Synthesis of balsaminone a, a naturally occurring pentacyclic dinaphthofuran quinone

Article abstract of DOI:10.1021/jo201395n

A short synthesis of the natural product balsami-none A, a dinaphthofuran quinone, is described. The key steps of the synthesis are base-induced coupling of 1,4-dihydroxy-2-naphthaldehyde with 2,3-dichloronaphthoquinone to give a pentacyclic dinaphthofura

Full text of DOI:10.1021/jo201395n

NOTE
pubs.acs.org/joc
Synthesis of Balsaminone A, a Naturally Occurring Pentacyclic
Dinaphthofuran Quinone
Jalindar Padwal, William Lewis, and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
S Supporting Information
b
ABSTRACT: A short synthesis of the natural product balsami-
none A, a dinaphthofuran quinone, is described. The key steps
of the synthesis are base-induced coupling of 1,4-dihydroxy-2-
naphthaldehyde with 2,3-dichloronaphthoquinone to give a
pentacyclic dinaphthofuran directly, followed by conversion
of the aldehyde into the desired methoxy group via the
corresponding phenol. The synthesis, in which the structure
of a key pentacyclic intermediate is corroborated by X-ray
crystallography, confirms the original structural assignment of
the natural product.
uinones, particularly naphthoquinones, are widespread in
Q
nature1 and are essential for many life processes. Although
quinones, a large group of natural pigments, do contribute to
natural color, their major role is in redox processes. For example,
pyrroloquinoline quinone (PQQ) is a redox cofactor, and the
naphthoquinone phylloquinone (vitamin K1) occurs in green
plants and participates in photosynthetic electron transport.
Other quinone natural products also possess potent biological
activity: for example, adriamycin (doxorubicin) is a front-line
cancer chemotherapy treatment.
Figure 1. Balsaminones A (1a) and B (1b) isolated from the pericarp of
fruit of the I. balsamina L. (Balsaminaceae).
balsaminone A (1a) could be formed from a suitable precursor
4 that itself resulted from reaction of naphthoquinone 2 with an
appropriate 1,4-dihydroxynaphthalene 5, where the R group can
be converted into a methoxy group following the formation of
the pentacyclic system (Scheme 1).
In considering the choice of 1,4-dihydroxynaphthalene start-
ing material 5, ideally a methoxy group or other oxygen-contain-
ing functionality was needed as the 2-substituent, R. A range of
such compounds 5 (R = OMe, OH, OAc, OMs) was prepared,
but all failed to condense with 2,3-dichloronaphthoquinone 2.
Therefore, it was decided to investigate substituents, R, that
possessed different electronic properties, starting with an acetyl
group on the basis that a subsequent BaeyerꢀVilliger reaction
would deliver the required oxygen functionality.
Thus, 2-acetyl-1,4-dihydroxynaphthalene (6), most conveni-
ently prepared by boron trifluoride mediated Fries rearrangement of
1,4-diacetoxynaphthalene,15 was reacted with 2,3-dichloronaphtho-
quinone (2) in pyridine in the presence of potassium carbonate. Pleas-
ingly, this reaction proceeded smoothly and gave the desired penta-
cyclic dinaphthofuran quinone 7 in good yield, the structure of which
was confirmed by X-ray crystallography (Figure 2). Subsequent ben-
zylation gave the corresponding benzyloxy compound 8 (Scheme 2).
In 1998, two unusual dinaphthofuran quinone derivatives
named balsaminone A (1a) and B (1b) were isolated from the
pericarp of fruit of Impatiens balsamina L. (Balsaminaceae)
(garden or rose balsam, sometimes known as touch-me-not) together
with the known compound 2-methoxy-1,4-naphthoquinone.2
The compounds have significant antipruritic activity, and the
aerial parts of the plant have been used for the treatment of
articular rheumatism, bruises, and beri-beri in Chinese traditional
medicine. Balsaminone A was isolated as red needles that
decomposed gradually in air but more rapidly in chloroform
solution. The structure was determined to be 5-hydroxy-6-
methoxydinaphtho[2,3-b:20,10-d]furan-7,12-dione (1a) by a
combination of spectroscopic methods. Balsaminone B was
determined to be the corresponding β-D-glucoside 1b (Figure 1).
Our own interest in quinone natural products dates back to
an early synthesis of coenzyme PQQ3 and more recently to
other families of benzoquinones,4ꢀ9 and we now report the first
synthesis of balsaminone A.
