A new route for the construction of the AB-ring core of Taxol

Article abstract of DOI:10.1016/S0040-4039(02)02868-X

A new method for the construction of the AB-ring core of Taxol was developed utilizing a new skeletal transformation protocol as a pivotal step. The acid-catalyzed rearrangement of the cyclopentenone-allene photoadduct gave a bridged seven-membered ketone, which was easily transformed, using the intramolecular Suzuki reaction and the oxidative cleavage of the vicinal diol, to the bicyclic diketone.

Full text of DOI:10.1016/S0040-4039(02)02868-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1401–1403
A new route for the construction of the AB-ring core of Taxol
Yumi Shimada,a Makoto Nakamura,b Toshimasa Suzuka,a Junji Matsui,a Ryo Tatsumi,a
Ken Tsutsumi,a Tsumoru Morimoto,a Hideo Kurosawab and Kiyomi Kakiuchia,*
aGraduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Takayama, Ikoma, Nara 630-0101,
Japan
bDepartment of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received 28 November 2002; revised 17 December 2002; accepted 19 December 2002
Abstract—A new method for the construction of the AB-ring core of Taxol was developed utilizing a new skeletal transformation
protocol as a pivotal step. The acid-catalyzed rearrangement of the cyclopentenone–allene photoadduct gave a bridged
seven-membered ketone, which was easily transformed, using the intramolecular Suzuki reaction and the oxidative cleavage of the
vicinal diol, to the bicyclic diketone. © 2003 Elsevier Science Ltd. All rights reserved.
Taxol 1 is one of the most powerful, naturally occur-
ring antitumor reagents known, and is widely and
routinely used in the treatment of breast, lung, and
ovarian cancers1 (Fig. 1). Due to its therapeutic poten-
tial and its limited availability, enormous efforts have
been directed towards the chemical synthesis of Taxol
in the past decade, and this remains one of the most
challenging targets for synthetic chemists because of its
unique structural features.2 The construction of the
AB-ring core of Taxol, which involves bicyclo-
[5.3.1]undecane moiety consisting of a ten-membered
ring bridged by one carbon, has been nonpractical yet.
As a solution to the problem, some efficient methods
for the construction of bicycloundecanes have recently
developed.3 We report here an new route for the con-
struction of the AB-ring core.
alyzed rearrangement of 6-substituted bicyclo-
[4.2.0]octanones (Eq. (1)), and demonstrated its
utility in the total synthesis of ( )-tetramethylmedi-
terraneol B.4 The skeletal rearrangement of cyclobutyl
ketones, which are easily derived from the photocy-
cloaddition of cyclohexen-2-one with alkenes, proved to
be an efficient route to bridged eight-membered ring
compounds.4a We envisioned a use of this rearrange-
ment for the construction of a bridged bicyclic system
corresponding to the AB-ring core of Taxol.
(1)
We have already reported an efficient method for the
construction of bicyclo[4.2.1]nonanones by the acid-cat-
Our strategy for preparing the AB-ring core of Taxol 1
was based on the initial construction of the isoproryli-
dene bridge of AB-ring. Thus, the skeletal rearrange-
ment of the 5-4 fused ketone 6 would result in the
formation of bicyclo[3.2.1]octanone 5 having an iso-
propylidene bridge (Scheme 1). A subsequent functional
group elaboration, based on the exo-methylene group
of 5, including an increase in the number of carbon
atoms and a ring-expansion, would lead to the AB-ring
core of 1.
Figure 1.
The irradiation of cyclopentenone 7, which is readily
synthesized from 6-methyl-5-hepten-2-one,5 with allene
in CH2Cl2 at −78°C gave the head-to-head adduct 6 in
84% yield, along with the head-to-tail adduct in 12%
* Corresponding author. Tel.: +81-743-72-6080; fax: +81-743-72-6089;
e-mail: kakiuchi@ms.aist-nara.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02868-X

