Total synthesis of aldehyde-containing Garcinia natural products isomorellin and gaudichaudione A

Article abstract of DOI:10.1016/j.tet.2011.05.029

The natural products, isomorellin and gaudichaudione A, with a 4-oxa-tricyclo[4.3.1.0^3,7] dec-8-en-2-one scaffold were synthesized for the first time using an efficient method. The key improvement of this method was the simultaneous bisalkylation of 5,6-dihydroxyxanthone with the bulky 2-methylbutyne group. This method obviously shortened the synthetic route and enhanced the total yield. Four analogues named forbesione, desoxymorellin, desoxygaudichaudione A, and gambogin containing the same caged structure were prepared using this method.

Full text of DOI:10.1016/j.tet.2011.05.029

Tetrahedron 67 (2011) 4774e4779
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Total synthesis of aldehyde-containing Garcinia natural products isomorellin
and gaudichaudione A
,
z
x
Zong-Liang Liu y, Xiao-Jian Wang y , Nian-Guang Li , Hao-Peng Sun, Jin-Xin Wang, Qi-Dong You
*
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
The natural products, isomorellin and gaudichaudione A, with a 4-oxa-tricyclo[4.3.1.03,7] dec-8-en-2-one
scaffold were synthesized for the first time using an efficient method. The key improvement of this
method was the simultaneous bisalkylation of 5,6-dihydroxyxanthone with the bulky 2-methylbutyne
group. This method obviously shortened the synthetic route and enhanced the total yield. Four ana-
logues named forbesione, desoxymorellin, desoxygaudichaudione A, and gambogin containing the same
caged structure were prepared using this method.
Article history:
Received 12 March 2011
Received in revised form 2 May 2011
Accepted 9 May 2011
Available online 13 May 2011
Keywords:
Total synthesis
Ó 2011 Elsevier Ltd. All rights reserved.
Isomorellin
Gaudichaudione A
Bisalkylation
Claisen/DielseAlder cascade reaction
1. Introduction
forward by Quillinan and Scheinmann.9 Unfortunately, they were
hampered by the O-alkylation of 5,6-dihydroxy groups with bulky
Gamboge, the dried resin collected from tropical trees of the
genus Garcinia, has been used as folk medicine for many years. A lot
of caged xanthones isolated from gamboge, which contain a unique
4-oxa-tricyclo[4.3.1.03,7]dec-2-one scaffold, possess potent anti-
tumor activity against a broad panel of cancer cell lines and draw
much attention of medicinal chemists.1 Gambogic acid is the most
studied compound among cytotoxic caged xanthones, which shows
promising anticancer effects both in vitro and in vivo against a va-
riety of cancer cell lines, such as human breast cancer T47D cells,2
human epatoma SMMC-7721 cells,3,4 human leukemia L-60 and
K562 cells etc.5 Gaudichaudione A6 activates caspase-3 and induced
the apoptosis of Jurkat human leukemic cells. It has notable cyto-
toxicity against parental murine leukemic P388 and P388/DOX-
resistant cells, but is less toxic toward normal human Chang liver
cells.7 Compared gaudichaudiones with gaudichaudiic acids, the
aldehydes show in general stronger cytotoxicity than the acids.6
The unusual 4-oxa-tricyclo[4.3.1.03,7] dec-8-en-2-one scaffold
has caught the attention of synthetic chemists. Over 30 years ago,
an elegant proposal for the biosynthesis of isomorellin8 was put
substituents. Till 2001 the first natural product with the caged
structure, 1-O-methylforbesione, was synthesized by Nicolaou.10
After that, Theodorakis et al. accomplished the total synthesis of
several nature products, such as forbesione and desoxymorellin etc.
in 2002 and 2003.11e13 The total synthesis of gambogin was
reported by Theodorakis in 2004 and Nicolaou in 2005.14,15 Nic-
olaou et al. carried out the bisalkylation of the 5,6-dihydroxyl of
xanthone by using isobutylaldehyde bromide through twice wittig
reaction, however the four-step synthetic route was too long and
the yield was unsatisfied. Meanwhile, Theodorakis substituted
3,5,6-trihydroxyl with 2-chloro-2-methylbutyne simultaneously,
however, the resulted caged compound was not suitable for the
further oxidative modification. To simplify the synthetic route as
well as to improve the yield of the total synthesis, we developed an
efficient alkylation route, which substituted the 5,6-dihydroxyl
with the bulky 2-chloro-2-methylbutyne simultaneously. This
method also enhanced the regioselectivity of the xanthone ring
and led to the synthesis of structurally diverse caged xanthone
compounds.
All the caged xanthones mentioned above contain an iso-
pentene group on the caged ring. Till now there is no report about
the synthesis of the natural products that contain an oxidized
isopentene group on the caged ring. As natural caged xanthones
coupled with an aldehyde group, such as gaudichaudione A always
show potent anti-tumor activity, we think it is worthy to develop an
efficient synthetic method for this series of compounds. Based on
* Corresponding author. Tel.: þ8602583271351; e-mail address: youqidong@
gmail.com (Q.-D. You).
y
These authors contributed equally to this work.
