The synthesis of xanthones, xanthenediones, and spirobenzofurans: Their antibacterial and antifungal activity

Article abstract of DOI:10.1016/j.bmcl.2011.09.088

Exposure of the phenol, (5-bromo-2-hydroxyphenyl)(2,4,5-trimethoxyphenyl) methanone 18 to ceric ammonium nitrate (CAN) resulted in the formation of 7-bromo-3,4a-dimethoxy-2H-xanthene-2,9(4aH)-dione 19 and 5-bromo-2′, 5′-dimethoxy-3H-spiro[benzofuran-2,1′-cyclohexa[2,5]diene]-3, 4′-dione 20. The brominated spirobenzofuran 20 was then subjected to Suzuki-Miyaura reactions to give six derivatives 22a-f. These compounds, related diones and xanthones displayed mostly noteworthy antimicrobial activity, particularly towards the yeasts Cryptococcus neoformans and Candida albicans. Diones 15 and 30 displayed significant activity (7.8 μg/mL) against C. albicans and C. neoformans, respectively. Furthermore, dione 10 displayed the most significant activity (3.6 μg/mL) against both yeasts.

Full text of DOI:10.1016/j.bmcl.2011.09.088

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7085–7088
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis of xanthones, xanthenediones, and spirobenzofurans: Their
antibacterial and antifungal activity
Justin J. Omolo a, Myron M. Johnson a, Sandy F. van Vuuren b, Charles B. de Koning a,
⇑
a Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Box Wits 2050, South Africa
b Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Exposure of the phenol, (5-bromo-2-hydroxyphenyl)(2,4,5-trimethoxyphenyl)methanone 18 to ceric
ammonium nitrate (CAN) resulted in the formation of 7-bromo-3,4a-dimethoxy-2H-xanthene-
2,9(4aH)-dione 19 and 5-bromo-20,50-dimethoxy-3H-spiro[benzofuran-2,10-cyclohexa[2,5]diene]-3,40-
dione 20. The brominated spirobenzofuran 20 was then subjected to Suzuki–Miyaura reactions to give
six derivatives 22a–f. These compounds, related diones and xanthones displayed mostly noteworthy
antimicrobial activity, particularly towards the yeasts Cryptococcus neoformans and Candida albicans.
Received 15 August 2011
Revised 19 September 2011
Accepted 21 September 2011
Available online 1 October 2011
Keywords:
Synthesis
Xanthones
Xanthenediones
Spirobenzofurans
Antimicrobial activity
Diones 15 and 30 displayed significant activity (7.8
lg/mL) against C. albicans and C. neoformans, respec-
tively. Furthermore, dione 10 displayed the most significant activity (3.6
l
g/mL) against both yeasts.
Ó 2011 Elsevier Ltd. All rights reserved.
Xanthones often display biological activities that allow them to
be classed as useful antibacterial and antifungal agents.1 For exam-
ple, laurentixanthone A 1 (Fig. 1) isolated from the roots of Vismia
Hence, we planned to take advantage of the methodology we
had developed to make griseofulvin-like spirobenzofurans, such
as 8, (albeit in poor yields) and make derivatives of these com-
pounds. By attempting the CAN-mediated reaction on a bromine
substituted equivalent of 5, we hoped that this would provide spi-
robenzofurans with a handle that could be utilized in Suzuki–
Miyaura reactions.8 Finally, we wished to ascertain if the xanthen-
ediones such as 7 could be converted into xanthones.
laurentii shows an MIC value of 2.44
while cudraxanthone S 2 shows good antifungal activity against
Cryptococcus neoformans (MIC 3
M).3
Meanwhile a simple structurally related compound, 6-deoxyj-
acareubin 3 showed an MIC of 4.6 M against Bacillus subtilis.
l
M against Candida glabrata,2
l
l
During the course of our work on the use of novel methodology
for the synthesis of xanthones and related compounds, we discov-
ered that oxidation of 5 with cerium(IV) ammonium nitrate (CAN)
resulted in the formation of three products (Scheme 1). The major
products were the dione 7 and xanthone 6, both produced in a sim-
ilar yield. In addition, we were also able to isolate a third product,
spirobenzofuran 8.5 Using other phenol substrates we were able to
generalize this reaction, however, all three products were not
formed in each case.5
As described previously,5 phenol 9 was exposed to CAN result-
ing in the formation of dione 10 exclusively, in good yield. In an
O
O
OH
O
O
OH
O
HO
OH
Closer examination of the third product 8 showed that the skel-
eton resembled griseofulvin, 4 ( Fig. 1) a commercial antifungal
agent that has mainly been used for the treatment of dermatomy-
coses.6a–c Griseofulvin has also been shown to exhibit an inhibitory
activity against the yeast Candida albicans over a large range of be-
OH
Cudraxanthone S
2
Laurentixanthone A
1
tween 20 and 500 l
g/mL.7a–c Therefore, we decided to explore this
OMe
O
OH
O
OMe
reaction further, and test all these products for antibacterial and
antifungal activity.
O
O
MeO
O
O
Cl
Griseofulvin 4
OH
6-Deoxyjacareubin 3
Figure 1. Biologically active xanthones and related compounds.4
⇑
Corresponding author. Tel.: +27 11 7176724; fax: +27 11 7176749.
E-mail address: Charles.deKoning@wits.ac.za (C.B. de Koning).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.088

