A practical and efficient synthesis of taxol C-13 side chain

Article abstract of DOI:10.1081/SCC-100107008

A practical and efficient synthesis of taxol C-13 side chain from cheap and easily available starting material is described.

Full text of DOI:10.1081/SCC-100107008

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A PRACTICAL AND EFFICIENT SYNTHESIS OF TAXOL
C-13 SIDE CHAIN
Zhongqiang Zhou a , Xingguo Mei a , Junli Chang a & Daijun Feng b
a School of Life Science and Technology, Huazhong University of Science and Technology ,
Wuhan, 430 074, P. R. China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 354 Fenglin
Road, Shanghai, 200 032, P. R. China
Published online: 16 Aug 2006.
To cite this article: Zhongqiang Zhou , Xingguo Mei , Junli Chang & Daijun Feng (2001) A PRACTICAL AND EFFICIENT
SYNTHESIS OF TAXOL C-13 SIDE CHAIN, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:23, 3609-3615, DOI: 10.1081/SCC-100107008
To link to this article: http://dx.doi.org/10.1081/SCC-100107008
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SYNTHETIC COMMUNICATIONS, 31(23), 3609–3615 (2001)
A PRACTICAL AND EFFICIENT
SYNTHESIS OF TAXOL
C-13 SIDE CHAIN
Zhongqiang Zhou,1, Xingguo Mei,1
*
Junli Chang,1 and Daijun Feng2
1School of Life Science and Technology,
Huazhong University of Science and Technology,
Wuhan 430 074, P. R. China
2Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200 032, P. R. China
ABSTRACT
A practical and efficient synthesis of taxol C-13 side chain
from cheap and easily available starting material is described.
Taxol 1, an antimicrotubule agent isolated from the bark of Taxus
brevifolia,1 has recently attracted much attention because of its efficacy
in the treatment of various types of cancer. In view of promising results
in cancer treatment, a demand for large quantities of taxol is anticipated
in the near future. The most favourable solution to supply the problem
is a semi-synthetic approach involving the synthesis and attachment of
*Corresponding author.
3609
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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ZHOU ET AL.
(2R,3S)-N-benzoyl-3-phenylisoserine 2 to baccatin III obtained from the
leaves of readily available taxus species.2 Several synthesis of chirally pure
phenylisoserine are known,3–9 but most are unsuitable for large scale pro-
duction. In view of the demand for large quantities of phenylisoserine. We
attempted to design a practical and efficient synthetic route to compound 2.
In our previous paper,10 we have reported the synthesis of
erythro-N- benzoyl-3-phenylisoserine, resolution of erythro-N-benzoyl-3-
phenylisoserine with S-(ꢀ)-a-methyl benzylamine provided (2S,3S)-N-ben-
zoyl-3-phenylisoserine 3. The compound 3 can be transformed to the
(2R,3S)-N-benzoyl-3-phenylisoserine 2 by inversion of configuration at the
C-2.11 The reaction sequence is illustrated in Scheme 1.
Scheme 1.
The present report describes a highly practical and efficient synthesis
of 2 in terms of production cost and handling of the reaction process.
Reaction of trans-epoxide 512 with HCl gas in benzene furnished
the highly stereoselective ring opened product 6 which upon treatment
with inexpensive Amberlite IRA-420(OHꢀ) resin gave cis-epoxide 7.
Ammonolysis of 7 by methanolic ammonia under high pressure provided
the isoserineamide 8 as the major product. Any serine byproduct was easily
removed by washing with methanol. Hydrolysis of the amide 8 using
Ba(OH)2 gave threo-3-phenylisoserine 9. This material was converted to

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TAXOL C-13 SIDE CHAIN
3611
threo-N-benzoyl-3-phenylisoserine (ꢁ)-2 by treatment with benzoyl chlor-
ide/NaHCO3 in a two-phase reaction in good yield. Resolution of (ꢁ)-2 with
R-(þ)-a-methyl benzylamine provided 2. (Scheme 2)
Scheme 2.
EXPERIMENTAL
Melting points were uncorrected. IR spectra were determined on a
IDP-435 infrared spectrometer. 1H NMR and 13C NMR spectra were
recorded at 300 and 75 MHz on a Varian Mercury 300 spectrometer using
TMS as an internal standard. Elemental analyses were performed by a
PE-2400 instrument. Optical rotations were measured using WZZ-T1
polarimeter.
(2S,3S)-N-Benzoyl-3-phenylisoserine (3)
To a refluxing solution of erythro-N-benzoyl-3-phenylisoserine (2.9 g,
10.0 mmol) in ethanol (20 ml) was added S-(ꢀ)-a-methylbenzylamine (1.2 g,
10.0 mmol). The resulting solution was cooled to room temperature and