Over a century ago, Liebermann reported that the reaction
of 2,3-dichloro-1,4-naphthoquinone (2) with resorcinol gave
naphthofuran 3.10 The reaction has subsequently been used by
others in routes to substituted naphthoquinones11 and a range of
tetra- and pentacyclic napthoquinone compounds with antic-
ancer activity,12ꢀ14 and therefore it seemed reasonable that
Received: July 6, 2011
Published: August 29, 2011
r
2011 American Chemical Society
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All that remained was to convert the ketone 8 into the
corresponding acetate ester by BaeyerꢀVilliger oxidation. A
number of reagents were tried—m-CPBA with sodium bicarbo-
nate in dichloromethane, sodium percarbonate and hydrogen per-
oxide under acidic and basic conditions, ureaꢀhydrogen per-
oxide adduct (UHP), hydrogen peroxideꢀTFA, UHPꢀTFA,
peracetic acid in acetic acid—but all without success. The reasons
for the lack of reactivity of ketone 8 under BaeyerꢀVilliger
conditions are not clear, although the X-ray structure does
suggest that the ketone is quite hindered. Therefore, the synth-
esis of the presumably less hindered and more reactive aldehyde
was investigated.
2-Bromo-1,4-dimethoxynaphthalene (9) readily underwent
lithiumꢀhalogen exchange, and quenching with DMF gave the
corresponding aldehyde 10 in good yield. Demethylation with
boron tribromide delivered the known dihydroxnaphthalene 11
in excellent yield.16 Condensation with 2,3-dichloronaphthoqui-
none (2) using potassium carbonate and pyridine gave the
desired pentacyclic ring system 12, albeit in disappointing but
unoptimized yield (20ꢀ25%), along with degradation products.
Benzylation gave the benzyloxy compound 13 (Scheme 3). X-ray
crystallographic analysis of compound 13 confirmed the penta-
cyclic quinone structure (Figure 3).
Scheme 1. Liebermann’s Synthesis of Naphthofuran Qui-
none 3 and Our Proposed Synthesis of Balsaminone A
Although the condensation of dihydroxnaphthalene 11 with
2,3-dichloronaphthoquinone (2) was low-yielding, it did allow
for completion of the synthesis by standard functional group
interconversions. Thus, in a sequence of high-yielding steps,
aldehyde 13 underwent BaeyerꢀVilliger/Dakin oxidation with
m-CPBA to give formate ester 14. Hydrolysis and methylation
gave the benzyloxy compound 16, deprotection of which by
hydrogenolysis over Pearlman’s catalyst gave balsaminone A
(1a) (Scheme 3). Finally, balsaminone A was converted into
its acetate 17 to aid comparison with the natural product. A
detailed comparison of the 1H and 13C NMR spectroscopic data
for balsaminone A and its acetate derivative showed that the data
for our synthetic material very closely matched those reported for
the natural product (see the Supporting Information).2
In conclusion, we have completed a short synthesis of the
pentacyclic dinaphthofuroquinone balsaminone A. The synth-
esis, in which the structure of a key pentacyclic intermediate is
corroborated by X-ray crystallography, confirms the original
structural assignment of the natural product.
Scheme 2. Synthesis of 6-Acetyl-5-hydroxydinaphtho[2,3-
b:2010-d]furan-7,12-dione (7)
’ EXPERIMENTAL SECTION
General Experimental Information. Commercially available
reagents were used throughout without further purification unless
otherwise stated. Anhydrous tetrahydrofuran and dichloromethane were
freshly distilled. Light petroleum refers to the fraction of petroleum
boiling between 40 and 60 °C. All reactions were carried out under a
nitrogen or argon atmosphere. Thin-layer chromatography was carried
out using aluminum-backed plates coated with silica gel. The plates were
Figure 2. X-ray crystal structure of 6-acetyl-5-hydroxydinaphtho[2,3-b:2010-d]furan-7,12-dione (7).
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visualized under UV light at 254 nm and/or by vanillin or permanganate
stains. Flash column chromatography was carried out using silica gel
with the eluent specified. Infrared spectra were recorded in the range
4000ꢀ600 cmꢀ1 as solutions in chloroform or as a solid in attenuated
total reflectance (ATR) mode. NMR spectra were recorded NMR
spectra were recorded at the frequencies stated. Chemical shifts are
quoted in ppm and J values in Hz. Chemical shift values are referenced
against residual proton in the deuterated solvents. In the 13C NMR
spectra, signals corresponding to CH, CH2, or CH3 are assigned from
DEPT-90 and -135 spectra; all others are quaternary C. High- and low-
resolution mass spectra were recorded on a time-of-flight spectrometer.
2-Acetyl-1,4-dihydroxynaphthoquinone (6). A stirred mix-
ture of boron trifluorideꢀTHF complex (4 mL) and 1,4-diacetoxy-
naphthalene17 (1.00 g, 4.09 mmol) was heated at 120 °C for 3 h. The
resulting solution was cooled to room temperature, poured into ice-
cooled water (100 mL), and extracted with dichloromethane (3 ꢁ
100 mL). The combined organic layers were washed with water
(100 mL) and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the residue was purified by flash column
chromatography (20% ethyl acetate in light petroleum) to give the title
compound (0.41 g, 50%) as an off-white solid: mp 205ꢀ207 °C (lit.16
mp 202ꢀ204 °C); MS found M ꢀ H+ 201.0551, calcd for C12H10O3 ꢀ
H+ 201.0557; νmax (CHCl3)/cmꢀ1 3691, 3603, 1629, 1604, 1466, 1396,
1325, 1273, 1241, 1066; δH (400 MHz; DMSO) 13.50 (1 H, s), 9.85
(1 H, s, br), 8.30 (1 H, m), 8.12 (1 H, m), 7.71(1 H, m), 7.60 (1 H, m),
7.10 (1 H, s) 2.66 (3 H, s); δC (100 MHz; DMSO) 205.2 (C), 154.7 (C),
145.1 (C), 130.0 (C), 129.8 (CH), 126.9 (CH), 125.5 (C), 124.1 (CH),
122.7 (CH), 113.0 (C), 105.5 (CH), 27.7 (Me).
