Fragmentations of 13-oxo-taxyunnansin A and their application to preparation of abeo-paclitaxel and abeo-docetaxel analogues

Article abstract of DOI:10.1016/j.tetlet.2010.11.008

Two interesting unprecedented fragmentations of 13-oxo-taxyunnansin A (3), initiated by treatment with ^tBuOK and Red-Al, respectively, have been discovered, optimized and successfully applied to the synthesis of novel abeo-paclitaxel and abeo-d

Full text of DOI:10.1016/j.tetlet.2010.11.008

Tetrahedron Letters 52 (2011) 139–142
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fragmentations of 13-oxo-taxyunnansin A and their application
to preparation of abeo-paclitaxel and abeo-docetaxel analogues
Yu Zhao a, Hong-Bin Zhang b, Ji-Kai Liu a, Jia Su a, Yan Li a, Zhu-Jun Yao c, , Qin-Shi Zhao a,
⇑
⇑
a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
b School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
c State Key Laboratory of Bioorganic and Natural Products Chemistry, EISU Chemical Biology Division, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two interesting unprecedented fragmentations of 13-oxo-taxyunnansin A (3), initiated by treatment
with BuOK and Red-Al, respectively, have been discovered, optimized and successfully applied to the
synthesis of novel abeo-paclitaxel and abeo-docetaxel derivatives. Eight new derivatives of abeo-paclit-
axel and abeo-docetaxel possessing the structurally simplified 11 (15?1)-abeo-taxane skeleton with
t
Received 20 September 2010
Revised 24 October 2010
Accepted 2 November 2010
Available online 5 November 2010
an oxetane ring and
anticancer activities.
p
bond conjugate system were accordingly prepared for the further evaluation of
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Taxyunnansin A
abeo-Taxoids
Fragmentation
abeo-Paclitaxel
Anticancer
Natural products are an abundant source of diverse bioactive
metabolites. Chemical study on various natural products has pro-
vided the impetus to great advances in organic chemistry, and
led to new discovery of diverse natural scaffolds, as well as huge
number of variously modified natural products with greater syn-
thetic accessibility or improved bioactivity.1 Paclitaxel (Fig. 1, 1a)
is a unique diterpenoid first isolated by Wall and Wani from Taxus
brevifolia Nutt.2 Paclitaxel and its semisynthetic analogue doce-
taxel (1b) have proved to be the most important anticancer drugs
today because of their clinical effectiveness and novel mechanism
of action.3 Since the discovery of paclitaxel, intense chemical stud-
ies on constituents of different yew trees have resulted in the iso-
lation and identification of approximately 400 taxoids.4 Among
these, the most frequently found core structure is the pentamethyl
[9.3.1.0] tricyclopentadecane skeleton, which is now often called
the normal taxane skeleton. The chemistry and bioactivity of this
type of taxoids have been thoroughly investigated.1b
such as introduction of acetyl, troc, N-benzoyl-(20R,30S)-30-phenyl
isoserine, and TES groups into the existing functional groups at
C-5, C-13 position(s).5 In addition, a small number of 11(15?1)-
abeo-paclitaxel analogues were also prepared via direct rearrange-
ment from the known paclitaxel analogues.6 Because of potential
biological and pharmaceutical importance of abeo-paclitaxel
derivatives, it still calls for new contents in the development of
novel modification methods and preparation of new abeo-taxoid
analogues possessing unique scaffolds for the corresponding
biological and pharmaceutical applications.
Taxyunnansin A (Fig. 1,2), which was firstly isolated from Taxus
wallichiana in 1993,7 possesses the 11(15?1)-abeo-taxane skele-
ton with an oxetane ring. To the best of our knowledge, no chem-
ical and biological studies on 2 have been reported yet. In the
course of our phytochemical study on the branches and leaves of
Tsuga chinensis,
a considerable amount of taxyunnansin A
In recent years, another type of taxoids with 11(15?1)-abeo-
taxane skeleton have also been found in increasing numbers, and
have become the second largest category of taxoids. However, only
very limited chemical properties have been disclosed of these
11(15?1)-abeo-taxoids. Simple modifications have been reported,
R1O
O
OH
OAc
19OAc
O
BzO
9
7
11
R2
NH
O
5
3
1
13
20 O
OAc
O
Ph
O
H
H
HO
OHOBz
15 OAc
OAc
OH
HO
Taxyunnansin A
⇑
Paclitaxel 1a R1 = Ac, R2 = C6H5
Docetaxel 1b R1 = H, R2 = OC(CH3)3
Corresponding authors. Tel.: +86 21 54925133; fax: +86 21 64166128 (Z.-J.Y.);
2
tel.: +86 871 5223058; fax: +86 871 5215783 (Q.-S.Z.).
E-mail addresses: yaoz@mail.sioc.ac.cn (Z.-J. Yao), qinshizhao@mail.kib.ac.cn (Q.-
S. Zhao).
Figure 1. Paclitaxel, doctaxel and taxyunnansin A.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.008

