Synthesis of docetaxel and butitaxel analogues through kinetic resolution of racemic β-lactams with 7-O-triethylsilylbaccatin III

Article abstract of DOI:10.1021/jo061339s

(Chemical Equation Presented) The kinetic resolution of racemic cis-4-phenyl- and cis-4-tert-butyl-3-hydroxy-β-lactam derivatives with 7-O-triethylsilylbaccatin III yielded paclitaxel and butitaxel analogues with high diastereoselectivity. The results demonstrated that the tert-butyldimethylsilyl protecting group at the C3-hydroxy group of the β-lactams provided optimum kinetic resolution in comparison with the sterically less demanding triethylsilyl group and the larger triisopropylsilyl group. In addition, it was found that the C4 β-lactam substituents also influenced diastereoselectivity. The C4 tert-butyl-β-lactams provided better diastereoselectivity than the corresponding C4 phenyl β-lactams.

Full text of DOI:10.1021/jo061339s

Synthesis of Docetaxel and Butitaxel Analogues through Kinetic
Resolution of Racemic â-Lactams with 7-O-Triethylsilylbaccatin III
Haibo Ge,† Jared T. Spletstoser,† Yan Yang,‡ Margaret Kayser,*,‡ and Gunda I. Georg*,†
Department of Medicinal Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe, UniVersity of Kansas,
Lawrence, Kansas 66045-7582, and Department of Physical Sciences, UniVersity of New Brunswick,
Saint John, NB, Canada E2L 4L5
georg@ku.edu
ReceiVed June 28, 2006
The kinetic resolution of racemic cis-4-phenyl- and cis-4-tert-butyl-3-hydroxy-â-lactam derivatives with
7-O-triethylsilylbaccatin III yielded paclitaxel and butitaxel analogues with high diastereoselectivity. The
results demonstrated that the tert-butyldimethylsilyl protecting group at the C3-hydroxy group of the
â-lactams provided optimum kinetic resolution in comparison with the sterically less demanding triethylsilyl
group and the larger triisopropylsilyl group. In addition, it was found that the C4 â-lactam substituents
also influenced diastereoselectivity. The C4 tert-butyl-â-lactams provided better diastereoselectivity than
the corresponding C4 phenyl â-lactams.
Introduction
a derivative of butitaxel (2a, Figure 1),6,7 is orally bioavailable8
and that TX-67 (1c, Figure 1) is able to cross the BBB in situ.9
Typically, paclitaxel analogues have been prepared by semi-
synthesis from baccatin III derivatives using nonracemic â-lac-
tams, which serve as the precursors for the C13 N-acyl-3′-
phenylisoserine side chain. The asymmetric ester enolate-imine
cyclocondensation or enzyme-catalyzed resolutions are excellent
methods to prepare enantiopure (3R,4S)-â-lactams.10-14 How-
ever, several groups have reported the synthesis of paclitaxel
Paclitaxel (1a, Taxol, Figure 1), a cytotoxic agent from the
bark of the Pacific yew (Taxus breVifolia),1 exerts its activity
by alteration of tubulin dynamics.2 Paclitaxel and its semisyn-
thetic analogue docetaxel (1b, Taxotere, Figure 1) are effective
agents for the treatment of ovarian and breast cancer, Kaposi’s
sarcoma, and non-small-cell lung cancer.3 The continued
evaluation of new analogues is important because of paclitaxel
drug-resistance, the inability of paclitaxel to cross the blood-
brain barrier (BBB), and its lack of oral bioavailability.4
In the course of structure-activity relationship studies, series
of highly potent second-generation analogues have been devel-
oped that overcome some of the deficiencies of paclitaxel.5 For
example, it has been reported that BMS-275183 (2b, Figure 1),
(6) Ali, S. M.; Hoemann, M. Z.; Aube´, J.; Mitscher, L. A.; Georg, G. I.;
McCall, R.; Jayasinghe, L. R. J. Med. Chem. 1995, 38, 3821-3828.
(7) Ali, S. M.; Hoemann, M. Z.; Aube´, J.; Georg, G. I.; Mitscher, L. A.
