1 ppm in place of the
carbonyl carbon of 4. The stereochemistry of C-2 was
confirmed by a NOESY spectrum, which showed correla-
tions between H-2R and H-3R and H-14R. The possibility
that epimerization had occurred at C-3 prior to reduction
was eliminated by the observation of NOESY correlations
in 5 or its benzoate 6 between H-3R and H-7R and H3-
18; no correlation was observed between H-3R and H3-
19.
The stereoselectivity of the reduction can be explained
by changes in the conformation of the eight-membered
B ring that favored attack of hydride ion from the less
hindered R-face of the molecule. The low energy confor-
mation of 4 as obtained from the Chem3D program is
shown in Figure 1 and indicates that the expected
complexation of borohydride with the C-1 OH group
would favor attack from the bottom face of the molecule,
and not from the top face as might be expected. Attack
from the top face is also hindered by the C-17 and the
C-19 methyl groups, which project over the approach
vector for â-attack; although the bottom face is also
hindered, the hindering groups on this face can rotate
away from the approach vector for R-attack.
Benzoylation of 5 under standard conditions (benzoic
acid/DCC/PP) gave the protected 2-epi-paclitaxel 6, and
deprotection of 6 with HF/pyridine furnished 2-epi-
1
paclitaxel 7. The H-NMR spectrum of 7 was similar to
that of paclitaxel, except that the signals for H-2R and
H-3R appeared as singlets at 5.41 and 3.69 ppm, respec-
tively. A NOESY spectrum of 7 showed correlations
between H-2R and H-20R, H-20â, H-3R, and H-14R, as
well as between H-3R and H-7R; this latter correlation
excluded the possibility that epimerization of H-3R of
ketone 4 had taken place. An additional prominent
correlation was observed between the ortho protons of
the C-2â benzoyloxy group and the C-17 and C-19 methyl
protons. All these correlations confirm the structural
assignment of 7 as 2-epi-paclitaxel.
Bioassay of 7 in a tubulin-assembly assay and an HCT
116 cytotoxicity assay indicated that the compound was
inactive in both assays. This result thus provides further
evidence for the importance of the nature and stereo-
chemistry of the 2-aroyl group for the bioactivity of
paclitaxel.
(1) (a) Chaudhary, A. G.; Chordia, M. D.; Kingston, D. G. I. J . Org.
Chem. 1995, 60, 3260-3262. (b) Chaudhary, A. G.; Gharpure, M. M.;
Rimoldi, J . M.; Chordia, M. D.; Gunatilaka, A. A. L.; Kingston, D. G.
I.; Grover, S.; Lin, C. M.; Hamel, E. J . Am. Chem. Soc. 1994, 116,
4097-4098. (c) Grover, S.; Rimoldi, J . M.; Molinero, A. A.; Chaudhary,
A. G., Kingston, D. G. I.; Hamel, E. Biochemistry 1995, 34, 3927-3934.
(2) (a) Chen, S.-H.; Wei, J .-M.; Farina, V. Tetrahedron Lett. 1993,
34, 3205-3206. (b) Chen, S.-H.; Huang, S.; Gao, Q.; Golik, J .; Farina,
V. J . Org. Chem. 1994, 59, 1475-1484. (c) Boge, T. C.; Himes, R. H.;
Vander Velde, D. G.; Georg, G. I. J . Med. Chem. 1994, 37, 3337-3343.
(d) Georg, G. I.; Ali, S. M.; Boge, T. C.; Datta, A.; Falborg, L.; Himes,
R. H. Tetrahedron Lett. 1994, 35, 8931-8934. (e) Chen, S.-H.; Farina,
V.; Wei, J .-M.; Long, B.; Fairchild, C.; Mamber, S. W.; Kadow, J . F.;
Vyas, D.; Doyle, T. W. Bioorg. Med. Chem. Lett. 1994, 4, 479-482. (f)
Nicolaou, K. C.; Couladouras, E. A.; Nantermet, P. G.; Renaud, J .; Guy,
R. K.; Wrasidlo, W. Angew. Chem., Int. Ed. Engl. 1994, 33, 1581-
1583. (g) Pulicani, J .-P.; Be´zard, D.; Bourzat, J .-D.; Bouchard, H.;
Zucco, M.; Deprez, D.; Commerc¸on, A. Tetrahedron Lett. 1994, 32,
9717-9720. (h) Georg, G. I.; Ali, S. M.; Boge, T. C.; Datta, A.; Falborg,
L.; Park, H.; Mejillano, M.; Himes, R. H. Bioorg. Med. Chem. Lett. 1995,
5, 259-264.
