Synthesis of graphislactones A-D through a palladium-mediated biaryl coupling reaction of phenyl benzoate derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.03.046

The chemical synthesis of graphislactones A-D was achieved through the Pd-mediated intramolecular biaryl coupling reaction of phenyl benzoate derivatives.

Full text of DOI:10.1016/j.tetlet.2005.03.046

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3197–3200
Synthesis of graphislactones A–D through a palladium-mediated
biaryl coupling reaction of phenyl benzoate derivatives
a
a
a
Hitoshi Abe,a,b, Keisuke Nishioka, Shigemitsu Takeda, Masatsugu Arai,
*
Yasuo Takeuchia and Takashi Harayamaa,*
aFaculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
bAdvanced Science Research Center, Okayama University, Okayama 700-8530, Japan
Received 7 February 2005; revised 3 March 2005; accepted 9 March 2005
Available online 24 March 2005
Abstract—The chemical synthesis of graphislactones A–D was achieved through the Pd-mediated intramolecular biaryl coupling
reaction of phenyl benzoate derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
Lichens and lichen substances are known as antibiotics,
UV absorbers, antioxidants, and dyes.1 However, their
practical utility has been thought to be difficult because
the growth rate of lichens is generally slow and it is not
easy to obtain a large amount of lichens from nature.
Thus, the chemical synthesis of the lichen constituents
would be a useful approach to extend the utility of
lichen substances. In 1997, Tanahashi et al. isolated four
phenolics from the cultured lichen mycobiont of Graphis
scripta var. pulverulenta, which were called graphislac-
tones A–D (Fig. 1).2 Since two of them, graphislactones
C and D, were found to exhibit antitumor activity
against the human bladder cancer cell 5637,3 our interest
has focused on the total synthesis of the graphislactones.
In this letter, we describe their synthesis through a Pd-
mediated biaryl coupling reaction of phenyl benzoate
derivatives as the key step.4,5
Graphislactones A–C have highly oxygenated 6H-di-
benzo[b,d]pyran-6-one skeletons, which are significantly
related to the lignan chemistry.6 To obtain these com-
pounds, we envisioned phenyl benzoate derivatives as
good precursors (Scheme 1). These esters should be pre-
pared by a simple esterification between the correspond-
ing phenols and benzoic acids furnishing the required
functionalities on each aromatic ring.
Initially, we prepared phenol 8 for the synthesis of
graphislactone C (3) (Scheme 2). After selective benzyl-
ation of 5,7,8 reduction of the resulting 6 with LiAlH4
followed by silylation of the benzylic hydroxy group
led to the phenol 8. For the preparation of the coupling
partner 13, we selected 3,5-dimethoxyaniline as the
starting material, which was subjected to the conven-
tional Sandmeyer aromatic substitution condition to af-
ford the iodide 9 (Scheme 3). The Vilsmeiyer reaction
afforded the aldehyde 10, and then it was demethylated
by NodeÕs method9 and successively benzylated to give
HO
OMe
R2H2C
OMe
OH
HO
MeO
MeO
O
O
OR1
O
MeO
O
Graphislactone A (1): R1 = R2 = H
Graphislactone B (2): R1 = Me, R2 = H
Graphislactone C (3): R1 = H, R2 = OH
Graphislactone D (4)
Figure 1. Structures of graphislactones A–D.
R'
I
R'
Pd
R
R
O
O
Keywords: Palladium; Phenyl benzoate; Graphislactone; Biaryl
coupling.
O
O
*
Corresponding authors. Tel.: +81 862517965; fax: +81 862517963;
e-mail: abe@pharm.okayama-u.ac.jp
Scheme 1. Formation of dibenzopyranone.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.046