Present address: Institute of Materia Medica, Chinese Academy of Medical
z
Sciences and Peking Union Medical College, 100050, China.
x
Present address: Nanjing University of Chinese Medicine, 210046, China.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.029

Z.-L. Liu et al. / Tetrahedron 67 (2011) 4774e4779
4775
the 5,6-bisalkylation method mentioned above, we successfully
carried out the total synthesis of two aldehyde coupled caged
xanthones named isomorellin and gaudichaudione A. Another four
caged compounds including forbesione, desoxymorellin, desoxy-
gaudichaudione A, and gambogin were also prepared in an obvi-
ously enhanced yield.
the condensation of 2,3,4-trihydroxybenzoic acid and 1,3,5-
trihydroxybenzene.14
Synthetic route of the key intermediate 3 was shown in Scheme 2.
Our synthetic studies commenced with a ZnCl2 mediated conden-
sation of phloroglucinol (6) and 2,3,4-trihydroxybenzoic acid (7) in
POCl3 to producexanthone 5 in 45% yield.14 Identifying the protection
stepisyieldlimiting step for thesyntheticroute, thenwe proposethat
the Ac on 1-hydoxyl of xanthone might have some impact, then tried,
then get better yield. Xanthone 10 was obtained from xanthone 5 via
selective protection of 5,6-dihydroxyl with Ph2CCl2, 3-hydroxyl with
MOMCl (Methyl chloromethyl ether), and 1-hydroxyl with Ac2O in
76% yield over three steps. Xanthone 10 was transformed to 11 via
hydrogenolysis at the presence of Pd/C (95%). With the electron-
withdrawing effect of Ac at 1-hydroxyl, the activities of 5,6-
dihydroxy groups were enhanced. So 5,6-dihydroxy groups were
alkylated simultaneously with 2-chloro-2-methylbutyne in the
2. Results and discussion
We have previously reported a selective protection of xan-
thone.16 Based on the method, we focused our attention on the
synthesis of natural products containing an oxidized isopentene
group on the caged ring, such as isomorellin and gaudichaudione
A. The retrosynthetic analysis was outlined in Scheme 1. In this
route, there is one main problem that needs to be solved: efficient
preparation of the key intermediate 3.
Scheme 1. Retrosynthetic analysis of isomorellin 1.
Scheme 2. Synthetic route of compound 3. Reagents and conditions: (a) ZnCl2, POCl3, 65 ꢀC, 3 h, 45%; (b) Ph2CCl2, DIPEA, Ph2O, 170 ꢀC, 0.5 h, 85%; (c) MOMCl, K2CO3, acetone, 25 ꢀC,
5 h, 95%; (d) Ac2O, DMAP, CH2Cl2, 25 ꢀC, 4 h, 94%; (e) H2, Pd/C, THF/MeOH, 50 ꢀC, 12 h, 95%; (f) (CH3)2CClChCH, KI, K2CO3, CuI, acetone, reflux, 1.5 h, 70%; (g) H2, Pd/BaSO4, EtOH/
EtOAc, 35 ꢀC, 4 h; (h) DMF, 120 ꢀC, 1 h, 65% (over two steps).
Isomorellin (1) would be constructed from compound 2 via
double alkylation, hydrogenation, and regioselective Claisen rear-
rangement. Compound 2 could be obtained from compound 3
via oxidation and selective deprotection of hydroxyl. Through
a sequence of hydrogenation and Claisen/DielseAlder cascade, cage
compound 3 could be generated from bisalkylated xanthone 4,
which was derived from xanthone 5 via a series of protection,
deprotection, and alkylation. Xanthone 5 was easily prepared from
presence of KI and K2CO3 with catalytic amount of CuI in 70% yield. By
contrast, when the 1-hydroxyl group of the xanthone was free or
protected with MOM or Me, our attempts to alkylate 5,6-dihydroxyl
groups under the same conditions were fruitless. We also attemp-
ted to protect 1-hydroxyl with other electron-withdrawing groups,
such as MsCl. Unfortunately, compound 9 could not fully react with
MsCl and the yield was below 60%. Compound 3 was easily formed
from compound 4 via hydrogenolysis atthe presenceofPd/BaSO4 and

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Z.-L. Liu et al. / Tetrahedron 67 (2011) 4774e4779
Claisen/DielseAlder cascade reaction in 65% yield over two steps.
