Efficient synthesis of the 3′-phenolic metabolite of paclitaxel

Full text of DOI:10.1021/jo0102516

J . Org. Chem. 2001, 66, 8211-8214
8211
Notes
Efficien t Syn th esis of th e 3′-P h en olic
Meta bolite of P a clita xel
S. Hari Krishna Reddy, Stephen Lee, Apurba Datta, and
Gunda I. Georg*
Department of Medicinal Chemistry, and the Drug
Discovery Program, Higuchi Biosciences Center,
University of Kansas, Lawrence, Kansas 66045
georg@ku.edu
F igu r e 1. Structures of paclitaxel, docetaxel, and paclitaxel
metabolites.
Received March 7, 2001
Paclitaxel (1; Taxol) and docetaxel (2; Taxotere) have
emerged as two of the most effective antitumor agents
in a variety of malignancies.1-5 Acting via a similar
mechanism of action, both these drugs bind to tubulin,
leading to microtubule stabilization, mitotic arrest, and
subsequent cell death. Despite the great similarity in the
chemical structures and their mode of action, the meta-
bolic profile of paclitaxel and docetaxel was found to be
quite different.6,7 These taxanes are metabolized in the
liver by the cytochrome P-450 enzymes and are elimi-
nated in the bile. Extensive in vitro and in vivo studies
in animals and humans have resulted in the isolation
and identification of the various metabolites of paclitaxel
and docetaxel.6,7 Thus, the two major human metabolites
of paclitaxel were found to be 6-R-hydroxypaclitaxel (3)
and the phenolic 3′-(4-hydroxyphenyl)paclitaxel 4 deriva-
tive (Figure 1), whereas the primary metabolites of
docetaxel results from hydroxylation of the tert-butyl
group of the C3′ carbamate. Because of the limited
availability of pure metabolites, several research groups
including ours have undertaken synthesis of the various
paclitaxel and docetaxel metabolites.8-11 In a recent
project, however, we needed to synthesize multigram
quantities of the 3′-phenolic metabolite 4 of paclitaxel,
and as our earlier reported method lacked efficiency in
terms of larger scale synthesis, we decided to explore and
develop an alternative pathway more suited to our
present requirement. The details of the synthesis thus
undertaken are reported herein.
The Sharpless asymmetric aminohydroxylation proto-
col has been shown to be among the most efficient
methods for the large scale synthesis of enantiomerically
pure 3-phenylisoserine side chain of taxanes.12a We
therefore decided to employ the above aminohydroxyla-
tion reaction to synthesize the required 4-hydroxy sub-
stituted phenylisoserine side chain precursor followed by
its coupling with a baccatin III derivative to form the
target phenolic metabolite of paclitaxel.
Toward this end, Wittig olefination of commercially
available substrates, 4-benzyloxybenzaldehyde (5) and
(carboethoxymethylene)triphenylphosphorane, provided
the corresponding adduct 6 (Scheme 1) in high yield and
good E-selectivity (E/Z ) 9/1). This cinnamate derivative
6, when subjected to the Sharpless aminohydroxylation
reaction under known conditions,12 formed the expected
3-(4-benzyloxyphenyl)isoserinate derivative 7 in good
yield and high enantiomeric excess (94% by HPLC). For
the determination of the enantiomeric excess achieved
in this reaction, ent-7, the enantiomer of compound 7 was
prepared as well.
* To whom correspondence should be addressed. Phone: 785-864-
4498. Fax: 785-864-5836.
(1) For Review: Paclitaxel in Cancer Treatment; McGuire, W. P.,
Rowinsky, E. K., Eds.; Marcel Dekker: New York, 1995; Vol. 8.
(2) For Review: Taxane Anticancer Agents: Basic Science and
Current Status; Georg, G. I.; Chen, T. T.; Ojima, I.; Vyas, D. M., Eds.;
ACS Symposium Series 583; American Chemical Society: Washington,
DC, 1995.
Selective deacylation of the acetamide functionality
and subsequent Boc-protection of the amine yielded the
corresponding N-Boc derivative 8 in 90% yield. Acetonide
protection of the amino alcohol moiety to form the fully
protected oxazolidine carboxylate 9, followed by hydroly-
sis of the ester linkage, afforded the required C13 side
chain precursor amino acid 10 in good overall yield.
