Synthesis of new baccatin III derivatives through transesterification of β-keto esters with a protected 10-deacetylbaccatin III

Article abstract of DOI:10.1016/S0040-4039(99)02055-9

Synthesis of a new array of baccatin III derivatives bearing a β-keto ester appendage on C-13 is successfully achieved through transesterification of a wide range of β-keto esters with a protected baccatin III.

Full text of DOI:10.1016/S0040-4039(99)02055-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 239–242
Synthesis of new baccatin III derivatives through
transesterification of β-keto esters with a protected
10-deacetylbaccatin III
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; accepted 25 October 1999
Abstract
Synthesis of a new array of baccatin III derivatives bearing a β-keto ester appendage on C-13 is successfully
achieved through transesterification of a wide range of β-keto esters with a protected baccatin III. © 1999 Elsevier
Science Ltd. All rights reserved.
Keywords: β-keto ester; 10-deacetylbaccatin III; transesterification; paclitaxel.
Paclitaxel (1) has been a challenging target for synthetic organic chemists because of its unique
and complex structure.1 In spite of a recent great success in total syntheses of 1 by six groups,2 a
semisynthesis is still definitely more advantageous in a practical sense owing to readily available 10-
deacetylbaccatin III (2).
Semisyntheses of 1 reported so far include procedures for attaching the C-13 side chain to a protected
derivative of 2 through esterification of suitably protected phenylisoserine (A), 3 ring opening of β-lactam
(B),4 and transesterification of thiol ester (C).5 Chiral epoxy carboxylic acid (D)6 is also utilized as the
∗
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)02055-9
tetl 15983

240
precursor, wherein the requisite NH2 should be introduced stereoselectively after the esterification. In
any case, costly chiral auxiliaries or asymmetric catalysts were used inevitably for the preparation of
enantiomerically enriched side chain precursors A–D.
We have been intrigued to establish a new semisynthetic method for paclitaxel (1) from 2, which
would be adaptable for industrial scale production. Our synthetic strategy is fundamentally different from
conventional methods described above on the point that none of a costly chiral auxiliary is used for the
preparation of the side chain through the semisynthesis. As can be seen from the retrosynthetic analysis
of 1 shown in Scheme 1, 20-hydroxy-30-oxime ether F would be one of ideal precursors. 30-Oxime ether
G would become an excellent intermediate of F if a diastereoselective introduction of 20-hydroxyl group
is feasible. For this purpose, we envisaged to take advantage of baccatin III nucleus in G as a promising
chiral auxiliary. Thus, we started our project to prepare a baccatin III derivative H bearing a β-keto ester
appendage which easily leads to the intermediate G.
Scheme 1.
To attach the β-keto ester appendage on the C-13 position of 2, we examined the transesterification7 of
commercially available ethyl benzoylacetate (4) with suitably protected derivatives of baccatin III (3a–c).
To our surprise, the present transesterification proceeded very smoothly without catalyst8 regardless of
the sterically hampered α-oriented 13-OH, the results being listed in Table 1. Initially, heating 3a with
an excess (20 equiv.) of 4 without any solvent at 90°C for 24 h provided 5a in 82% yield (entry 1). The
reaction was found to be accelerated markedly by a continuous removal of ethanol formed in vacuo (entry
2). The reaction proceeded at a reasonable rate at 70°C (entry 3). The reaction was, however, very slow at
50°C (entry 4) even under reduced pressure. More than 5 equiv. of 4 seems to be required for the smooth
transesterification due to the low solubility of 3a in 4 even at 90°C (entries 5 and 6).
This protocol is applicable to a wide range of β-keto esters 6 as shown in Table 2. In cases where R is
aromatic, the reactivity and the yields are not affected by the substituents (entries 1–6). As for the cyclic
and acyclic substituents, the reaction proceeded very smoothly to give 7 in excellent yields (entries 7–9).
2-Carbethoxy cyclopentanone also provided 7 efficiently (entry 10), whereas methyl-substituted ethyl
benzoylacetate gave 7 in lower yield (entry 11).

241
Table 1
Transesterificationa of ethyl benzoylacetate (4) with protected derivatives of baccatin III (3a–c)
Table 2
Transesterificationa of β-keto esters 6 with a protected 10-deacetylbaccatin III (3a)

242
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