First total synthesis of chapecoderin A: Absolute configuration of the natural product

Article abstract of DOI:10.1016/S0040-4039(01)01647-1

A seco-labdane, chapecoderin A 1, has been synthesized starting from (S)-(+)-Wieland-Miescher ketone analogue 9. The absolute configuration has been determined to be 5S,10S.

Full text of DOI:10.1016/S0040-4039(01)01647-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7629–7631
First total synthesis of chapecoderin A: absolute configuration
of the natural product
a,
b
b
b
b
Hisahiro Hagiwara, * Fumihide Takeuchi, Takashi Hoshi, Toshio Suzuki and Masayoshi Ando
a
Graduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
b
Faculty of Engineering, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Received 3 August 2001; revised 30 August 2001; accepted 31 August 2001
Abstract—A seco-labdane, chapecoderin A 1, has been synthesized starting from (S)-(+)-Wieland–Miescher ketone analogue 9.
The absolute configuration has been determined to be 5S,10S. © 2001 Elsevier Science Ltd. All rights reserved.
In their efforts to develop new pharmaceutical agents,
Kobayashi, Ohsaki and co-workers isolated a new
delineate herein the first total synthesis and determina-
tion of the absolute stereochemistry of chapecoderin A
1
seco-labdane type diterpenoid, chapecoderin A 1
accompanied by two new rearranged labdane-type
diterpenoids, chapecoderin B 2 and C 3, from the leaves
of the Brazilian medicinal plant Echinodorus
macrophyllus, which has been used to treat hepatitis,
rheumatism and difficulties in urination (Fig. 1).
Chapecoderins B 2 and C 3 exhibited cytotoxicity
against murine lymphoma L1210 cells with IC50 values
of 7.2 and 6.0 mg/ml, respectively.
1.
Our synthetic design is outlined in Scheme 1. The
butenolide ring might be introduced by nucleophilic
reaction of sulfur substituted g-butyrolactone 4 or 5
with halide 6, which would be obtained by cleavage of
tetrasubstituted olefin 7. The olefin 7, in turn, would be
synthesized from the known decalone 8
2b,3
derived from
4
(
S)-(+)-Wieland–Miescher ketone analogue 9.
Their gross structures were determined based on mod-
ern NMR techniques and the relative stereochemistries
were assigned by NOESY correlation. However, the
absolute stereochemistries are yet to be clarified. In
view of its interesting structure as a precursor of cyto-
toxic compounds 2 and 3 as well as our recent interest
With no inkling of the absolute configuration of the
natural product 1, we selected (S)-(+)-enantiomer of
Wieland–Miescher ketone analogue 9 as the starting
material. According to our previously reported proce-
dure, (S)-(+)-Wieland–Miescher ketone analogue 9
was transformed into the known decalone 8.
2b
4
2
in the synthetic studies of seco-norsesquiterpenoids, we
O
O
O
O
O
O
OH
O
O
O
H
H
H
O
1
2
3
Figure 1.
Keywords: chapecoderin A; seco-labdane; Wieland–Miescher ketone analogue.
*
0
Corresponding author. Tel./fax: +81-25-262-7368; e-mail: hagiwara@gs.niigata-u.ac.jp
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01647-1

7
630
H. Hagiwara et al. / Tetrahedron Letters 42 (2001) 7629–7631
O
O
X
O
O
O
O
+
H
R
H
O
O
4
5
R = SPh
R = SOPh
1
6
X
O
O
O
H
H
(
S)-(+)-9
8
7
Scheme 1.
O
At first, introduction of a hydroxyethyl unit to the
decalone 8 leading to primary alcohol 12 was examined
by addition of vinylmagnesium bromide followed by
dehydration and hydroxylation of the vinyl group.
However, various efforts for the selective hydrobora-
tion of the terminal double bond were all unsuccessful.
O
t
HO
H
O Bu
i
H
8
10
As an alternative hydroxyethyl addend, the tert-butyl
acetate anion was reacted with the ketone 8 to provide
hydroxy-ester 10 as a mixture of diastereomers (Scheme
ii
2
). Dehydration of the alcohol 10 by SOCl gave in
R
O
2
8
6% overall yield unsaturated ester 11 which was
t
O Bu
reduced with lithium aluminumhydride to afford the
primary alcohol 12 quantitatively. Bromination of the
iii
alcohol
12
with
carbon
tetrabromide
and
triphenylphosphine gave bromide 13 in 94% yield.
H
H
Substitution of the bromide 13 with sodium iodide was
incomplete to give a mixture of the bromide 13 and
iodide 14, and three repeated reactions were required
for complete conversion to the iodide 14 (98% yield).
Direct iodination of the alcohol 12 with sodium iodide
1
1
1
1
2: R = OH
3: R = Br
4: R = I
11
iv
v
vi
vii
5: R = OAc
5
mediated by cerium chloride also afforded the iodide
14 in 70% yield (Scheme 3).
viii
In order to introduce a butenolide moiety, alkylation of
the a-phenylthio 4 or the a-phenylsulfinyl-g-butyrolac-
H
6
tone 5 with the halide 13 or 14 was investigated.
1
6
However, the halide 13 or 14 was recovered completely.
An attempt to prepare the more reactive tri-
fluoromethanesulfonate of the alcohol 12 resulted in the
formation of cyclopropane derivative 16 exclusively in
Scheme 2. Reagents, conditions and yields: (i) LDA, HMPA,
CH CO t-Bu, −78°C; (ii) SOCl , DMAP, pyridine, rt, 86% in
two steps; (iii) LiAlH , Et O, rt, quant.; (iv) CBr , PPh ,
CHCl , rt, 94%; (v) NaI, acetone, reflux, repeated three times,
6%; (vi) NaI, CeCl ·7H O, CH CN, 70%; (vii) acetic anhy-
3
2
2
4
2
4
3
98% yield even at −78°C.
3
9
3 2 3
The order and method of introduction of the buteno-
lide and diketo moieties were then changed. Exposure
dride, DMAP, pyridine, rt, 97%; (viii) Tf
CH Cl , −78°C, 98%.
O, pyridine,
2
2
2