Scheme 3. Synthesis of 5-Benzyl-6-formyloxydinaphtho[2,3-
b:2010-d]furan-7,12-dione (13) and Its Subsequent Conver-
sion into Balsaminone A
6-Acetyl-5-hydroxydinaphtho[2,3-b:20,10-d]furan-7,12-
dione (7). A mixture of 2,3-dichloro-1,4-naphthoquinone 2 (0.10 g,
0.44 mmol), 2-acetyl-1,4-dihydronaphthalene 6 (0.13 g, 0.66 mmol),
and potassium carbonate (0.60 g, 4.40 mmol) in pyridine (10 mL) was
heated to 90 °C for 16 h. The reaction mixture was cooled to room
temperature, ice-cooled water (50 mL) was added, and the mixture was
extracted with dichloromethane (100 mL). The organic layer was
washed with hydrochloric acid solution (2 M; 2 ꢁ 100 mL) and brine
(100 mL), dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography (20% ethyl
acetate in light petroleum) to give the title compound (0.11 g, 73%) as a
red solid: mp 248ꢀ250 °C; found M + H+ 357.0746, calcd for C22H12O5
+ H+ 357.0757, M + Na+ 379.0570, C22H12O5 + Na+ 379.0577; νmax
(CHCl3)/cmꢀ1 3691, 3011, 1671, 1596, 1545, 1466, 1352, 1253, 1061;
λmax (MeOH)/nm 292 (log ε 3.87), 452 (3.43); δH (400 MHz; CDCl3)
Figure 3. X-ray crystal structure of 5-benzyl-6-formyloxydinaphtho[2,3-b:2010-d]furan-7,12-dione (13).
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13.03 (1 H, s), 8.55 (1 H, d, J 8.4), 8.45 (1 H, d, J 8.0), 8.30ꢀ8.23 (2 H,
m), 7.88ꢀ7.81 (3 H, m), 7.76ꢀ7.72 (1 H, m), 2.58 (3 H, s); δC (100
MHz; CDCl3) 203.6 (C), 180.8 (C), 174.3 (C), 159.3 (C), 153.0 (C),
148.5 (C), 134.3 (CH), 133.9 (CH), 133.7 (C), 132.1 (C), 131.2 (CH),
128.5 (CH), 127.3 (CH), 126.7 (CH), 126.6 (C), 126.3 (C), 125.8 (C),
124.1 (C), 121.3 (C), 115.9 (C), 109.8 (C), 30.6 (Me). Anal. Found: C,
74.23; H, 3.41. Calcd for C22H12O5: C, 74.16; H, 3.39.
(lit.19 mp 108ꢀ109 °C); found M + Na+ 239.0682, calcd for C13H12O3 +
Na+ 239.0679; νmax (CHCl3)/cmꢀ1 3011, 2939, 2846, 1676, 1623, 1596,
1460, 1371, 1165, 1128; δH (400 MHz; CDCl3) 10.64 (1 H, s) 8.30 (1 H,
m), 8.22 (1 H, m), 7.65 (2 H, m), 7.14 (1 H, s), 4.12 (3 H, s), 4.04 (3 H, s);
δC (100 MHz; CDCl3) 189.6 (CH), 157.1 (C), 152.3 (C), 130.4 (C),
128.9 (CH), 128.6 (C), 127.4 (CH), 124.7 (C), 123.0 (CH), 122.9 (CH),
96.4 (CH), 66.8 (Me), 56.8 (Me); m/z (ESI) 239 (M+, 100%), 183 (32).
Anal. Found: C, 72.09; H, 5.60. Calcd for C13H12O3: C, 72.21, H, 5.59.
