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;
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