14b-Hydroxy-10-deacetylbaccatin III as a convenient, alternative substrate for the improved synthesis of methoxylated second generation taxanes
Luciano Barboni,a,* Guido Giarlo,a Roberto Ballinia and Gabriele Fontanab
Abstract
This article describes a new, convenient, improved synthesis of the 2-debenzoyl-2-m-methoxybenzoyl-7-triethylsilyl-13oxo-14b-hydroxybaccatin III 1,14-carbonate, the key intermediate in the synthesis of two new second-generation antitumor taxanes. 2006 Elsevier Ltd. All rights reserved.n The antimitotic drugs Taxol (paclitaxel) and Taxotere (docetaxel) are two of the best anticancer agents in clinical use today for the treatment of ovarian cancer, breast cancer, and nonsmall cell lung cancer. Paclitaxel and docetaxel suffer from a series of disadvantages, including poor water solubility and the quick development of resistance,1 that have fuelled the search for analogues endowed with a better clinical profile.
In this context, we recently published the synthesis of two new biologically active compounds (1 and 2, Fig. 1),2 the methoxylated analogues of the norstatin esters IDN5109 and IDN5390 (3 and 4, respectively; Fig. 1)3 which have recently emerged as interesting clinical candidates to overcome resistance to paclitaxel and to allow oral administration.
The synthesis of both compounds 1 and 2 was accomplished starting from the naturally occurring 10-deacetylbaccatin III 5 (Scheme 1), through the key intermediate 6.
The synthesis of 6 from 5 proceeded in an unsatisfactory overall yield (7%), due to the presence of two critical steps. In fact, since 10-deacetylbaccatin III lacks the boxygen at C-14, the procedure required the diastereo- selective b-hydroxylation, followed by carbonylation of the crude 1,14-diol,4 with a low overall yield (30%). This prompted us to explore an alternative synthesis for the key compound 6, with the aim of avoiding the diastereoselective hydroxylation step and, in this way, to increase the yield of the synthesis. The new approach started from the readily available 14b-hydroxy-10-deacetylbaccatin III (7), a naturally occurring taxane isolated from
Keywords: 14b-Hydroxy-10-deacetylbaccatin III; Second-generation taxanes; Natural products; Terpenoids; Antitumor agents.
Summary
The first step of our procedure was the selective acetylation of the 10-hydroxyl group, which was carried out by treatment with Ac2O in the presence of CeCl3Æ7H2O,6 which gave compound 8 with a 98% yield, followed by the selective silylation of the 7-hydroxyl group7 (Scheme 2) to give 9 (55%). The obtained compound 9 was then debenzoylated at C-2 by treatment with benzyltrimethylammonium hydroxide (Triton B)8 giving the polyhydroxylated compound 10. The crude 10 was then selectively carbonylated at 1,14 with triphosgene9 to yield compound 11 (56% from 9). The latter was selectively oxidized at C-13 by treating with Nmethylmorpholine-N-oxide and a catalytic amount of OsO4,10 to yield ketone 12 (93%, Scheme 2). Finally, 12 was benzoylated at C-2 with anisic acid,11 allowing the target compound 6 to be obtained in an acceptable yield of 40% (Scheme 2).12 It is worth noting that, as far as we know, the benzoylation at C-2 of a taxane, in the presence of the 1,14-carbonate, has never been reported before. The limited yield of this step is probably due to the steric hindrance that the 1,14-carbonate and the 4-acetate are exerting on the C-2 hydroxyl group.
The overall yield of the synthesis was 11%, which represents a significant increase (>50%) compared to 7% of the previous procedure. Additionally, the chance to have two approaches for the synthesis of highly active 10-Deacetylbaccatin-III antitumor taxanes, from different naturally occurring compounds, could be very useful since the restricted availability of the starting material is, usually, one of the main limiting factor.13
In summary, a convenient preparation of the key intermediate 6 has been reported; the method includes the first benzoylation at C-2 of a taxane carrying a 1,14 carbonate. This synthetic procedure starts from a different precursor and involves simpler chemistry compared with those from 10-deacetylbaccatin III. Moreover, a substantial increase of the yield (>50%) with respect to the previous procedure is the crucial advantage of this method. Further studies on the synthesis of antitumor taxanes are in progress.
References and notes
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