1,4-Dihydroxy-2-naphthaldehyde (11). 1,4-Dimethoxy-2-
naphthaldehyde (10; 1.00 g, 4.62 mmol) was dissolved in dry
dichloromethane (70 mL) under an argon atmosphere. The solution
was cooled to ꢀ78 °C and boron tribromide (3.51 mL, 36.99 mmol)
in dry dichloromethane (10 mL) was added dropwise. The reaction
mixture was stirred at ꢀ78 °C for 2 h, warmed to room temperature,
and stirred at room temperature another 16 h. The reaction mixture
was diluted with water (100 mL) and extracted with ethyl acetate (3
ꢁ 100 mL). The combined organic layers were washed with brine
(100 mL), dried over MgSO4, and concentrated in vacuo. The residue
obtained was subjected to flash column chromatography in 20% ethyl
acetate in light petroleum to give the title compound (0.85 g, 98%) as
a greenish yellow solid: mp 202 °C (lit.16 mp 187ꢀ189 °C); found M
+ Na+, 211.0368, calcd for C11H8O3 + Na+ 211.0366; νmax (CHCl3)/
cmꢀ1 3690, 3601, 3011, 1724, 1651, 1606, 1577, 1377, 1320, 1271,
1176, 1122, 1067; δH (400 MHz; DMSO-d6) 11.25 (1 H, s) 10.21 (1
H, s), 9.96 (1 H, s), 8.33 (1 H, d, J 8.0), 8.16 (1 H, d, J 8.0), 7.70 (1 H,
m), 7.62 (1 H m), 7.02 (1 H, s); δC (100 MHz; DMSO-d6) 194.9
(CH), 153.5 (C), 146.4 (C), 129.9 (C), 129.7 (CH), 126.9 (CH),
126.0 (C), 124.2 (CH), 122.8 (CH), 116.1 (C), 104.8 (CH); m/z
(ESI) 188 (M+, 61%), 185 (32), 183 (21), 179 (100), 157 (34). Anal.
Found: C, 69.98; H, 4.26. Calcd for C11H8O3: C, 70.21, H, 4.29.
5-Hydroxy-7,12-dioxo-7,12-dihydrodinaphtho[2,3-b:20,10-
d]furan-6-carbaldehyde (12). A mixture of 1,4-dihydroxy-2-
naphthaldehyde (11; 0.50 g, 2.657 mmol), 2,3-dichloro-1,4-naphtho-
quinone (2; 0.48 g, 2.126 mmol), and potassium carbonate (3.60 g,
26.57 mmol) in anhydrous pyridine (20 mL) was heated at 95 °C under
an argon atmosphere for 16 h. The reaction mixture was cooled, diluted
with iceꢀwater (20 mL), and acidified with hydrochloric acid solution
(2 M). The aqueous layer was extracted with dichloromethane (3 ꢁ
100 mL). The combined organic layers were washed with water
(100 mL), dried (MgSO4), and concentrated in vacuo. The residue
was purified by flash column chromatography in dichloromethane to
give the title compound (0.17 g, 20%) as a bright orange solid: mp
6-Acetyl-5-(benzyloxy)dinaphtho[2,3-b:20,10-d]furan-7,12-
dione (8). To a solution of phenol 7 (0.65 g, 1.82 mmol) in acetone
(50 mL) were added potassium carbonate (0.75 g, 5.47 mmol) and
benzyl bromide (0.93 g, 5.47 mmol). The reaction mixture was heated to
reflux for 4 h with constant stirring. The acetone was removed under
reduced pressure, and the residue was diluted with dichloromethane
(100 mL). The organic layer was washed with water (50 mL) and brine
(50 mL), dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (20% ethyl acetate in light
petroleum) to give the title compound (0.76 g, 94%) as a yellow solid:
mp 192ꢀ194 °C; found M + Na+ 469.1030, calcd for C29H18O5 + Na+
469.1046; νmax (CHCl3)/cmꢀ1 3414, 3011, 1734, 1673, 1556, 1343,
1253, 1059, 993, 953; δH (400 MHz; CDCl3) 8.60 (1 H, m), 8.32ꢀ8.25
(3 H, m), 7.83ꢀ7.74 (4 H, m), 7.58 (2 H, m), 7.51ꢀ7.44 (3 H, m), 5.13
(2 H, s), 2.87 (3 H, s); δC (100 MHz; CDCl3) 202.0 (C), 180.6 (C),
174.6 (C), 153.2 (C), 150.6 (C), 149.6 (C), 136.5 (C), 134.3 (CH),
134.0 (CH), 133.2 (C), 132.3 (C), 128.8 (CH), 128.7 (CH), 128.6
(CH), 128.5 (CH), 128.2 (CH), 127.4 (C), 127.3 (CH), 126.9 (CH),
125.4 (C), 123.8 (CH), 121.9 (CH), 115.0 (C), 79.0 (CH2), 33.0 (Me).
2-Bromo-1,4-dimethoxynaphthalene (9). To a mixture of
2-bromo-1,4-naphthoquinone (4.00 g, 16.88 mmol) in tetrahydrofuran
(50 mL) under an argon atmosphere was added an aqueous solution of
sodium dithionite (11.6 g, 67.51 mmol) in deoxygenated water (50 mL)
with vigorous stirring at room temperature. After 30 min, an aqueous
solution of potassium hydroxide (9.47 g, 168.7 mmol) in water (20 mL)
was added and the resulting reaction mixture was stirred for 1 h.
