Synthesis of 2′-dealkylmumbaistatin

Article abstract of DOI:10.1016/j.tet.2005.10.063

The sterically congested 1,2,3-substituted 3′-dealkyl mumbaistatin derivatives 16, 20, and 21 were prepared for the first time by base-catalyzed cyclization of the 2,3-bis-substituted naphthoquinone precursor 11 followed by bromine mediated photooxidation

Full text of DOI:10.1016/j.tet.2005.10.063

Tetrahedron 62 (2006) 1223–1230
Synthesis of 20-dealkylmumbaistatin
*
Karsten Krohn, Jan Diederichs and Muhammad Riaz
Department of Chemistry, University of Paderborn, Warburger Str. 100, D-33098 Paderborn, Germany
Received 25 August 2005; revised 20 October 2005; accepted 24 October 2005
Dedicated to Professor Henning Hopf on the occasion of his 65th birthday
Available online 28 November 2005
Abstract—The sterically congested 1,2,3-substituted 30-dealkyl mumbaistatin derivatives 16, 20, and 21 were prepared for the first time by
base-catalyzed cyclization of the 2,3-bis-substituted naphthoquinone precursor 11 followed by bromine mediated photooxidation and methyl
ether cleavage.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the non-insulin-dependent type II diabetes mellitus
(NIDDM). The compound may therefore be a lead structure
in the design of new antidiabetic drugs. Because of this
potential biological importance, the group of Schmalz has
published two synthetic approaches to prepare mumbaistatin
(1) synthetically.2,3 The anthraquinone skeleton was either
constructed by the Hauser phthalide annulation method2,4 or
by a Diels–Alder reaction involving aryne intermediates, as
pioneered by Suzuki et al.3,5 In both cases, the substituted
benzoyl residue was subsequently attached using an
organometallic reaction of a 1-formyl anthracene, followed
by oxidation. However, both approaches failed to introduce
the carboxyl group at C-2 of the anthraquinone. We now
present a solution to this specific problem, disclosing the
synthesis of 20-dealkylmumbaistatin derivatives 16, 20,
and 21.
Mumbaistatin (1), a novel glucose-6-phosphate translocase
inhibitor produced by the Streptomyces sp. DSM 11641 was
isolated in 2001 by Laszlo et al.1 Its structure is composed of
a 3,8-dihydroxyanthraquinone, acylated at C-1 with a
sterically congested 20,60-disubstituted benzoic acid.
Moreover, a carboxylic group at C-2 adds to the steric
HO
O
O
2'
1'
4''
O
HO
O
HO
OH
O
OH OH
O
O
OH
8
O
OH
6'
O
1
OH
CO2H
2
3
OH
OH
O
O
In this work, we used an entirely different approach in the
construction of the anthraquinone skeleton in which the
steric congestion of the highly substituted ring A is
overcome by an intramolecular anionic reaction. We
recently investigated the reaction of the highly electron-
deficient 2-acetyl-1,4-naphthoquinone (2a, R1ZH, R2ZMe)
with the diene 3.6 Due to its fixed transoid configuration,
this diene is not capable of Diels–Alder type cyclo-
additions.7 However, the inherent silyl-ketene acetal
functionality of 3 allows Lewis acid-catalyzed nucleophilic
additions, in particular of the sterically less hindered
methylene group. The highly electron-deficient 2-acetyl-
1,4-naphthoquinones (2a and 2b) are particularly good
acceptors and no catalyst at all was required for the Michael
addition of 3 to afford the 2,3-bissubstituted naphtho-
quinone (4a) after oxidation of the intermediate adduct with
cerium ammonium nitrate (CAN) as shown in Scheme 1.6
mumbaistatin (1a)
1b
Chart 1. Structure of the open chain (1a) and cyclic hemiacetal form (1b)
of mumbaistatin.1
demand. The open chain form 1a is in equilibrium with the
hemiacetal form 1b (Chart 1).
Mumbaistatin (1) was found to be the strongest naturally
occurring inhibitor of glucose-6-phosphate translocase
(G6P-T1) known today.1 Inhibitors of G6Pase are of interest
for the regulation of blood glucose and for the treatment of
Keywords: 30-Dealkyl mumbaistatin; Anthraquinone synthesis; Base-
catalyzed aldol cyclization; Photooxidation.
Corresponding author. Tel.: C49 5251602172; fax: C49 5251603245;
e-mail: karsten.krohn@uni-paderborn.de
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.063

1224
K. Krohn et al. / Tetrahedron 62 (2006) 1223–1230
Scheme 1. Construction of contiguously 1,2,3-substituted anthraquinones 5a6 and 5b.8
Base treatment of 4a then furnished the 1-methyl-9,
10-anthraquinone 5a in 73% yield. This procedure was used
by Uno et al. to prepare the bioactive 1-ethylanthraquinone
aloesaponarin I and K1115A (5b; R1ZOMe, R2ZEt) via
the intermediates 2b and 4b.8 The strategy of the present
work was to replace the acetyl or propionyl residue on the
naphthoquinone core by a phenylacetyl residue (R2Z
CH2Ph) followed by oxidation of the resulting benzylic
methylene group at C-1 of the anthraquinone 5 (R2Z
CH2Ph) (see Schemes 3 and 4).
phenylacetic ester 8a and the phenylglyoxylic esters 8b.
The expected 2-acylation product 9 was isolated in the
reaction of ester 8a with boron trifluoride etherate in 87%
yield, but no Fries rearrangement products could be detected
from the reaction of the phenylglyoxylic ester 8b under a
variety of conditions. Thus, the missing oxygen atom at C-2
had to be introduced in a later step. However, we were
confident that this step would be possible photochemically,
based on the experience of photooxidation in the angucy-
clinone antibiotics series.10,11 Oxidation of the hydro-
quinone monomethyl ether 9 with cerium ammonium
nitrate (CAN) was possible on a multigram scale in 95%
yield to afford the acylated naphthoquinone 10. The transoid
fixed diene 3, prepared from the parent dioxin by
deprotonation with LDA and silylation of the enolate with
trimethylsilyl chloride,7 was used to introduce the ‘bottom’
part side chain at C-3 of the naphthoquinone. The best yields
in this reaction were attained using equimolar amounts of
cuprous triflate as a mild Lewis-acid catalyst. The
presumable silylated Michael addition intermediate A was
not isolated but immediately oxidized to the 2,3-bis-
substituted naphthoquinone 11 (42% over the two steps).
2. Results and discussion
2.1. Construction of the 2,3-dialylated naphthoquinone
11
Based on this concept, the synthesis of the 2,3-disubstituted
naphthoquinone 11 was tackled first (Scheme 2). The tight
hydrogen bond and thus low nucleophilicity of 4,
8-dimethoxynaphthol (6), was a problem using normal
acylation conditions in the reaction with 2-methoxyphenyl-
acetic acid (7a) or 2-oxo-2-phenylacetic acid (7b).
However, employing modified Steglich9 neat conditions,
with a melt of the reaction components 6 and 7a or 7b
together with the usual amounts of dicyclohexyl carbodii-
mide (DCC) and dimethylaminopyridine (DMAP) gave the
desired esters 8a and 8b in 50 and 48% yield, respectively.
Next, the Fries rearrangement was tried on both the
2.2. Base-catalyzed cyclization of 11 to the
1,3-dioxanaphthacene-4,6,11-trione 12
In their K1115A synthesis, Uno et al.8 showed that two
different cyclization modes can be adopted depending on
the strength of the base used, initiated by deprotonation at
Scheme 2. Construction of the 2,3-bis-substituted naphthoquinone 11.