140
Y. Zhao et al. / Tetrahedron Letters 52 (2011) 139–142
(2, approximately 20 g) has been accumulated. This provided us
with a rare opportunity to launch our study on the modification
of 11(15?1)-abeo-taxoids.
OAc
OAc
OAc
OAc
OAc
OAc
BzO
BzO
a
Starting from the natural material 2, development of new deriv-
atives with reduced structural complexity (compared to the parent
natural product) was attempted. After persistent screening of
chemical transformations of 2, it was found that treatment of
O
O
H
H
O
O
OAc
4
HO
3
t
13-oxo-taxyunnansin A (3) with BuOK and Red-Al, respectively,
OAc
OAc
OAc
OAc
16
led to three interesting compounds 4 (Scheme 1), 13 and 14
(Scheme 2) in good or reasonable yields. More interestingly, these
three products via eliminative fragmentation of 2 represent a novel
simplified structure type in this category of taxoids. With our
knowledge in taxoids, these compounds could be very unique
precursors for a series of new potentially useful derivatives of
abeo-paclitaxel and abeo-docetaxel by the simple conjugation with
b-phenylisoserine side chain. In this Letter, we wish to report our
interesting findings in the preparation of new abeo-paclitaxel and
abeo-docetaxel derivatives. These results are believed to be a
new addition to the few literatures on the chemistry of abeo-
taxoids.
15
12
11
+
3
1
13
17
2
O
O
H
H
RO
RO
OAc
OAc
13 R = H
15
14
16
R = H
R = Ac
b
b
R = Ac
Scheme 2. Reagents and conditions: (a) Red-Al, THF, ꢀ40 °C, 13 (26%), 14 (23%); (b)
Ac2O, Pyr., DMAP, 1 h, 100%.
13-Oxo-taxyunnansin A (3), the common precursor in this
work, was prepared by an efficient PDC oxidation of the C-13 hy-
droxyl of 2 (quantitative yield, Scheme 1). Treatment of 3 with
tBuOK resulted in an interesting fragmentation. The isopropanol
OAc
OAc
OAc
OAc
BzO
BzO
c
b
a
2
O
OAc
O
H
H
O
O
OAc
OAc
HO
3
4
OAc
OAc
OAc
OAc
OAc
BzO
BzO
+
O
O
H
H
HO
HO
OAc
BzO
5
6
d
Figure 2. X-ray crystallographic structure of 13.
OAc
H
OAc
OAc
O
chain. Following this idea, further reduction of the C-13 ketone
d
R
NH
O
with NaBH4 and CeCl3 was carried out, providing the C-13
a and
O
Ph
O
C-13b alcohols in 32% (5) and 54% (6) yields, respectively. In this
reaction, lowering the reaction temperature or use of other reduc-
ing reagents could not improve the diastereoselectivity. It is sup-
posed that the disappearance of b-oriented isopropanol moiety at
C-1 might lead to the deprivation of substrate-controlled diastere-
oselectivity. It is noteworthy that all of our attempts failed in direct
elimination of the isopropanol moiety at C-1 of the natural mate-
rial 2 (without pre-treatment with PDC). This mentions that the
C-13 ketone functionality is necessary for the above cascade elim-
inations, leading to a more stable conjugate system in product 4.
Parallel acylation of 5 and 6 with b-lactam 78 afforded abeo-pac-
litaxel analogues 9 and 10, respectively. Using b-lactam 8 as the
acylating reagent, two additional abeo-docetaxel analogues 11
and 12 were prepared, respectively (Scheme 1). These four com-
pounds 9–12, embedded with a simplified unusual abeo-taxane
skeleton with an oxetane ring and a 11:12,1:2-diene moiety, repre-
sent a novel class of new abeo-paclitaxle and abeo-docetaxel
derivatives.
OH
9 R = C6H5
11
R = OC(CH3)3
OAc
H
OAc
OAc
BzO
O
R
EEO
Ph
NH
O
N
R
O
O
Ph
O
O
OH
7 R = C6H5
10
R = C6H5
8
12
R = OC(CH3)3
R = OC(CH3)3
Scheme 1. Reagents and conditions: (a) PDC, CH2Cl2, rt, 100%; (b) tBuOK, THF, rt,
77%; (c) NaBH4, CeCl3, MeOH, 0 °C, 5 (32%), 6 (54%); (d) (i) NaHMDS, 7 or 8, THF,
ꢀ78 °C; (ii) 0.5 N HCl, THF 0 °C to rt, 9 (30%), 10 (30%), 11 (26%), 12 (73%).
moiety at C-1 and the acetyl group at C-2 were eliminated during
this process, giving a simpler conjugated dienone product 4 in 77%
yield.
Because C-13 ketone of 4 could be further reduced, it would
provide us an opportunity to introduce the b-phenylisoserine side
Another novel type of fragmentation was observed when
13-oxo-taxyunnansin A (3) was reduced with Red-Al. A previous
report has shown that 13-oxo-7-TES-baccatin III could be