J. Med. Chem. 1997, 40, 236-241.
(8) Mastalerz, H.; Cook, D.; Fairchild, C. R.; Hansel, S.; Johnson, W.;
Kadow, J. F.; Long, B. H.; Rose, W. C.; Tarrant, J.; Wu, M.-J.; Xue, M.-
Q.; Zhang, G.-F.; Zoeckler, M.; Vyas, D. M. Bioorg. Med. Chem. 2003,
11, 4315-4323.
(9) Rice, A.; Liu, Y.; Michaelis, M. L.; Himes, R. H.; Georg, G. I.; Audus,
K. J. Med. Chem. 2005, 48, 832-838.
(10) For review: Boge, T. C.; Georg, G. I. The Medicinal Chemistry of
â-Amino Acids: Paclitaxel as an Illustrative Example. In EnantioselectiVe
Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997;
pp 1-43.
(11) Kayser, M. M.; Mihovilovic, M. D.; Kearns, J.; Feicht, A.; Stewart,
J. D. J. Org. Chem. 1999, 64, 6603-6608.
(12) Kayser, M. M.; Yang, Y.; Mihovilovic, M. D.; Feicht, A.; Rochon,
F. D. Can. J. Chem. 2002, 80, 796-800. Yang, Y.; Wang, F.-Y.; Rochon,
F. D.; Kayser, M. M. Can. J. Chem. 2005, 83, 28-36.
† University of Kansas.
‡ University of New Brunswick.
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J. Am. Chem. Soc. 1971, 93, 2325-2327.
(2) For review: Zhou, J.; Giannakakou, P. Curr. Med. Chem.: Anti-
Cancer Agents 2005, 5, 65-71.
(3) For review: Spencer, C. M.; Faulds, D. Drugs 1994, 48, 794-
847.
(4) Ge, H.; Vasandani, V.; Huff, J. K.; Audus, K. L.; Himes, R. H.;
Seelig, A.; Georg, G. I. Bioorg. Med. Chem. Lett. 2006, 16, 433-436.
(5) For review: Kingston, D. G. I.; Jagtap, P. G.; Yuan, H.; Samala, L.
Prog. Chem. Org. Nat. Prod. 2002, 84, 53-225.
10.1021/jo061339s CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/10/2007
756
J. Org. Chem. 2007, 72, 756-759

Synthesis of Docetaxel and Butitaxel Analogues
SCHEME 1a
a (a) (i) LiOH in acetone or K2CO3 in MeOH; (ii) R′SiCl, imidazole/
DMAP, CH2Cl2, rt. (b) (i) Ce(NH4)2(NO3)6, aq CH3CN, -20 °C; (ii)
(Boc)2O, diisopropylethylamine, DMAP, CH2Cl2, rt. (c) (i) HF-Py in Py, 0
°C to rt; (ii) (TES)Cl, imidazole, CH2Cl2, rt.
FIGURE 1. Structures of paclitaxel (1a), docetaxel (1b), Tx-67 (1c),
butitaxel (2a), and BMS-275183 (2b).
the influence of the â-lactam substituents on the outcome of
the kinetic resolutions with 7-O-(triethylsilyl)baccatin III.