Dimethyl sulfate (21.3 g, 168.7 mmol) was added, and the reaction
mixture was stirred for another 16 h. To this reaction mixture were
added ammonia (50 mL, 1.5 M) and water (250 mL), and the mixture
was extracted with ethyl acetate (3 ꢁ 100 mL). The organic layers
were combined, washed with hydrochloric acid (2 M; 200 mL) followed
by water (2 ꢁ 200 mL) and brine (100 mL), and dried (MgSO4).
The solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography (eluted with 10% ethyl acetate
in light petroleum) to give the title compound (3.60 g, 80%) as a
colorless solid: mp 54ꢀ56 °C; (lit.18 mp 56ꢀ58 °C); found M + Na+
288.9848, calcd for C12H1179BrO2 + Na+ 288.9835; νmax (CHCl3)/
cmꢀ1 3011, 2938, 2839, 1619, 1583, 1508, 1414, 1364, 1261, 1107; δH
(400 MHz; CDCl3) 8.24 (1 H, m), 8.10 (1 H, m), 7.54ꢀ7.60 (2 H, m),
6.92 (1 H, s), 4.00 (3 H, s), 3.99 (3 H, s); δC (100 MHz; CDCl3) 152.3
(C), 146.8 (C), 129.0 (C), 127.4 (C), 125.8 (CH), 125.8 (C), 122.6
(CH), 121.9 (CH), 111.9 (C), 108.0 (CH), 61.5 (Me), 56.9 (Me); m/z
(ESI) 290 (M+, 19%), 288 (19), 273 (31), 257 (13), 183 (100).
1,4-Dimethoxy-2-naphthaldehyde (10). In a oven-dried round-
bottom flask, a solution of 2-bromo-1,4-dimethoxynaphthalene (9; 3.50 g,
13.10 mmol) in THF (50 mL) was cooled to ꢀ78 °C under argon. n-BuLi
(2.5 M in hexanes; 6.28 mL, 15.72 mmol) was added over 30 min. The
reaction mixture turned orange-red. The reaction mixture was warmed
to ꢀ50 °C over 1 h and cooled to ꢀ78 °C, and dimethylformamide
(5.00 mL, 65.51 mmol) was added over 30 min. The reaction mixture was
stirred at ꢀ78 °C for 2 h and then warmedto ꢀ40 °C. Water (20 mL) was
added, and the mixture was warmed to room temperature. The aqueous
layer was extracted with ethyl acetate (3 ꢁ 50 mL). The combined organic
layers were washed with water (50 mL) followed by brine (50 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by flash
column chromatography (10% ethyl acetate in light petroleum), which
gave the title compound (2.30 g, 82%) as an off-white solid: mp 112 °C
+
302 °C; found M+ 342.0523, calcd for C21H10O5 342.0535; νmax
(CHCl3)/cmꢀ1 3691, 2361, 1724, 1671, 1621, 1599, 1545, 1376, 1350,
1251, 1064, 949; λmax (CHCl3)/nm 273 (log ε 4.48), 285 (4.33), 462
(3.80); δH (500 MHz; CDCl3) 14.80 (1 H, s), 11.53 (1 H, s) 8.64 (1 H,
d, J 8.5), 8.52 (1 H, d, J 8.0), 8.34 (2 H, m), 7.92 (1 H, t, J 8.0), 7.86 (2 H,
m), 7.78 (1 H, t, J 8.0); δC (125 MHz; CDCl3) 199.5 (CH), 180.9 (C),
174.4 (C), 164.1 (C), 153.8 (C), 148.0 (C), 134.4 (CH), 134.2 (CH),
133.4 (C), 132.2 (CH), 132.0 (C), 128.5 (CH), 127.8 (CH), 126.8
(CH), 126.1 (C), 126.0 (C), 125.9 (CH), 124.8 (C), 121.4 (CH), 116.9
(C), 108.0 (C); m/z (EI) 342 (M+, 99%), 315 (23), 314 (100), 286
(15), 258 (46), 230 (26), 202 (21).
5-Benzyloxy-7,12-dioxo-7,12-dihydrodinaphtho[2,3-b:20,10-
d]furan-6-carbaldehyde (13). A mixture of 5-hydroxy-7,12-dioxo-
7,12-dihydrodinaphtho[2,3-b:20,10-d]furan-6-carbaldehyde (12; 0.22 g,
0.643 mmol), benzyl bromide (0.45 g, 3.856 mmol), and potassium
carbonate (0.53 g, 3.85 mmol) in DMF (10 mL) was stirred at room
temperature for 48 h. The reaction mixture was diluted with ice-cold
water (50 mL) and stirred vigorously for 1 h. The solution was filtered,
and the solid was dried and purified by flash column chromatography in
dichloromethane to give the title compound (0.21 g, 78%) as a yellow
solid: mp 252 °C; found M + Na+ 455.0892, calcd for C28H16O5 + Na+
455.0890; νmax (CHCl3)/cmꢀ1 1674, 1595, 1550, 1371, 1340, 1282,
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1244, 1060, 942; λmax (CHCl3)/nm 260 nm (log ε 4.01), 267 (4.14),
284 (4.22), 435 (3.86); δH (400 MHz; CDCl3) 11.14 (1 H, s) 8.56 (1 H,
d, J 8.0), 8.33 (3 H, m), 7.84 (3 H, m), 7.72 (1 H, m), 7.62 (2 H, m), 7.45
(3 H, m), 5.32 (2 H, s); δC (100 MHz; CDCl3) 191.5 (CH), 180.5 (C),
174.6 (C), 155.2 (C), 153.9 (C), 150.4 (C), 136.6 (C), 134.5 (CH),
134.0 (CH), 133.5 (C), 131.9 (C), 130.3 (CH), 129.4 (C), 128.9 (CH),
128.7 (CH), 128.7 (C), 128.6 (CH), 127.7 (CH), 126.7 (CH), 126.2
(C), 125.6 (CH), 123.5 (C), 121.6 (CH), 120.8 (C), 117.1 (C), 79.8
(CH2); m/z (ESI) 455(M+, 39%), 430 (32), 365 (31), 362 (25), 227 (24).
