The First Total Synthesis of Grandinal, a New Phloroglucinol Derivative Isolated from Eucalyptus grandis

Article abstract of DOI:10.1246/cl.2001.210

The first total synthesis of grandinal (1) is accomplished by biomimetic cycloaddition of the jensenone derivative (2) and the o-quinone methide (3) generated by oxidation of grandinol (4).

Full text of DOI:10.1246/cl.2001.210

210
Chemistry Letters 2001
The First Total Synthesis of Grandinal,
a New Phloroglucinol Derivative Isolated from Eucalyptus grandis
Takuya Matsumoto, Inder Pal Singh, Hideo Etoh,* and Hitoshi Tanaka†
Faculty of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422-8529
†Faculty of Pharmacy, Meijo University, Yagoto, Tempaku-ku, Nagoya 468-8503
(Received November 27, 2000; CL–001069)
The first total synthesis of grandinal (1) is accomplished by
biomimetic cycloaddition of the jensenone derivative (2) and the
o-quinone methide (3) generated by oxidation of grandinol (4).
5 (Scheme 1). An isovaleryl group was readily introduced by a
reaction with isovaleryl chloride. Reduction of the isovaleryl-
trimethoxybenzene with LAH and subsequent dehydration by
irradiation in CHCl3 gave the styrene compound (6).3
In order to investigate the feasibility of cycloaddition, we
have implemented Diels–Alder cycloaddition of grandinol (4)
and the styrene compound (6) using DDQ (Scheme 2).
Generation of the o-quinone methide as diene by DDQ led to
cycloaddition with the styrene compound (6) as dienophile.
The reaction was carried out in nitromethane at 60 °C4 and
consequently gave the desired product 7a and the regioisomer
7b. This result indicated that two o-quinone methide species
were generated by oxidation with DDQ leading to two regioiso-
mers. Thus, we succeeded Diels–Alder cycloaddition between
grandinol (4) and the styrene compound (6).
Grandinal (1) is an isopentyl phloroglucinol dimer, isolated
from Eucalyptus grandis, which showed attachment-inhibiting
activity against the blue mussel Mytilus edulis galloprovincialis,
and antibacterial activity against Staphylococcus aureus and
Bacillus subtilis.1 Grandinal (1) has a unique pyran skeleton and
this structure was established by spectral and chemical investi-
gations. Biogenetically, grandinal (1) is proposed to be formed
by Diels–Alder cycloaddition of the jensenone derivative (2')
and the o-quinone methide (3) generated by oxidation of
grandinol (4) (Figure 1).
Herein, we report an efficient total synthesis of grandinal
(1) via biomimetic cycloaddition of the jensenone derivative (2)
and the o-quinone methide (3).
Further, the styrene compound (6) was reduced by treat-
ment with Pt2O under H2 atomosphere to yield the alkylben-
zene. Aromatic bromination of the alkylbenzene using Br2
gave 8. Two methyl ester groups of 9 were introduced adding
ClCO2Me via lithium–bromide exchange reaction of 8 using t-
BuLi. Allyl bromination of 9 with NBS in the presence of
We prepared grandinol (4) by an alternate and improved
procedure in three steps in 13% overall yield.2
Synthesis of the jensenone derivative (2) was started from
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
211
References and Notes
1
2
3
I. P. Singh, R. Hayakawa, H. Etoh, M. Takasaki, and T.
Konoshima, Biosci. Biotechnol. Biochem., 61, 921 (1997).
K. Umehara, I. P. Singh, H. Etoh, M. Takasaki, and T.
Konoshima, Phytochemistry, 49, 1699 (1998).
1
Spectral data of 6 : H NMR (CDCl3, 270 MHz) δ ppm:
6.54 (1H, d, J = 16.5 Hz), 6.45 (1H, dd, J = 16.5 Hz, 6.7
Hz), 6.13 (2H, s), 3.82 (6H, s), 3.80 (3H, s), 2.44 (1H,
octet, J = 6.7 Hz), 1.08 (6H, d, J = 6.7 Hz) ; 13C NMR
(CDCl3, 67.8 MHz) δ ppm: 159.4 (s), 158.9 (2s), 140.1 (d),