(3) (a) Paloma, L. G.; Guy, R. K.; Wrasidlo, W.; Nicolaou, K. C. Chem.
Biol. 1994, 1, 107-112. (b) Vander Velde, D. G.; Georg, G. I.;
Grunewald, G. L.; Gunn, C. W.; Mitscher, L. A. J . Am. Chem. Soc.
1993, 115, 11650-11651. (c) Dubois, J .; Gue´nard, D.; Gue´ritte-
Voegelein, F.; Guerida, N.; Potier, P.; Gillet, B.; Beloeil, J .-C. Tetra-
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Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were procured from Aldrich
Chemical Co. and were used without further purification. All
anhydrous reactions were performed under argon. THF was
dried over sodium/benzophenone. All reactions were monitored
0022-3263/96/1961-0799$12.00/0 © 1996 American Chemical Society

800 J . Org. Chem., Vol. 61, No. 2, 1996
Notes
Sch em e 1a
a
t
Key: (a) BuMe2SiCl, imidazole, DMF, 60 °C, 1 h, and then Et3SiCl, imidazole, rt; (b) Triton B, CH2Cl2, -78 to -10 °C; (c) TPAP,
NMO, CH2Cl2, rt, 3 h; (d) NaBH4, THF, MeOH, rt, 1 h; (e) PhCOOH, DCC, pyrrolidinopyridine, toluene, 60 °C; (f) HF/pyridine, THF, rt,
2 h.
1 h, the reaction mixture was diluted with ethyl acetate and
washed successively with water and brine. Drying of the organic
layer over Na2SO4 and evaporation under reduced pressure
yielded crude material, which was purified by column chroma-
tography over silica gel (EtOAc:hexanes, 1:2) to give 2′-(tert-
butyldimethylsilyl)-7-(triethylsilyl)paclitaxel (2) (325 mg, 95%)
as an amorphous solid: mp 130-131 °C; 1H-NMR δ -0.20 (s,
3H), -0.02 (s, 3H), 0.62 (q, J ) 7.8, 6H), 0.79 (s, 9H), 0.92 (t, J
) 7.8, 9H), 1.17 (s, 3H), 1.21 (s, 3H), 1.70 (s, 3H), 2.02 (bs, 3H),
2.16 (s, 3H), 2.40 (m, 1H), 2.55 (m, 1H), 2.58 (s, 3H), 3.83 (d, J
) 7.0, 1H), 4.19 (d, J ) 8.3, 1H), 4.30 (d, J ) 8.3, 1H), 4.48 (dd,
J ) 9.4,6.6, 1H), 4.67 (d, J ) 2.1, 1H), 4.94 (bd, J ) 8.8, 1H),
5.69 (d, J ) 7.0, 1H), 5.74 (dd, J ) 9.0,2.1, 1H), 6.26 (bt, 1H),
6.45 (s, 1H), 7.10 (d, J ) 8.9, 1H), 7.30-7.60 (m, 11H), 7.74 (dd,
J ) 8.5,1.5, 2H), 8.13 (dd, J ) 8.5,1.4, 2H). 13C-NMR δ -5.86,
-5.20, 5.27, 6.73, 10.11, 14.24, 18.11, 20.85, 21.50, 23.10, 25.49,
26.54, 35.55, 37.21, 43.31, 46.64, 55.63, 58.39, 71.36, 72.19, 74.92,
74.95, 75.10, 76.55, 78.82, 81.17, 84.22, 126.40, 126.97, 127.92,
128.68, 128.70, 128.71, 129.19, 130.20, 131.76, 133.60, 133.66,
134.03, 138.26, 140.14, 166.88, 167.03, 169.28, 170.13, 171.38,
201.67; MS m/ z (rel int) [M + Na]+ 1104 (5), 705 (3) 422 (40),
354 (12), 105 (100); HRMS calcd for C59H79NO14Si2Na [M + Na]+
m/ z 1104.4937, found 1104.4936.