Anal. Found: C, 77.74; H, 3.74. Calcd for C28H16O5: C, 77.77, H, 3.73.
5-Benzyloxy-7,12-dioxo-7,12-dihydrodinaphtho[2,3-b:20,10-
d]furan-6-yl formate (14). To a solution of 5-benzyloxy-7,12-dioxo-
7,12-dihydrodinaphtho[2,3-b:20,10-d]furan-6-carbaldehyde (13; 0.08 g,
0.185 mmol) in dichloromethane (10 mL) was added m-CPBA (0.15 g,
0.925 mmol). The mixture was stirred at room temperature under argon
for 16 h. Saturated aqueous sodium thiosulfate (10 mL) was added, and
the reaction mixture was extracted with dichloromethane (50 mL). The
organic layer was washed with water (50 mL) and brine (50 mL), dried
over MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography in dichloromethane to give the title
compound (0.07 g, 85%) as a yellow-orange solid: mp 255 °C; found
M + Na 471.0839, calcd for C28H16O6 + Na+ 471.0860; νmax (CHCl3)/
cmꢀ1 1745, 1675, 1597, 1552, 1521, 1473, 1346, 1258, 1160, 1131, 1061,
946; λmax (CHCl3)/nm 285 nm (log ε 4.02), 295 (4.19), 343 (3.81), 439
(3.77); δH (400 MHz; CDCl3) 8.63 (1 H, s), 8.54 (1 H, m), 8.27 (3 H,
m), 7.82 (2 H, m), 7.72 (2 H, m), 7.57 (2 H, m), 7.57 (2 H, m), 7.45
(3H, m), 5.26(2H, s);δC (100MHz;CDCl3) 180.0 (C), 174.5 (C), 159.6
(CH), 153.4 (C), 150.3 (C), 145.2 (C), 136.8 (C), 134.3 (CH), 134.0
(CH), 133.4 (C), 132.6 (C), 132.1 (C), 129.5 (C), 128.7 (CH), 128.6
(CH), 128.5 (CH), 128.0 (CH), 127.9 (CH), 127.4 (CH), 126.8 (CH),
125.0 (C), 123.7 (CH), 121.6 (CH), 120.2 (C), 115.6 (C), 76.7 (CH2).
5-Benzyloxy-6-hydroxydinaphtho[2,3-b:20,10-d]furan-7,12-
dione (15). To a solution of 5-benzyloxy-7,12-dioxo-7,12-dihydro-
dinaphtho[2,3-b:20,10-d]furan-6-yl formate (14; 0.01 g, 0.022 mmol) in
methanol (2 mL) was added a solution of potassium hydrogen carbonate
(0.007 g, 0.066 mmol) in water (1 mL) at room temperature with
constant stirring. The reaction mixture was stirred at room temperature
for 6 h. The volatiles were removed under reduced pressure, and the
aqueous layer was extracted with dichloromethane (3 ꢁ 10 mL). The
combined organic layers were washed with brine (10 mL), dried over
MgSO4, and concentrated in vacuo. The residue was subjected to flash
column chromatography in dichloromethane, which gave the title
compound (0.0085 g, 91%) as a dark brown solid: mp 260ꢀ262 °C;
found M + Na+ 443.0890, calcd for C27H16O5 + Na+ 443.0899; νmax
(CHCl3)/cmꢀ1 3691, 3245, 3011, 1674, 1654, 1600, 1558, 1527, 1376,
1341, 1288, 1260, 1058, 1002, 952; δH (500 MHz; CDCl3) 9.75 (1 H, s)
8.40 (1 H, d, J 8.0), 8.35 (2 H, m), 8.23 (1 H, d, J 8.0), 7.88 (2 H, m), 7.63
(3 H, m), 7.54 (1 H, m), 7.44 (2 H, m), 7.36 (1 H, m), 5.34 (2 H, s); δC
(125 MHz; CDCl3) 184.3 (C), 173.7 (C), 152.2 (C), 150.4 (C), 139.3
(C), 137.6 (C), 136.7 (C), 135.6 (CH), 134.2 (CH), 132.9 (C), 132.1
(C), 131.4 (C), 128.5 (CH), 128.5 (CH), 128.4 (CH), 128.1 (CH),
127.6 (CH), 127.6 (CH), 126.6 (C), 125.0 (CH), 122.8 (CH), 121.1
(CH), 116.2 (C), 113.7 (C), 75.0 (CH2).