analogues through kinetic resolution using racemic cis-â-lactams
with moderate to high diastereoselectivities.8,15-17 Recently,
dynamic kinetic resolution of racemic 3-oxo-4-phenyl-â-lactam
was achieved by recombinant Esherichia coli (E. coli), over-
expressing yeast reductase Ara1p.18 Holton was the first to
disclose the kinetic resolution of N-benzoyl- and N-Boc-4-
phenyl-3-(triethylsilyloxy)-â-lactams with the lithium alkoxide
of 7-O-(triethylsilyl)baccatin III and 10-deacetyl-7,10-bis(tri-
ethylsilyl)baccatin III and reported diastereoselectivities of 6:1
and 100%, respectively.15 Excellent kinetic resolution was also
observed by Ojima and co-workers when they employed
O-ethoxyethyl-protected 3-hydroxy-4-(trifluoromethyl)-â-lac-
tams in this reaction.16 During these studies, it was found that
variation of the baccatin III substituents typically had little effect
on the stereoselectivity of the reaction. However, the kinetic
resolution with N-Boc-3-(triethylsilyloxy)-4-tert-butyl-â-lactam
was influenced by the structure of the baccatin III derivative.8
Reaction between N-Boc-4-tert-butyl-3-(triethylsilyloxy)-â-lac-
tam and 7-O-(diisopropylmethoxysilyl)baccatin III provided a
3:1 diastereomeric ratio, whereas the reaction with a 7-deoxy-
9â-dihydro-9,10-acetalbaccatin III yielded only one diastereo-
isomer.17
Results and Discussion
The synthesis of the racemic â-lactams 5 and 6 is shown in
Scheme 1. 4-Phenylazetidin-2-one (3a) and 4-tert-butylazetidin-
2-one (3b) were prepared according to reported procedures.8
The acetyl group on 3 was removed with lithium hydroxide in
acetone (for 3a) or potassium carbonate in methanol (for 3b),
followed by protection with a trialkylsilyl chloride to furnish
3-(trialkylsilyloxy)-â-lactams (4a-e) in high to excellent
yields.19,20 The 4-methoxyphenyl moiety (PMP) of 4 was
removed oxidatively with ceric ammonium nitrate (CAN)21 and
then treated with tert-butyl dicarbonate to afford racemic
3-(trialkylsilyloxy)-4-phenylazetidin-2-ones (5a-c) and 3-(tri-
alkylsilyloxy)-4-tert-butylazetidin-2-ones (5d,e). 3-(Triethyl-
silyloxy)-4-tert-butylazetidin-2-one (6) was prepared from 5d
by removal of the tert-butyldimethylsilyl protecting group with
HF-pyridine, followed by triethylsilyl protection in 77% yield.
First, we investigated the kinetic resolution between racemic
5a and 7-O-(triethylsilyl)baccatin III (7)22 under several different
reaction conditions (Table 1). The resulting reaction products
were subsequently treated with hydrogen fluoride in pyridine
to furnish 10-acetyldocetaxel (8, Scheme 2). The isomeric ratios
of 8 were determined by HPLC analysis (Table 1).
We surmised from these studies that the structure of the
â-lactam plays a major role in controlling the stereoselectivity
of the kinetic resolution and that this effect would warrant some
further study. We therefore decided to investigate in more detail
The results for the kinetic resolution are shown in Table 1.
It was found that the diastereoselectivity of the reaction
decreased slightly with an increase in reaction temperature (see
entries 1-3). Although the stereoselectivity was not significantly
influenced, the yield dramatically decreased when the amount
(13) Patel, R. N.; Howell, J.; Chidambaram, R.; Benoit, S.; Kant, J.
Tetrahedron: Asymmetry 2003, 14, 3673-3677.
(14) Carr, J. C.; Al-Azemi, T. F.; Long, T. E.; Shim, J.-Y.; Coates, C.
M.; Turos, E.; Bisht, K. S. Tetrahedron 2003, 59, 9147-9160.
(15) Holton, R. A.; Biedinger, R. J.; Boatman, P. D. Semisynthesis of
Taxol and Taxotere. In Taxol Science and Applications; Suffness, M., Ed.;
CRC: Boca Raton, FL, 1995; pp 97-121.
(16) Ojima, I.; Slater, J. C. Chirality 1997, 9, 487-494.
(17) Takeda, Y.; Uoto, K.; Iwahana, M.; Jimbo, T.; Nagata, M.; Atsumi,
R.; Ono, C.; Tanaka, N.; Terasawa, H.; Soga, T. Bioorg. Med. Chem. Lett.
2004, 14, 3209-3215.
(18) Yang, Y.; Drolet, M.; Kayser, M. M. Tetrahedron: Asymmetry 2005,
16, 2748-2753.
(19) Lin, S.-N.; Geng, X.-D.; Qu, C.-X.; Tynebor, R.; Gallagher, D. J.;
Pollina, E.; Rutter, J.; Ojima, I. Chirality 2000, 12, 431-441.
(20) Spletstoser, J. T.; Flaherty, P. T.; Himes, R. H.; Georg, G. I. J.
Med. Chem. 2004, 47, 6459-6465.
