A facile semisynthesis of 2'7-Bisacetyltaxol from 10-dab

Full text of DOI:10.1007/s10600-012-0357-3

Chemistry of Natural Compounds, Vol. 48, No. 4, September, 2012 [Russian original No. 4, July–August, 2012]
A FACILE SEMISYNTHESIS OF 2ꢀ,7-BISACETYLTAXOL
a
FROM 10-DAB
1,2
2
2
1*
Min Gu, Yang-Ming Zhang, Wei Luo , Wei Lu,
UDC 547.913.6
2*
and Fa-Jun Nan
Paclitaxel (taxol)(1) ꢁ1ꢂ, originally isolated from the Pacific yew tree in the early 1960s, holds great promise as a
treatment for various forms of cancer, including ovarian cancer, breast cancer, and other cancers ꢁ2ꢂ. Paclitaxel is a novel
antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing
depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that
is essential for vital interphase and mitotic cellular functions ꢁ3ꢂ.
In the meantime, a large number of taxol derivatives and taxanes were isolated from natural sources or partially
synthesized from a simple and more easily accessible taxol congener ꢁ4ꢂ. 2ꢀ,7-Bisacetyltaxol (2), an acetylated taxol derivative,
was first isolated from the acetylated “post-taxol” fraction of Taxus brevifolia Nutt. ꢁ5ꢂ; later it was prepared by acetylation of
taxol in the presence of acetic anhydride/dicyclohexylcarbodiimide/4-dimethylaminopyridine in dichloromethane ꢁ6bꢂ.
3
Biological activity evaluation showed that this compound does not promote microtubule assembly nor inhibit [ H]
taxol binding to microtubule protein competitively in vitro; it showed moderate activity in cytotoxicity assay toward the
macrophage-like cell line J774.2 in vivo, approximately 10-fold less active than taxol in the same assay ꢁ6ꢂ. These results
suggested that this compound might be converted intracellularly to either taxol, 7-acetyltaxol, or other unknown active taxol
metabolites. In addition, no further activity study regarding this compound is available so far, and there is a need to explore an
easier method for large-scale preparation of taxol acetate for further biological research. In the present paper, we describe a
facile preparation of 2ꢀ,7-bisacetyltaxol from 10-deacetylbaccatin III (10-DAB), which is readily available in relatively high
yield from the needle of the European yew T. baccata. Employing the present method, we obtained grams of sample in high
overall yield. The starting material, acid 6, can be the easily prepared by literature method ꢁ7ꢂ.
In a pervious attempt, we employed the acetyl group to protect the hydroxyl groups at the 7- and 10-positions, which
is required in title compound 2 (Scheme 1). Although the esterification reaction of acid 6 with 3a afforded 4a in modest yield,
subsequent deprotection by formic acid gave a very complex mixture due to the partial deacetylation under these conditions.
After benzoylation in ethyl acetate–H O, compound 5a was only obtained in 20% yield from 4a. However, when the procedure
2
reported in ꢁ7ꢂ, was used, the 7- and 10-position hydroxyl groups were protected by 2,2,2-trichloroethoxycarbonyl (Troc).
Esterification of acid 6 with 3 afforded the corresponding ester 4 in almost quantitative yield. Deprotection in formic acid at
room temperature and removal of the formic acid under reduced pressure, followed by benzoylation without further treatment,
yielded compound 5 in 98% overall yield. Significant improvement was observed compared to the separate procedure reported
in ꢁ7ꢂ. The Troc group was then removed, followed by acetylation in Ac O–pyridine in the presence of DMAP. The title
2
compound 2 was obtained in 60% overall yield from 5. All the spectral data of compound 2 from the present experiment are in
agreement with those reported previously.
______
a
th
Materials presented at the 9 International Symposium on the Chemistry of Natural Compounds (SCNC, Peopleꢀs Republic
of China, Urumqi, Oct. 16–19, 2011).
1) Shanghai Engineering Research Center of Molecular Therapetics and New Drug Development, East China Normal
University, 3663 North Zhong Shan Road, 200062, Shanghai, P. R. China, fax: +86 21 508 009 54, e-mail:
wlu@chem.ecnu.edu.cn; 2) The National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, 201203, Shanghai, P. R. China, e-mail:
fjnan@mail.shcnc.ac.cn. Published in Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2012, pp. 625–626. Original article
submitted March 5, 2011.
702
0009-3130/12/4804-0702 02012 Springer Science+Business Media, Inc.

2ꢀ,7-Bisacetyltaxol (2), mp 207–208ꢃC, [ꢄ] –49.2ꢃ (c 1, CHCl ). H NMR (300 MHz, CDCl , ꢅ, ppm, J/Hz): 1.16
D 3 3
O
RO
RO
O
OR
OR
O
COOH
a
O
HO
O
O
H
OBz
BocN
O
Boc
N
O
H
HO
HO
OBz
OAc
OAc
6
10-DAB, 3, 3a
4, 4a
b
10-DAB: R = H; 3: R = COOCH CCl
4: R = COOCH CCl (99%)
2
3
2
3
3a: R = Ac
4a: R = Ac (60%)
O
O
AcO
O
RO
O
OR
OAc
OAc
NH
O
NH
O
c
O
O
OH
OAc
O
O
H
OBz
H
HO
HO
2 (60%)
OBz
OAc
5, 5a
5: R = COOCH CCl (98%); 5a: R = Ac (20%)
2
3
a. 6, DCC, DMAP, toluene; b. i) HCOOH, ii) benzoyl chloride, NaHCO , EtOAc/H O; c. i) Zn, AcOH/MeOH, ii) Ac O/Py
3
2
2
Scheme 1. Semisynthesis of 2ꢀ,7-bisacetyltaxol from 10-DAB.
20
1
(3H, s), 1.21 (3H, s), 1.81 (3H, s), 1.87 (3H, s), 2.03 (3H, s), 2.16 (6H, 2s), 2.37 (1H, m), 2.44 (3H, s), 2.62 (1H, m), 3.95 (1H,
d, J = 7.2), 4.26 (2H, dd, J = 8.4, 8.1), 4.96 (1H, d, J = 8.1), 5.58 (2H, m), 5.69 (1H, d, J = 6.9), 5.94 (1H, d, J = 3.3), 5.97 (1H,
d, J = 3.0), 6.24 (2H, m), 6.92 (1H, d, J = 9.0), 7.44 (7H, m), 7.51 (3H, t), 7.61 (1H, t) 7.75 (2H, d, J = 7.2), 8.12 (2H, d, J = 6.9).
13
C NMR (75 MHz, CDCl , ꢅ): 10.07, 14.32, 14.64, 20.68, 20.92, 21.30, 21.46, 22.80, 22.86, 26.67, 31.79, 33.54, 35.64,
3
43.48, 47.15, 53.03, 56.22, 71.58, 71.98, 73.98, 74.78, 75.47, 76.57, 77.43, 78.90, 81.12, 84.23, 126.77, 127.29, 128.68,
128.97, 129.28, 129.36, 130.41, 132.24, 132.71, 133.93, 137.17, 141.35, 167.15, 167.36, 168.41, 169.08, 169.82, 170.01,
170.54, 202.28.
The above reaction sequence is suitable for large-scale synthesis. Following the present route, we can efficiently
prepare multigrams of the target taxol acetate 2 in high overall yield.
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