Y. Zhao et al. / Tetrahedron Letters 52 (2011) 139–142
141
OAc
H
OAc
OAc
H
H
H
OAc
H
OAc
H
BzO
OAc
OAc
OAc
O
BzO
OAc
H
OAc
H
H
a-b
O
Me
R
NH
O
Me
Me
Me
H
H
O
H
Ph
O
H
H
H
H
H
H
H
HO
OAc
H
H
OH
OAc
AcO
H
H
H
H
AcO
HO
H
OAc
H
H
H
O
O
HO
H
21 R = C6H5
22
AcO
2
R = OC(CH3)3
15
16
Scheme 4. Reagents and conditions: (a) NaHMDS, 7 or 8, THF, ꢀ78 °C; (b) 0.5 N HCl,
THF 0 °C to rt, 21 (59%), 22 (29%).
Figure 3. Selected ROESY correlations of 15 and 16.
In summary, chemical transformations of natural product tax-
yunnansin A (2) have been explored and two unique types of elim-
inative fragmentations have been discovered in this work. The
products generated from these fragmentations were successfully
applied to the synthesis of a series of new abeo-paclitaxel and
abeo-docetaxel analogues 9–12 and 17–20, which possess the sim-
pler taxoids core structures. This study not only provides a new
class of paclitaxel derivatives with novel structures, but also sheds
a new light into the unique chemical behaviour of the 11(15?1)-
abeo-taxoids. The interesting fragmentations found in this work
could be further applied in other abeo-taxoids, and will therefore
benefit those efforts to synthesizing biologically and pharmaceuti-
cally important taxoid derivatives.
OAc
OAc
H
OAc
OAc
OAc
OAc
O
R
NH
O
a-b
O
O
H
Ph
O
HO
OH
17R = C6H5
19R
13
= OC(CH3)3
OAc
OAc
OAc
OAc
OAc
O
R
NH
O
a-b
O
H
Ph
O
O
H
HO
OAc
OH
18 R = C6H5
14
20
Acknowledgements
R = OC(CH3)3
Scheme 3. Reagents and conditions: (a) NaHMDS, then 7 or 8, THF, ꢀ78 °C; (b)
0.5 N HCl, THF 0 °C to rt; 17 (24%), 18 (28%), 19 (26%), 20 (40%).
This work was financially supported by the National Natural
Science Foundation of China (20802083, 90813004, 20921091 and
21032002), the West Doctor Foundation of CAS (2908026212W1),
the Ministry of Science and Technology (2009CB522303 and
2010CB833200), and MOH (2009ZX09501).
selectively debenzoylated at the C-2 position using Red-Al as the
hydride-transfer reagent.9 In this case, a very fast sequential reac-
tion was observed when the abeo-taxoid 3 was treated with Red-Al
in THF at ꢀ40 °C. During this process, compound 4 was firstly gen-
erated and then completely converted into two new compounds 13
and 14 (Scheme 2). Lowing the reaction temperature to ꢀ78 °C
made no difference to the results. The structure of 13 was deter-
mined by spectroscopic analyses and further confirmed by the sin-
gle-crystal X-ray diffraction study (Fig. 2).10
Supplementary data
Supplementary data (experimental details and full spectral data
for new compounds) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.008.
References and notes
After comparison of the ROESY spectrum of 13 and 14, it was
difficult to assign the relative configuration of C-13-OH and C-