K. Krohn et al. / Tetrahedron 62 (2006) 1223–1230
1225
MeO
O
MeO
O
OMe O
OMe O
Ca(OAc)2,
1
K2CO3, MeOH
2
2'
M
O M
O
1''
O
O
O
O
H
O
O
B
B
11
K2CO3, MeOH
24, 10 %
2'
MeO
MeO
MeO
1'
OMe O
O
OMe O
O
O
HO
24 h,
37 %
OMe O
O
H
6
5
4
3
2
O
O
OMe
OH
O
1
O 11
12
O
O
C
13
Scheme 3. Cyclization of the disubstituted naphthoquinone 11 to the 1,3-dioxanaphthacene-4,6,11-trione 12 and the methyl ester 13.
either 20 or 100-C in compound 11. In fact, the choice of the
suitable base was crucial to induce the desired cyclization
and after some experimentation a mixture of potassium
carbonate buffered by addition of calcium acetate gave the
best results in the multistep aldol-type condensation
proceeding via the enolate B and the alcohol C. A
simultaneous transesterification using the stronger base
potassium carbonate gave the anthraquinone methyl ester
13, however in only 10% yield because these conditions
were appropriate for transesterification but not optimal to
induce the desired cyclization.
observed the facile photooxidation of the benzylic position
of the angularly condensed benzo[a]anthraquinone
system.11 Therefore, anthraquinone 12 was subjected to
irradiation with sunlight in dichloromethane solution as in
the previous experiments with angucyclinones. However,
not the expected carbonyl oxidation product 16 but rather
the
10-hydroxy-4-methoxy-1-(2-methoxyphenyl)an-
thra[2,1-c]furan-3,6,11(1H)-trione (14) was isolated. In
line with earlier evidence, we suggest that the biradical D,
formed upon light induced excitation of the anthraquinone
12, cyclizes with the proximate lactone carbonyl to yield an
anthra[2,1-c]furan intermediate E. In fact, proximity seems
to be a decisive factor for this reaction since the ester 13
with more rotational flexibility did not undergo similar
photochemical cyclization reactions. The intermediate E
may then further react with molecular oxygen in a multistep
fashion to yield the stable anthra[2,1-c]furan lactone 14, as
2.3. Oxidation of the benzylic position at C-5
With the 1-benzyl-anthraquinone 12 in hand, the oxidation
of the benzylic position was studied next (Scheme 4). In
connection with the angucyclinone antibiotics series, we
OMe
O
OMe
O
MeO
H
H
OMe O
OMe O
O
OMe O
MeI
K2CO3
O
hν
O
O
94 %
65 %
OMe
O
h
OH
O
O
O
12
14
15
MeO
MeO
MeO
H
H
H
OMe OH
O
O
OMe OH
O
O
OMe O
O
O
OH
O
O2
O
O
O
O
O
O
D
E
F
MeO
MeO
Br
O
Br2, hν,
CCl4, H2O
Br2, h ,
CCl4 traces H2O
O
OMe O
O
O
OMe O
O
O
12
O
79 %
82 %
O
O
O
16
17
Scheme 4. Photooxidation of 1,3-dioxanaphthacene-4,6,11-trione 12 to the anthra[2,1-c]furan 15 and bromination of 12 to the ketones 16 and 17.

1226
K. Krohn et al. / Tetrahedron 62 (2006) 1223–1230
observed in the angucyclinone series.11 Chemically, the first
oxidation step was performed in the photooxidation and
further oxidative transformation of 14 was certainly
possible.
groups, the methoxy group of the side chain even by three
carbonyls. In fact, the C-20 methoxyl group was cleaved first
upon boron tribromide treatment and the monophenol 20
was isolated in 95% yield. Prolonged reaction also affected
the dioxolane protecting group and the bisphenol 21 was
isolated in only 20% yield (Scheme 5).
However, we were looking for a shorter pathway to study a
direct conversion of 12 to the carbonyl compound 16. Thus,
the light induced radical bromination of 12 was investi-
gated, again leading to a surprising result. By accident, we
used tetrachloromethane solvent of different quality, for
example, water content, obtaining mixtures of the desired
carbonyl compound 16 in addition to various amounts of the
monobrominated compound 17. Later it was found that
water saturated tetrachloromethane solutions of 12 afforded
the carbonyl compound 16 in 79%, whereas, on a small
scale, solutions with only traces of water gave the bromo
compound 17 in 82% yield. The reaction can be rationalized
assuming a displacement reaction of the bromine with the
hydroxyl compound to yield an intermediate alcohol, which
is further oxidized to the ketone 16 with excess of bromine,
or possibly by photochemical oxidation.10 With a compara-
tively high content of water, this reaction may be faster than
bromination of the aromatic nucleus. The electron deficient
aromatic 16 does not undergo further bromination.
In summary, the 1,2,3-contiguously substituted 30-dealkyl
mumbaistatin derivatives 16, 20, and 21 were prepared for
the first time, employing an intramolecular base-catalyzed
condensation reaction of a 2,3-bisalkylated naphthoquinone
precursor 11 followed by photooxidation and methyl ether
cleavage. The attachment of the side chain, present in
mubaistatin (1), can be effected at a late stage by a
palladium mediated coupling reaction starting from an
appropriate 6’’’ brominated precursor 18.
3. Experimental
3.1. General
For general methods and instrumentation see Ref.12
3.1.1. 4,8-Dimethoxynaphthalen-1-yl-2-(2-methoxyphe-
nyl)acetate (8a). A mixture of finely ground 4,8-dimethoxy-
naphthol (6) (prepared from 1,5-dihydroxynaphthalene by
formylation and Bayer–Villiger oxidation13) (8.07 g,
39.6 mmol), 2-methoxyphenylacetic acid (7a) (9.85 g,
59.3 mmol), dicyclohexyl carbodiimide (DCC, 12.24 g,
59.3 mmol) and dimethylaminopyridine (DMAP, 7.26 g,
59.3 mmol) was heated in a flask to ca. 120 8C. The mixture
was maintained at this temperature for 1 min after the entire
solid was molten. The cooled mixture was then dissolved in
CH2Cl2 (800 ml) and left in the refrigerator at K20 8C
overnight. The precipitated urea was filtered off, the solvent
removed under reduced pressure and the residue purified by
silica gel column chromatography using a gradient of
CH2Cl2 to CH2Cl2/MeOH 98:2 to afford the ester 8a as
white needles (6.71 g, 50%, mp 109 8C): IR (KBr) 3001
(CH), 2956 (CH), 2937 (CH), 2837 (OCH3), 1761 (C]O),
1601 (CH), 1514 (CH), 1412, 1271, 1250, 1228, 1147,
1068 cmK1; UV (methanol) lmax (log 3) 270 nm (4.78), 331
2.4. Methyl ether and acetonide cleavage
Finally, the cleavage of the acetonide group in 11 as a model
compound and of the two methyl ether groups in anthraqui-
none 12 was studied. The dioxolane ring was easily cleaved by
base-catalyzed transesterification as demonstrated in the
conversion of 11 to the methyl ester 13 using K2CO3 in
methanol (see Scheme 3). As expected, acetonide cleavage
was also possible under mild acidic conditions but simul-
taneous reduction of the acylated naphthoquinone 11 by the
methanol present was observed to yield the hydroquinone 18
in 94% yield. Oxidation of 18 with CAN gave the
naphthoquinone 19 in good yield (91%). These experiments
demonstrate the easy cleavage of the acetonide that may be of
importance in the late steps of mumbaistatin synthesis.