Esterification of the acid 10 with 7-Cbz-baccatin III (11)13
under standard conditions14 uneventfully afforded the
(3) For Review: Taxol Science and Applications; Suffness, M. Ed.;
CRC: Boca Raton, FL, 1995.
(4) For Review: The Chemistry and Pharmacology of Taxol and its
Derivatives; Farina, V., Ed.; Elsevier: Amsterdam, 1995.
(5) Eisenhauer, E. A.; Vermorken, J . B. Drugs 1998, 55, 5-30.
(6) Vuilhorgne, M.; Gaillard, C.; Sanderink, G. J .; Royer, I.; Mon-
sarrat, B.; Dubois, J .; Wright, M. In Taxane Anticancer Agents: Basic
Science and Current Status; Georg, G. I., Chen, T. T., Ojima, I., Vyas,
D. M., Eds.; ACS Symposium Series 583; American Chemical Society:
Washington, DC, 1995; pp 98-110.
(7) Wright, M.; Monsarrat, B.; Royer, I.; Rowinsky, E. K.; Done-
hower, R. C.; Cresteil, T.; Gue´nard, D. In The Chemistry and
Pharmacology of Taxol and its Derivatives; Farina, V., Ed.; Elsevier:
New York, 1995; pp 131-164.
(12) (a) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem.
1997, 109, 1580-1583. Angew. Chem., Int. Ed. Engl. 1997, 36, 1483-
1486. (b) Nicolaou, K. C.; Natarajan, S.; Li, H.; J ain, N. F.; Hughes,
R.; Solomon, M. E.; Ramanjulu, J . M.; Boddy, C. N. C.; Takayanagi,
M. Angew. Chem. 1998, 110, 2872-2878. Angew. Chem., Int. Ed. 1998,
37, 2708-2714.
(13) Sisti, N.; Swindell, C. S. Method for the Production of C(7)-
Cbz-Baccatin III as an Intermediate for the Preparation of Taxanes.
US Patent 6,133,462, 2000.
(8) Park, H.; Hepperle, M.; Boge, T. C.; Georg, G. I.; Himes, R. H.
J . Med. Chem. 1996, 39, 2705-2709.
(9) Yuan, H.; Kingston, D. G. I. Tetrahedron Lett. 1998, 38, 4967-
4970.
(10) Commerc¸on, A.; Bourzat, J . D.; Bezard, D.; Vuilhorgne, M.
Tetrahedron 1994, 50, 10289-10298.
(11) Wittman, M. D.; Kadow, J . F.; Vyas, D. M. Tetrahedron Lett.
2000, 41, 4729-4731.
10.1021/jo0102516 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

8212 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
Sch em e 1a
overall yield. Finally, a one-flask reductive debenzylation
of the O7-Cbz and 3′-phenolic hydroxy protecting groups
cleanly afforded the required paclitaxel metabolite 4 in
high yield.
The above reaction sequence is easily amenable to large
scale synthesis and by following the described route we
could efficiently prepare multigram quantities of the
target paclitaxel derivative 4 in high overall yield.
Exp er im en ta l Section 15
Eth yl E-(4-Ben zyloxy)cin n a m a te (6). A solution of 4-benz-
yloxybenzaldehyde (50.0 g, 0.236 mol) and (carboethoxymeth-
ylene)triphenylphosphorane (98.5 g, 0.282 mol) in anhydrous
CH2Cl2 (650 mL) was stirred at room temperature for 24 h. The
solvent was removed under reduced pressure, and the residue
was purified by flash column chromatography on silica gel.
Elution with 10% EtOAc/hexane afforded the E-cinnamate
[Rf (10% EtOAc/hexane): Z-6 ) 0.58; E-6 ) 0.47], which was
crystallized from EtOAc-hexane providing the pure product 6
as a white solid (60 g, 90%): mp 65-67 °C; IR (KBr) 1712, 1633
cm-1 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J ) 7.1 Hz, 3H),
;
a
(a) Ph3PdCHCO2Et, CH2Cl2; b K2[OsO2(OH)4], LiOH, (DHQ)2-
4.25 (q, J ) 7.0 Hz, 2H), 5.09 (s, 2H), 6.31 (d, J ) 15.8 Hz, 1H),
6.97 (d, J ) 8.6 Hz, 2H), 7.45-7.28 (m, 5H), 7.47 (d, J ) 8.6 Hz,
2H), 7.64 (d, J ) 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
167.32, 160.49, 144.20, 136,46, 129.72, 128,67, 128.16, 127.48,
127.42, 115,87, 115.18, 70.04, 60.35, 14.38; HRMS (FAB+) m/z
calcd for C18H19O3 [MH+]: 283.1334, found 283.1334.