Generally, caged and isocaged compounds would be produced but
isocaged compound was not monitored in our experiments.
hydroxyl and acetic anhydride at 1-hydroxyl in 78% yield over two
steps. The subsequent hydrogenolysis of the three benzyl groups led
to xanthone 20 (95%). Then the next steps were similar to Theodor-
akis’s method.14
With compound 3 in hand, the most important task was the in-
troduction of diverse substituent groups to C2 and C20 to construct
other caged xanthones outlined in Scheme 3. C20 was selectively
oxidized to aldehyde with SeO2 and PCC (pyridinium chlor-
ochromate). Considering that the Ac at 1-hydroxyl was unstable, we
chose the reaction conditions of NaI in acetone with one drop HCl
(2 N) as catalyst to selectively deprotect MOM. Compound 2 was
alkylated with 2-chloro-2-methylbutyne (16) in the presence of KI
and K2CO3 under CuI catalysis to afford compound 14 in 85% yield.
Compound 15 was firstly hydrogenated under Pd/BaSO4 catalysis in
EtOAc and then rearranged in DMF at 120 ꢀC to get compound 16
in 80% yield over two steps. Because the caged structure was un-
stable in basic aqueous solution, Ac at 1-hydroxyl was deprotected
under the reaction conditions of HCl (6 N) in acetone and the yield
was 75%. After compound 17 was obtained, gaudichaudione A (18)
was easily constructed in the same procedure from compound 14 to
15 in 68% yield over three steps. Compound 17 was heated in DMF at
120 ꢀC via Claisen reaction to form isomorellin (1) in 85% yield.
During our research work, we found 1-hydroxyl in xanthone 5
played an important role for the reaction capabilities of 5,6-
dihydroxyl and the regioselectivity of Claisen rearrangement.
Xanthone without 1-hydroxyl would be bialkylated at 5,6-
dihydroxy groups with 1,1-dimethylpropenyl isobutyl carbonate
under Pd(0) catalysis.17 However, the bisalkylation could barely
happen under the same reaction conditions when there existed
1-hydroxyl, no matter it was protected or exposed. As shown in
Scheme 4, the reaction capabilities of 5,6-dihydroxy groups in
compound 11b and 11c were too low to be bialkylated. The yield
of compound 21b was only 25% when 1-hydroxy was exposed.12
Furthermore, compound 4b and 4c were not observed on TLC.
These above results may be explained by the electronic effects of
the C9 carbonyl group and the 1-hydroxyl. The electron-
withdrawing effect of the carbonyl group was increased by the
presence of the 1-o-acetyl but attenuated by the presence of the
1-O-methoxymethyl.
Scheme 3. Synthetic route of isomorellin (1) and gaudichaudione A (18). Reagents and conditions: (a) SeO2, t-BuOOH, DCM, 25 ꢀC, 24 h; (b) PCC, DCM, 25 ꢀC, 2 h, 60% (over two
steps); (c) HCl (2 N), NaI, acetone, 40 ꢀC, 4 h, 75%; (d) (CH3)2CClChCH, KI, K2CO3, CuI, acetone, reflux, 1.5, 85%; (e) H2, Pd/BaSO4, EtOAc, 25 ꢀC, 10 min; (f) DMF, 120 ꢀC, 1 h, 80% (over
two steps); (g) HCl(6 N), acetone, 50 ꢀC, 75%; (h) (CH3)2CClChCH, KI, K2CO3, CuI, acetone, reflux, 1.5, 85%; (i) DMF, 120 ꢀC, 4 h, 85%; (j) H2, Pd/BaSO4, EtOAc, 25 ꢀC, 10 min; (k) DMF,
120 ꢀC, 1 h, 80% (over two steps).
Based on the fact that 1-acetoxyl enhanced the reaction abilities of
5,6-dihydroxyl at xanthone 5, an efficient synthetic route for the
caged xanthone analogues was provided as shown in Supplementary
data. Xanthone 514 was protected with benzyl chloride at 3,5,6-
3. Summary and conclusions
In conclusion, we reported the first total syntheses of iso-
morellin and gaudichaudione A and provided a more efficient

Z.-L. Liu et al. / Tetrahedron 67 (2011) 4774e4779
4777
Scheme 4. Effect of C1 group on alkylation.
synthesis of forbesione, gambogin, desoxygaudichaudione A, and
desoxymorelin. Our strategy highlighted the selective protection
of the different hydroxyls of xanthone to increase the reactivity of
5,6-O-bisalkylation and regioselectivity of Claisen/DielseAlder
cascade reaction. Our exploration of such effects could lead to the
synthesis of other Garcinia natural products as well as designed
analogues.
(d, J¼2.2 Hz, 1H), 7.13 (d, J¼8.5 Hz, 1H), 7.48 (m, 6H), 7.66
(m, 4H), 7.82 (d, J¼8.5 Hz, 1H), 9.83 (s, 1H), 12.99 (s, 1H); EI-MS
(m/z) 424 (M)þ.