Both methyl ethers were activated towards Lewis-acid-
mediated cleavage by neighboring aromatic carbonyl
MeO
MeO
O
MeO
O
2'''
OMe OH
1'
OMe O
OMe O
O
HCl
1''
2''
CAN
6'''
O
4
MeOH,
94 %
4'
91 %
OH
O
O
O
O
H
OH
OMe
OH
OMe
O
1
11
O
18
19
HO
O
HO
O
OMe O
O
O
OH
O
O
BBr3, 24 h
20%
BBr3, 3 h
95 %
O
O
16
O
O
20
O
21
Scheme 5. Methyl ester and methyl ether cleavage of 11 and 16 using HCl/MeOH or boron tribromide.

K. Krohn et al. / Tetrahedron 62 (2006) 1223–1230
1227
(4.01), 344 (3.92); 1H NMR (200 MHz, CDCl3) d 3.94
(s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.03
13C NMR (50 MHz, CDCl3) d 41.59 (t, C-2), 55.92/56.08/
56.76 (3!q, 3!OCH3), 103.19 (d, C-30), 107.68 (d, C-70),
111.07 (d, C-50), 113.04 (s, C-20), 115.00 (d, 0C0 -300), 117.20
(s, C-8a0), 121.22 (d, C-500), 124.29 (0s0, C-1 ), 128.89 (0d,
C-60), 130.42 (0d, C-400), 131.30 (d, C-6 ), 132.92 (s, C-4a ),
147.13 0(0 s, C-1 ), 157.39 (s, C-40), 159.11 (s, C-80), 159.75
(s, C-2 ), 203.04 (s, C-1); MS (EI, 70 eV) m/z (%) 352
(27) [MC], 231 (100) [MCKC7H7OCH3], 204 (41)
[C10H5(OCH3)2OHC], 189 (54) [C10H5(OCH3)2OHC–
CH3], 174 (12) [C10H5(OCH3)2OHC–2!CH3], 121 (20)
[C7H6OCHC3 ], 91 (13) [C7HC7 ]; HR EIM calculated for
C21H20O5 352.13107. Found: 352.1310G2 ppm. Anal.
Calcd for C21H20O5: C, 71.20; H, 5.53. Found: C, 71.58;
H, 5.72.
3
(s, 2H, 2-H), 60.80 (d, JZ8.3 Hz, 1H, 30-H), 6.90–7.05
(m, 4H, 40-H, 5 -H, 60-H, 700-H), 7.34–7.45 (m, 3H, 200-H,
3
300-H, 600-H), 7.91 (d, JZ8.5 Hz, 1H, 500-H); 13C NMR
(50 MHz, CDCl3) d 35.89 (d, C-2), 55.98/56.16/56.38
(3!s, 3!OCH3), 104.19 (d, C-300), 107.21 (d, C-700),
111.06 (d, C-500), 115.24 (d, C-30), 119.12 (d, C-200), 120.14
(s, C-8a00), 121.00 (d,00 C-50), 123.28 (s0, C-10), 126.21 (0d,
C-600), 128.68 (s, C-4a ), 128.98 (d, C-4 ), 131.5000(d, C-6 ),
140.36 0(s, C-100), 153.64 (s, C-800), 155.64 (s, C-4 ), 158.09
(s, C-2 ), 171.64 (s, C-1); MS (EI, 70 eV) m/z (%) 352
(12) [MC], 204 (100) [C10H5(OCH3)2OHC], 189 (44)
[C10H5(OCH3)2OHC–CH3], 121 (19) [C7H6OCHC3 ], 91
(28) [C7HC7 ], 57 (57) [C3H5OC], 28 (75) [COC]; HR EIMS
calculated for C21H20O5: 352.13107, Found: 352.13101G
2 ppm. Anal. Calcd for C21H20O5: C, 71.58; H, 5.72. Found:
C, 71.40; H, 5.60.
3.1.4.
8-Methoxy-2-[2-(2-methoxyphenyl)-acetyl]-
[1,4]naphthoquinone (10). A solution of the hydroquinone
derivative 9 (7.42 g, 21.0 mmol) in acetonitrile (150 ml)
was reacted with a 1 M aqueous solution of cerium
ammonium nitrate (CAN, 42.00 ml, 42.0 mmol) and stirred
for 15 min. The mixture was diluted by addition of water
(300 ml) and extracted three times with CH2Cl2 (3!
200 ml). The combined organic phase was dried
(Na2SO4), the solvent evaporated at reduced pressure, and
the residue purified by column chromatography on silica gel
to afford the pure quinone 10 as red-brown crystals (6.68 g,
95%), mp 118 8C after recrystallization from EtOAc/
petroleum ether (50–70 8C): UV (methanol) lmax (log 3)
269 nm (4.78), 399 (3.62); IR (KBr) 3039 (CH), 3006 (CH),
2943 (CH), 2841 (OCH3), 1716 (C]O), 1651 (C]O),
3.1.2. 4,8-Dimethoxynaphthalen-1-yl 2-(2-methoxyphe-
nyl)-2-oxoacetate (8b). 4,8-Dimethoxynaphthol (6)
(3.00 g, 14.7 mmol) was reacted according to the procedure
described for 8a using phenylglyoxylic acid (7b) (3.31 g,
22.1 mmol), DCC (12.24 g, 59.3 mmol) and DMAP (7.26 g,
59.3 mmol) to afford ester 8b (2.37 g, 48%, mp 150 8C,
decomp.) as a red-brown solid: IR (KBr) 2935 (CH), 2852
(OCH3), 1759 (C]O), 1705 (C]O), 1608, 1448, 1408,
1377, 1068 cmK1; UV (methanol) lmax (log 3) 333 nm
1
(3.15), 348 (3.23); H NMR (200 MHz, CDCl3) d 3.74 (s,
3H, 400-OCH3), 4.08 (s, 3H, 800-OCH3), 6.90 (d, 3JZ7.4 Hz,
1H, 200-H), 7.36–7.45 (m, 5H, 30-H, 50-H, 300-H, 600-H, 700-H),
1585, 1495, 1469, 1296, 1250, 1047 cmK1 1H NMR
;
3
7.60–7.68 (m, 3H, 20-H, 40-H, 60-H), 7.85 (dd, JZ8.5 Hz,
(200 MHz, CDCl3) d 3.77 (s, 3H, 200-OCH3), 4.07 (s, 3H,
8-OCH3), 4.17 (s, 2H, 20-H), 6.83 (d, 3JZ8.2 Hz, 1H, 300-H),
6.87 (s, 1H, 3-H), 6.89–6.97 (m, 2H, 500-H, 600-H), 7.24 (d,
3JZ7.2 Hz, 1H, 7-H), 7.37 (dd, 3J1Z3J2Z4.8 Hz, 1H,
400-H), 7.72–7.78 (m, 2H, 5-H, 6-H); 13C NMR (50 MHz,
CDCl3) d 45.77 (t, C-20), 55.61/56.97 (2!s, 2!OCH3),
110.76 (d, C-300), 118.84 (d, C-7), 119.43 (d, C-500), 121.17
(s, C-5), 122.82 (s, C-100), 129.33 (s, C-8a), 132.20 (d, C-400),
133.75 (d, C-600), 134.30 (d, C-6), 135.77 (s, C-4a),00149.57
(d, C-3), 157.73 (s, C-2), 160.34/160.46 (2!s, C-2 , C-8),
185.44 (s, C-10); MS (EI, 70 eV) m/z (%) 336 (13) [MC],
308 (3) [MCKCO], 121 (100) [C7H6OCH3C], 91 (62)
[C7HC7 ]; HR MS calculated for C20H16O5: 336.09977.