PHAL, AcNHBr, MeCN-H2O, 4 °C; c (i) HCl-EtOH, 90 °C; (ii)
d
Boc2O, NaHCO3, THF; Me2C(OMe)2, PPTS, toluene, 90 °C;
e LiOH, MeOH-THF-H2O.
Sch em e 2a
Eth yl (2R,3S)-3-(Acetyla m in o)-3-[4-(ben zyloxy)p h en yl]-
2-h yd r oxyp r op a n oa te (7). In 335 mL of an aqueous solution
of LiOH‚H2O (7.59 g, 181 mmol) was dissolved K2[OsO2(OH)4]
(2.6 g, 7.1 mmol, 4 mol %) with stirring. After addition of t-BuOH
(665 mL), (DHQ)2PHAL (6.91 g, 8.87 mmol, 5 mol %) was added,
and the mixture was stirred for 10 min to give a clear solution.
The solution was then diluted with additional water (665 mL)
and immersed in a cooling bath set to 0 °C. A solution of the
cinnamate 6 (50.0 g, 177 mmol) in acetonitrile (335 mL) was
then added to the mixture, followed by addition of N-bromo-
acetamide (26.91 g, 195.1 mmol) in one lot, and the mixture was
vigorously stirred between 0 and 5 °C. After stirring for 24 h,
the reaction mixture was treated with Na2SO3 (89 g) and stirred
at room temperature for 30 min, and ethyl acetate (1 L) was
added to it. The organic layer was separated, and the water layer
was extracted three times with EtOAc. The combined organic
extracts were washed with brine and dried over MgSO4. After
evaporation of the solvent under reduced pressure, the crude
product was purified by flash chromatography on silica gel.
Elution with EtOAc/hexane (1:1) afforded 10% of the diol
byproduct followed by 40 g (70%) of the required amino alcohol
7 as a white crystalline solid: mp 124-126 °C; IR (KBr) 3359,
1
1716, 1650 cm-1; H NMR (400 MHz, CDCl3) δ 1.33 (t, J ) 7.1
Hz, 3H), 2.02 (s, 3H), 3.26 (d, J ) 4.0 Hz, 1H, exchangeable with
D2O), 4.28-4.33 (m, 2H), 4.49 (dd, J ) 3.6, 2.1 Hz, 1H), 5.08 (s,
2H), 5.51 (d, J ) 9.2 Hz, 1H), 6.24 (d, J ) 9.2 Hz, 1H,
exchangeable with D2O), 6.98 (d, J ) 8.7 Hz, 2H), 7.35 (d, J )
8.7 Hz, 2H), 7.29-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
172.94, 169.65, 158.32, 136.87, 131.30, 128.61, 128.21, 128.00,
127.44, 127.16, 114.91, 114.64, 73.38, 69.99, 62.44, 54.07, 23.13,
14.10; HRMS (FAB+) m/z calc′d for C20H24NO5 [MH+]: 358.1654,
found 358.1647; [R]22 +33 (c ) 1.0, CHCl3). HPLC: Chiralcel
D
ODH, 40% i-PrOH/hexane, 0.5 mL/min, 254 nm, retention time
for the major isomer ) 7.5 min, 94% ee; retention time for the
minor isomer ) 6.8 min.
a
b
DCC, DMAP, toluene, 90 °C; (i) HCO2H; (ii) PhCOCl, aq
NaHCO3, EtOAc; c 10% Pd-C, H2, MeOH.
Eth yl (2S,3R)-3-(Acetyla m in o)-3-[4-(ben zyloxy)p h en yl]-
2-h yd r oxyp r op a n oa te (en t-7). K2[OsO2(OH)4] (8.12 mg., 0.022
mmol, 4% equiv) was dissolved in a 5 mL of aqueous solution of
LiOH (24 mg, 0.56 mmol). After addition of t-BuOH (10 mL),
(DHQD)2PHAL (21 mg, 0.026 mmol) was added to give a cloudy
solution. The reaction mixture was then diluted with water (10
mL) and subsequently cryocooled in a bath set to 0 °C and stirred
for 30 min at that temperature. Then, a solution of cinnamate
coupled product 12 (Scheme 2) in 90% yield. Subsequent
formic acid assisted simultaneous removal of the N,O-
acetonide and the Boc-protecting group, followed by
reaction of the resulting free amine with benzoyl chloride,
formed the diprotected taxane derivative 13 in 80%
(14) Ali, S. M.; Hoemann, M. Z.; Aube´, J .; Mitscher, L. A.; Georg,
G. I.; McCall, R.; J ayasinghe, L. R. J . Med. Chem. 1995, 38, 3821-
3828 and references therein.