3198
H. Abe et al. / Tetrahedron Letters 46 (2005) 3197–3200
HO
HO
CO2Me
HO
CO2Me
MeO
I
a
a
Me
I
OMe
OBn
10
7
(70%)
COOH
BnO
(98%)
MeO
(75%)
c
MeO
OMe
b
OMe
17
5
6
O
HO
Me
HO
MeO
Me
O
b
OR
19
(50%)
BnO
BnO
OMe
(91%)
OMe
18
7: R = H
c (71%)
OMe
OH
Me
OMe
OBn
8: R = TBS
MeO
MeO
Scheme 2. Synthesis of phenol 8. Reagents and conditions: (a) BnBr,
K2CO3, DMF; (b) LiAlH4, THF; (c) TBSCl, imidazole, CH2Cl2.
d
e
O
O
(93%)
(88%)
MeO
O
MeO
O
20
Graphislactone B (2)
12. After oxidation into benzoic acid 13, the
esterification with the phenol 8 successfully afforded
the phenyl benzoate 14. The Pd-mediated intramolecu-
lar biaryl coupling reaction of 14 produced the lactone
15 in high yield. Finally, the debenzylation into 16 and
desilylation with TBAF were carried out to complete
graphislactone C (3).
Scheme 4. Synthesis of graphislactone B. Reagents and conditions:
(a) 30% H2O2, 80% NaClO2, NaH2PO4, CH3CN, H2O; (b) (i) Ph3P,
CBr4, THF; (ii) LiAlH4, THF; (c) EDC, DMAP, CH2Cl2; (d)
Pd(OAc)2, nBu3P, K2CO3, DMA; (e) H2, 10% Pd/C, AcOEt.
lowed by the Pd-mediated biaryl coupling reaction pro-
duced the lactone 22. In order to remove the two benzyl
groups, the hydrogenolysis of 22 was carried out.
For the synthesis of graphislactone B (2), we needed two
starting materials 17 and 18, which were easily derived
from 10 and 7, respectively (Scheme 4). Their conden-
sation afforded 19 in good yield. The Pd-mediated reac-
tion under the conditions similar to the above case also
smoothly proceeded to give the lactone 20. After cata-
lytic hydrogenolysis, graphislactone B (2) was obtained.
Unlike the above graphislactones A–C, graphislactone
D has a different ring system, 5H-dibenzo[c,e]oxepin-7-
one.10 We thought that this skeleton would be synthe-
sized by the reconstruction of the lactone ring from
the 6H-dibenzo[b,d]pyran-6-one. Thus, the lactone 25
was envisioned as a key intermediate for graphislactone
D. The transformation into 25 was achieved by a similar
route to graphislactone C (Scheme 6). The ester 23
A similar strategy was attempted for the synthesis of
graphislactone A (1) (Scheme 5). The preparation of
the ester 21 by the condensation between 13 and 18, fol-
MeO
I
MeO
NH2
MeO
I
c
d
a, b
CHO
(60%)
(64%)
(55%, 2 steps)
MeO
MeO
MeO
10
9
OTBS
I
OMe
OBn
MeO
I
MeO
I
MeO
g
f
O
CHO
COOH
(65%)
(98%)
RO
BnO
BnO
O
11: R = H
e (87%)
12: R = Bn
13
14
OTBS
OR
OMe
OBn
OMe
OH
h
i
MeO
MeO
(90%)
(76%)
O
O
BnO
O
OH
O
15
16: R = TBS
j (94%)
Graphislactone C (3): R = H
Scheme 3. Synthesis of graphislactone C. Reagents and conditions: (a) NaNO2, concd HCl, H2O; (b) KI, H2O; (c) POCl3, DMF; (d) AlCl3, NaI,
CH3CN, CH2Cl2; (e) BnBr, K2CO3, DMF; (f) 30% H2O2, 80% NaClO2, NaH2PO4, CH3CN, H2O; (g) 8, EDC, DMAP, CH2Cl2; (h) Pd(OAc)2,
nBu3P, K2CO3, DMA; (i) H2, 10% Pd/C, AcOEt; (j) TBAF, THF.