Found: 336.09958G2 ppm. Anal. Calcd for C20H16O5: C,
71.42; H, 4.79. Found: C, 71.09; H, 4.68.
4JZ0.9 Hz, 1H, 500-H); 13C NMR (50 MHz, CDCl3) d 55.69
(q, 400-OCH3), 56.22 (q, 800-OCH3), 105.59 (d, C-200), 108.98
(d, C-300), 115.22 (d, C-700), 115.83 (d,00C-500), 116.01 (s,
C-8a00), 126.36 (d, C-600), 126.57 (s, C-4a ), 128.23 (d, C-30,
C-500), 128.58 (d, C-20, C-60), 138.12 (d, C-40), 143.50 (s,
C-1 ), 147.31 (s, C-100), 148.08 (s, C-800), 156.40 (s, C-1),
174.36 (C-2); MS (EI, 70 eV) m/z (%) 334 (9) [MCKH],
307 (8), 279 (18), 205 (20), 167 (46), 149 (89) [C7H5OC3 ],
105 (89), 57 (99), 44 (100) [COC2 ]. Anal. Calcd for
C21H20O5: C, 71.42; H, 4.79. Found: C, 70.98; H, 4.31.
3.1.3. 1-(1-Hydroxy-4,8-dimethoxynaphthalen-2-yl)-2-
14
(2-methoxyphenyl)-ethanone (9). A melt of esters 8a
(ca. 110 8C, 8.84 g, 25.1 mmol) was treated rapidly under
nitrogen with BF3–etherate (3.76 ml, 29.9 mmol). The
reaction was terminated after 3 min resulting in a solid.
After cooling, the product was dissolved in CH2Cl2 (200 ml)
and washed with water. The aqueous phase was extracted
with another charge of CH2Cl2 (100 ml), the combined
organic phase was dried (Na2SO4), the solvent was
evaporated at reduced pressure, and the residue purified
by column chromatography on silica gel (CH2Cl2) to afford
naphthol 9 (7.69 g, 87%, mp 139 8C) as yellow needles: UV
(methanol) lmax (log 3) 269 nm (4.76), 395 (3.91); IR (KBr)
3097 (OH), 2947 (CH), 2929 (CH), 2831 (OCH3), 1626
(C]O), 1574, 1379, 1273, 1242, 1072, 891, 754 cmK1; 1H
NMR (200 MHz, CDCl3) d 3.86 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3), 4.07 (s, 3H, OCH3), 4.40 (s, 2H, 2-H), 6.93–7.02
(m, 3H, 300-H, 500-H, 70-H), 7.15 (s, 1H, 30-H), 7.27–7.30 (m,
2H, 400-H, 600-H), 7.56 (dd, 3JZ8.2, 8.0 Hz, 1H, 60-H), 7.84
(dd, 3JZ8.3 Hz, 4JZ1.0 Hz, 1H, 50-H), 13.91 (s, 1H, OH);
3.1.5. 2-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-ylmethyl)-
5-methoxy-3-[2-(2-methoxyphenyl)-acetyl]-[1,4]naphtho-
quinone (11). A solution of diene 37 (3.892 g, 17.84 mmol)
in dry CH2Cl2 (20 ml) was stirred for 20 min under nitrogen
at K20 8C with Cu(II)–triflate (2.156 g, 5.95 mmol). The
solution was cooled to K60 8C and naphthoquinone 10
(2.000 g, 5.95 mmol) was added in one portion. The mixture
was stirred for 6 h at K20 8C and the reaction was then
quenched by addition of 2 N HCl (30 ml). The phases were
separated and the aqueous phase extracted twice with
CH2Cl2 (2!30 ml). The solvent was removed under
reduced pressure and the crude product dissolved in
acetonitrile (40 ml) and treated with a solution of CAN
(6.527 g, 11.90 mmol) in water (10 ml). After stirring for
15 min the mixture was diluted with CH2Cl2 (150 ml) and
water (150 ml). The phases were separated and the organic

1228
K. Krohn et al. / Tetrahedron 62 (2006) 1223–1230
phase was extracted twice with CH2Cl2 (2!100 ml). The
combined organic phase was dried (Na2SO4), the solvent
was evaporated at reduced pressure, and the residue purified
by column chromatography on silica gel (CH2Cl2/MeOH
99:1) to afford the bisalkylated naphthoquinone 11 (1.170 g,
42%, mp 57 8C) as orange needles: UV (methanol) lmax
(log 3) 269 nm (4.88), 400 (3.62); IR (KBr) n~ (cmK1) 2997
(CH), 2925 (CH), 2844 (OCH3), 1732 (C]O), 1662
(C]O), 1635, 1392, 1263, 1203, 1014, 756; 1H NMR
(200 MHz, CDCl3) d 1.64 (s, 6H, 2!CH3), 3.32 (s, 2H,
3-CH2), 3.71 (s, 3H, 2000-OCH3), 4.05 (s, 3H, 5-OCH3), 4.11
(s, 2H, 200-CH), 5.11 (s, 1H, 50-H), 6.84 (d, 3JZ8.2 Hz, 1H,
C27H22O7: 458.13655. Found: 458.13623. Anal. Calcd for
C27H22O7: C, 70.73; H, 4.84. Found: C, 70.51; H, 4.49.
3.1.7. Methyl 3-hydroxy-8-methoxy-1-(2-methoxy-
benzyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxy-
late (13). A solution of naphthoquinone 11 (200 mg,
0.42 mmol) in methanol (3 ml) was treated with dry
K2CO3 (70 mg, 0.51 mmol) and stirred for 24 h at 208.
The reaction was quenched by addition of 0.1 M HCl
(10 ml), extracted with CH2Cl2 (2!10 ml), the combined
organic phase was dried (Na2SO4), the solvent evaporated at
reduced pressure, and the residue purified by column
chromatography on silica gel (CH2Cl2/MeOH 99:1) to
afford the methyl ester 13 (18 mg, 10%, mp 198 8C) as
orange-red needles: UV (methanol) lmax (log 3) 269 nm
(5.00), 420 (4.08); IR (KBr) n~ (cmK1) 3002 (CH), 2952
(CH), 2918 (CH), 2848 (OCH3), 1741 (C]O), 1670
(C]O), 1631, 1583, 1282, 1242, 1173, 1020, 754; 1H
3
3000-H), 6.91–6.94 (m, 1H, 5000-H), 7.21 (d, JZ7.2 Hz, 1H,
6000-H), 7.24–7.29 (m, 1H, 4000-H), 7.37 (dd, 3JZ6.9 Hz,
4JZ2.3 Hz, 1H, 6-H), 7.70–7.74 (m, 2H, 7-H, 8-H); 13C
NMR (50 MHz, CDCl3) d 25.32 (q, 20-CH3), 31.22 (t,
3-CH2), 46.54 (t, C-200), 55.55/57.05 (2!OCH3), 94.62 (d,
C-50), 107.39 (s, C-20), 110.85 (d, C-3000), 118.94 (d, C-6),
119.45 (s, C-1000), 119.94 (0d00, C-5000), 121.38 (d, C-8), 121.47
(s, C-4a), 129.66 (d, C-4 ), 132.23 (d, C-6000), 133.77 (s,
C-8a), 136.11 00(0d, C-7), 137.34 (s, C-3), 149.600 (s, C-2),
157.740(s, C-2 ), 160.28 (s, C-5), 161.20 (s, C-6 ), 168.00
(s, C-4 ), 182.75/184.40 (2!s, C-1, C-4), 200.60 (s, C-100);
MS (EI, 70 eV) m/z (%) 376 (20) [MCKC4H6O3C2H], 255
(100) [MCKC4H6O3–C7H6OCH3C2H], 240 (19) [MCK
C4H6O3–C7H6OCH3–CH3C2H], 121 (12) [C7H6OCHC3 ],
91 (23) [C7H7C], 44 (10) [CO2C]. Anal. Calcd for C27H24O8:
C, 68.06; H, 5.08. Found: C, 67.64; H, 5.02.