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ZHOU ET AL.
allowed to stand at room temperature overnight. It was then filtered and S-
(ꢀ)-a-methylbenzylamine salt of the desired product (1.7 g) was obtained
after drying. The resulting salt was dissolved in water (45 ml). The resulting
solution was acidified to pH ¼ 2 and then was extracted with diethyl ether
(3 Â 50 ml), dried over MgSO4. The solvent was removed. The residue was
dissolved in acetone (10 ml) and petroleum ether (400 ml) was added sub-
sequently. The desired product (1.1 g, 39%) was obtained by filtration. Mp
160–162ꢂC. [a]2D5 - 35.0 (C 0.9, EtOH). IR (KBr) n: 3600, 3500–2600, 1750,
1640, 1520, 700 cmꢀ1. 1H NMR (acetone-d6) d: 4.75 (d, J ¼ 4.5 Hz, 1H), 5.65
(dd, J ¼ 4.5 Hz, 1H), 7.20–7.70 (m, 10H), 7.80–8.00 (d, J ¼ 4.5 Hz, 1H).
13C NMR (CDCl3) d: 57.2, 74.6, 128.8, 129.1, 129.5, 129.9, 130.0, 136.1,
141.6, 167.4, 175.4. Anal. Calcd. for C16H15NO4: C, 67.36; H, 5.30; N,
4.91. Found: C, 67.31; H, 5.26; N, 4.87.
Threo-3-chloro-2-hydroxy-3-phenylisoserine Ethyl Ester (6)
Dry HCl gas was bubbled into a solution of 5 (38.4 g, 0.2 mol) in
dry benzene (400 ml) for 3 h and the excess HCl was removed under partial
vacuo. The solvent was evaporated and the residue was recrystallized from
benzene-petroleum ether (1 : 3) to furnish pure crystalline product 6 (31.9 g,
70%). Mp 74–75ꢂC. IR (KBr) n: 3400, 1740 cmꢀ1 1H NMR (CDCl3)
.
d: 1.32 (t, J ¼ 7.0 Hz, 3H), 3.30 (d, J ¼ 7.5 Hz, 1H), 4.30 (q, J ¼ 7.0 Hz,
2H), 4.49 (dd, J ¼ 2.3 Hz, 1H), 5.27 (d, J ¼ 2.3 Hz, 1H), 7.30–7.54
(m, 5H). Anal. Calcd. for C11H13ClO3: C, 57.78; H, 5.73. Found: C,
57.67; H, 5.78.
cis-Ethyl-3-phenylglycidate (7)
A suspension of chlorohydrin 6 (9.8 g, 43 mmol) and Amberlite IRA-
420(HOꢀ) resin (80 g) in dry THF (180 ml) was stirred at room temperature
for 3 h under N2 atmosphere. The resin was filtered and washed with THF
(3 Â 200 ml). The solvent was evaporated and the oily residue was dried
under high vacuo to provide the cis-epoxide 7 (5.0 g, 61%) which was
pure enough for the subsequent step. IR (neat) n: 1755 cmꢀ1 1H NMR
.
(CDCl3) d: 1.02 (t, J ¼ 7.2 Hz, 3H), 3.83 (d, J ¼ 4.8 Hz, 1H), 3.9–4.1 (m,
2H), 4.27 (d, J ¼ 4.8 Hz, 1H), 7.2–7.5 (aromatic, 5H). 13C NMR (CDCl3)
d: 13.8, 55.7, 57.3, 126.6, 127.9, 128.3, 132.8, 166.5. Anal. Calcd. for
C11H12O3: C, 68.73; H, 6.29. Found: C, 68.63; H, 6.37.