4.1.3. 7-Hydroxy-9-(methoxymethoxy)-2,2-diphenyl-6H-[1,3]dioxolo
[4,5-c]xanthen-6-one (9). At room temperature K2CO3 (1.1 g,
8 mmol) was added to the solution of compound 8 (1.70 g,
4 mmol) in acetone (50 mL). After stirred for 15 min, to this mix-
ture was added MOMCl (0.46 mL, 6 mmol). The reaction mixture
was stirred for 6 h and poured into H2O (150 mL). The precipitate
was collected by filtration and washed with water, which was
purified by silica gel column chromatography (petroleum ether/
EtOAc 8:1) to give the compound 9 (1.68 g, 90%) as a white solid:
4. Experimental section
4.1. General
For 1H NMR data the chemical shifts are based on TMS peak at
d
¼0.00 ppm for proton NMR and CDCl3 peak at
d
¼77.00 ppm (t) in
mp 125e127 ꢀC; 1H NMR (300 MHz, CDCl3):
d 3.50 (s, 3H), 5.24
(s, 2H), 6.45 (d, J¼2.2 Hz, 1H), 6.65 (d, J¼2.2 Hz, 1H), 6.97
(d, J¼8.5 Hz, 1H), 7.40 (m, 6H), 7.64 (m, 4H), 7.87 (d, J¼8.5 Hz, 1H),
12.89 (s, 1H); EI-MS (m/z): 468 (M)þ.
carbon NMR. When the middle peak of the triplet is not marked at
d
¼77.00 ppm, it is taken to this value and the subsequent difference
is added or subtracted from all other peaks. HRMS were recorded
using Electrospray Ionization (ESI) using a Time of Flight mass
spectrometer.
4.1.4. 9-(Methoxymethoxy)-6-oxo-2,2-diphenyl-6H-[1,3]dioxolo
[4,5-c]xanthen-7-yl acetate (10). Ac2O (1.7 g, 16.7 mmol) was added
to a solution of compound 9 (6.0 g, 12.8 mmol) and DMAP (2.35 g,
0.193 mmol) in dichlormethane (100 mL). The reaction mixture
was stirred for 0.5 h at room temperature. Another dichlormethane
(100 mL) was added to dilute and the reaction mixture was washed
with H2O (100 mLꢁ3). The organic layer was dried with Na2SO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/EtOAc 4:1) to
give the compound 10 (5.9 g, 91%) as a white solid: mp 192e193 ꢀC;
4.1.1. 1,3,5,6-Tetrahydroxy-9H-xanthen-9-one (5). To
a
round-
bottomed flask containing phloroglucinol (10.0 g, 79.3 mmol),
2,3,4-trihydroxybenzoic acid (13.5 g, 79.3 mmol), and ZnCl2 (70.0 g,
515 mmol) was added POCl3 (150 mL). The reaction mixture was
stirred for 3.5 h at 65 ꢀC under N2. It was then cooled to 25 ꢀC and
poured into a beaker of ice. The reaction mixture was filtered and
the filter cake was washed with saturated NaCl to get the crude
material, which was purified by silica gel column chromatography
(EtOAc) to yield compound 5 (9.1 g, 40%): yellow solid; mp>200 ꢀC;
EI-MS (m/z) 259 (MH)þ.
1H NMR (300 MHz, CDCl3):
d 2.46 (s, 3H), 3.51 (s, 3H), 5.27 (s, 2H),
6.67 (d, J¼2.1 Hz, 1H), 6.94 (d, J¼8.4 Hz, 1H), 7.09(d, J¼2.1 Hz, 1H),
7.26 (m, 6H), 7.41 (m, 4H), 7.87 (d, J¼8.4 Hz, 1H); EI-MS (m/z):
510 (M)þ.
4.1.2. 7,9-Dihydroxy-2,2-diphenyl-6H-[1,3]dioxolo[4,5-c]xanthen-
6-one (8). Compound
5 (0.13 g, 0.5 mmol) was added to
diphenyl ether (10 mL) and then dichlorodiphenylmethane
(0.18 g, 0.75 mmol) was added. The reaction mixture was heated
to 175 ꢀC for 0.5 h under N2. The reaction mixture was cooled to
room temperature and poured into petroleum ether (100 mL).
The precipitate was collected by filtration and washed with
petroleum ether, which was purified by silica gel column chro-
matography (petroleum ether/EtOAc 8:1). Compound 8 (0.18 g,
85%) was obtained: light yellow solid; mp: 212e214 ꢀC; 1H
4.1.5. 5,6-Dihydroxy-3-(methoxymethoxy)-9-oxo-9H-xanthen-1-yl
acetate (11). To a solution of compound 10 (5.9 g, 11.6 mmol)
in THF/MeOH (40 mL/40 mL) was added 10% Pd/C (0.59 g).
