A semisynthesis of paclitaxel via a 10-deacetylbaccatin III derivative bearing a β-keto ester appendage

Article abstract of DOI:10.1016/S0040-4039(99)02056-0

A semisynthesis of paclitaxel has successfully been accomplished starting from a newly developed baccatin III derivative bearing a β-keto ester appendage on C-13.

Full text of DOI:10.1016/S0040-4039(99)02056-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 243–246
A semisynthesis of paclitaxel via a 10-deacetylbaccatin III
derivative bearing a β-keto ester appendage
Tadakatsu Mandai,a,∗ Akiyoshi Kuroda,a Hiroshi Okumoto,a Katsuyoshi Nakanishi,b
Katsuhiko Mikuni,b Ko-ji Hara b and Ko-zo Hara b
aDepartment of Chemical Technology, Kurashiki University of Science & the Arts, 2640 Nishinoura, Tsurajima-cho,
Kurashiki 712-8505, Japan
bBio Research Corporation of Yokohama, 13-46 Daikoku-cho, Tsurumi-ku, Yokohama 230-0053, Japan
Received 24 September 1999; revised 25 September 1999; accepted 29 October 1999
Abstract
A semisynthesis of paclitaxel has successfully been accomplished starting from a newly developed baccatin III
derivative bearing a β-keto ester appendage on C-13. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: β-keto ester appendage; 10-deacetylbaccatin III; paclitaxel; semisynthesis.
In the preceding paper, we reported a remarkably efficient preparative method for a 10-
deacetylbaccatin III derivative 3 by the transesterification of ethyl benzoylacetate with a protected
10-deacetylbaccatin III (2). Here we wish to describe a new semisynthetic method for paclitaxel (1)1
from 3 via a regio- and diastereoselective construction of the 20-α-OH-30-α-NH2 alignment requisite
for 1.
Our protocol is outlined in Scheme 1. The key intermediate 3 was treated with O-benzylhydroxylamine
hydrochloride in pyridine at room temperature for 3 h to give oxime ether 4 in a quantitative yield. Then,
introduction2 of 20-OH of 4 was extensively examined. However, all the efforts were unfruitful, which
involved the oxidation with m-CPBA, the air oxidation of the carbanion, and the bromination with NBS
and ensuing acetoxylation. To our great delight, an elegant synthetic method for α-acyloxyketone by
∗
Corresponding author. Fax: +0081 86 440 1062; e-mail: ted@chem.kusa.ac.jp (T. Mandai)
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02056-0
tetl 15984

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Cu(acac)2-catalyzed insertion reaction of α-diazoketone to carboxylic acid has been reported by Shinada
and Ohfune.3 Their protocol stimulated us to synthesize diazo compound 5, which was uneventfully
prepared in 93% yield based on 3 by the treatment of 4 with a combination of TsN3/Et3N/cat. DBU
(1.1/1.3/0.3 equiv. each) in acetonitrile at room temperature for 16 h. The insertion reaction of 5 thus
obtained was carried out according to their standard procedure, whereas the reaction was very sluggish
with a slight excess of acetic acid in toluene at room temperature. Compound 5, stabilized by both the
C_N and C_O bonds, seemed much less reactive than α-diazoketones. Consequently, the reaction of 5
in HOAc as the solvent proceeded at 60°C for 70 h at a reasonable rate to give acetate 6 in 80% yield. The
diastereoselectivity of the reaction was ambiguous at this stage since 6 was found to be an inseparable
mixture of four diastereomers composed of both E/Z isomers of the oxime, and α and β-OAc. Next,
attempted alkaline hydrolysis of the 20-OAc of 6 using weak bases did not proceed chemoselectively, the
other acetoxy group on C-4 position being damaged. To overcome this crucial problem, 6 was subjected
to bis(dibutylchlorotin)oxide-catalyzed transesterification4 in boiling ethanol for 24 h, giving rise to a
chromatographically separable mixture of alcohols 7a and 7b in 89% combined yield. Eventually, the
diastereoselectivity of the insertion reaction of 5 was unambiguously determined to be 2/1.5
Scheme 1.
At first, the minor isomer 7b seemed to be an ideal intermediate, if the stereoselective reduction of the
oxime to α-NH2 could be realized. However, all the attempted reductions with various metal hydrides6
were entirely unsuccessful because the baccatin III nucleus was fatally damaged. Furthermore, the
attempted catalytic hydrogenation7 using Pd/C (10%), Pd black, PtO2, Rh/Al2O3, Rh/C (5%), or Raney-
nickel resulted in either the entire recovery of 7b or at most the deprotection of 10-Cbz. Fortunately,
the oxime was only amenable to reduction using HCO2NH4/cat. Pd/C (10%)8 in acetic acid9 to provide
β-NH2 smoothly with simultaneous deprotection of 10-Cbz.
From these observations, we turned our attention to the major isomer 7a, examining its efficient
transformation into 1 (Scheme 2). Simultaneous deprotection of 10-Cbz and reduction of the oxime
ether of 7a were affected with a combination of HCO2NH4/cat. Pd/C (10%)/HOAc at room temperature
for 3 h to provide 9 in 78% yield in two steps via protection of 30-NH2 of 8 as a benzamide. The relative
configuration of the 20-OH and 30-N-Bz in 9 was found to be anti, with none of the syn isomer being
detected. Inversion of the stereochemistry of the β-OH in 9 was successfully achieved via oxazoline
formation and ensuing acid hydrolysis. Namely, 9 was treated with DEAD/PPh3 at 0°C for 1 h to give

245
oxazoline 1010 in 87% yield. Acetylation of 10 (Ac2O/py/cat. DMAP) followed by the acid-mediated
hydrolysis of the oxazoline moiety10 (0.1N HCl in methanol at 60°C for 3 h) provided paclitaxel (1) in
83% yield in two steps.
Scheme 2.
From a synthetic point of view, we examined the transformation of 7b into 7a (Scheme 3). Swern
oxidation (90%) of 7b followed by the reduction with NaBH3CN/HOAc provided 7a (73%) accompanied
by 7b (20%). In addition, 7b was amenable to the reduction with NaBH4/MeOH to give rise to 2 (92%),
which can be reused.
Scheme 3.
In summary, a new semisynthesis of paclitaxel has successfully been accomplished starting from a
readily available protected 10-deacetylbaccatin III, which involves both introduction of β-keto ester
appendage into C-13 position via catalysis-free transesterification with β-keto ester and construction of
20-OH-30-NH2 in regio- and diastereoselective manners without any asymmetric auxiliaries. We believe
this protocol would be helpful for a large scale production of paclitaxel from 10-deacetylbaccatin III.
Acknowledgements
The authors are grateful to Profs. T. Shinada and Y. Ohfune, Osaka City University, for their
helpful discussions, and Prof. J. Otera, Okayama University of Science, for the generous gift of
bis(dibutylchlorotin)oxide.
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