F igu r e 1.
2′-(ter t-Bu tyld im eth ylsilyl)-2-d eben zoyl-7-(tr ieth ylsilyl)-
by TLC (silica gel, GF) and analyzed with UV light and
developed with vanillin spray. FTIR spectra were recorded on
a Nicolet Impact 400 spectrophotometer. 1H NMR and 13C NMR
spectra were obtained in CDCl3 at 270 and 400 MHz for proton
spectra and assigned primarily by comparison of chemical shifts
and coupling constants with those of related compounds and by
appropriate 2D NMR techniques. Coupling constants are
reported in Hz. 13C NMR spectra were assigned with the aid of
HETCOR and DEPT spectra. Some 1H NMR spectra showed
the presence of traces of ethyl acetate; paclitaxel and its
derivative retain ethyl acetate very tightly, and it cannot be
removed completely even on prolonged treatment in vacuo at
38 °C. FAB mass spectra and exact mass measurements were
obtained at the Nebraska Center for Mass Spectrometry.
Biological evaluation was carried out at the Bristol-Myers Squibb
Pharmaceutical Research Institute, Princeton.
p a clita xel (3). To a solution of 2′-(tert-butyldimethylsilyl)-7-
(triethylsilyl)paclitaxel (2) (110.4 mg, 0.1 mmol) in anhydrous
CH2Cl2 (5mL) was added benzyltrimethylammonium hydroxide
(100 mL, 40% w/w solution in methanol) at -78 °C. The reaction
mixture was stirred at -78 °C for 10 min, and the reaction flask
was transferred to a -10 °C bath (diethylene glycol, dry ice) and
stirred at -10 °C for 10-15 min. During this time, the progress
of the reaction was monitored by TLC, which indicated the
formation of a more polar compound. The mixture was then
diluted with cold CH2Cl2 (-78 °C, 10 mL) and quenched with 5
mL of 0.1 N HCl. The organic layer was washed successively
with water, dilute NaHCO3, and brine and dried over Na2SO4.
Concentration under reduced pressure gave crude residue, which
was purified by preparative TLC (silica gel, 1000 µm, EtOAc:
hexanes, 2:3) to yield compound 3 (73.0 mg, 75%) and starting
material (11.0 mg, 10%). Compound 3: mp 133-35 °C; 1H-NMR
δ -0.28 (s, 3H), -0.04 (s, 3H), 0.57 (q, J ) 7.8, 6H), 0.80 (s, 9H),
0.92 (t, J ) 7.8, 9H), 1.07 (s, 3H), 1.15 (s, 3H), 1.62 (s, 3H), 1.96
(bs, 3H), 2.14 (s, 3H), 2.40 (m, 1H), 2.51 (m, 1H), 2.42 (s, 3H),
2.79 (d, J ) 5.9, 1H), 3.46 (d, J ) 7.0, 1H), 3.92 (t, J ) 6.3, 1H),
4.41 (dd, J ) 9.4, 6.6, 1H), 4.60 (d, J ) 1.6, 1H), 4.63 (bs, 2H),
4.95 (bd, J ) 8.6, 1H), 5.67 (dd, J ) 9.2, 1.6, 1H), 6.24 (bt, 1H),
6.37 (s, 1H), 7.05 (d, J ) 9.2, 1H), 7.30-7.54 (m, 8H), 7.74 (dd,
J ) 8.3, 1.5, 2H); MS m/ z (rel int) [M + Na]+ 1000 (3), 400 (22)
2′-(ter t-Bu tyldim eth ylsilyl)-7-(tr ieth ylsilyl)paclitaxel (2).
To a stirred solution of paclitaxel 1 (270 mg, 0.316 mmol) in 2.5
mL of anhydrous DMF were added imidazole (107 mg, 1.58
mmol) and tert-butyldimethylsilyl chloride (238 mg, 1.58 mmol).
