Synthesis of toxyloxanthone B

Article abstract of DOI:10.1016/j.tet.2013.12.055

A synthesis of the naturally occurring xanthone toxyloxanthone B is described, in which the key step is the regioselective addition of a methyl salicylate to a substituted benzyne, followed by cyclization of the intermediate aryl anion to form the xanthon

Full text of DOI:10.1016/j.tet.2013.12.055

Tetrahedron 70 (2014) 1283e1288
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Tetrahedron
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Synthesis of toxyloxanthone B
,
Daniele Giallombardo a b, Adam C. Nevin a, William Lewis a, Christopher C. Nawrat a,
,
Russell R.A. Kitson a, Christopher J. Moody a
*
a School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
b Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Sezione di chimica farmaceutica e biologica, Via Archirafi 32,
90123 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 October 2013
Received in revised form 4 December 2013
Accepted 20 December 2013
Available online 8 January 2014
A synthesis of the naturally occurring xanthone toxyloxanthone B is described, in which the key step is
the regioselective addition of a methyl salicylate to a substituted benzyne, followed by cyclization of the
intermediate aryl anion to form the xanthone, the regiochemistry of the aryne addition being confirmed
by X-ray crystallography. Subsequent introduction of the pyran ring by [3,3]-rearrangement and de-
protection completed the synthesis.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Xanthones
Oxygen heterocycle
Benzyne addition
Claisen rearrangement
1. Introduction
derived side chains.3e5 Indeed it was prenylated xanthones such
as
a
-mangostin 1, rubraxanthone 2, and toxyloxanthone B 3a (Fig.1)
-Mangostin 1, from Garcinia man-
Xanthones are widely distributed in Nature, occurring in a wide
range of organisms from bacteria to higher plants.1 Not only are
xanthones highly colored (Greek xanthos¼yellow), they are also
endowed with significant biological activity. Plants and trees of the
Garcinia genus are a particularly rich source of bioactive xanthones,
and recently isolated examples possess activity against platelet
that attracted our attention.
a
gostana, is a potent inhibitor of sphingomyelinase,7,8 whereas
rubraxanthone 2, isolated from various members of the Garcinia
genus,9,10 has a range of biological properties.11,12 The cytotoxic
xanthone toxyloxanthone B 3a on the other hand is not Garcinia-
derived being originally isolated from Maclura pomifera and Toxylon
pomiferum,13e16 and subsequently from the Hypericum genus, in-
cluding Hypericum perforatum (St John’s Wort).17,18 Surprisingly,
aggregation,2
a
-glucosidases,3 cancer,4 and MRSA.5,6 In higher
plants, xanthones are of mixed polyketide and shikimic acid bio-
synthetic origin, with many examples also possessing isoprene-
despite their relative structural simplicity, a-mangostin 1 is the only
Fig. 1. Some naturally occurring prenylated xanthones.
one of the three compounds to be synthesized.8 We now report the
synthesis of toxyloxanthone 3 that not only constitutes the first
synthesis of the natural material, but also, as far as we are aware,
* Corresponding author. Fax: þ44 115 951 3564; e-mail address: c.j.moody@
nottingham.ac.uk (C.J. Moody).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.055

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D. Giallombardo et al. / Tetrahedron 70 (2014) 1283e1288
illustrates the first use of the aryne-based methodology developed
THF in the presence of the methyl salicylate 4 as described by
Larock and co-workers gave the desired xanthone 9, but in 1:1
admixture with the ortho-aryloxy benzoate 10 (Scheme 2). Rea-
soning that the only source of protonation of the intermediate aryl
anion was the salicylate 4 itself, a change in conditions involving
the addition of sodium hydride for prior deprotonation of the
phenol resulted in an improved yield (40%) of the desired xanthone
9, although the benzoate 10 was still formed (30%). As expected, the
nucleophilic addition to the unsymmetrical benzyne derived from
triflate 5 was highly regioselective resulting in the formation of the
1,3,6-tribenzyloxyxanthone 9. The alternative regioisomer, the
2,4,6-tribenzyloxyxanthone, that would result from attack on the
other aryne carbon was not observed. In terms of obtaining quan-
tities of xanthone 9, the formation of benzoate 10 was in-
consequential since ester hydrolysis and cyclization onto the
electron rich aromatic ring in the presence of trifluoroacetic acid
anhydride provided further material.
by Larock19,20 in the synthesis of bioactive natural products.