(21) Georg, G. I.; Kant, J.; Gill, H. J. J. Am. Chem. Soc. 1987, 109,
1129-1135.
(22) Denis, J.-N.; Greene, A. E.; Gue´nard, D.; Gu’eritte-Voegelein, F.;
Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917-5919.
J. Org. Chem, Vol. 72, No. 3, 2007 757

Ge et al.
TABLE 1. Results from Reactions of â-Lactam 5a with 7 To
Furnish 8 under Varied Reaction Conditions (Scheme 2)
SCHEME 3
lactam
equiv
reaction
temp (°C)
yield (%) isomeric
entry
base equiv
8a
ratiob
1
2
3
4
5
4
4
4
2
4
1.5 LiHMDS
1.5 LiHMDS
1.5 LiHMDS
1.5 LiHMDS
1.5 NaHMDS
-40
81
82
84
46
62
41:1
36:1
34:1
32:1
7:1
-40 to 0
0
-40 to 0
-40 to 0
a Yields for two steps. b The isomeric ratio (2′R,3′S):(2′S,3′R) was
determined by HPLC.
SCHEME 2
provided higher stereoselectivity than the smaller triethylsilyl
group (entry 3). However, the tert-butyldimethylsilyl group
proved to be optimal (entry 2), providing a 41:1 ratio of
diastereoisomers. The results imply that the size of the C3-
hydroxyl protecting group influences diastereoselectivity and
that the tert-butyldimethylsilyl group, which is more sterically
demanding than the triethylsilyl group, but smaller than the
triisopropylsily protecting group, was optimal in this sequence
of reactions.
We also examined the effects of different substituents at the
C4 position toward resolution. As is illustrated in Table 2, we
observed increased stereoselectivity for the reaction of 5d (entry
5) with 7 compared to the reaction of 5a with 7 (entry 2), which
indicates that the size of the C4 substituent also influences
diastereoselectivity. To evaluate whether the C3-hydroxy pro-
tecting groups have an effect for the 4-tert-butyl â-lactam
derivatives, we replaced the tert-butyldimethylsilyl with the
larger triisopropylsilyl group (entry 4) and the smaller trieth-
ylsilyl group (entry 6). Again, it was found that the triisopro-
pylsilyl group provided higher diastereoselectivity than the
triethylsilyl group, while the tert-butyldimethylsilyl group
afforded the best resolution. These results suggest that at least
one sterically demanding substituent is required at either C3 or
C4 for satisfactory selectivity. This is supported by Ojima’s
observation that 3-(triisopropylsilyloxy)-4-(trifluoromethyl)-,
3-(triisopropylsilyloxy)-4-isobutyl-, and 3-(triisopropylsilyloxy)-
4-isobutenyl-â-lactams gave high yields and stereoselectivities
for the kinetic resolution with modified baccatins.19
To unambiguously prove the identity of the major product,
we synthesized 10-acetyldocetaxel (8), as shown in Scheme 4.
Starting from 2′-O-(tert-butyldimethylsilyl)docetaxel (10), pre-
pared from commercially available docetaxel, triethylsilyl
protection of the C7-hydroxy group followed by acylation of
the C10-hydroxy group with acetic anhydride afforded inter-
mediate 11, which was converted to 8 by treatment with
hydrogen fluoride in pyridine. Spectral data and HPLC retention
times were identical for the products obtained by both methods,
confirming that the major diastereomer obtained in the kinetic
resolution had the same (2′R,3′S) configuration as docetaxel.
10-Acetylbutitaxel (9) has been synthesized previously and
matched the reported spectroscopic data.23
TABLE 2. Results of Reaction between â-Lactams 5a-e, 6, and
7-O-triethylsilylbaccatin III (7, Scheme 3) for the Formation of 8
(Entries 1-3) and 9 (Entries 4-6)
Entry
R1
R2
yielda (%)
isomeric ratiob
1
TIPS
TBS
TES
TIPS
TBS
TES
Ph
Ph
Ph
tert-butyl
tert-butyl
tert-butyl
80
81
84
76
84
78
32:1
41:1
10:1
57:1
82:1
40:1
2c
3
4
5
6
a Yields of 8 (entries 1-3) and of 9 (entries 4-6) for two steps. b The
isomeric ratio (2′R,3′S):(2′S,3′R) was determined by HPLC. c Same as entry
1, Table 1.