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Y. Shimada et al. / Tetrahedron Letters 44 (2003) 1401–1403
diastereoselective reduction of ketone 5 with DIBALH
and protection of the resulting hydroxy group afforded
the bridged bicyclic olefin 8 in quantitative yield. The
olefin 8 was hydroborated and subsequently oxidized to
form alcohols 9 as a diastereomeric mixture (88/12).
The alcohols 9 were converted to ketone 4 in 92% yield,
via a Swern oxidation and subsequent oxidative cleav-
age with oxygen.7
Allylation of ketone 4 with excess LDA and allyl iodide
in THF/HMPA gave a mixture of C-allylated ketone
10 and the C,O-bis-allylated compound, which, on
treatment with acetic acid gave ketone 10 as a
diastereomeric mixture (88/12) in 98% yield based on a
91% conversion (Scheme 3). Triflation of the allylke-
tone 10 with KHMDS and PhNTf2 in THF gave the
triflate in 99% yield based on an 80% conversion, and
hydroboration of the triflate with 9-BBN followed by
palladium-catalyzed intramolecular Suzuki–Miyaura
coupling afforded the tricyclic olefin 11 in 85% yield.8
The diene 3 was obtained in three steps utilizing the
oxygen functional group in 11, removal of the silyl
group, catalytic oxidation with TPAP,9 and Wittig
olefination. The osmium-catalyzed dihydroxylation10 of
diene 3 gave diol 12 as a single diastereomer with the
exo-methylene group intact in 94% overall yield from
11. The 1,2-glycol unit of diol 12 was oxidatively
cleaved with Pb(OAc)4 to quantitatively give diketone
13 corresponding to the AB-ring system of the Taxanes.
The target diketone 2 was obtained by isomerization of
diketone 13 in 94% yield based on a 97% conversion
under basic conditions which consisted of t-BuOK (2.0
equiv.) in DMSO/DMF (1/1) at −10°C.11
Scheme 1. Retrosynthetic analysis of the AB-ring core of
Taxol.
Scheme 2. Reagents and conditions: (a) hw, allene, CH2Cl2,
−78°C, head-to-head adduct 6, 84% (head-to-tail adduct,
12%); (b) TiCl4, CH2Cl2, rt, 78%; (c) DIBALH, Et2O, −78°C,
98%; (d) TBSCl, imidazole, DMF, rt, quant.; (e) BH3–THF,
rt; H2O, NaOH, H2O2, rt, 97%; (f) (COCl)2, DMSO, Et3N,
CH2Cl2, 0°C; (g) O2, t-BuOK, THF/DMSO (4/1), −20°C,
92% (two steps).
In summary, we report on the development of an
efficient route to the bridged bicyclic compound 2
corresponding to the AB-ring core of Taxol 1, which
was obtained in 42% in 16 steps from 7. Compound 2
possesses the framework included in the family of
highly bioactive Taxanes, and the present route estab-
lishes its applicability to the chemical synthesis of all of
them, including derivatives thereof.
yield (Scheme 2).6 The rearrangement of ketone 6 with
TiCl4 (5 equiv.) proceeded at room temperature to give
bicyclo[3.2.1]heptanone 5 in 78% yield. For this rear-
rangement, the use of other acid catalysts, such as
H2SO4, AlCl3, and BCl3, resulted in lower yield. The
Scheme 3. Reagents and conditions: (a) LDA, HMPA, allyliodide, THF, −78 to 0°C; (b) AcOH, THF, H2O, rt, 98% based on 91%
conversion (two steps); (c) KHMDS, PhNTf2, THF, −78°C, 99% based on 80% conversion; (d) 9-BBN, THF, rt; H2O, K3PO4,
Pd(PPh3)4, dioxane, 80°C, 85%; (e) TBAF, THF, rt, quant.; (f) TPAP, NMO, CH2Cl2, rt, quant.; (g) PPh3CH3Br, NaNH2,
toluene, reflux; (h) OsO4 (cat.), K3Fe(CN)6, K2CO3, MsNH2, quinuclidine, t-BuOH/H2O, rt, 94% (two steps); (i) Pb(OAc)4,
benzene, rt, quant.; (j) t-BuOK, DMSO/DMF (1/1), −10°C, 94% based on 97% conversion.

Y. Shimada et al. / Tetrahedron Letters 44 (2003) 1401–1403
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Acknowledgements
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This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, the
Nagase Science and Technology Foundation, and the
Sasakawa Scientific Research Grant (Y.S.) from The
Japan Science Society. We thank Shin-Etsu Chemical
Co. and Central Glass Co. for a generous gift of
organosilicon reagent and triflate reagent, respectively.
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