2. Results and discussion
The toxyloxanthones were first isolated from M. pomifera,13 al-
though the originally assigned structure of toxyloxanthone B was
corrected some two years later. Specifically, the position of the two
methyl groups at C-3 was confirmed by NMR spectroscopy,14 and
subsequently confirmed by an unambiguous synthesis of the tri-
methyl ether 3b,15,16 although the natural product itself has not
been synthesized. In common with many other routes to xan-
thones, the synthesis of toxyloxanthone B trimethyl ether 3b was
achieved in a classical sense by way of a suitably substituted ben-
zophenone,16 but we were attracted by the more contemporary
aryne-based method introduced by Larock.19,20 There has been
a recent resurgence in interest in aryne chemistry, and their ap-
plication in natural product synthesis is extremely topical.21e23 The
Larock method involves the nucleophilic addition of the hydroxy
group of a methyl salicylate to a benzyne followed by cyclization of
the resulting aryl anion onto the methyl ester (Scheme 1). In the
case of toxyloxanthone B 3a, the required coupling partners would
be the methyl salicylate 4 and the ortho-trimethylsilyl triflate aryne
precursor 5, with benzyl protecting groups chosen for the three
phenolic hydroxy groups, with the remaining phenol in 4 orthog-
onally protected as its MOM-ether. The substituted benzyne de-
rived from precursor 5 is unsymmetrical and therefore could lead
to two nucleophilic addition products. However, Stoltz and co-
workers have previously shown that the aryne derived from 5
undergoes regioselective attack as indicated in Scheme 1,24 and
therefore we were confident that the correct xanthone would result
from our projected coupling reaction.
With the xanthone 9 available in quantity, the MOM-ether was
cleaved under acidic conditions, and the resulting phenol 11 was
Scheme 1. Larock benzyne-based route to xanthones, and the proposed precursors to
toxyloxanthone B.
The methyl salicylate
4 was obtained from methyl 2,4-
hydroxybenzoate 6 by selective protection of the non-hydrogen
bonded phenol to give salicylate 7. Subsequent Elbs persulfate ox-
idation25 gave the hydroquinone 8 albeit in poor yield, although the
64% recovery of starting material 7 rendered the process viable.
Selective protection of the non-hydrogen bonded phenol as its
MOM-ether gave the required methyl salicylate 4 (Scheme 2). The
aryne precursor 5 was prepared from phloroglucinol as described
by Stoltz and co-workers,24 setting the stage for the key step.
Generation of the aryne from the triflate 5 with cesium fluoride in
Scheme 2. Reagents and conditions: (a) BnBr, K2CO3, acetone, rt (82%); (b) K2S2O8,
NaOH, water, rt (15%þ64% recovered 7); (c) MOMCl, i-Pr2NEt, CH2Cl2, rt (70%); (d) NaH,
CsF, THF, 65 ꢀC (40%þ30% 10); (e) LiOH, MeOH, aq THF, then TFAA, CH2Cl2, rt (99%); (f)
TFA, CH2Cl2, rt (94%); (g) MgBr2, toluene, reflux (10%); (h) HCCCMe2Cl, KI, K2CO3, ac-
etone, reflux (75%); (i) toluene, reflux (100%); (j) BCl3 (1 M in hexane), pentam-
ethylbenzene, CH2Cl2, ꢁ78 ꢀC, then rt (64%).

D. Giallombardo et al. / Tetrahedron 70 (2014) 1283e1288
1285
further deprotected by selective removal of the benzyl group peri-
to the carbonyl by treatment with magnesium bromide in boiling
toluene. The structure of the resulting phenol 12 was confirmed by
X-ray crystallography (Fig. 2), providing unambiguous evidence for
the regiochemistry of the aryne addition. Alkylation of phenol 11
with 3-chloro-3-methylbutyne gave the propargyl ether 13 in good
yield. Claisen rearrangement under mild conditions26 resulted in
formation of the fused pyran ring to give protected toxyloxanthone
14 in quantitative yield (Scheme 2). The final step required the
removal of three benzyl protecting groups, and although this could
not be carried out under catalytic transfer hydrogenation with
ammonium formate as hydrogen donor,27 treatment with boron
trichloride in dichloromethane in the presence of pentam-
ethylbenzene28 at ꢁ78 ꢀC initially removed two of the benzyl
groups. For full deprotection, the reaction mixture required
warming to room temperature with extra boron trichloride, which
pleasingly gave the xanthone 3a (toxyloxanthone) in 64% yield.
shifts are quoted in parts per million (ppm), and are referenced to
residual H in the deuterated solvent as the internal standard.
