Synthesis of 5(20)deoxydocetaxel, a new active docetaxel analogue

Article abstract of DOI:10.1016/S0040-4039(00)00379-8

5(20)Deoxydocetaxel was prepared from 13-oxo-10-deacetyl baccatin III. This compound is the first docetaxel analogue with a modified D-ring which is as active as paclitaxel off microtubules. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00379-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3331–3334
Synthesis of 5(20)deoxydocetaxel, a new active docetaxel
analogue
Joëlle Dubois,∗ Sylviane Thoret, Françoise Guéritte and Daniel Guénard
Institut de Chimie des Substances Naturelles, CNRS 91198, Gif sur Yvette, Cedex, France
Received 28 January 2000; accepted 1 March 2000
Abstract
5(20)Deoxydocetaxel was prepared from 13-oxo-10-deacetyl baccatin III. This compound is the first docetaxel
analogue with a modified D-ring which is as active as paclitaxel on microtubules. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: taxoids; docetaxel; oxetane; 10-deacetyl baccatin III; microtubules.
Taxoids are a series of anticancer drugs1 which inhibit cell growth by interacting with microtubules.2
Paclitaxel (Taxol®) 1a3 and docetaxel, (Taxotere®) 1b,4 the leading compounds of this series, are
effective clinical agents for the treatment of various cancers. Due to their original activity and their
efficiency in cancer treatment, extensive studies have been made on structure–activity relationships in
order to find out the minimal structural requirements to maintain microtubule binding.5 These studies
have established that the C-13 side chain, and the ester groups at C-2 and C-4 are essential for biological
activity. Because of the inactivity of D-secopaclitaxel 2,6 the oxetan ring is also described to be essential
for microtubule binding, but this compound lacks the C-4 ester group, known to be important for activity
(Fig. 1).
Fig. 1.
∗
Corresponding author. Fax: (33) 01 69 07 72 47; e-mail: joelle.dubois@icsn.cnrs-gif.fr (J. Dubois)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00379-8
tetl 16659

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Only few taxoid analogues bearing modified D-ring have been synthesized: 5(20)aza derivative of a
baccatin VI analogue,7 5(20)azadocetaxel and its N-derivatives 58 and a close analogue of 5(20)thiopa-
clitaxel 69 (Fig. 2). All demonstrated reduced interaction with microtubules, suggesting effectively an
important role for the oxetan in microtubule binding. However, in the course of our structure–activity
relationship studies on the oxetan ring, we have synthesized 5(20)deoxydocetaxel 7, a new docetaxel
analogue with a modified D-ring as active as paclitaxel on cold-induced microtubule disassembly. We
wish to report in this letter its synthesis and its biological evaluation.
Fig. 2.
5(20)Deoxydocetaxel has been synthesized according to the same scheme as 5(20)azadocetaxel.8 In
order to further carry out selective deprotection of the C-13 alcohol, the C-7 and C-10 hydroxyl groups
of 13-oxo,10-deacetylbaccatin III 8,10 were protected as triethylsilyl ethers (Scheme 1). Removal of the
C-2 and C-4 ester groups and formation of the C-1,C-2 carbonate were realized as previously described.
The oxetan ring of the completely protected compound 9 was opened according to our procedure8 and
led to compound 10 with a fairly good yield (63%).
Scheme 1. Reagents: (a) TESCl, imidazole, DMF, rt (69%); (b) Red-Al (4 equiv.), THF, 0°C (59%); (c) (CCl3O)2CO,
CH2Cl2:pyridine (85:15), −15°C, (93%); (d) Et4NBr, BF3·OEt2, CH2Cl2, rt (63%)
Our strategy for the construction of the cyclopropane ring was based on the Wurtz type reaction
between two alkyl halides. Introduction of a halide at the C-20 position revealed to be troublesome.
Classical methods for direct substitution were ineffective and substitution by means of a sulfonate only
led to the C-4,C-20 epoxyde formation. Therefore, this compound was used for introduction of the
halide. Direct formation of the epoxyde 11 was achieved with an acceptable yield with tributylphosphine
and diethylazodicarboxylate.11 The formation of the iodhydrin 12 was performed by treatment of the
epoxide 11 with tetrabutylammonium iodide and BF3·OEt2.12 Cyclisation with Zn dust13 afforded the
cyclopropyl derivative 13 in good yield (Scheme 2).
Afterwards, we achieved the subsequent steps to complete the synthesis of the docetaxel analogue
under the same conditions as for the 5(20)azadocetaxel derivatives. After acetylation of compound 13, the
C-1,C-2 carbonate was readily opened by phenyllithium in acceptable yield (14, 59%) without affecting
the C-13 ketone. This function was then reduced with NaBH4 to afford the C-13α isomer 15 in 49% yield.
These two last steps occurred with lower yields than with the parent compounds bearing an oxetan or an
azetidine ring. This may be due to the increased strain caused by the presence of the cyclopropane ring.
Esterification was then realized with the 2-(4-OMe)phenyl 1,3-oxazolidine of N-Boc-phenylisoserine