The reaction mixture was stirred at 50 ꢀC under an atmosphere of
hydrogen overnight. The reaction mixture was filtered and con-
centrated under reduced pressure. The residue was pulped with
petroleum ether/EtOAc (50 mL/10 mL) and filtered to give the
compound 11 (3.6 g, 90%) as white solid: mp 149e151 ꢀC; 1H NMR
NMR (300 MHz, CD3COCD3):
d
6.26 (d, J¼2.2 Hz, 1H), 6.46
(300 MHz, CDCl3): d 2.50 (s, 3H), 3.51 (s, 3H), 5.22 (s, 2H), 6.65

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Z.-L. Liu et al. / Tetrahedron 67 (2011) 4774e4779
(d, J¼2.4 Hz, 1H), 6.86 (d, J¼9 Hz, 1H), 6.94 (d, J¼2.4 Hz, 1H) 7.64
(d, J¼9 Hz, 1H); EI-MS (m/z): 346 (M)þ.
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (petro-
leum ether/EtOAc 4:1) to give the compound 2 (41 mg, 75%) as
4.1.6. 3-(Methoxymethoxy)-5,6-bis(2-methylbut-3-yn-2-yloxy)-
9-oxo-9H-xanthen-1-yl acetate (4). To a solution of xanthone 11
(0.55 g, 1.6 mmol) in dried acetone (5 mL) was added KI (0.79 g,
4.8 mmol), K2CO3 (0.66 g, 4.8 mmol), CuI (0.03 g, 0.16 mmol), and
2-chloro-2-methylbut-3-yne (1.6 g, 16 mmol). The reaction mix-
ture was heated at reflux for 1.5 h under nitrogen. It was then
cooled to 25 ꢀC and filtered. The filtration was concentrated and
the residue was purified by silica gel column chromatography
(petroleum ether/EtOAc 8:1) to give the compound 4 (0.56 g,
70%) as a light yellow solid: mp 133e136 ꢀC; 1H NMR (300 MHz,
a yellow oil; 1H NMR (300 MHz, CDCl3):
d 1.28e1.35 (m, 7H), 1.71
(s, 3H), 2.30e2.37 (m, 4H), 2.78e2.86 (m, 2H), 2.82 (dd, 1H, J¼16.0,
5.6 Hz), 3.48e3.51 (m, 1H), 6.21 (d, 1H, J¼2.2 Hz), 6.25 (d, 1H,
J¼2.2 Hz), 6.60e6.65 (m, 1H), 7.45 (d, 1H, J¼6.9 Hz), 8.67 (br, 1H),
9.26 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 8.8, 21.1, 25.0, 28.9, 28.9,
30.0, 46.6, 48.7, 62.2, 83.4, 84.3, 91.0, 101.8, 106.6,134.5, 135.6, 139.9,
149.1, 152.66, 162.0, 164.4, 169.7, 173.6, 196.1, 202.7; m/z (ESI): 451
MꢂHþ; HRMS(ESI-TOF) found 451.1399 (calcd for C25H24O8ꢂHþ
451.1393).
CDCl3):
d
1.75 (s, INS> 6H), 1.80 (s, 6H), 2.34(s, 1H), 2.48(s, 3H),
4.1.10. Caged xanthone (14). To a solution of xanthone 2
2.64 (s, 1H), 3.51 (s, 3H), 5.26 (s, 2H), 6.69 (d, J¼2.1 Hz, 1H), 7.03
(d, J¼2.1 Hz, 1H), 7.57 (d, J¼9 Hz, 1H), 7.93 (d, J¼9 Hz, 1H); ESI-MS
(m/z): 479 MþHþ.
(20 mg, 0.044 mmol) in dried acetone (3 mL) was added KI
(14.7 mg, 0.088 mmol), K2CO3 (12.1 mg, 0.088 mmol), and CuI
(0.88 mg, 0.0044 mmol). Then 2-chloro-2-methylbut-3-yne
(9.02 mg, 0.088 mmol) was added, and the reaction mixture was
heated to reflux for half hour. The reaction was then cooled to
25 ꢀC and filtered. The filtration was concentrated and the residue
was purified by silica gel column chromatography (petroleum
ether/EtOAc 8:1) to give the compound 14 (22 mg, 85%) as a light
4.1.7. Caged xanthone (3). To a solution of xanthone 4 (0.22 g,
0.46 mmol) in alcohol (10 mL) was added 10% Pd/BaSO4 (22 mg).
The reaction mixture was degassed using hydrogen and stirred
under an atmosphere of hydrogen for 0.5 h at room temperature.
The reaction mixture was filtered and concentrated under re-
duced pressure. The residue need not be purified and dissolved in
DMF (5 mL). The solution was heated at 120 ꢀC for 1 h under N2.