Coupling constants, J, are quoted in hertz (Hz). In the 13C NMR
spectra, signals corresponding to CH, CH2, or CH3 groups are
assigned from DEPT. Mass spectra were recorded on a time-of-flight
mass spectrometer using electrospray ionization (ESI), or an EI
magnetic sector instrument.
3.2. 3,5-Dibenzyloxy-2-trimethylsilylphenyl trifluoromethane
sulfonate 5
The title compound was prepared by the method of Stoltz and
co-workers.24
3.3. Methyl 4-benzyloxy-2-hydroxybenzoate 7
A
mixture of methyl 2,4-dihydroxybenzoate 6 (4.00 g,
23.8 mmol) and anhydrous potassium carbonate (4.90 g,
35.7 mmol) in acetone (22 mL) was stirred at room temperature for
5 min. Benzyl bromide (2.83 mL, 23.8 mmol) was added dropwise
and the mixture was stirred at 10e15 ꢀC for 3 h. Water (30 mL) and
ethyl acetate (30 mL) were added and the two phases were sepa-
rated. The aqueous phase was extracted with further ethyl acetate
(3ꢂ40 mL). The combined organic layers were washed with brine
(40 mL), dried over MgSO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash column chro-
matography (9:1 light petroleum/ethyl acetate) to give the title
compound (5.06 g, 82%) as a colorlþess solid, mp 103e105 ꢀC (lit.,29
quires 281.0784; nmax (CHCl3)/cmꢁ1 3008, 2956, 1668, 1623, 1583,
1505, 1441, 1382, 1349, 1255, 1183, 1142, 1099, 1014; dH (400 MHz;
DMSO-d6) 10.78 (1H, s), 7.74 (1H, d, J 7.2), 7.47e7.36 (5H, m),
6.64e6.61 (2H, m), 5.18 (2H, s), 3.88 (3H, s); dC (100 MHz; DMSO-d6)
169.8 (C), 164.7 (C), 163.0 (C), 136.8 (C), 131.8 (CH), 128.9 (CH), 128.5
(CH), 128.2 (CH), 108.5 (CH), 105.9 (C), 102.4 (CH), 70.1 (CH2), 52.7
(Me).
Fig. 2. X-ray crystal structure of 3,6-dibenzyloxy-1,7-dihydroxy-9H-xanthen-9-one 12
(with one molecule of chloroform) CCDC number 973933.
The 1H spectroscopic properties of the synthetic material closely
matched those described for the natural product,17,18 although the
13C NMR gave a systematic difference in the chemical shifts of
0.8e1.1 ppm. We assumed that this was due to incorrect calibration
of the original spectrum, and indeed when we re-referenced the
residual acetone peak, a near perfect match to the reported litera-
ture values was observed. Additionally, for further comparison,
toxyloxanthone B 3a was converted into the known trimethyl ether
3b by reaction with dimethyl sulfate, the 1H NMR spectroscopic
data of which were identical with those reported.16 The first syn-
thesis of the naturally occurring xanthone toxyloxanthone B fur-
ther demonstrates the use of arynes in synthesis, and in particular
that the Larock xanthone methodology can be successfully applied
in the synthesis of relatively complex natural products.
þ
mp 103e105 ꢀC). Found: [MþNa ], 281.0781. C15H14NaO4 re-
3. Experimental section
3.1. General information
3.4. Methyl 4-benzyloxy-2,5-dihydroxybenzoate 8
Commercially available reagents were used throughout without
purification unless otherwise stated. All anhydrous solvents were
used as supplied, except tetrahydrofuran and dichloromethane that
were freshly distilled according to standard procedures. Reactions
were routinely carried out under an argon atmosphere unless
otherwise stated, and all glassware was flame-dried before use.
Light petroleum refers to the fraction with bp 40e60 ꢀC. Ether re-
fers to diethyl ether.
Analytical thin layer chromatography was carried out on alu-
minum backed plates coated with silica gel, and visualized under
UV light at 254 and/or 360 nm and/or by chemical staining. Flash
chromatography was carried out using silica gel, with the eluant
specified.
