Synthesis of the 2α-benzoylamido analogue of docetaxel

Article abstract of DOI:10.1016/S0040-4039(00)02243-7

The 2α-benzoylamido analogue of docetaxel 2 was synthesized with a double inversion of the C-2 configuration as the key step, and its cytotoxic activity towards three tumor cell lines was tested.

Full text of DOI:10.1016/S0040-4039(00)02243-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1331–1333
Synthesis of the 2a-benzoylamido analogue of docetaxel
Wei-Shuo Fang,* Qi-Cheng Fang and Xiao-Tian Liang
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, PR China
Received 11 October 2000; revised 27 November 2000; accepted 6 December 2000
Abstract—The 2a-benzoylamido analogue of docetaxel 2 was synthesized with a double inversion of the C-2 configuration as the
key step, and its cytotoxic activity towards three tumor cell lines was tested. © 2001 Elsevier Science Ltd. All rights reserved.
The chemistry of paclitaxel (=Taxol®, 1a), a clinically
important anticancer drug, has been extensively
explored since the late 1980s. A variety of its analogues
with modified core structures and C-13 substituted
phenylisoserine side chains have been synthesized and
biologically evaluated.1,2 The marketing of docetaxel
(=Taxotere®, 1b), a paclitaxel derivative with better
solubility in water and more potent cytotoxicities, is
one of the fruitful results of these research efforts. It is
now widely accepted that the southern hemisphere of
the molecule, including the C-13 side chain, the C-2a
aroyl and C-4 alkyl esters, is critical to the cytotoxicity
of paclitaxel. ‘Hydrophobic collapse’ and other postu-
lates were proposed to explain and predict the confor-
mations of paclitaxel analogues binding to tubulin
dimers.3
logues with different aroyl ester groups at the C-2
position in place of benzoate have been synthesized.6
Replacement of the 2-ester with other heteroatom-con-
taining linkages, such as amide or thioester, have not
yet been realized. The synthesis and biological evalua-
tion of 2-amido analogues will help to enrich our
knowledge of the structural requirements of the 2-sub-
stituted groups. Herein we report a synthesis of the
2a-benzoylamido analogue of docetaxel 2 (Fig. 1).
Our strategy for the introduction of the 2a nitrogen
substituted group depended on the preparation of a key
intermediate, the 2a-azido baccatin III derivative 6,
which was expected to be formed from a 2a-sulfonate
by a double SN2 substitution reaction.
10-Deacetylbaccatin III 3 was converted into 13-keto-7-
TES-baccatin III 4 by the known procedure7–9 with
slight modification (Scheme 1).
Studies on the SAR at the C-2 position showed that
both the nature and stereochemistry of the 2-aroyl
group are of great importance to activity. Loss of the
2-aroyl ester4 or change of its orientation from a to b5
were detrimental to its activity. Many paclitaxel ana-
Among the various methods for 2-debenzoylation,10
Red-Al seemed to be the best choice for baccatin III
Figure 1.
Keywords: paclitaxel; docetaxel; 2-benzoylamido analogue of docetaxel; SN2 double inversion.
* Corresponding author. Fax: 86-10-63017757; e-mail: wfang@imm.ac.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02243-7

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W.-S. Fang et al. / Tetrahedron Letters 42 (2001) 1331–1333
analogues. Unfortunately, treatment of 4 with Red-Al
gave the desired product 5 in only 50% yield. After
several experiments, 5 was finally obtained in 90% yield
The b-orientation of H-2 was further confirmed by
strong NOEs between H-2b, Me-16 and Me-19.
with Triton
B
(a modified Kingston’s method).5
With the key intermediate 6 in hand, we embarked on
further transformations to give the desired 2a-amido
product. Stereoselective reduction of the 13-keto group
in 6 to the 13a-hydroxyl compound 7 using NaBH4
proceeded uneventfully. The attachment of the C-13
side chain was realized by coupling 7 with the b-lactam
8.13 The 2a-azido taxol analogue 9, on catalytic hy-
drogenation, was transformed into the 2-amino com-
pound 10 as the major product. Finally, 10 was sub-
jected to benzoylation, and successive desilylation to
obtain 2.
Attempts to prepare the 2-O-triflate of 5 failed, whilst
mesylation of 5 proceeded smoothly. Almost a single
spot was detected as the product on TLC after mesyla-
tion. To our surprise, a mixture of two compounds in a
2:1 ratio was obtained after chromatography. It was
1
shown by H NMR that the major compound in this
mixture is the 2-mesylate 5a, and the minor one may be
the 1,2-epoxide 5b arising from intramolecular attack
on the 2-mesylate by the 1-hydroxyl.11
It was reasoned that the 2-mesylate may not be stable
to chromatography, hence we treated the mixture with
sodium azide directly after aqueous workup. The
desired 2a-azidobaccatin 6 was obtained in 72% yield
over the two steps. The 1H NMR of 6 showed the
resonance of H-2 as a triplet (J=6.0 Hz), coupling to
the 1-OH and H-3a.12 The coupling constant between
H-2 and H-3a revealed they are in a trans relationship.
Compound 2 showed antitumor activities towards three
tumor cell lines, A-549, KB and A2780, although it was
less potent than paclitaxel (IC50/IC50(paclitaxel) 20.5, 16.8,
0.8). It is quite interesting to note that C-13 amido
analogues of paclitaxel were inactive14 whilst the C-2
amido analogue of docetaxel 2 retained activity to a
great extent.
Scheme 1. (I) Triton B, CH2Cl2, −20°C, 88%; (II) (a) MsCl, Et3N, CH2Cl2, −20°C; (b) NaN3, DMF, 50°C, 72% for two steps;
(III) NaBH4, MeOH–THF, 0°C, 90%; (IV) LHMDS, THF, −15°C, 77% on 80% conversion; (V) H2/Pd–C, EtOAc, rt, 60%; (VI)
(a) BzCl, EtOAc–H2O–NaHCO3, rt; (b) HF–Py, rt, 46% for two steps.

W.-S. Fang et al. / Tetrahedron Letters 42 (2001) 1331–1333
1333
Acknowledgements
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The authors would like to thank Ms. Hong-Yan Liu for
her assistance in cytotoxicity evaluation of 2 and pacli-
taxel. Financial support by funding to Outstanding
Doctor Thesis Authors of Chinese Universities (grant
No. 199949) from the Ministry of Education P. R.
China is gratefully acknowledged (W.-S. Fang).
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