(15) For general experimental details, see: Georg, G. I.; Cheruval-
lath, Z. S.; Himes, R. H.; Mejillano, M. R.; Burke, C. T. J . Med. Chem.
1992, 35, 4230-4237.

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8213
6 (150 mg, 0.53 mmol) in acetonitrile (5 mL) was added to the
mixture, followed by the addition of N-bromoacetamide (88 mg,
0.63 mmol) in one portion. More water (3-5 mL) was poured
into the reaction mixture, and stirring was continued for 22 h
at 0 °C. Then the mixture was treated with solid Na2SO3 (300
mg) and stirred at room temperature for 30 min. The reaction
mixture was extracted with EtOAc three times. The combined
extracts were washed with water and brine and dried over
MgSO4. After evaporation of the solvent under reduced pressure,
the crude product was immediately purified by flash column
chromatography on silica gel (EtOAc/hexane ) 1:1) to give 96
mg (51%) of a colorless solid product: mp 124-126 °C; 1H NMR
and 13C NMR (CDCl3) were identical to 7. HRMS (FAB+) m/z
1.80 (s, 3H), 4.54 (d, J ) 5.3 Hz, 1H), 5.09 (s, 3H), 6.98 (1/2 ABq,
J ) 8.6 Hz, 2H), 7.50-7.25 (series of m, 7H), 8.85 (br s, 1H); 13
C
NMR (100 MHz, CDCl3) δ 174.98, 158.30, 151.66, 136,88, 133.14,
128.63, 128.04, 127.58, 127.53, 114.95, 96.86, 80.55, 70.07, 63.38,
28.13, 26.62, 25.97; HRMS (FAB+) m/z calcd for C24H30NO6
[MH+]: 428.2073, found 428.2051; [R]22 +2.4 (c ) 1.0, CHCl3).
D
7-Ben zyloxyca r b on ylb a cca t in III 13-O-[(4S,5R)-4-{4-
(Ben zyloxy)p h en yl}-3-(ter t-bu toxyca r bon yl)-2,2-d im eth yl-
1,3-oxa zolid in e-5-ca r boxyla te] (12). To a stirred solution of
7-Cbz-baccatin III (11)12 (2.81 g, 3.90 mmol) and the oxazolidine
carboxylic acid 10 (2.50 g, 5.86 mmol) in dry toluene (60 mL)
were added DCC (1.43 g, 6.95 mmol) and a catalytic amount of
DMAP (40 mg). The resulting mixture was stirred at 90 °C for
90 min, when TLC monitoring revealed completion of the
reaction. Toluene was then removed under reduced pressure,
and the residue was purified by silica gel flash column chroma-
tography. Elution with EtOAc/methylene chloride (1:19) afforded
the pure coupled product 12 as a white solid (4.0 g, 90%): mp
calcd for C20H24NO5 [MH+]: 358.1654, found 358.1670; [R]23
D
-32 (c ) 1.0, CHCl3). HPLC: Chiralcel ODH, 40% i-PrOH/
hexane, 0.5 mL/min, 254 nm, retention time for the major isomer
) 6.8 min, >99% ee; retention time for the minor isomer ) 7.5
min.
Eth yl (2R,3S)-3-(ter t-Bu toxyca r bon yla m in o)-3-[4-(ben z-
yloxy)p h en yl]-2-h yd r oxyp r op a n oa te (8). To a solution of the
amino alcohol 7 (22.0 g, 61.6 mmol) in ethanol (200 mL) was
added 50 mL of EtOH/HCl (saturated) and the resulting solution
refluxed at 90 °C for 4 h. Ethanol was removed under reduced
pressure, and the resulting amine hydrochloride was dried under
vacuum for 1 h. The salt was then taken up into anhydrous THF
(100 mL), and solid NaHCO3 (52 g, excess) was added to it. The
resulting heterogeneous mixture was stirred for 5 min followed
by addition of Boc-anhydride (20.18 g, 92.46 mmol, 1.5 equiv).