To a stirred mixture of methyl 4-benzyloxy-2-hydroxybenzoate
7 (3.50 g, 13.5 mmol) in an aqueous solution of NaOH (1 M; 135 mL)
at 0 ꢀC was added over 30 min, a solution of potassium persulfate
(7.70 g, 28.5 mmol) in water (135 mL). After stirring for 20 h at room
temperature, the reaction mixture was acidified to pH 4 with
concentrated hydrochloric acid. The mixture was filtered to remove
the unreacted starting material (2.25 g, 64% recovery). Further
concentrated hydrochloric acid (30 mL) was added to the aqueous
phase and the mixture heated to 80 ꢀC for 2 h. After cooling to room
temperature, ethyl acetate (150 mL) was added, and then the
aqueous layer was extracted with further ethyl acetate (3ꢂ200 mL).
The combined organic phases were dried over MgSO4 and
Infrared spectra were recorded using an FT-IR spectrometer over
the range 4000e600 cmꢁ1. NMR spectra were recorded at 400 or
500 MHz (1H frequency, 100 or 125 MHz 13C frequency). Chemical

1286
D. Giallombardo et al. / Tetrahedron 70 (2014) 1283e1288
evaporated to give a dark oil that was purified by column chro-
matography (9:1 light petroleum/ethyl acetate). The product was
crystallized from methanol to give the title compound as a colorless
solid (560 mg, 15%), mp 165e167 ꢀC. Found: [MþNaþ], 297.0716.
5.27 (2H, s), 5.25 (2H, s), 5.14 (2H, s), 3.56 (3H, s); dC (100 MHz;
CDCl3) 174.3 (C), 163.3 (C), 160.7 (C), 159.7 (C), 154.6 (C), 151.6 (C),
143.9 (C), 136.4 (C), 135.9 (C), 135.8 (C), 128.8 (CHꢂ2), 128.6 (CH),
128.4 (CH), 128.3 (CH), 127.7 (CH), 127.6 (CH), 127.2 (CH), 126.8 (CH),
116.6 (C), 113.2 (CH), 107.5 (C), 101.0 (CH), 97.2 (CH), 96.1 (CH2), 94.0
(CH), 71.0 (CH2), 70.8 (CH2), 70.5 (CH2), 56.4 (Me).
þ
C
15H14NaO5 requires 297.0733; nmax (CHCl3)/cmꢁ1 3684, 3555,
3011, 2956, 1669, 1635, 1509, 1440, 1399, 1374, 1276, 1239, 1168,
1082, 1000; dH (400 MHz; DMSO-d6) 10.33 (1H, s), 8.94 (1H, s),
7.50e7.35 (5H, m), 7.18 (1H, s), 6.63 (1H, s), 5.18 (2H, s), 3.86 (3H, s);
dC (100 MHz; DMSO-d6) 170.0 (C), 156.1 (C), 154.2 (C), 140.1 (C),
136.9 (C), 128.9 (CH), 128.4 (CH), 128.2 (CH), 114.4 (CH), 103.7 (C),
102.1 (CH), 70.2 (CH2), 52.6 (Me).
Also formed was methyl 4-benzyloxy-2-(3,5-dibenzyloxy)phe-
noxy-5-methoxymethoxybenzoate 10 (235 mg, 30%), mp 70e71 ꢀC.
3.5. Methyl 4-benzyloxy-2-hydroxy-5-methoxymethoxybenzo
ate 4
þ
Found: [MþNaþ], 629.2125. C37H34NaO8 requires 629.2146; nmax
(CHCl3)/cmꢁ1 3091, 3068, 3009, 1715, 1605, 1509, 1455, 1265, 1155,
1129; dH (400 MHz; CDCl3) 7.73 (1H, s), 7.44e7.28 (15H, m), 6.60
(1H, s), 6.35 (1H, t, J 2.1), 6.12 (2H, d, J 2.1), 5.24 (2H, s), 5.05 (2H, s),
4.97 (4H, s), 3.75 (3H, s), 2.90 (3H, s); dC (100 MHz; CDCl3) 165.0 (C),
160.7 (C), 160.3 (C), 153.6 (C), 151.5 (C), 143.1 (C), 136.7 (C), 135.8 (C),
128.7 (CH), 128.6 (CH), 128.2 (CH), 128.1 (CH), 127.6 (CH), 127.4 (CH),
120.1 (CH), 115.3 (C), 108.0 (CH), 96.9 (CH), 96.5 (CH), 96.1 (CH2),
70.7 (CH2), 70.1 (CH2), 56.5 (Me), 52.0 (Me).