of 5a was reduced from 4 to 2 equiv (entries 2 and 4). It has
been hypothesized that chelation between the C13 lithium
alkoxide of the baccatin III derivative and the carbonyl group
of the â-lactam is important for the high diastereoselectivity.16
We therefore replaced LiHMDS with NaHMDS (entry 5) to
study the effect of the presumably less chelating C13 sodium
alkoxide on diastereoselectivity. Under these conditions, we
noted a marked decrease in stereoselectivity and yield, confirm-
ing the hypothesis (see entries 2 and 5) that chelation is
important for high diastereoselectivity.
We next investigated the effects of different substituents at
the â-lactam skeleton on the kinetic resolution (Table 2). Since
it had been previously reported that the 1-tert-butoxycarbonyl
group was important to generate high diastereoselectivity in the
kinetic resolution, we retained this group in our experiments.15,16
We first probed the effects of different 3-hydroxylsilyl protecting
groups. Reactions of â-lactams 5a-e and 6 with 7 (Scheme 3)
were carried out using the conditions of entry 1, in Table 1.
The results are shown in Table 2. As expected, it was found
that the large triisopropylsilyl protecting group (entry 1)
In conclusion, a systematic study of the kinetic resolution of
racemic 4-phenyl- and 4-tert-butyl-â-lactams with 7-O-(trieth-
ylsilyl)baccatin III was carried out. It was found that the size
of the silyl protecting groups at the 3-hydroxy moiety of
758 J. Org. Chem., Vol. 72, No. 3, 2007

Synthesis of Docetaxel and Butitaxel Analogues
SCHEME 4a
The reaction mixture was warmed to room temperature overnight
and then diluted with EtOAc, washed with aqueous NaHCO3, water
and brine, dried over MgSO4, and concentrated under reduced
pressure to afford a white solid. To a solution of the solid thus
obtained was added imidazole (43.8 mg, 0.643 mmol), (TES)Cl
(108 µL, 96.9 mg, 0.643 mmol) in CH2Cl2 (5.0 mL). The reaction
mixture was stirred under argon at room temperature for 24 h,
diluted with CH2Cl2, and quenched with water (50 mL). The
aqueous layer was extracted with CH2Cl2, and the combined organic
layers were washed with brine (50 mL), dried over MgSO4, and
concentrated under reduced pressure. Flash column chromatography
(silica gel) with EtOAc/hexanes afforded 96 mg (77%) of a colorless
oil. The compound showed spectroscopic properties in agreement
with the literature.8
Synthesis of 10-Acetyldocetaxel (8) and 10-Acetylbutitaxel (9).
A solution of 5 or 6 (0.1696 mmol) and 7-O-(triethylsilyl)baccatin
III (7, 30.0 mg, 0.042 mmol) in tetrahydrofuran (THF; 2.5 mL)
under argon was cooled to -40 to 50 °C, and a solution of LiHMDS
(64 µL, 0.064 mmol, 1.0 M in THF) was added. The reaction
mixture was stirred for 50 min at the same temperature and then
quenched with saturated aqueous NH4Cl solution and extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure to afford a white
solid. To a solution of the solid thus obtained in pyridine (2.0 mL)
under argon were added 8 drops of a HF-pyridine solution
dropwise at 0 °C under argon. The reaction mixture was stirred for
30 min at the same temperature, and then another 10 drops of HF-
pyridine solution were added dropwise. The reaction mixture was
warmed to room temperature overnight, diluted with EtOAc (30
mL), washed with saturated aqueous NaHCO3 solution, water, and
brine, dried over MgSO4, and concentrated under reduced pressure.
Flash column chromatography (silica gel) with EtOAc/hexanes
afforded the product.
a (a) (i) (TES)Cl, imidazole, DMAP, CH2Cl2, rt; (ii) acetic anhydride,
DMAP, pyridine, 0 °C to rt (96%). (b) HF-Py in pyridine, 0 °C to rt (90%).