3333
Scheme 2. Reagents: (a) PBu3, DEAD, DMF, rt (72%); (b) nBu4NI, BF3·OEt2, CH2Cl2, rt (53%); (c) Zn, THF, ∆ (70%)
16,14 DCC and DMAP in toluene at room temperature in good yield (17, 92%). Deprotection of 17 with
p-toluenesulfonic acid in methanol afforded the desired compound 715 (74% yield) (Scheme 3).
Scheme 3. Reagents: (a) DMAP, Ac2O, CH2Cl2, rt (83%); (b) PhLi, THF, −72°C (59%); (c) NaBH4, EtOH:THF (75:25), rt
(49%); (d) 16, DCC, DMAP, toluene, rt (92%); (e) PTSA, MeOH, rt (74%)
We then measured for compound 7 the concentration required to inhibit 50% of the rate of cold-induced
microtubule disassembly.16 The ratio IC50:IC50(paclitaxel) gives the activity with respect to paclitaxel.
The result is reported in Table 1 and compared with paclitaxel 1a, docetaxel 1b and 5(20)azadocetaxel 5.
Table 1
Biological evaluation of 5(20)-deoxydocetaxel
5(20)Deoxydocetaxel is thus the first compound without an oxetan ring that is as active as paclitaxel.
Therefore, the oxetan ring is not essential for the interaction with microtubules. The cyclopropyl ring
might act, as the oxetan, to rigidify the C-ring and point the C-4 acetoxy group in the appropriate
direction for binding. The presence of the oxygen is not absolutely required but likely participates in the
stabilization of the taxoid–tubulin complex as exemplified by the twofold decrease of activity compared
to docetaxel 1b. Other D-ring modified compounds are being synthesized in our laboratory to fully
explore the actual contribution of this oxetan ring in microtubules binding.

3334
Acknowledgements
We wish to thank Professor Potier for his unfailing interest in this work. The authors thank Dr Alain
Commerçon for a gift of the docetaxel acid side-chain and gratefully acknowledge financial support from
Rhône-Poulenc Rorer S. A. and the European Community (AIR3-CT94-1979). Jean-François Gallard is
also acknowledged for performing NMR spectra.
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15. Spectroscopic data of compound 7: 1H NMR (300 MHz, CDCl3) δ 0.67 (2H, d, J=8.5 Hz), 1.06 (1H, m), 1.10 (3H, s), 1.30
(3H, s), 1.32 (3H, s), 1.38 (9H, s), 1.39 (1H, m), 1.91 (3H, s), 2.20 (3H, s), 2.36 (2H, m), 2.57 (1H, m), 3.41 (1H, d, J=5.0
Hz), 4.07 (1H, dd, J=5.0 Hz, J0=11.0 Hz), 4.28 (1H, s), 4.41 (1H, d, J=6.5 Hz), 4.61 (1H, bs), 5.14 (1H, s), 5.27 (1H, bd,
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