H. Hagiwara et al. / Tetrahedron Letters 42 (2001) 7629–7631
7631
I
OAc
lowed by DBU-promoted conjugate addition of the
g-lactone 5 to the resulting vinylketone 19 and subse-
quent thermal elimination of sulfinic acid. The vinylke-
tone 19 was actually isolated by the treatment of the
acetate 17 with DBU in 80% yield. The diketo-iodide 18
also provided chapecoderin A 1 by the treatment with
potassium carbonate and tetrabutylammonium iodide
in DME in 19% yield. Spectral data ( H and C NMR
and IR) of the synthetic 1 were completely identical
with those of natural chapecoderin A 1. Since the value
and sign of optical rotation of the synthetic compound
H
H
i
15
14
1
13
ii
I
OAc
1
{[h] +6.0 (c 0.86, CHCl ), lit. [h] +5.5 (c 0.86,
D
3
D
1
CHCl ) } were identical with those of natural chape-
3
coderin A 1, the absolute stereostructure was unam-
biguously determined to be 5S,10S as depicted in
structure 1 (Fig. 1).
O
O
H
H
O
O
1
8
17
In summary, we have completed the first enantioselec-
tive total synthesis of chapecoderin A 1 in 25% overall
yield in six steps from the known ketone 8, which
establishes the absolute stereostructure of the natural
product 1.
iii or v
iv
O
O
Acknowledgements
O
O
We thank Professor J. Kobayahi, Hokkaido University
for providing spectral data of chapecoderin A 1.
Thanks are also due to Tokyo Ohka Foundation for
the Promotion of Science and Technology for partial
financial support.
H
H
O
O
19
1
Scheme 3. Reagents, conditions and yields: (i) O /O , CH OH,
3
2
3
−
20°C, Me S, 75%; (ii) O /O , CH Cl , Me S, −78°C, 41%;
2 3 2 2 2 2
(
iii) 17+5, DBU, benzene, rt“90°C, 40%; (iv) 18+5, K CO ,
References
2
3
n-Bu NI, DME, 0“98°C, 19%; (v) DBU, benzene, 80%.
4
1. Kobayashi, J.; Sekiguchi, M.; Shigemori, H.; Ohsaki, A. J.
Nat. Prod. 2000, 63, 375.
of the iodide 14 to ozone provided diketo-iodide 18 in
1% yield. The acetate 15 derived by acetylation of the
alcohol 12 in 97% yield was also cleaved by ozonolysis
to give diketo-acetate 17 in 52% yield in
dichloromethane. The yield was considerably improved
2. (a) Hagiwara, H.; Nagatomo, H.; Yoshii, F.; Hoshi, T.;
Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2000,
2645; (b) Hagiwara, H.; Nagatomo, H.; Kazayama, S.;
Sakai, H.; Hoshi, T.; Suzuki, T.; Ando, M. J. Chem. Soc.,
Perkin Trans. 1 1999, 457.
4
to 75% by carrying out the reaction in methanol at
3. Abad, A.; Agullo, C.; Castelblanque, L.; Cunat, A. C.;
7
−20°C in 0.01 M solution.
Navarro, I.; Ramirez de Arellano, M. C. J. Org. Chem.
2000, 65, 4189.
Installation of the butenolide moiety and completion of
total synthesis were finally achieved as follows. Treat-
ment of the diketo-acetate 17 and the a-phenylsulfinyl-
g-lactone 5 with DBU in benzene at room temperature
followed by gradual warming to 90°C furnished chape-
coderin A 1 in 40% yield. The reaction proceeded via
b-elimination of acetic acid from the acetate 17 fol-
4. Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
5. Di Deo, M.; Marcantoni, E.; Torregiani, E.; Bartoli, G.;
Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem.
2000, 65, 2830.
6. Iwai, K.; Kosugi, H.; Uda, H.; Kawai, M. Bull. Chem.
Soc. Jpn. 1977, 50, 242.
7. Neble, C. J. Chem. Soc., Chem. Commun. 1968, 101.