To a solution of methyl 4-benzyloxy-2,5-dihydroxybenzoate 8
(450 mg,1.64 mmol) in dichloromethane (18 mL) at 0 ꢀC, was added
DIPEA (0.51 mL, 2.95 mmol), and after a few minutes, MOMCl
(0.14 mL, 1.8 mmol). The mixture was stirred for 2 h at room tem-
perature. Water (15 mL) was added and the mixture was extracted
with ethyl acetate (3ꢂ15 mL). The combined organic extract was
dried over MgSO4, and evaporated. The residue was purified by
flash column chromatography (9:1 light petroleum/ethyl acetate)
to give the title compound asþa colorless solid (410 mgþ, 70%), mp
103e105 ꢀC. Found: [MþNa ], 341.0994. C17H18NaO6 requires
341.0996; nmax (CHCl3)/cmꢁ1 3154, 3011, 2955, 1668, 1620, 1511,
1497, 1441, 1355, 1259, 1192, 1162, 1097, 1070, 988; dH (400 MHz;
DMSO-d6) 10.58 (1H, s), 7.48e7.37 (6H, m), 6.73 (1H, s), 5.20 (2H, s),
5.09 (2H, s), 3.88 (3H, s), 3.39 (3H, s); dC (100 MHz; DMSO-d6) 169.7
(C), 158.4 (C), 156.3 (C), 139.5 (C), 136.6 (C), 129.0 (CH), 128.6 (CH),
128.3 (CH), 117.8 (CH), 103.9 (C), 102.4 (CH), 96.2 (CH2), 70.5 (CH2),
56.2 (Me), 52.7 (Me).
3.7. 1,3,6-Tribenzyloxy-7-methoxymethoxy-9H-xanthen-9-
one 9 (method 2)
To a solution of methyl 4-benzyloxy-2-(3,5-dibenzyloxy)phe-
noxy-5-methoxymethoxybenzoate 10 (500 mg, 0.83 mmol) in
methanol (14 mL) at 0 ꢀC was added a solution of LiOH (395 mg,
16.5 mmol) in a mixture of THF/water (1:1, 7 mL), and the mixture
was stirred at room temperature for 7 h. The mixture was concen-
trated under reduced pressure, the residue diluted with water (5 mL)
andacidified to pH 6 with hydrochloric acid (2 M), andthen extracted
with ethyl acetate (3ꢂ20 mL). The combined organic extracts were
dried with MgSO4 and concentrated under reduced pressure, to give
the benzoic acid that was used immediately in the next step.
The above acid was taken up in dichloromethane (9 mL) and the
solution cooled to 0 ꢀC. Trifluoroacetic anhydride (0.69 mL,
4.95 mmol) was added slowly and the mixture was stirred for 3 h at
room temperature. After this period, the mixture was concentrated
under reduced pressure and diluted with a saturated solution of
sodium hydrogen carbonate (10 mL). The mixture was extracted
with dichloromethane (3ꢂ15 mL) and the combined organic frac-
tions were dried over MgSO4 and concentrated under reduced
pressure to give the title compound as a light brown solid (465 mg,
99%) that did not require further purification.
3.6. 1,3,6-Tribenzyloxy-7-methoxymethoxy-9H-xanthen-9-
one 9
To
a
solution of methyl 4-benzyloxy-2-hydroxy-5-
(409 mg, 1.28 mmol) in THF
methoxymethoxybenzoate
4
3.8. 7-Hydroxy-1,3,6-tribenzyloxy-9H-xanthen-9-one 11
(15 mL) at room temperature was added sodium hydride ([60%
dispersion in mineral oil] 52 mg, 1.29 mmol) and the mixture was
left to stir for 45 min. The mixture was heated to 65 ꢀC and cesium
fluoride (780 mg, 5.14 mmol) was added, followed by a solution of
3,5-dibenzyloxy-2-trimethylsilylphenyl trifluoromethanesulfonate
5 (720 mg,1.41 mmol) in THF (10 mL), over 30 min. The mixture was
stirred for 24 h at 65 ꢀC, then cooled, diluted with ether (100 mL),
and washed with brine (100 mL). The aqueous layer was extracted
with ethyl acetate (2ꢂ60 mL), the combined organic extracts dried
over MgSO4, filtered, and evaporated. The residue was purified by
flash column chromatography (8:2 light petroleum/ethyl acetate)
to give the title compound as a light brown solid (295 mg, 40%), mp
To
a solution of 1,3,6-tribenzyloxy-7-methoxymethoxy-9H-
xanthen-9-one 9 (380 mg, 0.66 mmol) in anhydrous dichloro-
methane (24 mL) at 0 ꢀC was added trifluoroacetic acid (4 mL), and
the reaction mixture was stirred for 30 min at room temperature.