yellow-orange solid: mp 211ꢀ213 °C; found M + Na+ 457.1066, calcd for
C28H18O5 + Na+ 457.1046; νmax (CHCl3)/cmꢀ1 3690, 3011, 2932, 1674,
1597, 1550, 1516, 1471, 1346, 1256, 1065, 1014; λmax (CHCl3)/nm 354
(log ε 3.53), 369 (3.53), 375 (3.32), 439 (3.61); δH (500 MHz; CDCl3)
8.53 (1 H, m), 8.33 (2 H, m), 8.28 (1 H, m), 7.84 (2 H, m) 7.67 (2 H, m),
7.64 (2H, m), 7.47 (2 H, m), 7.41 (1H, m), 5.32 (2H, s), 4.22 (3 H, s); δC
(125 MHz; CDCl3) 179.9 (C), 174.8 (C), 153.4 (C), 150.8 (C), 145.3
(C), 143.6 (C), 137.4 (C), 134.3 (C), 133.8 (CH), 133.7 (CH), 132.0
(C), 130.2 (C), 128.6 (CH), 128.5 (CH), 128.3 (CH), 127.5 (CH), 126.8
(CH), 126.6 (CH), 125.8 (C), 123.1 (CH), 121.4 (CH), 118.9 (C), 116.2
(C), 76.1 (CH2), 62.6 (Me).
Balsaminone A: 5-Hydroxy-6-methoxydinaphtho[2,3-b:20,10-
d]furan-7,12-dione (1a). 5-Benzyloxy-6-methoxydinaphtho-
[2,3-b:20,10-d]furan-7,12-dione (16; 0.01 g, 0.0115 mmol) was dissolved
in ethyl acetate (10 mL), and Pearlman’s catalyst (0.002 g) was added.
The reaction mixture was flushed with nitrogen followed by hydrogen.
The reaction mixture was stirred for 3 h under a hydrogen atmosphere
and filtered through a Celite pad with exhaustive washing with 5%
methanol in chloroform (100 mL). The filtrate was concentrated under
reduced pressure, and the residue was subjected to silica gel flash column
chromatography in chloroform to give the title compound (0.008 g,
99%) as a red solid: mp 270ꢀ272 °C (lit.2 mp >300 °C); found M + Na+
367.0562, calcd for C21H12O5 + Na+ 367.0577; νmax (KBr)/cmꢀ1 3501,
1673, 1591, 1547, 1513, 1470, 1420, 1215, 1065, 1015, 803; λmax
(MeOH)/nm 224 (log ε 4.74), 267 (5.24), 287 (4.12), 476 (3.40);
δH (500 MHz; CDCl3); 8.50 (1 H, m), 8.36 (1 H, m), 8.32 (2 H, m),
7.83 (2 H, m) 7.70 (2 H, m), 6.39 (1 H, s), 4.10 (3 H, s); δC (125 MHz;
CDCl3) 180.2 (C), 174.7 (C), 153.1 (C), 148.7 (C), 142.8 (C), 134.6
(C), 134.2 (CH), 133.8 (CH), 133.6 (C), 132.2 (C), 127.9 (CH), 127.4
(CH), 127.1 (CH), 126.7 (CH), 125.5 (C), 124.9 (C), 123.0 (CH),
121.2 (CH), 118.8 (C), 114.5 (C), 63.5 (Me).
6-Methoxy-7,12-dioxo-7,12-dihydrodinaphtho[2,3-b:2010-
d]furan-5yl Acetate (17). Balsaminone A (1a; 0.005 g, 0.0145 mmol)
and 4-dimethylaminopyridine (0.004 g, 0.029 mmol) were added to acetic
anhydride (1 mL) at room temperature, and the reaction mixture was
stirred at room temperature for 4 h. The reaction mixture was diluted with
water (5 mL) andextracted with ethyl acetate (3ꢁ 10 mL). The combined
organic layers were washed with hydrochloric acid solution (1 M; 10 mL),
followed by saturated sodium hydrogen carbonate (10 mL) and brine
(10mL). The organic layerwas driedoverMgSO4 and concentrated under
reduced pressure. The residue was purified by flash column chromatogra-
phy in chloroform to give the title compound (0.005 g, 99%) as an
orange-red solid: mp 272ꢀ274 °C; found M + Na+ 409.0687, calcd for
C23H14O6 + Na+ 409.0683; νmax (CHCl3)/cmꢀ1 3011, 2962, 1769, 1676,
1551, 1520, 1258, 1192, 1059, 1014, 820; λmax (CHCl3)/nm 260 (log ε
4.69), 279 (4.57), 289 (4.08), 429 (3.60); δH (500 MHz; CDCl3) 8.55 (1
H, m), 8.32 (2 H, m), 7.92 (1 H, m), 7.84 (2 H, m) 7.71 (2 H, m), 4.11
(3 H, s), 2.58 (3 H, s); δC (125 MHz; CDCl3) 179.5 (C), 174.8 (C), 169.1
(C), 153.4 (C), 152.2 (C), 143.7 (C), 137.2 (C), 134.4 (CH), 133.8
(CH), 133.7 (C), 132.0 (C), 128.9 (CH), 128.6 (C), 127.5 (CH), 127.0
(CH), 126.7 (CH), 125.6 (C), 122.0 (CH), 121.7 (CH), 118.8 (C), 115.4
(C), 63.0 (Me), 20.7 (Me).