DMF was removed under reduced pressure and the residue was
purified by silica gel column chromatography (petroleum ether/
EtOAc 8:1) to give the compound 4 (0.14 g, 65%) as a yellow solid:
yellow oil: 1H NMR (300 MHz, CDCl3):
d 1.21 (s, 3H), 1.25e1.31
(m, 4H), 1.64e1.71 (s, 9H), 2.23e2.30 (m, 4H), 2.46 (d, 1H,
J¼9.6 Hz), 2.57e2.74 (m, 3H), 3.45 (m, 1H), 6.33e6.37 (m, 1H),
6.70 (d, J¼2.4 Hz, 1H), 6.62 (d, J¼2.4 Hz, 1H), 7.37 (d, 1H, J¼6.9 Hz),
9.19 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 7.8, 20.1, 24.1, 27.9, 28.1,
28.3, 28.6, 29.0, 45.6, 47.5, 72.1, 74.8, 75.7, 82.0, 83.1, 89.8, 103.4,
105.8, 107.5, 133.6, 134.5, 139.3, 145.8, 150.8, 160.2, 161.8, 168.2,
172.7, 193.7, 201.6; m/z (ESI): 541 MþNaþ, 519 MþHþ; HRMS(ESI-
TOF) found 541.1841 (calcd for C30H30O8þNaþ 541.1838).
mp 169e171 ꢀC; 1H NMR (300 MHz, CDCl3):
d 1.41 (s, 3H), 1.31
(s, 3H), 1.35 (d, 1H, J¼9.9 Hz), 1.53 (s, 3H), 1.69 (s, 3H), 2.30
(dd, 1H, J¼13.5, 4.5 Hz), 2.38 (s, 3H), 2.42 (d, 1H, J¼9.6 Hz), 2.60
(d, 2H, J¼8.1 Hz), 3.49 (m, 4H), 4.47e4.48 (m, 1H), 5.22 (s, 2H),
6.41 (d, 1H, J¼2.4 Hz), 6.58 (d, 1H, J¼2.4 Hz), 7.30 (d, 1H,
4.1.11. Caged xanthone (15). To a solution of xanthone 14 (0.22 g,
0.04 mmol) in EtOAc (10 mL) was added 10% Pd/BaSO4 (22 mg). The
reaction mixture was degassed using hydrogen and stirred under
an atmosphere of hydrogen for 10 min. The reaction mixture was
filtered and concentrated under reduced pressure. The residue does
not need purification and dissolved in DMF (2 mL). The solution
was heated to 120 ꢀC for 1 h under nitrogen. DMF was removed
under reduced pressure and the residue was purified by silica gel
column chromatography (petroleum ether/EtOAc 6:1) to give the
compound 3 (0.20 g, 80% over two steps) as a light yellow oil: 1H
J¼6.9 Hz); 13C NMR (CDCl3, 75 MHz)
d 17.0, 21.1, 25.4, 29.0, 30.4,
46.8, 48.7, 56.6, 83.3, 84.4, 90.5, 94.2, 102.1, 106.3, 107.3, 118.3,
133.1, 135.1, 135.1, 152.3, 162.1, 163.2, 169.4, 173.9, 203.1; m/z (EI):
505 MþNaþ, 483 MþHþ; HRMS(ESI-TOF) found 505.1834 (calcd
for C27H30O8þNaþ 505.1838).
4.1.8. Caged xanthone (13). To dichloromethane (5 mL) was added
SeO2 (0.5 mg, 0.00455 mmol), 2-hydroxybenzoic acid (3.2 mg,
0.023 mmol), 75% t-BuOOH (993.6 mg, 8.28 mmol). The mixture
was stirred for 0.5 h at room temperature and then caged xanthone
5 (110 mg, 0.23 mmol) was added. The reaction mixture was stirred
for 24 h and washed with a solution of Na2SO3 (3 g) in water
(15 mL). The organic layer was dried with Na2SO4 and concentrated
under reduced pressure. The residue was dissolved in dichloro-
methane (3 mL) and PCC (98 mg, 0.46 mmol) was added. The re-
action mixture was stirred for 2 h and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc 5:1) to give the com-
pound 13 (68 mg, 60% over two steps) as a light yellow solid; mp
NMR (300 MHz, CDCl3):
d 1.19e1.24 (m, 7H), 1.65e1.68 (m, 9H),
2.23e2.31 (m, 4H), 2.50e2.64 (m, 3H), 3.30 (m, 2H), 3.42 (m, 1H),
5.11 (t, 1H, J¼6.9 Hz), 6.20 (s, 1H), 6.36 (t, 1H, J¼7.2 Hz), 7.39 (d, 1H,
J¼6.9 Hz), 9.15 (s, 1H); 13C NMR (CD3COCD3, 75 MHz)
d 8.7, 18.2,
21.2, 23.0, 25.8, 26.0, 28.3, 28.6, 29.2, 47.8, 49.8, 84.4, 84.5, 92.1,
106.1, 106.8, 114.5, 122.9, 132.8, 135.3, 136.4, 140.7, 147.0, 151.3, 160.7,
162.7, 169.4, 174.5, 194.6, 204.0; m/z (ESI):519 MꢂHþ; HRMS(ESI-
TOF) found 519.2023 (calcd for C30H32O8ꢂHþ 519.2019).