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TAXOL C-13 SIDE CHAIN
Threo-3-phenylisoserineamide (8)
3613
A solution of 7(20.0 g, 104 mmol) in methanol saturated with ammo-
nia (prepared by passing anhydrous NH3 through methanol at ꢀ 15ꢂC) was
sealed in a steel bomb and heated at 100ꢂC for 22 h. The solution was cooled
to room temperature. The solvent was evaporated and the residue was
triturated with ethanol to provide a yellowish solid which was recrystallized
from methanol to furnish pure crystalline product (12.2 g, 65%). Mp
193–194ꢂC. IR (KBr) n: 3400, 3360, 3306, 1660 cmꢀ1. H NMR (DMSO-
1
d6/D2O) d: 3.87 (d, J ¼ 3.3 Hz, 1H), 4.08 (d, J ¼ 3.3 Hz, 1H), 7.0–7.5(aro-
matic, 5H). 13C NMR (DMSO-d6/D2O) d: 57.1, 75.5, 127.1, 128.1, 142.7,
175.9. Anal. Calcd. for C9H12N2O2: C, 59.98; H, 6.71; N, 15.55. Found: C,
59.91; H, 6.67; N, 15.25.
Threo-3-phenylisoserine (9)
Threo-3-phenylisoserineamide (1.63 g, 9.05 mmol) was combined with
2.88 g (9.1 mmol) of BaðOHÞ2 ꢃ8H2O and water (16 ml). The resulting sus-
pension was heated to reflux under nitrogen for 8 h. The reaction mixture
was then cooled to 80ꢂC, and water (120 ml) was added. The temperature of
the solution was maintained at 80ꢂC for 20 min before a solution of 0.91 g
H2SO4 in 8 ml of water was added. The temperature of the mixture was
maintained at 80ꢂC for another 10 min, and then the mixture was cooled to
room temperature. The resulting precipitate (BaSO4) was removed by filtra-
tion, and the solvent of the filtrate was removed under vacuum to provide
the product as a white solid (1.44 g, 88%). Mp 263–264ꢂC. IR (KBr) n: 3500,
1
1710, 1580, 1140, 700 cmꢀ1. H NMR (D2O/NaOD) d: 3.94 (d, J ¼ 3.9 Hz,
1H), 4.01 (d, J ¼ 3.9 Hz, 1H), 7.0–7.5 (aromatic, 5H). Anal. Calcd. for
C9H11NO3: C, 59.66; H, 6.07; N, 7.73. Found: C, 59.21; H, 6.09; N, 7.58.
Threo-N-benzoyl-3-phenylisoserine ((6)ꢀ 2)
Threo-3-phenylisoserine (0.40 g, 2.2 mmol) was dissolved in 10% aque-
ous NaHCO3 (55 ml) with stirring. The solution was cooled to 4ꢂC and
benzoyl chloride (0.89 g, 6.25 mmol) was added. This mixture was stirred
at 4ꢂC for 6 h and then acidified to pH ¼ 1 by addition of aqueous HCl
solution (18%). The mixture was extracted with THF/CH2Cl2
(4:1,3 Â 60 ml), and the organic phases were combined, dried over MgSO4.
The solvent was removed under reduce pressure and the residue was dis-
solved in acetone (10 ml), then hexane (200 ml) was added subsequently.

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ZHOU ET AL.
The desired product was isolated as a white solid by filtration (0.43 g, 69%).
Mp 199–200ꢂC. IR (KBr) n: 3500, 3350, 1700, 1640, 1515, 1360, 1110 cmꢀ1
.
1H NMR (DMSO-d6) d: 4.36 (d, J ¼ 4.2 Hz, 1H), 4.00–4.60 (br, 1H), 5.45
(dd, J ¼ 8.7, 4.2 Hz, 1H), 7.22–7.54 (m, 9H), 7.83 (d, J ¼ 6.6 Hz, 1H), 8.55 (d,
J ¼ 9.3 Hz, 1H). 13C NMR (acetone-d6) d: 56.3, 74.1, 127.9, 128.1, 129.0,
129.1, 131.9, 135.7, 141.1, 167.0, 173.8. Anal. Calcd. for C16H15NO4: C,
67.36; H, 5.30; N, 4.91. Found: C, 67.31; H, 5.26; N, 4.87.
(2R,3S)-N-benzoyl-3-phenylisoserine (2)
To a suspension of (ꢁ)ꢀ 2 (400 mg) in ethyl acetate (4.4 ml) was added
R-(þ)-a-methyl benzylamine (190 ml). The resulting solution was allowed to
stand at room temperature for 2 h. It was then filtered and 536 mg of the salt
was obtained after drying. The salt (200 mg) was dissolved in hot ethanol
(1.8 ml). The solution was set aside at room temperature for 16 h. The
resulting crystals were filtered and washed with cold ethanol, and dried in
vacuum to furnish 90 mg of the R-(þ)-a-methyl benzylamine salt of title
product. The salt obtained was stirred in ethyl acetate (8.0 ml) and 5%
aqueous KHSO4 (8.0 ml). The aqueous layer was separated and extracted
with ethyl acetate (3 Â 8 ml). The combined organic layer was washed with
brine (8 ml), dried over MgSO4, filtered and concentrated to dryness to
afford 2 (64 mg). [a]2D5 - 31.7 (C 1.0, EtOH) (Lit.,13 [a]2D5 ꢀ 37.78, C 0.9,
EtOH). Mp 166–168ꢂC (Lit.,13 167–169ꢂC). IR and NMR are consistent
with those of the corresponding racemic acid.
ACKNOWLEDGMENT
Financial support of this work by the Ninth-Five-Years-Plan of
National Science and Technology Key Project of China 96-C02-03-01 is
gratefully acknowledged.
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Received in Japan October 20, 2000

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