5-Benzyloxy-6-methoxydinaphtho[2,3-b:20,10-d]furan-7,12-
dione (16). To a solution of 5-benzyloxy-6-hydroxydinaphtho[2,3-
b:20,10-d]furan-7,12-dione (15; 0.004 g, 0.010 mmol) in acetone (1 mL)
were added potassium carbonate (0.004 g, 0.028 mmol) and iodo-
methane (0.004 g, 0.028 mmol) at room temperature with stirring. The
reaction mixture was heated at 50 °C for 6 h. The volatiles were removed
under reduced pressure, and the residue was diluted with water (10 mL)
and extracted with dichloromethane (10 mL). The organic layer was
washed with brine (10 mL), dried overMgSO4, and concentratedin vacuo.
The residue obtained was purified by flash column chromatography
in dichloromethane to give the title compound (0.004 g, 96%) as a
’ ASSOCIATED CONTENT
Supporting Information. Figures giving 1Hand13C NMR
S
b
spectra and CIF files giving data for the X-ray crystal structures. This
material is available free of charge via the Internet at http://pubs.acs.
org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: c.j.moody@nottingham.ac.uk
8086
dx.doi.org/10.1021/jo201395n |J. Org. Chem. 2011, 76, 8082–8087

The Journal of Organic Chemistry
NOTE
’ ACKNOWLEDGMENT
We thank the University of Nottingham for support.
’ REFERENCES
(1) Thomson, R. H. Naturally Occurring Quinones IV: Recent Ad-
vances, 4th ed.; Blackie: London, 1997.
(2) Ishiguro, K.; Ohira, Y.; Oku, H. J. Nat. Prod. 1998, 61, 1126–1129.
(3) MacKenzie, A. R.; Moody, C. J.; Rees, C. W. J. Chem. Soc., Chem.
Commun. 1983, 1372–1373.
(4) Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J. J. Org. Chem.
2005, 70, 4414–4422.
(5) McErlean, C. S. P.;Moody, C. J.J. Org. Chem. 2007, 72, 10298–10301.
(6) Coombes, C. L.; Moody, C. J. J. Org. Chem. 2008, 73, 6758–6762.
(7) Guillonneau, L.; Taddei, D.; Moody, C. J. Org. Lett. 2008, 10,
4505–4508.
(8) Padwal, J.; Lewis, W.; Moody, C. J. Org. Biomol. Chem. 2011, 9,
3484–3493.
(9) Smith, M. J.; Nawrat, C. C.; Moody, C. J. Org. Lett. 2011, 13,
3396–3398.
(10) Liebermann, C. Chem. Ber. 1899, 32, 916–925.
(11) Tandon, V. K.; Maurya, H. K. Tetrahedron Lett. 2009, 50,
5896–5902.
(12) Sartori, M. F. Chem. Rev. 1963, 63, 279–&.
(13) Cheng, C. C.; Dong, Q.; Liu, D. F.; Luo, Y. L.; Liu, L. F.; Chen,
A. Y.; Yu, C.; Savaraj, N.; Chou, T. C. J. Med. Chem. 1993, 36, 4108–4112.
(14) Lee, K. I.; Park, Y.; Park, S. J.; Hwang, J. H.; Lee, S. J.; Kim,
G. D.; Park, W. K.; Lee, S.; Jeong, D.; Kong, J. Y.; Kang, H. K.; Cho, H.
Bioorg. Med. Chem. Lett. 2006, 16, 737–742.
(15) Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T.
J. Org. Chem. 2000, 65, 4712–4714.
(16) Brimble, M. A.; Elliott, R. J. R. Tetrahedron 1997, 53, 7715–7730.
(17) Fieser, L. F. J. Am. Chem. Soc. 1948, 70, 3165–3174.
(18) Johnson, M. M.; Naidoo, J. M.; Fernandes, M. A.; Mmutlane,
E. M.; van Otterlo, W. A. L.; de Koning, C. B. J. Org. Chem. 2010, 75,
8701–8704.
(19) Nyland, R. L.; Luo, M. H.; Kelley, M. R.; Borch, R. F. J. Med.
Chem. 2010, 53, 1200–1210.
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