â-lactams had an important influence on the diastereoselectivity
of the resolution. The tert-butyldimethylsilyl protecting group
was found to be superior to the smaller triethylsilyl group and
the larger triisopropylsilyl group in the reactions investigated.
The size of the 4-substituents at the â-lactams also influenced
diastereoselectivity. The sterically more demanding 4-tert-butyl
â-lactams gave rise to better kinetic resolution than the
corresponding 4-phenyl â-lactams. Therefore, it can be con-
cluded that high stereoselectivity can be obtained either by using
sterically demanding C3-hydroxy protecting groups or C4
substituents.
10-Acetyldocetaxel (8). Yield ) 46-84%, off-white solid. The
compound showed spectroscopic properties in agreement with the
literature.24
10-Acetylbutitaxel (9). Yield ) 78-84%, off-white solid. The
compound showed spectroscopic properties in agreement with its
structure.25
Experimental Section
HPLC Conditions Used in Tables 1 and 2. Jupiter 5 µ C4-
reversed phase column (10 × 250 mm) from Phenomenex USA,
employing a gradient of water-acetonitrile (0-70%, v/v) with 0.1%
trifluoroacetic acid as the solvent system with a flow rate of 2.0
mL/min for 70 min. Average retention time for the major isomer
(2′R,3′S)-8 ) 46.56 min; minor isomer (2′S,3′R)-8 ) 45.98 min.
Average retention time for the major isomer (2′R,3′S)-9 ) 47.92
min; minor isomer (2′S,3′R)-9 ) 46.70 min.
cis-(()-1-(tert-Butoxycarbonyl)-3-(tert-butyldimethylsilyloxy)-
4-phenylazetidin-2-one (5a).23 Yield ) 48%, yellow solid; mp )
93-95 °C; 1H NMR (400 MHz, CDCl3) δ -0.15 (s, 3H), 0.06 (s,
3H), 0.65 (s, 9H), 1.42 (s, 9H), 5.04-5.07 (m, 2H), 7.27-7.37
(m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.0, -4.5, 18.2, 25.6
(3C), 28.2 (3C), 62.4, 77.7, 83.8, 128.2 (2C), 128.4 (2C), 128.6,
134.3, 148.3, 166.6; HRMS (ES+) m/z calcd for C20H31NO4SiNa
[MNa+] 400.1920, found 400.1910.
Acknowledgment. The authors thank the National Cancer
Institute for financial support of this research (Grants NIH
CA82801 and NIH CA105305) and Tapestry Pharmaceuticals
(Boulder, CO) for a generous gift of 10-deacetylbaccatin III.
J.T.S. was a recipient of an American Foundation for Pharma-
ceutical Education predoctoral fellowship and a Department of
Defense predoctoral fellowship (Grant DAMD 17-99-1-9243).
We also thank Christopher Schneider for his help with the
HPLC.
Supporting Information Available: Full experimental proce-
dures and characterization data for compounds 4a-e, 5a-e, 8, and
11 and HPLC traces for the experiments in Tables 1 and 2. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Synthesis of cis-1-(tert-Butoxycarbonyl)-3-(triethylsilyloxy)-
4-tert-butylazetidin-2-one (6). To a solution of 5d (115.0 mg,
0.3216 mmol) in pyridine (6.0 mL) were added 12 drops of a HF-
pyridine solution dropwise at 0 °C under argon. The reaction
mixture was stirred for 30 min, and then another 20 drops of HF-
pyridine solution were added dropwise at the same temperature.
JO061339S
(24) Mangatal, L.; Adeline, M.-T.; Gue´nard, D.; Gue´ritte-Voegelein, F.;
Potier, P. Tetrahedron 1989, 45, 4177-4190.
(25) Compound 9 showed spectroscopic properties in agreement with
the data reported: Holton, R. A.; Chai, K.-B.; Idmoumaz, H.; Nadizadeh,
H.; Rengan, K.; Suzuki, Y.; Tao, C. U.S. Pat. 5739362, 1998.
(23) Ojima, I.; Sun, C.-M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk,
S. Tetrahedron Lett. 1993, 34, 4149-4152.
J. Org. Chem, Vol. 72, No. 3, 2007 759