Phytochemical medicinal agents. a quinone-based route to pterocarpins

Article abstract of DOI:10.1016/j.tetlet.2005.09.010

The synthesis of 6,9 di-demethoxy kushecarpin A has been achieved by the coupling of a benzofuran anion with a quinone monoketal followed by a regioselective cyclization and a stereoselective hydrogenation reaction.

Full text of DOI:10.1016/j.tetlet.2005.09.010

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7511–7513
Phytochemical medicinal agents. A quinone-based
route to pterocarpins
George A. Kraus* and Jingqiang Wei
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 24 June 2005; revised 1 September 2005; accepted 2 September 2005
Available online 19 September 2005
Abstract—The synthesis of 6,9 di-demethoxy kushecarpin A has been achieved by the coupling of a benzofuran anion with a
quinone monoketal followed by a regioselective cyclization and a stereoselective hydrogenation reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Kushecarpin A (1) was recently isolated from Sophora
flavescens by methanol extraction of the roots. This no-
vel pterocarpin exhibited significant antibacterial activi-
ties against the Gram-positive bacteria Staphylococcus
aureus, Bacillus subtilis, S. epidermidis, and Propioni-
bacterium acnes.1 Related compounds 2a and 3 have
been reported.2,3 The benzofuran 4 has been reported
to be a constituent of Lespedeza species.4 Despite their
novel structures and potentially valuable biological
activity, no synthetic approaches to 1 or 2 have been re-
ported. As part of a program to identify useful plant
medicinal agents,5 we report herein a convenient and
direct preparation of 2b featuring the addition of the
anion of a benzofuran to a synthetic equivalent of
methoxy-1,4-benzoquinone.
Cyclohexadienone 5 was viewed as a key intermediate
because hydroxyl-directed hydrogenation6 was expected
to install the dihydrobenzofuran unit with the methine
hydrogens on the same face of the molecule as the hy-
droxyl group. Compound 5 in turn would be synthesized
from readily available benzofuran 6 and benzoquinone
7.7 If G represents an electron-donating substituent, reg-
ioselective reaction of an organolithium reagent with the
benzoquinone at the carbonyl required for the synthesis
of 5 has good precedent.8
MeO
6
H
O
H
O
H
In order to test this hypothesis, we metalated benzo-
furans 8a and 8b with n-butyl lithium (THF, 0 °C, 1 h)
and treated the resulting anion with benzoquinones.
Unfortunately, neither methoxybenzoquinone nor phen-
ylthiobenzoquinone reacted with 8a or 8b to generate
the desired hydroxy cyclohexadienone. Transmetalation
with zirconium salts, a strategy used effectively in a re-
lated system,9 did not result in the formation of an ad-
duct. However, 8a and 8b reacted with benzoquinone
to afford 9a and 9b, respectively, in 96% and 71%
yields.10
4
H
O
O
O
O
HO
HO
MeO
MeO
X
9
1
2a: X = OMe
2b: X = H
MeO
H
O
O
H
OH
O
1
O
O
MeO
HO
4
3
G
X
O
+
O
O
O
O
O
HO
MeO
MeO
7
5
6
*
Corresponding author. Tel.: +1 5152947794; fax: +1 5152940105; e-mail: gakraus@iastate.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.010