The solution was heated at 60 °C for 2 h. The mixture was
cooled to room temperature, and additional amounts of imidazole
(107 mg, 1.58 mmol) and triethylsilyl chloride (150 µL, 1.34
mmol) were added. After being stirred at room temperature for

Notes
J . Org. Chem., Vol. 61, No. 2, 1996 801
354 (84), 105 (100); HRMS calcd for C52H75NO13Si2Na [M + Na]+
m/ z 1000.4675, found 1000.4632.
mixture was diluted with EtOAc and filtered through a pad of
Celite and silica gel to remove a white solid. The filtrate was
concentrated and purified by preparative TLC (silica gel, 500
µm, EtOAc:hexane, 1:4, 3-fold elution) to yield compound 6 (20.0
mg, 82%): 1H-NMR δ -0.28 (s, 3H), -0.02 (s, 3H), 0.58 (q, J )
7.8, 6H), 0.80 (s, 9H), 0.93 (t, J ) 7.8, 9H), 1.14 (s, 3H), 1.42 (s,
3H), 1.71 (s, 3H), 1.99 (bs, 3H), 2.19 (s, 3H), 2.40 (dd, J ) 9.2,
15.4, 1H), 2.50 (s, 3H), 3.73 (s, 1H), 4.25 (d, J ) 8.0), 4.47 (dd,
J ) 6.4, 10.4, 1H), 4.49 (d, J ) 8.0, 1H), 4.64 (d, J ) 2.0, 1H),
5.01 (bd, J ) 8.4, 1H), 5.36 (s, 1H), 5.72 (dd, J ) 9.2, 2.0, 1H),
6.25 (bt, J ) 9.2, 1H), 6.49 (s, 1H), 7.05 (d, J ) 9.2, 1H), 7.30-
7.60 (m, 8H), 7.78 (dd, J ) 1.6, 7.2, 2H), 8.01 (dd, J ) 1.6, 7.2,
2H); 13C-NMR δ -5.84, -5.18, 5.35, 6.73, 12.46, 14.29, 18.11,
20.85, 22.98, 24.91, 25.50, 26.22, 37.56, 40.83, 43.34, 44.24, 55.38,
58.35, 71.00, 73.25, 74.59, 75.05, 75.27, 77.83, 80.41, 81.55, 83.33,
126.41, 127.00, 127.92, 128.68, 128.78, 128.97, 130.17, 131.83,
133.62, 134.09, 134.72, 138.19, 139.77, 166.93, 167.00, 169.35,
169.92, 171.31, 202.71; MS m/ z (rel int) [M + Na]+ 1104 (11);
HRMS calcd for C59H79NO14Si2Na [M + Na]+ m/ z 1104.4937,
found 1104.4928.
Oxid a tion of 2′-(ter t-Bu tyld im eth ylsilyl)-2-d eben zoyl-7-
(tr ieth ylsilyl)p a clita xel (3) w ith TP AP /NMO. To a solution
of 2′-(tert-butyldimethylsilyl)-2-debenzoyl-7-(triethylsilyl)pacli-
taxel (3) (49.0 mg, 0.05 mmol) in dry CH2Cl2 were added
tetrapropylammonium perruthenate (5.0 mg, 0.014 mmol, cata-
lytic) and N-methylmorpholine N-oxide (23.0 mg, 0.196 mmol).