Saturated aqueous sodium hydrogen carbonate (30 mL) was added
slowly and the mixture extracted with ethyl acetate (3ꢂ30 mL). The
combined organic extracts were washed with saturated brine
(10 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The residual oil was purified by flash column chroma-
tography (7:3 light petroleum/ethyl acetate) to give the title
þ
148e150 ꢀC. Found: [MþHþ], 575.2062. C36H31O7 requires
575.2064; nmax (CHCl3)/cmꢁ1 3068, 3010, 2931, 1715, 1644, 1624,
1606, 1499, 1453, 1438, 1376, 1268, 1182, 1156, 1122, 1076; dH
(400 MHz; CDCl3) 8.00 (1H, s), 7.67 (2H, d, J 7.1), 7.51e7.34 (13H, m),
6.87 (1H, s, H-5), 6.55 (1H, d, J 2.3), 6.50 (1H, d, J 2.3), 5.31 (2H, s),

D. Giallombardo et al. / Tetrahedron 70 (2014) 1283e1288
1287
compound as a colorless solidþ(330 mg, 94%), mp 173e175 ꢀC. Found:
[MþHþ], 531.1814. C34H27O6 requires 531.1802; nmax (CHCl3)/cmꢁ1
3687, 3603, 3011,1630, 1602, 1500,1438,1272,1239,1174,1118,1017;
dH (400 MHz; CDCl3) 7.82 (1H, s), 7.62 (2H, d, J 7.3), 7.48e7.35 (13H,
m), 6.91 (1H, s), 6.54 (1H, s), 6.48 (1H, s), 5.27 (2H, s), 5.24 (2H, s),
5.13 (2H, s); dC (100 MHz; CDCl3) 175.0 (C), 163.5 (C), 160.7 (C), 159.8
(C), 151.2 (C), 150.2 (C), 143.0 (C), 136.3 (C), 135.7 (C), 135.0 (C), 129.0
(CH), 128.9 (CH), 128.8 (CH), 128.7 (CH), 128.4 (CH), 127.9 (CH), 127.8
(CH),127.6 (CH),126.8 (CH),117.0 (C),109.9 (CH), 107.3 (C), 99.6 (CH),
97.1 (CH), 94.0 (CH), 71.6 (CH2), 70.8 (CH2), 70.5 (CH2).
163.2 (C), 160.7 (C), 159.7 (C), 157.4 (C), 152.5 (C), 142.2 (C), 136.4 (C),
136.9 (C), 135.7 (C), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.4 (CH),
128.1 (CH), 127.7 (CH), 127.6 (CH), 127.2 (CH), 126.8 (CH), 119.9 (CH),
116.4 (C),107.6 (C),100.7 (CH), 97.2 (CH), 94.1 (CH), 85.5 (C), 74.9 (C),
74.3 (CH), 70.9 (CH2), 70.8 (CH2), 70.5 (CH2), 29.6 (Me).
3.11. 5,9,11-Tribenzyloxy-3,3-dimethylpyrano[3,2-a]xanthen-
12(3H)-one 14
3.9. 3,6-Dibenzyloxy-1,7-dihydroxy-9H-xanthen-9-one 12
A solution of 7-(2,2-dimethylbut-3-ynyl)-1,3,6-tribenzyloxy-
9H-xanthen-9-one 13 (10 mg, 0.02 mmol) in toluene (2 mL) was
heated under reflux for 2.5 h. The solvent was evaporated and the
residue purified by flash column chromatography (4:1 light pe-
troleum/ethyl acetate) to give the title compound as a colorless solid
(10 mg, 100%), mp 174e175 ꢀC. Found: [MþHþ], 597.2283.