The mixture was then stirred at room temperature for 5 h. The
reaction mixture was diluted with EtOAc (500 mL), quenched
with 10% HCl, and the layers were separated. The organic layer
was washed with brine, dried over MgSO4, and concentrated in
vacuo, and the residue was purified by column chromatography
on silica gel. Elution with EtOAc/methylene chloride (1:19)
furnished 23 g (90%) of the N-Boc-amino alcohol 8 as a white
solid: mp 130-131 °C; IR (KBr) 3384, 1718, 1684 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.31 (t, J ) 7.1 Hz, 3H), 1.40 (s, 9H), 3.27
(br d, J ) 3.4 Hz, 1H), 4.20-4.35 (m, 2H), 4.40 (br s, 1H), 5.04
(s, 2H), 5.17 (d, J ) 8.7 Hz, 1H), 5.40 (d, J ) 9.3 Hz, 1H), 6.95
(d, J ) 8.7 Hz, 2H), 7.25-7.44 (m, 7H); 13C NMR (100 MHz,
CDCl3) δ 172.99, 158.31, 155.11, 136.99, 131.77, 128.61, 127.99,
127.48, 114.89, 79.76, 73.69, 70.04, 62.42, 55.49, 28.30, 14.15;
HRMS (FAB+) m/z calcd for C23H30NO6 [MH+]: 416.2073, found
153-156 °C; IR (KBr) 3428, 3326, 1746, 1688 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 1.17 (s, 9H), 1.23 (s, 6H), 1.72 (s, 3H), 1.75
(s, 3H), 1.79 (s, 3H), 1.89 (s, 3H),1.95-1.98 (m, 1H), 2.05 (s, 3H),
2.21 (s, 3H), 2.23 (br s, 2H), 2.58-2.65 (m, 1H), 3.96 (d, J ) 7.0
Hz, 1H), 4.13 (d, J ) 9.3 Hz, 1H), 4.30 (d, J ) 8.5 Hz, 1H), 4.48
(d, J ) 6.7 Hz, 1H), 4.93 (d, J ) 8.5 Hz, 1H), 5.04 (br s, 1H),
5.13 (s, 2H), 5.19 (ABq, J ) 12.0 Hz, 1H), 5.26 (ABq, J ) 11.9
Hz, 1H), 5.55 (dd, J ) 10.7, and 7.1 Hz, 1H), 5.67 (d, J ) 7.0
Hz, 1H), 6.27 (t, J ) 8.6 Hz, 1H), 6.43 (s, 1H), 7.01 (d, J ) 8.1
Hz, 2H), 7.28-7.58 (m, 15H), 8.0 (d, J ) 8.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 201.67, 170.03, 168.95, 166.96, 158.40,
154.12, 151.62, 141.12, 136.81, 135.37, 133.85, 132.83, 129.10,
128.79, 128.68, 128.65, 128.46, 128.34, 128.14, 127.74, 127.58,
115.13, 96.83, 83.97, 81.07, 80.53, 79.01, 77.29, 76.23, 75.37,
75.29, 74.49, 71.30, 70.17, 63.71, 50.02, 47.01, 43.26, 35.48, 33.31,
28.11, 21.45, 21.21, 20.83, 14.72, 10.77; HRMS (CI) m/z calcd
for C63H75N2O18 [M+ + NH4]: 1147.5015, found 1147.4991; [R]22
D
-34 (c ) 1.0, CHCl3).
7-Ben zyloxyca r bon yl-3′-(4-ben zyloxyp h en yl)-3′-d ep h en -
ylp a clita xel (13). The baccatin III-coupled product 12 (7.80 g,
6.92 mmol) was dissolved in 96% formic acid (300 mL) and
stirred for 2 h at 22 °C. Excess formic acid was removed under
reduced pressure at room temperature and the residual solid
dried under high vacuum for 12 h. The crude free amine salt
was then dissolved in EtOAc (150 mL), and saturated aq
NaHCO3 solution (200 mL) was added to it carefully. To the
resulting solution was added benzoyl chloride (0.88 mL, 7.6
mmol, 1.1 equiv) slowly at 0 °C. After stirring for 5 min, TLC
examination indicated the disappearance of starting material.