12-Me based on the ROESY spectrum of 14. Treatment of com-
pounds 13 and 14 with Ac2O afforded compounds 15 and 16,
respectively (Scheme 2). Inspection of ROESY spectra of 15 and
16 showed that there was ROESY correlation between H-13 and
1. (a) Nicolaou, K.; Montagnon, T. Molecules that Changed The World; Wiley-VCH:
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Shigemori, H.; Kobayashi, J. J. Nat. Prod. 2004, 67, 245–256.
H-3
in 16. Those results suggested that the H-13 in 13 and 15 were
-oriented and the H-13 in 14 and 16 were b-oriented. Further-
a in compound 15, while such a correlation was not observed
5. Tremblay, S.; Soucy, C.; Towers, N.; Gunning, P. J.; Breau, L. J. Nat. Prod. 2004, 67,
838–845.
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10. Crystallographic data of compound 13: C23H30O8, MW = 434.49; monoclinic,
a
more, ROESY correlation between H-13b and H-15 was observed
in compound 16, and no ROESY correlation between H-13b and
H-12 of 16 was detected. These indicated that the C-12-Me was
b-oriented in compounds 14 and 16 (Fig. 3).
Using the similar procedures as those in Scheme 1, abeo-paclit-
axel analogues 17 and 18, and abeo-doctaxel analogues 19 and 20
were prepared from compounds 13 and 14, respectively (Scheme
3). These four new derivatives 17–20 are characterized by a simpli-
fied abeo-taxane skeleton with an oxetane ring and a 1,3-conju-
gated diene in the seven-member ring.
For future comparison in the biological activity screening, we
also prepared analogues 21 and 22 by direct introduction the
b-phenylisoserine side chain to the starting material 2 (Scheme
4). Derivative 21 was previously reported by Liang’s group and
space group P21; a = 10.304 (1) Å, b = 10.498 (1) Å, c = 11.017 (1) Å,
b = 109.24 (1),
= 90.00, V = 1125.2 (1) Å3, Z = 2, d = 1.282 g/cm3, crystal
dimensions 0.05 ꢁ 0.10 ꢁ 0.30 mm was used for measurements on a MAC
DIP-2030K diffractometer with graphite monochromator
ꢀ 2h scans,
a = 90.00,
c
its cytotoxicity against KB cell line with an ED50 of 11.0
l
g/mL.6c
a
(x

142
Y. Zhao et al. / Tetrahedron Letters 52 (2011) 139–142
2hmax = 50.0°), Mo K
measured was 2455, of which 2422 were observed (|F|2 P 3
indices: Rf = 0.0504, Rw = 0.1481 (w = 1/
|F|2). The crystal structure of
compound 13 was solved by direct method SHLXS-97 (Sheldrick, 1990) and
expanded using the difference Fourier technique, refined by the programme
SHLXL-97 (Sheldrick, 1997), and the full-matrix least-squares calculations.
a
radiation. The total number of independent reflections
Crystallographic data for the structure of compound 13 have been deposited
r
|F|2). Final
with the Cambridge Crystallographic Data Centre (deposition no. CCDC
791662). These data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
r