Anhydrous magnesium bromide (118 mg, 0.641 mmol) was
added to 7-hydroxy-1,3,6-tribenzyloxy-9H-xanthen-9-one 11
(68 mg, 0.128 mmol) in toluene (2 mL) and the yellow suspension
was heated to reflux and stirred for 15 h, turning deep red. Hydro-
chloric acid (5 mL) was added, and the aqueous phase was extracted
with ethyl acetate (3ꢂ10 mL). The combined organic extracts were
washed with water (30 mL) and brine (30 mL), dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (2:3 ethyl acetate/light petroleum) to
give the title compound as a pale yellow solid (5 mg,þ10%); mp
173e174 ꢀC. Found: [MþNaþ], 463.1149. C27H20NaO6 requires
463.1200; nmax (CHCl3)/cmꢁ1 3632, 3550, 3071, 3013, 2947, 2890,
2852, 1654, 1614, 1488, 1289, 1174; dH (400 MHz; DMSO-d6) 13.07
(1H, s), 9.87 (1H, s), 7.53e7.56 (10H, m), 7.23e7.21 (2H, m), 6.65 (1H,
d, J 2.2), 6.46 (1H, d, J 2.2), 5.31 (2H, s), 5.25 (2H, s); dC (100 MHz;
DMSO-d6) 179.6 (C),165.2 (C),162.8 (C),157.6 (C),154.7 (C),151.2 (C),
145.2 (C),136.6 (C ꢂ 2),129.0 (CH),128.8 (CH),128.7 (CH),128.6 (CH),
128.43 (CH), 128.40 (CH), 113.3 (C), 108.2 (CH), 103.2 (C), 101.8 (CH),
97.9 (CH), 93.7 (CH), 70.8 (CH2), 70.5 (CH2).
þ
C
39H33O6 requires 597.2272; nmax (CHCl3)/cmꢁ1 3011, 2928, 1701,
1615, 1438, 1378, 1274, 1192, 1166, 1125, 1059, 1016; dH (400 MHz;
CDCl3) 8.14 (1H, d, J 9.8), 7.62 (2H, d, J 7.3), 7.49e7.35 (13H, m), 6.74
(1H, s), 6.48 (1H, d, J 2.1), 6.43 (1H, d, J 2.1), 5.85 (1H, d, J 9.8), 5.30
(4H, s), 5.09 (2H, s),1.53 (6H, s); dC (100 MHz; CDCl3) 176.9 (C),162.9
(C), 160.5 (C), 158.8 (C), 152.3 (C), 151.3 (C), 139.8 (C), 136.6 (C), 136.4
(C), 135.8 (C), 131.8 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.4
(CH), 128.0 (CH), 127.6 (CHꢂ2), 126.9 (CH), 126.7 (CH), 121.6 (CH),
120.9 (C), 111.8 (C), 108.5 (C), 101.1 (CH), 97.3 (CH), 93.5 (CH), 75.3
(C), 70.8 (CH2), 70.7 (CH2), 70.4 (CH2), 27.1 (Me).
3.12. 5,9,11-Trihydroxy-3,3-dimethylpyrano[3,2-a]xanthen-
12(3H)-one (toxyloxanthone B) 3a
3.10. 7-(2,2-Dimethylbut-3-ynyl)-1,3,6-tribenzyloxy-9H-
xanthen-9-one 13
To a stirred solution of 5,9,11-tribenzyloxy-3,3-dimethylpyrano
[3,2-a]xanthen-12(3H)-one 14 (2 mg, 0.005 mmol), and pentam-
ethylbenzene (7 mg, 0.048 mmol) in dry dichloromethane (1 mL) at
ꢁ78 ꢀC was added BCl3 (solution 1.0 M in dichloromethane; 0.03 mL)
dropwise over 10 min. After 30 min at ꢁ78 ꢀC, the reaction mixture
was warmed to room temperature and stirred for 16 h. TLC and MS
analysis showed the presence of the mono-benzylated compound, so
extra BCl3 (solution 1.0 M in dichloromethane; 0.03 mL) was added
and the reaction mixture was stirred for a further 1 h, before being
quenched with a mixture of chloroform and methanol (9:1, 2 mL).
The excess solvent was removed under reduced pressure. The resi-
due was purified by flash chromatography (4:1 light petroleum/ethyl
acetate) to give the title compound as a pale yellow solid (1 mg, 64%),
mp 318e319 ꢀC (lit.,17 mp 304e306 ꢀC). Found: [MþHþ], 327.0864.