4
NMR (200 MHz, CDCl3) d 3.57 (d, JZ1.9 Hz, 2H, 1-
CH2), 3.64 (s, 3H, 20-OCH3), 3.78 (s, 3H, CO2CH3), 4.10 (s,
3H, 8-OCH3), 7.07 (d, 3JZ8.3 Hz, 1H, 30-H), 7.13 (d, 3JZ
7.4 Hz, 1H, 50-H), 7.22 (dd, 3JZ7.4 Hz, 4JZ1.9 Hz, 1H, 60-
H), 7.39–7.47 (m, 2H, 7-H, 40-H), 7.79 (dd, 3JZ8.4, 7.7 Hz,
3
4
1H, 6-H), 7.84 (s, 1H, 4-H), 8.03 (dd, JZ7.7 Hz, JZ
1.0]Hz, 1H, 5-H); 13C NMR (50 MHz, CDCl3) d 39.84 (t,
1-CH2), 52.47 (q, CO2CH3), 55.95 (q, 20-OCH3), 57.12 (q,
8-OCH3), 111.57 (d, C-4), 116.21 (s, C-8a), 118.60 (d, C-
30), 120.54 (d, C-7), 120.84 (d, C-5), 121.13 (d, C-50),
121.37 (s, C-9a), 123.41 (s, C-2), 130.49 (d, C-6), 131.71 (s,
C-10a), 131.86 (s, C-1), 135.31 (s, C-10), 136.12 (s, C-60),
136.14 (s, C-4a), 142.40 (s, C-8), 157.03 (s, C-3), 161.31 (s,
C-20), 171.16 (s, CO2CH3), 183.04 (s, C-10), 189.09 (s,
C-9); MS (EI, 70 eV) m/z (%) 432 (59) [MC], 401 (100)
[MCKOCH3], 359 (42) [MCKC3H5O2], 327 (17) [MCK
OCH3–C3H6O2], 296 (19), 186 (20), 149 (20), 57 (66)
[C3H5OC], 43 (54) [CH3COC]; HR MS calculated for
C25H20O7: 432.12090. Found: 432.12209.
3.1.6. 7-Methoxy-5-(2-methoxybenzyl)-2,2-dimethyl-1,
3-dioxanaphthacene-4,6,11-trione (12). A solution of
naphthoquinone 11 (1.000 g, 2.10 mmol) in methanol
(20 ml) was treated with dry CaCl2 (1.000 g, 6.33 mmol)
and subsequently with dry K2CO3 (145 mg, 1.05 mmol) and
the mixture was stirred for 24 h at 20 8C. The reaction was
quenched by addition of 1 M HCl (20 ml), the mixture
extracted with CH2Cl2 (2!30 ml), and the combined
organic phase was dried (Na2SO4), the solvent evaporated
at reduced pressure, and the residue purified by column
chromatography on silica gel (CH2Cl2/MeOH 99:1) to
afford the cyclization product 12 (352 mg, 37%, mp 177 8C)
as orange crystals: UV (methanol) lmax (log 3) 269 nm
(5.02), 375 (3.80); IR (KBr) n~ (cmK1) 3072 (CH), 3001
(CH), 2925 (CH), 2839 (OCH3), 1741 (C]O), 1672
(C]O), 1595, 1323, 1275, 1248, 1014, 750; 1H NMR
(200 MHz, CDCl3) d 1.70 (s, 6H, 2!2-CH3), 3.83 (s,
3H, 20-OCH3), 3.98 (s, 3H, 7-OCH3), 5.27 (s, 2H, CH2),
6.70–6.78 (m, 2H, 50-H, 60-H), 6.83 (d, 3JZ8.6 Hz, 1H, 30-
H), 7.07–7.16 (m, 1H, 40-H), 7.32 (dd, 3JZ8.3 Hz,
3.1.8. 4-Hydroxy-10-methoxy-1-(2-methoxyphenyl)-
anthra[1,2-c]furan-3,6,11(1H)-trione (14). The benzoy-
lanthraquinone 12 (20 mg, 0.04 mmol) was dissolved in
CH2Cl2 (ca. 25 ml), the solution placed in 10 NMR tubes
and irradiated for 1 day in the sunlight. The solvent was
removed under reduced pressure to afford the lactone 14
(17 mg, 94%, mp 238 8C) as yellow needles from diethyl
ether: UV (methanol) lmax (log 3) 270 nm (4.79), 358
(4.02); IR (KBr) n~ (cmK1) 3086 (CH), 2951 (CH), 2922
(CH), 2850 (OCH3), 1745 (C]O), 1653 (C]O), 1585,
1331, 1261, 1014, 756; 1H NMR (500 MHz, CD2Cl2) d 3.91
(s, 3H, 20-OCH3), 3.94 (s, 3H, 10-OCH3), 6.88 (dd, 3JZ7.4,
7.0 Hz, 1H, 50-H), 6.96 (br s, 1H, 60-H), 7.03 (d, 3JZ8.2 Hz,
1H, 30-H), 7.37–7.42 (m, 3H, 1-H, 9-H, 40-H), 7.76 (dd, 3JZ
3
4JZ1.1 Hz, 1H, 8-H), 7.68 (dd, JZ8.3, 7.7 Hz, 1H, 9-H),
3
4
7.74 (s, 1H, 12-H), 7.81 (dd, JZ7.7 Hz, JZ1.1 Hz, 1H,
10-H); 13C NMR (50 MHz, CDCl3) d 25.44/25.99 (2!q,
2!2-CH3), 30.16 (t, 5-CH2), 55.94 (q, 20-OCH3), 57.00 (q,
7-OCH3), 106.13 (s, C-2), 110.74 (d, C-12), 114.56 (d, C-8),
118.89 (d, C-10), 119.35 (d, C-30), 120.52 (d, C-40), 125.54
(s, C-6a), 127.27 (d, C-50), 129.08 (d, C-9), 130.57 (s, C-5a),
132.54 (s, C-10), 134.41 (d, C-60), 134.97 (s, C-10a), 139.08
(s, C-4a), 150.15 (s, C-11a), 158.01 (s, C-5), 158.86 (s,
C-12a), 159.57 (s, C-20), 169.05 (s, C-4), 183.40 (s, C-11),
184.63 (s, C-6); MS (EI, 70 eV) m/z (%) 458 (38) [MC], 400
(100) [MCKC3H6O], 385 (76) [MCKC3H6O–CH3], 279
(16) [MCKC3H6O–C7H6OCH3], 121 (34) [C7H6OCHC3 ],
91 (24) [C7HC7 ], 28 (49) [COC]; HR MS calculated for
3
7.8, 7.3 Hz, 1H, 8-H), 7.86 (s, 1H, 5-H), 7.96 (dd, JZ
4
7.8 Hz, JZ1.1 Hz, 1H, 7-H), 8.69 (br s, 1H, OH); 13C
NMR (125 MHz, CDCl3) d 55.78 (q, 20-OCH3), 56.49 (q,
10-OCH3), 83.18 (d, C-1), 111.40 (d, C-60), 114.15 (d, C-5),
117.72 (s, C-3a), 118.81 (d, C-9), 119.920(d, C-7), 120.86 (s,
C-10a), 123.580(s, C-11a), 123.70 (s, C-1 ), 128.71 (d, C-30),
130.73 (d, C-4 ), 135.14 (d, C-8), 135.26 (s, C-6a), 139.78
(s, C-5a), 151.33 (s, C-11b), 158.06 (s, C-20), 159.21 (s,
C-4), 160.52 (s, C-10), 171.00 (s, C-3), 179.74 (s, C-11),
182.52 (s, C-6); MS (EI, 70 eV) m/z (%) 416 (100) [MC],
385 (12) [MCKOCH3], 372 (37) [MCKCO2], 357 (33)

K. Krohn et al. / Tetrahedron 62 (2006) 1223–1230
1229
[MCKCO2–CH3], 327 (11) [MCKCO2–CH3–CH2O], 91
(29) [C7HC7 ], 57 (33) [C3H5OC], 41 (29) [C3HC5 ], 29 (13)
[CHOC]; HR MS calculated for C24H16O7: 416.08960.