4.1.12. Caged xanthone (16). HCl (1 mL, 6 N) was added to the so-
lution of compound 3 (17 mg, 0.03 mmol) in THF/MeOH (1 mL/
1 mL). The reaction mixture was heated to 50 ꢀC. After 5 h, EtOAc
(10 mL) was added to the reaction mixture, which was washed with
brine (10 mLꢁ3). Organic layer was dried with Na2SO4 and con-
centrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/EtOAc 4:1) to
give the compound 16 (12 mg, 80%) as a yellow oil: 1H NMR
148e149 ꢀC; 1H NMR (300 MHz, CDCl3):
d 1.30e1.35 (m, 7H), 1.73
(s, 3H), 2.31e2.40 (m, 5H), 2.53 (d, J¼9.6 Hz, 2H), 3.49 (s, 4H), 5.21
(s, 2H), 6.42 (m, 2H), 6.51 (m,1H), 7.46 (d, J¼6.9 Hz,1H), 9.30 (s,1H);
13C NMR (CDCl3, 75 MHz)
d 8.8, 21.1, 25.03, 29.7, 30.2, 30.9, 46.7,
48.7, 56.7, 83.2, 84.1, 91.1, 94.4, 101.8, 106.7, 107.0, 134.5, 135.7, 140.2,
147.0, 152.5, 161.8, 163.9, 169.2, 173.6, 194.7, 202.5; m/z (ESI): 519
MþNaþ, 497 MþHþ; HRMS(ESI-TOF) found 519.1625 (calcd for
C27H28O9þNaþ 519.1631).
(300 MHz, CDCl3): d 1.28e1.32 (m, 7H), 1.71e1.77 (m, 9H), 2.38 (dd,
1H, J¼14.4, 6 Hz), 2.57e2.64 (m, 2H), 2.66e2.78 (m, 1H), 3.30e3.37
(m, 2H), 3.53e3.57 (m, 1H), 5.12 (t, 1H, J¼6 Hz), 6.06 (s, 1H), 6.46
(t, 1H, J¼7.2 Hz), 7.02 (s, 1H), 7.58 (d, 1H, J¼6.9 Hz), 9.23 (s, 1H),
4.1.9. Caged xanthone (2). To a solution of caged xanthone 13
(60 mg, 0.12 mmol) in acetone (5 mL) was added NaI (36 mg,
0.24 mmol) and 2 N HCl (one drop). The mixture was stirred at
40 ꢀC for 6 h and diluted by 15 mL EtOAc, which was washed with
saturated NaHCO3 (3ꢁ10 mL). The organic layer was dried with
12.53 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 8.7, 18.1, 25.1, 28.8, 29.1,
29.7, 30.1, 32.0, 46.8, 49.1, 70.6, 84.1, 90.9, 97.0, 100.6, 106.9, 121.3,
127.3, 133.2, 136.1, 139.9, 147.7, 157.8, 163.5, 163.7, 178.9, 195.3,

Z.-L. Liu et al. / Tetrahedron 67 (2011) 4774e4779
4779
202.8; m/z (ESI):477 MꢂHþ; HRMS(ESI-TOF) found 477.1908 (calcd
for C28H30O7ꢂHþ 477.1913).
2.34 (dd, 1H, J¼13.5, 4.5 Hz), 2.55 (d, 1H, J¼9.3 Hz), 2.68 (d, 2H,
J¼7.5 Hz), 3.31e3.36 (m, 4H), 3.51e3.54 (m, 1H), 5.13 (m, 1H), 5.22
(m, 1H), 6.38 (m, 1H), 6.55 (s, 1H), 7.57 (d, 1H, J¼6.9 Hz), 9.23 (s, 1H),
4.1.13. Caged xanthone (17). To a solution of caged xanthone 16
(21 mg, 0.044 mmol) in dried acetone (3 mL) was added KI
(14.7 mg, 0.088 mmol), K2CO3 (12.1 mg, 0.088 mmol), and CuI
(0.88 mg, 0.0044 mmol). Then 2-chloro-2-methylbut-3-yne
(9.02 mg, 0.088 mmol) was added, and the reaction mixture was
heated to reflux for half hour, which was then cooled to 25 ꢀC and
filtered. The filtration was concentrated under reduced pressure
and the residue was purified by silica gel column chromatography
(petroleum ether/EtOAc 8:1) to give the compound 17 (20 mg, 85%)
12.80 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 8.7, 17.9, 18.1, 21.3, 22.2,
25.4, 25.8, 25.9, 28.9, 29.1, 30.0, 47.0, 49.0, 83.3, 83.9, 90.7, 100.7,
106.4, 107.7, 121.2, 121.6, 133.5, 134.4, 135.8, 135.8, 140.3, 146.5,
155.8, 163.8, 168.6, 179.1, 194.5, 203.1; m/z (ESI):545 MꢂHþ;
HRMS(ESI-TOF) found 545.2546 (calcd for C33H38O7ꢂHþ 545.2539).