Potassium carbonate (82 mg, 0.594 mmol) and potassium iodide
(82 mg, 0.49 mmol) were added to a solution of 7-hydroxy-1,3,6-
tribenzyloxy-9H-xanthen-9-one 11 (150 mg, 0.283 mmol) in ace-
tone (15 mL). 3-Chloro-3-methyl-1-butyne (80
mL, 0.707 mmol)
was added in a single portion and the reaction mixture was heated
to reflux and stirred for 48 h. After cooling, ether (60 mL) was
added, and the ethereal solution was washed with aqueous NaOH
(1 M; 3ꢂ10 mL). The organic layer was dried over MgSO4 and
concentrated under reduced pressure to give a solid. This was pu-
rified by flash column chromatography (8:2 light petroleum/ethyl
acetate) to give the title compounþd as a colorless solid (125 mg, 75%),
þ
C
18H15O6 requires 327.0863; nmax (CHCl3)/cmꢁ1 3691, 3607, 1701,
1602, 1456, 1249, 1028, 850; dH (500 MHz; acetone-d6) 13.38 (1H, s,
11-OH), 9.60 (1H, br s, 5-OH), 9.18 (1H, br s, 9-OH), 8.03 (1H, d, J 10.2,
H-1), 6.82 (1H, s, H-6), 6.34 (1H, d, J 2.1, H-8), 6.21 (1H, d, J 2.1, H-10),
5.94 (1H, d, J 10.2, H-2),1.46 (6H, s, Me-13); dC (125 MHz; acetone-d6)
180.5 (C]O), 165.3 (C-7a), 163.3 (C-11), 157.0 (C-9), 157.0 (C-6a),
155.6 (C-5), 141.3 (C-4a), 129.6 (CH-2), 122.2 (CH-1), 118.0 (C-12b),
103.2 (CH-6), 102.0 (C-11a), 101.6 (C-12a), 97.6 (CH-10), 93.0 (CH-8),
74.9 (C-3), 26.2 (Me-13).
þ
mp 161e163 ꢀC. Found: [MþH ], 597.2287. C39H33O6 requires
597.2272; nmax (CHCl3)/cmꢁ1 3305, 3011, 1645, 1623, 1605, 1498,
1443, 1379, 1270, 1182, 1119, 1048, 1028; dH (400 MHz; CDCl3) 8.28
(1H, s), 7.65 (2H, d, J 7.3), 7.52 (2H, d, J 7.3), 7.46e7.34 (11H, m), 6.89
(1H, s), 6.55 (1H, d, J 1.8), 6.49 (1H, d, J 1.8), 5.28 (2H, s), 5.20 (2H, s),
5.13 (2H, s), 2.57 (1H, s), 1.72 (6H, s); dC (100 MHz; CDCl3) 174.5 (C),

1288
D. Giallombardo et al. / Tetrahedron 70 (2014) 1283e1288
3.13. 5,9,11-Trimethoxy-3,3-dimethylpyrano[3,2-a]xanthen-
12(3H)-one (toxyloxanthone B trimethyl ether) 3b
References and notes
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Found: [MþHþ], 369.1343. C21H21O6 requires 369.1333; nmax
(CHCl3)/cmꢁ1 3156, 2903, 2254, 1795, 1618, 1467, 1383, 1097, 905,
650; dH (500 MHz; acetone-d6) 8.10 (1H, d, J 10.2, H-1), 6.73 (1H, s,
H-6), 6.42 (1H, d, J 2.3, H-8), 6.32 (1H, d, J 2.3, H-10), 5.77 (1H, d, J
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OMe), 1.48 (6H, s, 3-Me); dC (125 MHz; acetone-d6) 177.2 (C), 164.1
(C), 161.8 (C), 158.9 (C), 153.4 (C), 151.6 (C), 139.2 (C), 131.6 (CH),
121.5 (CH), 120.7 (C), 111.2 (CH), 107.9 (C), 98.7 (C), 95.0 (CH), 92.1
(CH), 75.4 (C), 56.3 (OMe), 56.2 (OMe), 55.6 (OMe), 27.1 (Me).
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We thank Professor G. Cirrincione (University of Palermo) for his
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Copies of NMR spectra. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.12.055.