Found: 416.08960. Anal. Calcd for C24H16O7: C, 69.23; H
3.87. Found: C, 69.34; H 4.30.
10-H), 8.30 (d, 3JZ7.5 Hz, 1H, 60-H); 13C NMR (50 MHz,
CDCl3) d 25.49/25.57 (2!q, 2!2-CH3), 55.57 (q, 20-
OCH3), 56.42 (q, 7-OCH3), 106.97 (s, C-2), 111.86 (d, C-
30), 114.63 (d, C-12), 115.02 (s, C-4a), 118.87 0(d, C-8),
119.52 (d, C-10), 121.03 (d0, C-50), 126.58 (s, C-1 ), 128.03
(s, C-11a), 129.81 (d, C-6 ), 134.03 (d, C-40), 134.18 (s,
C-6a), 134.89 (s, C-5a), 135.27 (d, C-9), 135.38 (s, C-10a),
138.61 (s, C-5), 158.17 (s, C-4), 158.98/159.01 (2!s,
C-12a, C-20), 160.71 (s, C-7), 180.15 (s, C-6), 182.21 (s,
C-11), 191.64 (s, 5-CO); MS (EI, 70 eV) m/z (%) 472 (16)
[MC], 414 (13) [MCKC3H6O], 383 (100) [MCK
C3H6O–OCH3], 352 (12) [MCKC3H6O–OCH3–OCH3],
294 (12), 279 (6) [MCKC3H6O–C8H7O2], 149 (16), 135
(16) [C8H7OC2 ], 57 (11) [C3H5OC], 43 (7) [CH3COC]; HR
MS calculated for C27H20O8: 472.11582. Found:
472.11420. Anal. Calcd for C27H20O8: C, 68.64; H, 4.27.
Found: C, 68.14; H, 4.17.
3.1.9. 4,10-Dimethoxy-1-(2-methoxyphenyl)anthra[2,1-
c]furan-3,6,11(1H)-trione (15). A solution of lactone 14
(9 mg, 0.02 mmol) at 0 8C in Et2O (2 ml) was treated at 0 8C
with an ethereal solution of diazomethane (0.4 M, 0.15 ml).
The mixture was kept for 12 h at room temperature and the
solvent was removed under reduced pressure. The crude
product was purified by preparative layer chromatography
on silica gel (1 mm, CH2Cl2/MeOH 98:2) to afford the
trimethyl ether 15 (6 mg, 65%, mp 244 8C) as yellow
needles: UV (methanol) lmax (log 3) 271 nm (3.77); IR
(KBr) n~ (cmK1) 3086 (CH), 3012 (CH), 2937 (CH), 2837
(OCH3), 1763 (C]O), 1674 (C]O), 1603, 1468, 1335,
1
1254, 1207, 1074, 1011, 968, 754; H NMR (500 MHz,
3.1.11. 5-(5-Bromo-2-methoxybenzoyl)-7-methoxy-2,2-
dimethyl-4H-anthra[2,3-d][1,3]dioxin-4,6,11-trione (17).
A solution of the benzylanthraquinone 12 (55 mg,
0.12 mmol) was irradiated in the presence of bromine
(56 mg, 0.35 mmol) as described for 16, however, without
addition of water. The brominated benzoylanthraquinone 17
was obtained (55 mg, 86%, mp 241 8C) as a yellow solid:
UV (methanol) lmax (log 3) 272 nm (4.51), 389 (3.92); IR
(KBr) n~ (cmK1) 2999 (CH), 2937 (CH), 2843 (OCH3), 1743
(C]O), 1668 (C]O), 1593, 1481, 1448, 1340, 1282, 1271,
1230, 1030 (C–Br), 964; 1H NMR (500 MHz, CDCl3) d 1.79
(s, 6H, 2!2-CH3), 3.41 (s, 3H, 20-OCH3), 3.93 (s, 3H,
CDCl3) d 3.84 (s, 3H, 20-OCH3), 3.90 (s, 3H, 10-OCH3),
4.23 (s, 3H, 40-OCH3), 6.70–6.73 (m, 2H, 50-H, 60-H), 6.90
(d, 3JZ8.3 Hz, 1H, 30-H), 7.18 (s, 1H, 1-H), 7.22–7.26 (m,
2H, 9-H, 40-H), 7.62 (dd, 3JZ8.2, 7.9 Hz, 1H, 8-H), 7.77 (s,
3
4
1H, 5-H), 7.82 (dd, JZ7.6 Hz, JZ1.00 Hz, 1H, 7-H); 13C
NMR (125 MHz, CDCl3) d 55.78 (q, 2 -OCH3), 56.71 (q,
10-OCH3), 57.03 (q, 4-OCH3), 80.48 (d, C-1), 108.85 (d,
C-5), 111.40 (d, C-30), 118.99 (d, C-9), 120.04 (d, C-7),
120.25 (d, C-50), 120.61 (s, C-3a), 121.28 (s0, C-10a), 123.31
(s, C-11a), 124.15 (s, C-10), 128.95 (d, C-6 ), 130.32 (d, C-
40), 134.98 (d, C-8), 135.00 (s, 0 C-6a), 138.95 (s, C-5a),
154.01 (s, C-11b), 158.20 (s, C-2 ), 160.42 (s, C-4), 161.02
(s, C-10), 166.98 (s, C-3), 179.98 (s, C-11), 182.99 (s, C-6);
MS (EI, 70 eV) m/z (%) 430 (67) [MC], 371 (20) [MCK
CO2–CH3], 366 (16) [MCKCO2–CH3–CH3], 326 (15), 279
(14), 233 (18), 160 (42), 149 (42), 135 (67), 57 (70)
[C3H5OC], 44 (73) [CO2C] 43 (100) [CH3COC]; HR MS
calculated for C25H18O7: 430.10525. Found: 430.10520.
Anal. Calcd for C25H18O7: C, 69.76; H, 4.22. Found: C,
69.87; H, 4.01.