The reaction mixture was diluted with more EtOAc (100 mL),
and the layers were separated. The organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel flash column chromatography.
Gradient elution with EtOAc/methylene chloride (1:9 to 1:5)
furnished the protected paclitaxel derivative 13 as a white solid
(6.1 g, 80%): mp 153-156 °C; IR (KBr) 3432, 2949, 1739, 1663
416.2085. [[R]22 +16.4 (c ) 1.05, CHCl3).
D
E t h yl (4S,5R)-4-[4-(Ben zyloxy)p h en yl]-3-(ter t-b u t oxy-
ca r bon yl)-2,2-d im eth yl-1,3-oxa zolid in e-5-ca r boxyla te (9).
A solution of the amino alcohol 8 (21.0 g, 50.6 mmol), 2,2-
dimethoxypropane (18.64 mL, 151.8 mmol), and a catalytic
amount of pyridinium p-toluenesulfonate (100 mg) in toluene
(100 mL) was stirred at 90 °C for 8 h. Removal of the solvent
under vacuum and purification of the resulting oily residue by
flash column chromatography (silica gel) using EtOAc/hexane
(1:19) as eluent afforded the pure oxazolidine derivative 9 (17
g, 75%) as a light yellow viscous liquid: IR (KBr)1756, 1699
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.18 (br s, 9H), 1.30 (t, J )
cm-1 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 3H), 1.24 (s, 3H),
;
7.1 Hz, 3H), 1.72 (s, 3H), 1.79 (s, 3H), 4.28 (q, J ) 7.1 Hz, 2H),
4.47 (d, J ) 5.4 Hz, 1H), 5.04 (br s, 1H), 5.10 (s, 2H), 6.97 (d, J
) 8.7 Hz, 2H), 7.22-7.48 (m, 7H); 13C NMR (100 MHz, CDCl3)
δ 170.20, 158.12, 151.58, 136.89, 133.44, 128.50, 127.88, 127.51,
127.39, 114.80, 96.37, 81.01, 80.09, 69.96, 63.32, 61.55, 28.06,
26.56, 25.83, 14.08. HRMS (FAB+) m/z calcd for C26H34NO6
1.83 (s, 3H), 1.91 (s, 3H), 1.94-2.01 (m, 1H), 2.21 (s, 3H), 2.35-
2.38 (m, 2H), 2.40 (s, 3H), 2.58-2.66 (m, 1H), 3.70 (br d, J ) 3.9
Hz, 1H), 3.96 (d, J ) 7.0 Hz, 1H), 4.20 (d, J ) 8.5 Hz, 1H), 4.33
(d, J ) 8.5 Hz, 1H), 4.78 (br s, 1H), 4.96 (d, J ) 9.0 Hz, 1H),
5.09 (s, 2H), 5.19 (ABq, J ) 12.0 Hz, 1H), 5.26 (ABq, J ) 11.9
Hz, 1H), 5.52 (dd, J ) 10.7 and 7.1 Hz, 1H), 5.70 (d, J ) 7.2 Hz,
1H), 5.76 (d, J ) 8.4 Hz, 1H), 6.19 (t, J ) 8.6 Hz, 1H), 6.43 (s,
1H), 7.03 (m, 3H), 7.34-7.54 (m, 17H), 7.61 (m, 1H), 7.77 (d, J
) 7.6 Hz, 2H), 8.13 (d, J ) 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 201.57, 172.49, 170.35, 168.96, 167.23, 166.70, 158.61,
154.07, 136.68, 135.24, 133.64, 133.01, 131.84, 130.30, 130.09,
128.67, 128.60, 128.53, 128.39, 128.37, 128.02, 127.43, 127.05,
115.15, 83.82, 80.86, 78.41, 76.85, 75.44, 75.30, 74.28, 73.26,
72.01, 70.11, 70.02, 56.11, 54.54, 46.93, 43.19, 26.49, 22.47, 20.92,
20.77, 14.64, 10.66; HRMS (FAB+) m/z calc′d for C62H64NO17
[MH+]: 1094.4174, found 1094.4183; [R]22D -52 (c ) 1.0, CHCl3).