116.9 (d), 108.4 (s), 91.0 (2d), 55.7 (2q), 55.3 (q), 33.1 (d),
22.9 (2q). Spectral data of 2 : 1H NMR (CDCl3, 270 MHz)
δ ppm: 10.33 (2H, s), 6.47 (1H, dd, J = 16.2 Hz, 6.8 Hz),
6.28 (1H, d, J = 16.2 Hz), 3.93 (3H, s), 3.81 (6H, s), 2.51
(1H, octet, J = 6.8 Hz), 1.10 (6H, d, J = 6.8 Hz) ; 13C NMR
(CDCl3, 67.8 MHz) δ ppm: 188.1 (2d), 165.7 (2s), 164.0
(s), 145.5 (d), 123.5 (s), 120.5 (2s), 114.9 (d), 65.1 (q),
62.2 (2q), 32.6 (d), 22.1 (2q).
4
5
6
7
K. Chiba, T. Arakawa, and M. Tada, Chem. Commum.,
1996, 1763.
T. Tanaka, H. Mikamiyama, K. Maeda, and C. Iwata, J.
Org. Chem., 63, 9782 (1998).
K. Tatsuta, T. Tamura, and T. Mase, Tetrahedron Lett.,
1999, 1925.
Spectral data of 11a : HRFAB-MS [m/z 543.2230 (M+H)+
+ 0.1 mmu for C29H35O10] ; UV λmax. (MeOH) nm (log ε) :
250 (4.10), 275 (4.35), 334 (3.38) ; IR νmax. (NaCl) cm–1
:
1695, 1624, and 1127 ; 1H NMR (CDCl3, 500 MHz) δ
ppm: 15.50 (1H, s), 14.34 (1H, s), 10.33 (2H, s), 9.87 (1H,
s), 5.38 (1H, d, J = 10.6 Hz), 4.04 (3H, s), 3.88 (6H, s),
2.98 (2H, d, J = 6.7 Hz), 2.76 (1H, dd, J = 17.1 Hz, 5.2
Hz), 2.75 (1H, m), 2.32 (1H, dd, J = 17.0 Hz, 13.3 Hz),
2.24 (1H, septet, J = 6.7 Hz), 1.55 (1H, double septet, J =
6.7 Hz, 3.6 Hz), 0.97 (6H, d, J = 6.7 Hz), 0.96 (3H, d, J =
6.7 Hz), 0.75 (3H, d, J = 6.7 Hz) ; 13C NMR (CDCl3, 125
MHz) δ ppm: 206.5 (s), 190.9 (d), 187.2 (2d), 172.0 (s),
167.9 (4s), 161.5 (s), 122.3 (s), 120.2 (2s), 103.8 (s), 103.4
(s), 102.6 (s), 76.5 (d), 66.0 (q), 65.0 (2q), 52.7 (t), 37.8
(d), 27.6 (d), 25.0 (d), 22.7 (2q), 21.1 (q), 18.3 (t), 15.3 (q).
Spectral data of 11b : HRFAB-MS [m/z 543.2230 (M+H)+
– 0.2 mmu for C29H35O10] ; UV λmax. (MeOH) nm (log ε):
AIBN as a radical initiator and subsequent elimination with
DBU gave 10. DIBAL reduction led to the desired diol styrene
compound. Finally, oxidation of the diol styrene compound
was accomplished using PDC. The jensenone derivative (2)
was thus synthesized in nine steps in 13% overall yield as
shown in Scheme 1.3,5,6
Having successfully prepared the desired compounds, the
jensenone derivative (2) was subjected to Diels–Alder cyclo-
addition under the same conditions (Scheme 2). Purification by
column chromatography of the reaction mixture furnished the
desired product 11a in 14% yield and the regioisomer 11b in
18% yield.7
Finally, 11a was subjected to deprotection of the hydroxy
groups with BBr3S(Me)2.6 Since the reaction product was iden-
tical with the natural product on the basis of comparisons of
spectral data and HPLC,1 we accomplished the first synthesis of
grandinal (1) (Scheme 2).
250 (4.29), 283 (4.40), 334 (3.66) ; IR νmax. (NaCl) cm–1
:
1
1686, 1616, and 1131 ; H NMR (CDCl3, 500 MHz) δ
ppm: 15.26 (1H, s), 13.30 (1H, s), 10.32 (2H, s), 10.20
(1H, s), 5.45 (1H, d, J = 10.7 Hz), 4.03 (3H, s), 3.91 (6H,
s), 2.80 (1H, dd, J = 16.2 Hz, 4.9 Hz), 2.68 (1H, m), 2.64
(1H, dd, J = 15.0 Hz, 6.4 Hz), 2.48 (1H, dd, J = 15.0 Hz,
7.3 Hz), 2.35 (1H, dd, J = 16.2 Hz, 12.4 Hz), 2.02 (1H,
septet, J = 6.7 Hz), 1.60 (1H, double septet, J = 7.0 Hz, 3.0
Hz), 0.99 (3H, d, J = 7.0 Hz), 0.80 (3H, d, J = 7.0 Hz), 0.66
(3H, d, J = 6.7 Hz), 0.61 (3H, d, J = 6.7 Hz) ; 13C NMR
(CDCl3, 125 MHz) δ ppm: 205.1 (s), 192.5 (d), 186,8 (2d),
169.8 (s), 168.7 (s), 167.5 (3s), 163.1 (s), 121.5 (s), 119.2
(2s), 104.7 (s), 103.9 (s), 101.6 (s), 76.5 (d), 66.2 (q), 64.8
(2q), 52.7 (t), 37.7 (d), 27.5 (d), 24.8 (d), 22.5 (q), 22.2 (q),
21.1 (q), 18.3 (t), 15.5 (q).
We are grateful to Prof. K. Tatsuta and Dr. K. Chiba,
Waseda University and Tokyo University of Agriculture and
Technology, for helpful discussions and suggestions, and also
to Prof. T. Tanaka, Osaka University, for providing the spectral
data of 8 and 9.