The mixture was stirred at room temperature for 3 h. The
mixture then diluted with CH2Cl2 and filtered through a short
column of Celite and silica gel. The crude compound thus
obtained was purified by column chromatography over silica gel
to give compound 4 as a colorless glassy solid (42.0 mg, 86%):
FTIR (CHCl3) 1751, 1740, 1736, 1724, 1700, 1663 cm-1; 1H NMR
δ -0.32 (s, 3H), -0.04 (s, 3H), 0.57 (q, J ) 7.8, 6H), 0.80 (s, 9H),
0.92 (t, J ) 7.8, 9H), 1.20 (s, 3H), 1.58 (s, 3H), 1.94 (m, 1H),
1.94 (s, 3H), 1.99 (bs, 3H), 2.03 (dd, J ) 9.2,15.2, 1H), 2.14 (s,
3H), 2.31 (dd, J ) 8.8, 15.2, 1H), 2.43 (s, 3H), 2.52 (m, 1H), 4.12
(s, 1H), 4.35 (dd, J ) 6.8, 10.4, 1H), 4.43 (d, J ) 8.8, 1H), 4.62
(d, J ) 1.6, 1H), 4.69 (s, 1H), 4.96 (bd, J ) 8.0, 1H), 5.46 (d, J )
8.8, 1H), 5.69 (dd, J ) 1.6, 9.2, 1H), 6.35 (bt, J ) 8.0, 1H), 6.45
(s, 1H), 7.02 (d, J ) 9.2, 1H), 7.24-7.54 (m, 8H), 7.75 (dd, J )
8.3, 1.5, 2H); 13C-NMR δ -5.88, -5.19, 5.20, 6.74, 10.68, 14.53,
18.11, 20.76, 22.64, 22.96, 25.18, 25.50, 34.51, 38.03, 43.00, 49.75,
55.38, 58.33, 70.62, 72.25, 74.81, 75.21, 75.77, 82.15, 82.77, 83.36,
126.35, 127.00, 127.93, 128.70, 128.80, 131.86, 134.04, 134.64,
138.22, 140.50, 166.89, 169.18, 170.38, 171.14, 199.94, 210.94;
MS m/ z (rel int) [M + Na]+ 998.4 (40), 599 (14) 422 (100), 354
(21), 172 (17); HRMS calcd for C52H73NO13Si2Na [M + Na]+m/ z
998.4518, found 998.4523.
2-epi-P a clita xel (7). To a solution of 2-epi-2′-(tert-butyldi-
methylsilyl)-7-(triethylsilyl)paclitaxel (6) (18.0 mg, 0.017 mmol)
in dry THF (0.5 mL) was added HF/pyridine (0.1 mL) in a Teflon
vial. The mixture was stirred at room temperature for 2 h. The
mixture was then diluted with EtOAc (10 mL) and washed
throughly with dilute NaHCO3, dilute HCl, H2O, and finally
brine. The organic layer was separated, dried over Na2SO4, and
evaporated to yield crude product, which was purified by
preparative TLC (silica gel, 500 µm, EtOAc:hexane, 1:1, double
elution) to yield compound 7 (11.4 mg, 80%): FTIR (Nujol) 1739,
R ed u ct ion of 2′-(ter t-Bu t yld im et h ylsilyl)-2-d eb en zoyl-
2-oxo-7-(tr ieth ylsilyl)p a clita xel (4) w ith Sod iu m Bor oh y-
d r id e. To a solution of the 2-oxo compound 4 (35.0 mg, 0.036
mmol) in THF (1.0 mL) and MeOH (100 µL) was added NaBH4
(6.0 mg, 0.15 mmol), and the mixture was stirred at room
temperature for 1 h. TLC analysis indicated the formation of a
more polar spot (Rf 0.2 in EtOAc:hexane, 40:60). The mixture
was diluted with EtOAc (5 mL) and washed successively with
water, and the organic layer was separated, dried over Na2SO4,
and concentrated under reduced pressure. The crude material
obtained as syrup was purified by preparative TLC (silica gel,
500 µm, EtOAc:hexane, 40:60, double elution) to yield 2-epi-2′-
(tert-butyldimethylsilyl)-2-debenzoyl-7-(triethylsilyl)paclitaxel (5)
(27.5 mg, 78%) as an amorphous white solid: 1H-NMR δ -0.28
(s, 3H), -0.02 (s, 3H), 0.57 (q, J ) 7.8, 6H), 0.79 (s, 9H), 0.92 (t,
J ) 7.8, 9H), 1.05 (s, 3H), 1.27 (s, 3H), 1.68 (dd, J ) 9.2, 15.6,