3
7-OCH3), 6.73 (d, JZ8.8 Hz, 1H, 30-H), 7.35 (dd,
4
3
3JZ8.5 Hz, JZ0.8 Hz, 1H, 8-H), 7.55 (dd, JZ8.8 Hz,
4JZ2.6 Hz, 1H, 40-H), 7.73 (dd, 3JZ8.4, 7.7 Hz, 1H, 9-H),
3
4
7.85 (s, 1H, 12-H), 7.92 (dd, JZ7.7 Hz, JZ1.1 Hz, 1H,
10-H), 8.47 (br s, 1H, 60-H); 13C NMR (125 MHz, CDCl3) d
25.65/25.86 (2!q, 2!2-CH3), 55.96 (q, 20-OCH3), 56.66
(q, 7-OCH3), 107.01 (s, C-2), 113.85 (d, C-30), 114.91 (d,
C-12), 115.130(s, C-4a), 118.87 (d, C-8), 119.76 (d, C-10),
121.06 (s, C-5 ), 128.05 (s, C-10), 128.30 (s, C-11a), 132.94
(d, C-9), 134.78 (s, C-6a), 135.33 (d, C-60), 136.38 (d, C-40),
136.54 (s, C-10a), 138.49 (s, C-5a), 149.78 (s, C-5), 157.91
(s, C-4), 158.15 (s, C-12a), 158.86 (s, C-20), 160.65 (s, C-7),
180.17 (s, C-6), 182.25 (C-11), 190.89 (s, 5-CO); MS (EI,
70 eV) m/z (%) 552 (12) [MC(81Br)], 550 [MC(79Br)], 463
(70) [MC(81Br)–C3H6O–OCH3], 461 (68) [MC(79Br)–
C3H6O–OCH3], 401 (31), 352 (27), 326 (30), 283 (57),
173 (43), 157 (41), 135 (24) [C8H7OC2 ], 111 (100), 57 (35)
[C3H5OC], 43 (65) [CH3COC]; HR MS calculated for
C27H19BrO8: 550.02633 (79Br). Found: 550.02655 (79Br).
Anal. Calcd for C27H19BrO8: C, 58.82; H, 3.47. Found: C,
58.91; H, 3.39.
3.1.10. 7-Methoxy-5-(2-methoxybenzoyl)-2,2-dimethyl-
4H-anthra[2,3-d][1,3]dioxin-4,6,11-trione (16). A solu-
tion of the benzylanthraquinone 12 (20.0 mg, 0.044 mmol)
in CCl4 (1 ml) was treated with elemental bromine (6.7 ml
0.132 mmol) and two drops of water and the mixture was
irradiated with a 100 W tungsten lamp. The mixture was
diluted with CH2Cl2 (10 ml) and washed with saturated
aqueous NaHCO3 solution (10 ml) and water (10 ml). The
organic phase was dried (Na2SO4), the solvent evaporated at
reduced pressure, and the residue purified by column
chromatography on silica gel (CH2Cl2/MeOH 99:1) to
yield the benzoylanthraquinone 16 (18 mg, 88%, mp
249 8C) as pale yellow crystals: UV (methanol) lmax
(log 3) 270 nm (4.54), 391 (3.95); IR (KBr) n~ (cmK1
)
3.1.12. Methyl 4-{1,4-dihydroxy-5-methoxy-3-[2-(2-
methoxyphenyl)-acetyl]-naphthalen-2-yl}-3-hydroxy-
but-2-enoate (18). A solution of naphthoquinone 11
(40 mg, 0.08 mmol) in 1 M HCl/MeOH (3 ml) was stirred
at room temperature for 1 h. The solvent was evaporated at
reduced pressure to afford the hydroquinone methyl ester 18
(36 mg, 94%) as a polar red-brown oil: 1H NMR (200 MHz,
CDCl3) d 3.80 (br s, 6H, 1-OCH3, 2000OCH3), 3.94 (s, 2H,
4-H), 4.12 (s, 3H, 50-OCH3), 4.50 (s, 2H, 200-H), 6.89–6.99
(m, 3H, 60-H, 3000-H, 5000-H), 7.14 (s, 1H, 2-H), 7.22–7.36 (m,
3093 (CH), 3001 (CH), 2927 (CH), 2841 (OCH3), 1743
(C]O), 1670 (C]O), 1595, 1446, 1344, 1282, 1232, 1016,
962, 856, 752; 1H NMR (500 MHz, CD2Cl2) d 1.80 (s, 3H,
2-CH3), 1.82 (s, 3H, 2-CH3), 3.45 (s, 3H, 20-OCH3), 3.97 (s,
3
3H, 7-OCH3), 6.94 (d, JZ8.2 Hz, 1H, 30-H), 7.24 (ddd,
4
3
3J1Z3J24Z7.5 Hz, JZ0.8 Hz, 1H, 50-H), 7.41 (dd, JZ
3
8.4 Hz, JZ0.8 Hz, 1H, 8-H), 7.59 (ddd, JZ8.2, 7.5 Hz,
4JZ1.8 Hz, 1H, 40-H), 7.78 (dd, 3JZ8.4, 7.9 Hz, 1H, 9-H),
3
4
7.87 (s, 1H, 12-H), 7.95 (dd, JZ7.9 Hz, JZ1.1 Hz, 1H,

1230
K. Krohn et al. / Tetrahedron 62 (2006) 1223–1230
2H, 4000-H, 6000-H), 7.59 (dd, 3JZ8.1, 8.0 Hz, 1H, 70-H), 7.84
(dd, 3JZ8.1 Hz, 4JZ0.8 Hz, 1H, 80-H), 12.99 (s, 1H, OH);
13C NMR (50 MHz, CDCl3) d 34.98 (t, C-4), 45.49 (t, C-200),
52.88 (q, 1-OCH3), 55.81/56.82 (2!q, 50-OCH3,
2000-OCH3), 106.06 (d, C-2), 108.12 (d, C-60), 110.83 (d,
C-80), 111.14 (s, C-20), 113.52 (s, C-4a0), 113.70 0(00d, C-3000),
120.97 (d, C-5000), 122.97 (s, C-30), 124.70 (s, C-1 ), 126.80
(s, C-8a0), 128.74 (d, 0C-4000), 130.70 (d, C-70), 131.64 (0d,
C-6000), 144.64 (s, C-4 ), 151.02 (s, C-10), 157.97 (s, C-5 ),
159.35 (s, C-2000), 159.66 (s, C-1), 169.74 (s, C-3), 201.69 (s,
CO).
143.65 (s, C-5), 157.28 (s, C-7), 159.39 (s, C-4), 160.86 (s,
C-12a), 161.49 (s, C-20), 179.40 (s, C-6), 181.79 (s, C-11),
199.85 (s, 5-CO); MS (EI, 70 eV) m/z (%) 458 (100) [MC],
400 (78) [MCKC3H6O], 383 (52) [MCKC3H6O–OH], 372
(81) [MCKC3H6O–CO], 355 (55) [MCKC3H6-
O–CO–OH], 121 (49) [C7H6OCHC3 ], 57 (38) [C3H5OC],
43 (37) [CH3COC]; HR MS calculated for C26H18O8:
458.10017. Found: 458.10015.
3.1.15. 7-Hydroxy-5-(2-hydroxybenzoyl)-2,2-dimethyl-
4H-anthra[2,3-d][1,3]dioxin-4,6,11-trione (21). A solu-
tion of the monomethoxyanthraquinone 20 (16 mg,
0.035 mmol) was treated by portion-wise addition of
5 equiv of boron tribromide. The reaction was monitored
by TLC and worked up as described above before the entire
amount of starting material was consumed. The crude
product was purified by preparative TLC on silica gel
(1 mm) to yield the bisphenol 21 (3 mg, 20%, mp 94 8C) as
an orange-red solid: 1H NMR (500 MHz, CDCl3) d 1.84 (s,
3.1.13. Methyl 3-hydroxy-4-{5-methoxy-3-[2-(2-
methoxyphenyl)-acetyl]-1,4-dioxo-1,4-dihydronaphtha-
len-2-yl}-but-2-enoate (19). A solution of the hydro-
quinone 18 (60 mg, 0.13 mmol) in acetonitrile (3 ml) was
treated with a solution of CAN (145 mg, 0.27 mmol) in
water (1 ml) and the mixture was stirred for 15 min at 20 8C.