7512
G. A. Kraus, J. Wei / Tetrahedron Letters 46 (2005) 7511–7513
in THF at 140 °C afforded 14 plus isomer 15 in a
X
X
ratio of 5:1. The use of sodium hydride at 25 °C gener-
ated only 15. The use of triethylamine at 140 °C
resulted in returned starting material. The use of acid
catalysts such as BF3–Et2O afforded only 15. Attempts
to convert 15 into 14 using base catalysis were
unsuccessful.
nBuLi
O
7
O
O
HO
8a: X = H
8b: X = CH2OH
8c: X = CH2OEVE
9a: X = H
9b: X = CH2OH
The next step was to transform benzofuran 9b. Com-
pound 9b reacted readily under basic conditions to
afford alcohol 10. The most convenient conditions for
scale up involved sodium hydride in THF at 25 °C. With
the tetracyclic system in hand, the reduction of the ben-
zofuran was examined. Surprisingly, alcohol 10 did not
react using the iridium-based directed hydrogenation
conditions. Catalytic hydrogenation using Pd/C affor-
ded a single stereoisomer based on the proton and car-
bon NMR spectra. The structure of 11 was determined
by X-ray crystallography.11
Catalytic hydrogenation of 14 using palladium on car-
bon followed by treatment of the reduced product with
trifluoroacetic acid in toluene at 110 °C provided 2b in
71% overall yield.13 The structure of 2b is supported
by proton and carbon NMR and mass spectrometry.
A 2D NOE experiment on the acetate of 2b showed
interactions between the methyl group of the acetate
and hydrogens on C-1, C-11a, and C-6, supporting the
relative stereochemistry assigned to 2b. The hydrogen
on C-6a showed NOE interactions with hydrogens on
C-6, C-7 and C-11a.
H
H
O
H
O
H
NaH
H2
9b
O
O
O
Pd/C
O
HO
HO
10
11
Attempts to introduce the C-4–C-4a double bond (see 1
for numbering) in ketone 10 by enol silyl ether forma-
tion and subsequent oxidation were unsuccessful
because the enol silyl ether could not be formed (2
TMSOTf, Et3N; TMSCl, DBU). The efforts to oxidize
10 had become necessary because the benzofuran anions
failed to react with methoxybenzoquinone. We next syn-
thesized quinone monoketal 1212 as a synthetic equiva-
lent of methoxybenzoquinone.
The route to 2b from 8c requires only five steps and
should be compatible with considerable structural varia-
tion. The use of quinone monoketal 12 as a synthetic
equivalent of methoxybenzoquinone extends the range
of quinols that can be produced by carbanion reactions.
Certain heterocyclic quinol adducts show promising
in vivo antitumor activity.10
Acknowledgements
O
O
We thank the National Institutes of Health (grant P01
ES12020) and the Office of Dietary Supplements for par-
tial financial support through the Center for Research
on Botanical Dietary Supplements at Iowa State
University.
OMe
OMe
MeO OMe
O
12
The reaction of the anion of 8c with quinone mono-
ketal 12 followed by acetic acid-mediated hydrolysis of
the ethyl vinyl ether (EVE) protecting group afforded
adduct 13 in 80% yield. Cyclization of 13 with DBU
References and notes
1. Kuroyanagi, M.; Arakawa, T.; Hirayama, Y.; Hayashi, T.
J. Natural Prod. 1999, 62, 1595–1599.
HO
MeO
n-BuLi
HOAc
O
8c
13
O
12
HO
13
H
O
OMe
O
DBU
O
O
+
O
O
HO
MeO
HO
5:1
1. H2, Pd/C
2. CF3CO2H
15
14
2b

G. A. Kraus, J. Wei / Tetrahedron Letters 46 (2005) 7511–7513
7513
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database.
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13. 2b data: 1H NMR (300 MHz, CD3COCD3) d 2.03 (m,
1H), 2.27 (m, 1H), 2.73 (m, 2H), 4.04 (m, 1H), 4.30 (d, 1H,
J = 10.8 Hz), 4.84 (dd, 1H, J = 10.8 Hz, J = 4.2 Hz), 4.97
(d, 1H, J = 10.8 Hz), 5.25 (s, –OH), 5.42 (s, 1H), 6.73 (d,
1H, J = 8.1 Hz), 6.92 (t, 1H, J = 7.5 Hz), 7.15 (t, 1H,
J = 8.1 Hz), 7.37 (d, 1H, J = 7.5 Hz).
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10. Compound 9a is known: Wells, G.; Berry, J. M.; Brad-
shaw, T. D.; Burger, A. M.; Seaton, A.; Wang, B.;
CMR (75 MHz, CD3COCD3) d 32.1, 32.2, 40.6, 67.3, 67.7,
82.4, 108.2, 109.1, 121.4, 125.0, 128.7, 129.1, 159.5, 171.6,
197.1. MS: m/z 258, 257, 172, 131, 130, 117. HRMS:
m/z for C15H14O4 calcd. 258.0892; measured 258.0897.
TLC (ethyl acetate/hexane = 2:1) Rf = 0.25. Mp 198–
200 °C.