1H), 1.78 (s, 3H), 1.93 (bs, 3H), 2.13 (s, 3H), 2.36 (s, 3H), 2.38
(m, 1H), 2.51 (m, 1H), 3.14 (s, 1H), 3.41 (s, 1H), 3.46 (bs, 1H),
3.62 (d, J ) 2.4, 1H), 4.40 (dd, J ) 6.4, 10.0, 1H), 4.49 (d, J )
7.2, 1H), 4.60 (d, J ) 1.6, 1H), 4.99 (m, 2H), 5.64 (dd, J ) 9.2,
1.6, 1H), 6.25 (bt, J ) 7.6, 1H), 6.35 (s, 1H), 7.07 (d, J ) 9.2,
1H), 7.30-7.51 (m, 8H), 7.71 (dd, J ) 6.8, 1.6, 2H); 13C-NMR δ
-5.83, -5.16, 5.30, 6.76, 12.84, 14.06, 18.11, 20.88, 22.56, 22.86,
25.49, 26.08, 37.56, 40.49, 43.72, 44.25, 55.32, 58.28, 71.02, 73.07,
74.77, 75.05, 75.14, 76.75, 81.77, 83.12, 83.61, 126.33, 126.95,
128.02, 128.72, 128.87, 132.01, 133.77, 135.31, 137.97, 138.64,
167.42, 169.41, 169.00, 171.14, 202.15; MS m/ z (rel int) [M +
Li]+ 984 (28), 585 (10), 406 (100), 177 (16); HRMS calcd for
1735, 1718, 1458, 1376, cm-1 1H-NMR δ 1.19 (s, 3H), 1.36 (s,
;
3H), 1.68 (s, 3H), 1.77 (bs, 3H), 1.87 (m, 2H), 2.21 (s, 1H), 2.25
(s, 3H), 2.27 (s, 3H), 2.52 (m, 1H), 2.56 (d, J ) 4.4, 1H), 2.68
(dd, J ) 9.2, 15.2, 1H), 3.69 (s, 1H), 3.71 (d, J ) 5.2, 1H), 4.24
(d, J ) 8.4, 1H), 4.39 (m, 1H), 4.47 (d, J ) 8.4, 1H), 4.77 (dd, J
) 2.4, 5.2, 1H), 4.99 (d, J ) 8.4, 1H), 5.41 (s, 1H), 5.76 (dd, J )
1.6, 9.2, 1H), 6.20 (bt, J ) 8.0, 1H), 6.32 (s, 1H), 7.02 (d, J )
9.2, 1H), 7.35-7.62 (m, 8H), 7.75 (dd, J ) 7.2, 1.5, 2H), 7.99
(dd, J ) 7.2, 1.2, 2H); 13C-NMR δ 11.92, 14.88, 20.85, 22.48,
23.14, 26.41, 36.03, 41.19, 42.62, 43.97, 54.76, 58.44, 72.03, 72.91,
73.30, 74.61, 75.75, 77.71, 80.23, 81.55, 83.42, 127.03, 127.06,
128.33, 128.72, 128.78, 128.85, 128.98, 130.10, 131.99, 133.58,
133.74, 134.38, 137.96, 141.25, 166.92, 167.12, 170.18, 171.17,
172.60, 204.25; MS m/ z (rel int) [M + Li]+ 860 (40), 669 (57),
281 (41), 221 (65), 147 (100); HRMS calcd for C47H51NO14Li [M
+ Li]+ m/ z 860.3469, found 860.3458.
Ack n ow led gm en t. We are grateful to the National
Cancer Institute for financial support, Grant CA-55131.
A gift of crude paclitaxel-containing fractions from T.
brevifolia by Dr. K. Snader, NCI, is also gratefully
acknowledged. We thank Drs. Byron Long, Craig
Fairchild, and Kathy J ohnston (Bristol-Myers Squibb
Pharmaceutical Research Institute, Princeton) for the
biological evaluation.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 4-7, NOESY spectra of com-
pounds 5 and 7, and a listing of 1H-NMR peak assignments of
compounds 2-7 (12 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from ACS;
see any current masthead page for ordering information.
C
52H75NO13Si2Li [M + Li]+ m/ z 984.4937, found 984.4934.
Ben zoyla tion of 2-epi-2′-(ter t-Bu tyld im eth ylsilyl)-2-d e-
ben zoyl-7-(tr ieth ylsilyl)p a clita xel (5). To a mixture of the
title compound 5 (22.0 mg, 0.022 mmol), dicyclohexylcarbodi-
imide (45.3 mg, 0.22 mmol), benzoic acid (24.1 mg, 0.20 mmol),
and pyrrolidinopyridine (1.0 mg, catalytic) was added dry toluene
(0.1 mL), and the resulting heterogenous mixture was stirred
at 80 °C for 8 h. After being cooled to room temperature, the
J O951530U