The reaction was quenched by addition of CH2Cl2 (25 ml)
and water (25 ml) and the aqueous phase was extracted with
CH2Cl2 (2!25 ml). The combined organic phase was dried
(Na2SO4), the solvent evaporated at reduced pressure, and
the residue purified by column chromatography on silica gel
(CH2Cl2/MeOH 99:1) to afford the naphthoquinone 19
(54 mg, 91%) as orange needles: 1H NMR (200 MHz,
CDCl3) d 3.53 (s, 3H, 1-OCH3), 3.72 (s, 2000OCH3), 3.79–
3.90 (m, 4H, 4-H, 200-H), 3.97 (s, 50-OCH3), 4.62 (s, 1H,
2-H), 6.76–6.86 (m, 2H, 3000-H, 5000-H), 7.13–7.40 (m, 3H,
3
6H, 2!2-CH3), 6.73 (dd, JZ8.0, 7.6 Hz, 1H, 50-H), 6.97
3
3
(d, JZ8.0 Hz, 1H, 60-H), 7.15 (d, JZ8.5 Hz, 1H, 8-H),
3
3
7.34 (d, JZ8.4 Hz, 1H, 30-H), 7.48 (dd, JZ8.4, 7.6 Hz,
1H, 40-H), 7.75 (d, 3JZ8.5, 8.2 Hz, 1H, 9-H), 8.01 (d,
3JZ8.2 Hz, 1H, 10-H), 8.08 (s, 1H, 12-H), 11.94 (s, 1H,
20-OH), 12.61 (s, 1H, 7-OH); MS (EI, 70 eV) m/z (%) 444
(14) [MC], 386 (9) [MCKC3H6O], 358 (19) [MCK
C3H6O–CO], 330 (7) [MCKC3H6O–CO–CO], 257 (8),
236 (8), 149 (17), 97 (41), 69 (58), 57 (84) [C3H5OC], 43
(100) [CH3COC]; HR MS calculated for C25H16O8:
444.08452 Found: 444.08427.
3
600-H, 700-H, 800-H), 7.69 (dd, JZ8.1, 7.9 Hz, 1H, 4000-H),
3
7.93 (d, JZ6.6 Hz, 1H, 6000-H); 13C NMR (50 MHz,
CDCl3) d 32.73 (t, C-4), 46.01 (t, C-200), 52.27 (q,
1-OCH3), 56.01/56.13 (2!q, 50-OCH3, 2000-OCH3), 102.07
(d, C-2), 113.76 (d, C-3000), 119.57 (s, C-1000), 120.07 (d,
C-5000), 121.420(00d, C-80), 121.74 (d C-4a0), 129.57 (d, C-4000),
132.170(d, C-6 ), 133.98 (s, C-8a0), 135.95 (d, C-70), 137.59
(s, C-2 ), 148.72 (s, C-30), 150.38 (s, C-1), 170.43 (s, C-3),
183.23/184.27 (2!s, C-10, C-40), 200.34 (s, C-100).
References and notes
1. Vertesy, L.; Kurz, M.; Paulus, E. F.; Schummer, D.;
Hammann, P. J. Antibiot. 2001, 54, 354–363.
2. Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H.-G. J. Org.
Chem. 2002, 67, 9248–9256.
3.1.14. 5-(2-Hydroxybenzoyl)-7-methoxy-2,2-dimethyl-
4H-anthra[2,3-d][1,3]dioxin-4,6,11-trione (20). A solu-
tion of the dimethoxyanthraquinone 16 (18 mg, 0.04 mmol)
in dry CH2Cl2 (3 ml) was treated with a solution of boron
tribromide (1.0 M in CH2Cl2, 114 ml, 0.12 mmol). After
stirring for 3 h at room temperature, 1 M HCl (5 ml) was
added and the mixture was extracted with CH2Cl2 (2!
10 ml). The combined organic phase was dried (Na2SO4),
the solvent evaporated at reduced pressure, and the residue
purified by column chromatography on silica gel (CH2Cl2)
to yield the monomethoxyanthraquinone 20 (16 mg, 95%)
as a yellow solid: 1H NMR (500 MHz, CDCl3) d 1.81 (s, 6H,
2!2-CH3), 3.95 (s, 3H, 7-OCH3), 6.70 (ddd, 3JZ7.9,
3. Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H.-G. Tetra-
hedron 2003, 59, 3201–3217.
4. Hauser, F. M.; Prasanna, S. J. Org. Chem. 1979, 44,
2596–2598.
5. Matsumoto, T.; Hosoya, T.; Katsuki, T.; Suzuki, K.
Tetrahedron Lett. 1991, 32, 6735–6736.
¨ ¨
6. Krohn, K.; Boker, N.; Gauhier, A.; Schafer, G.; Werner, F.
J. Prakt. Chem. 1996, 338, 349–354.
7. Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzmann,
S. W.; Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.;
Daffner, M.; Stevens, J. E. J. Org. Chem. 1991, 56, 91–95.
8. Uno, K.; Nagamachi, Y.; Honda, E.; Matsumoto, A.; Ono, N.
Chem. Lett. 2000, 1014–1015.
4
7.7 Hz, JZ0.6 Hz, 1H, 50-H), 6.98 (dd, 3JZ7.9 Hz,
9. Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556.
10. Krohn, K.; Ballwanz, F.; Baltus, W. Liebigs Ann. Chem. 1993,
911–913.
3
4JZ1.6 Hz, 1H, 60-H), 7.12 (d, JZ8.3 Hz, 1H, 8-H), 7.37
3
(d, JZ8.4 Hz, 1H, 30-H), 7.42 (ddd, 3JZ8.4, 7.7 Hz,
4JZ1.6 Hz, 1H, 40-H), 7.76 (dd, 3JZ8.3, 7.8 Hz, 1H, 9-H),
7.96 (d, 3JZ7.8 Hz, 1H, 10-H), 8.00 (s, 1H, 12-H), 11.61 (s,
1H, OH); 13C NMR (50 MHz, CDCl3) d 25.79/26.05 (2!q,
2!2-CH3), 56.68 (q, 7-OCH3), 107.24 (s, C-2), 116.20 (s,
C-10), 116.91 (d, C-12), 118.41 0(d, C-8), 118.75 (d, C-10),
119.03 (d, C-30), 119.86 (d, C-5 ), 120.96 (s, C-4a), 121.34
(s, C-6a), 128.77 (s, C-10a), 129.55 (d, C-40), 134.66 (s,
C-11a), 135.21 (d, C-9), 135.55 (d, C-60), 138.87 (s, C-5a),
11. Krohn, K. Eur. J. Org. Chem. 2002, 8, 1351–1362.
¨
12. Dai, J.; Krohn, K.; Gehle, D.; Kock, I.; Florke, U.; Aust, H.-J.;
Draeger, S.; Schulz, B.; Rheinheimer, J., Eur. J. Org. Chem.
2005, 4009–4016.
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