Acknowledgements
This work was supported by 2008ZX09401-001, 2009ZX09501-
003 and 2010ZX09401-401 of National Major Science and Tech-
nology Project of China (Innovation and Development of New
Drugs), 90713038 and 21072231 of National Natural Science
Foundation of China (Key Program).
as a light yellow oil: 1H NMR (300 MHz, CDCl3):
d 1.28 (s, 4H), 1.30
(s, 3H), 1.65e1.71 (m, 6H), 1.73e1.74 (m, 9H), 2.34(dd, 1H, J¼13.5,
4.5 Hz), 2.60 (d, 1H, J¼6.4 Hz), 2.62e2.68 (m, 3H), 3.16e3.53
(m, 2H), 3.53e3.57 (m, 1H), 5.06e5.08 (m, 1H), 6.38 (t, 1H,
J¼6.6 Hz), 6.89 (s, 1H), 7.58 (d, 1H, J¼6.9 Hz), 9.22 (s, 1H), 12.48 (s,
1H); 13C NMR (CDCl3, 75 MHz)
d 8.5, 18.2, 22.1, 25.3, 25.7, 29.0, 29.1,
Supplementary data
29.9, 30.0, 46.9, 49.0, 73.0, 75.5, 83.5, 84.0, 84.0, 90.67, 97.2, 101.5,
110.4,122.2,131.8,132.5,136.0,140.1,146.5,156.4,162.8,164.2,179.1,
194.5, 202.8; m/z (ESI): 567 MþNaþ, 545 MþHþ; HRMS(ESI-TOF)
found 567.2363 (calcd for C33H36O7þNaþ 567.2359).
Preparation of the caged xanthone analogues is provided. Copies
of 1H and 13C NMR spectra are provided. Supplementary data as-
sociated with this article can be found in the online version, at
doi:10.1016/j.tet.2011.05.029. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
4.1.14. Isomorellin (1). A solution of caged xanthone 17 (10 mg,
0.018 mmol) in DMF (2 mL) was heated to 120 ꢀC for 4 h under
nitrogen. DMF was removed under reduced pressure and the resi-
due was purified by silica gel column chromatography (petroleum
ether/EtOAc 10:1) to give isomorellin 1 (8.5 mg, 85%) as a yellow
References and notes
solid: 1H NMR (300 MHz, CDCl3):
d 1.19 (s, 3H), 1.22 (s, 4H),
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1.40e1.42 (m, 6H), 1.52 (s, 3H), 1.59 (s, 3H), 1.70 (s, 3H), 2.34 (dd, 1H,
J¼13.5, 4.5 Hz), 2.60 (d, 1H, J¼6.4 Hz), 2.63 (m, 2H), 3.24 (m, 2H),
3.50 (m, 1H), 5.06 (t, 1H, J¼6 Hz), 5.47 (d, 1H, J¼9.9 Hz), 6.35 (t, 1H,
J¼6.6 Hz), 6.56 (d, 1H, J¼9.9 Hz), 7.52 (d, 1H, J¼6.9 Hz), 9.19 (s, 1H),
12.70 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 8.6, 18.2, 21.7, 25.8, 27.8,
28.5, 29.0, 29.0, 29.7, 30.0, 46.9, 49.1, 83.4, 83.5, 84.0, 90.3, 97.4,
101.3, 108.1, 115.3, 121.9, 126.4, 132.9, 133.4, 135.6, 140.1, 146.4, 157.5,
157.6, 157.8, 178.9, 194.4, 203.0; m/z (ESI): 567 MþNaþ, 545 MþHþ;
HRMS(ESI-TOF) found 567.2354 (calcd for C33H36O7þNaþ
567.2359).
4.1.15. Gaudichaudione A (18). To a solution of xanthone 17 (10 mg,
0.018 mmol) in EtOAc (3 mL) was added 10% Pd/BaSO4 (1 mg). The
reaction mixture was degassed using hydrogen and stirred under
an atmosphere of hydrogen for 10 min. The reaction mixture was
filtered and concentrated under reduced pressure. The residue does
not need purification and dissolved in DMF (2 mL). The solution
was heated to 120 ꢀC for 0.5 h under nitrogen. DMF was removed
under reduced pressure and the residue was purified by silica gel
column chromatography (petroleum ether/EtOAc 8:1) to give
gaudichaudione A 18 (8 mg, 80% over two steps) as a yellow solid:
17. Chantarasriwong, O.; Cho, W. C.; Batova, A.; Chavasiri, W.; Moore, C.; Rheingold,
A. L.; Theodorakis, E. A. Org. Biomol. Chem. 2009, 7, 4886e4894.
1H NMR (300 MHz, CDCl3):
d 1.28e1.32 (m, 7H), 1.71e1.82 (m, 15H),