H. Abe et al. / Tetrahedron Letters 46 (2005) 3197–3200
3199
molecular biaryl coupling reaction of phenyl benzoate
derivatives as the key step.
Me
I
OMe
OBn
MeO
b
a
13
18
+
O
(88%)
(61%)
Acknowledgements
BnO
O
21
A part of this work was supported by the Japan Society
for the Promotion of Science to H.A. (15590007). We
thank Professor Tanahashi and Dr. Takenaka of Kobe
Pharmaceutical University for providing us with the
authentic samples of graphislactones A–D. All NMR
experiments were carried out at the SC-NMR Labora-
tory of Okayama University.
Me
OMe
OH
Me
OMe
OBn
MeO
MeO
c
O
O
(89%)
HO
O
BnO
O
22
Graphislactone A (1)
Scheme 5. Synthesis of graphislactone A. Reagents and conditions:
(a) EDC, DMAP, CH2Cl2; (b) Pd(OAc)2, nBu3P, K2CO3, DMA;
(c) H2, 10% Pd/C, AcOEt.
References and notes
1. Yamamoto, Y. In Plant Cell Culture in Japan; Komamine,
A., Misawa, M., DiCosmo, F., Eds.; CMC: Tokyo, 1991,
pp 58–71.
2. (a) Tanahashi, T.; Takenaka, Y.; Nagakura, N.; Hamada,
N. Phytochemistry 2003, 62, 71–75; (b) Tanahashi, T.;
Kuroishi, M.; Kuwahara, A.; Nagakura, N.; Hamada, N.
Chem. Pharm. Bull. 1997, 45, 1183–1185.
derived from 8 and 17 was subjected to the Pd-mediated
biaryl coupling reaction, and then desilylated with
TBAF. The treatment of the resulting 25 with an excess
amount of K2CO3 in MeOH was very effective for the
direct formation of the seven-membered ring lactone
27. Final deprotection of the benzyl group was also
successful and the synthesis of graphislactone D was
accomplished.
3. Takenaka, Y. Ph.D. Thesis, Okayama University, 2003.
´
4. For a review, see: (a) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1469;
(b) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New
York, 1995, pp 125–252.
All spectral data of the synthetic graphislactones A–D
agreed with those of the authentic samples.
5. The Pd-mediated aryl–aryl coupling reaction of the phenyl
benzoate derivatives has been reported: (a) Harayama, T.;
Yasuda, H.; Akiyama, T.; Takeuchi, Y.; Abe, H. Chem.
Pharm. Bull. 2000, 48, 861–864; (b) Harayama, T.;
Yasuda, H. Heterocycles 1997, 46, 61–64.
In summary, we succeeded in the chemical synthesis of
graphislactones A–D utilizing the Pd-mediated intra-
OTBS
OMe
OTBS
OMe
OBn
I
MeO
MeO
c
OBn
b
a
8
17
+
O
O
(90%)
(85%)
(61%)
MeO
O
MeO
O
24
23
BnO
HO
OH
OH
OMe
OMe
OBn
OMe
OBn
MeO
MeO
MeO
d
OH
O
O
COOMe
(85%)
MeO
MeO
O
MeO
O
26
25
27
HO
OMe
HO
e
(58%)
MeO
O
MeO
O
Graphislactone D (4)
Scheme 6. Synthesis of graphislactone D. Reagents and conditions: (a) EDC, DMAP, CH2Cl2; (b) Pd(OAc)2, nBu3P, K2CO3, DMA; (c) TBAF,
THF; (d) K2CO3, MeOH; (e) H2, 10% Pd/C, AcOEt.

3200
H. Abe et al. / Tetrahedron Letters 46 (2005) 3197–3200
6. Recent examples: (a) Abe, H.; Takeda, S.; Fujita, T.;
D.; Ruterbories, K. J.; Lindstrom, T. D.; Wikel, J. H.;
Morgan, E.; Hahn, R. A. J. Med. Chem. 1993, 36, 1262–
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9540.
9. Node, M.; Kajimoto, T.; Nishide, K.; Fujita, E.; Fuji, K.
Bull. Inst. Chem. Res., Kyoto Univ. 1992, 70, 308–
317.
10. Few methods for the direct construction of the 5H-
dibenzo[c,e]oxepin-7-one skeleton are known: Bringmann,
G.; Hinrichs, J.; Henschel, P.; Peters, K.; Peters, E.-M.
Synlett 2000, 1822–1824.
7. (a) Tanaka, M.; Ikeya, Y.; Mitsuhashi, H.; Maruno, M.;
Wakamatsu, T. Tetrahedron 1995, 51, 11703–11724; (b)
Jurd, L. J. Am. Chem. Soc. 1959, 81, 4606–4610.
8. Yu, M. J.; McCowan, J. R.; Phebus, L. A.; Towner, R. D.;
Ho, P. P. K.; Keith, P. T.; Luttman, C. A.; Saunders, R.