3′-Deph en yl-3′-(4-h ydr oxyph en yl)paclitaxel (4). The dipro-
tected paclitaxel derivative 13 (4.80 g, 4.39 mmol) was dissolved
in dry methanol (50 mL), and a catalytic amount of 10% Pd/C
was added to it. The resulting heterogeneous mixture was stirred
at 22 °C for 24 h under a hydrogen atmosphere at atmospheric
pressure. The reaction mixture was then filtered through a small
[MH+]: 456.2386, found 456.2371; [R]22 -10. (c ) 1.0, CHCl3).
D
(4S,5R)-4-[4-(Ben zyloxy)ph en yl]-3-(ter t-bu toxycar bon yl)-
2,2-d im eth yl-1,3-oxa zolid in e-5-ca r boxylic Acid (10). To an
ice-cooled solution of the ester 9 (19.8 g, 43.5 mmol) in 1.7 L of
THF/MeOH/water (10:5:4) was added solid LiOH‚H2O (3.65 g,
87.0 mmol, 2.0 equiv) in small portions, and the resulting
mixture was stirred for 2 h at 22 °C. The reaction mixture was
then diluted with EtOAc (2 L) acidified with dil HCl (pH ) 5),
and the layers were separated. The aqueous layer was extracted
three times with EtOAc. The combined organic layers were
washed with brine and dried over MgSO4. The solvent was
removed under reduced pressure and the residue dried for 12 h
under high vacuum to yield the oxazolidine carboxylic acid 10
(17.7 g, 95%) as a white solid and was used as such without
further purification: mp 111-112 °C; IR (KBr) 2977, 1725, 1697
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.19 (br s, 9H), 1.75 (s, 3H),

8214 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
pad of silica gel, solvent was removed under reduced pressure,
and the residue was purified by silica gel column chromatogra-
phy. Elution with EtOAc/methylene chloride (1:5) afforded a
white solid, which was further purified by crystallization (me-
thylene chloride/hexane) affording the pure 3′-phenolic metabo-
lite of paclitaxel 4 as a white solid (3.3 g, 86%): mp 192-194 °C
(dec) [lit.8 mp 184-189 °C]; IR (KBr) 3416, 1728, 1651 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.15 (s, 3H), 1.24 (s, 3H), 1.69 (s, 3H),
1.79 (s, 3H), 1.80-1.93 (m, 2H), 2.24 (s, 3H), 2.26-2.37 (m, 2H),
2.38 (s, 3H), 2.46 (br d, J ) 3.7 Hz, 1H), 2.48-2.60 (m, 1H),
3.55 (d, J ) 5.3 Hz, 1H), 3.80 (d, J ) 7.0 Hz, 1H), 4.20 (1/2 ABq,
J ) 8.6 Hz, 1H), 4.31 (1/2 ABq, J ) 8.5 Hz, 1H), 4.38-4.47 (m,
1H), 4.75 (dd, J ) 5.1, 2.70 Hz, 1H), 4.95 (d, J ) 7.6 Hz, 1H),
5.23 (s, 1H), 5.62-5.75 (m, 2H), 6.22 (t, J ) 9.2 Hz, 1H), 6.27 (s,
1H), 6.84 (d, J ) 8.6 Hz, 2H), 6.96 (d, J ) 8.7 Hz, 1H), 7.28-
7.64 (m, 8H), 7.74 (1/2 ABq, J ) 7.1 Hz, 2H), 8.13 (1/2 ABq, J )
7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 203.68, 172.59,
171.33, 170.75, 167.92, 166.84, 156.31, 141.79, 133.77, 133.45,
133.12, 132.09, 130.13, 129.11, 128.72, 128.27, 127.15, 115.85,
84.37, 81.08, 78.77, 77.29, 75.63, 74.82, 73.34, 72.05, 58.43, 54.99,
45.84, 43.12, 35.70, 26.73, 22.55, 21.70, 20.88, 14.77, 9.65; HRMS
(FAB+) m/z calcd for
C
47H52NO15 [MH+]: 870.3337, found
870.3318; [R]22 -53 (c ) 1.0, CHCl3) {lit.8 [R]22 -54 (c ) 0.70,
D
D
CHCl3)}.
Ack n ow led gm en t. We thank NaPro Biotherapeu-
tics, Inc., Boulder, CO, for financial assistance and for
providing the taxane starting material. This work was
supported in part by the Kansas Technology Enterprise
Corporation through the Centers of Excellence Program.
Su p p or tin g In for m a tion Ava ila ble: Proton and carbon
NMR spectra of compounds 6, 7, 8, 9, 10, 12, 13, and 4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0102516