7086
J. J. Omolo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7085–7088
OMe
MeO
HO
O
O
O
MeO
O
O
Cl
Ar
MeO
MeO
Cl
Br
i
(i)
O
MeO
HO
OMe
O
O
5
6
OMe 22a-f
OMe 20
O
O
MeO
Cl
O
Cl
OMe
O
OMe
O
MeO
O
OMe
OMe
8
7
(22c, 57%)
(22b, 53%)
(22a, 60%)
CHO
O
Scheme 1. Reagents and conditions: (i) CAN, H2O/MeCN/CHCl3, rt, 6, 21%, 7, 29%,
8, 9%.
Ar=
O
(22f, 55%)
(22d, 70%)
(22e, 67%)
CN
OMe
O
OMe
O
OH
O
O
Scheme 4. Reagents and conditions: (i) 5% Pd(PPh3)4, ArB(OH)2, DME, CsF, micro-
wave, 10 min, 150 °C, 120 W, yields see scheme.
(i)
(ii)
O
OMe
9
10
OMe
OMe
O
O
O
O
O
O
Cl
O
HO
O
O
MeO
MeO
O
23
24
12
11
O
O
OMe
O
OMe
OMe
O
OBn
Br
OMe
O
OH
Br
Cl
Cl
OMe
(iii)
(iv)
O
MeO
O
O
OMe
O
25
27
26
O
13
OMe
HO
14
Cl
OMe
O
O
Br
O
OMe
O
Br
(v)
OMe
OMe
O
O
28
O
O
16
O
Cl
OMe Cl
O
O
OMe
15
Scheme 2. Reagents and conditions: (i) CAN, H2O/MeCN/CHCl3, rt, 10 min 72%; (ii)
DME, microwave, 10 min, 150 °C, 120 W, 50%; (iii) 5% Pd/C, EtOAc, H2, 24 h, 1 atm,
72%; (iv) CAN, H2O/MeCN/CHCl3, rt, 10 min, 45%; (v) DME, microwave, 10 min,
150 °C, 120 W, 10%.
O
29
MeO
O
30
MeO
O
31
OMe
O
OBn
OMe
O
OH
Figure 2. Structures of compounds previously synthesized tested for antibacterial
and antifungal activity.
(i)
(ii)
MeO
MeO
OMe
Br
OMe
MeO
Br
17
18
attempt to convert the dione into a xanthone, dione 10 was placed
in DME in a Discovery microwave and heated for 10 min. The xan-
thone 11 was formed in a 50% yield presumably by means of an
intermediate Michael acceptor 12 as shown in Scheme 2. In order
to assemble xanthones or the related diones containing an aro-
matic bromine atom for possible Suzuki–Miyaura reactions, we at-
tempted the same reaction on phenol 14, which was easily
prepared from the O-benzylated precursor 13 by exposure to
hydrogen gas and a palladium on carbon catalyst. Subjecting 14
to CAN resulted in the formation of only the dione 15 but in a dis-
appointing yield of 45%. Dione 15 was then subjected to the micro-
wave conditions developed previously to give xanthone 16 in a
poor yield of 10%.
O
O
O
O
Br
Br
O
MeO
O
OMe
19
OMe
20
(iii)
O
O
HO
Br
Undeterred by this result, we wished to use substrates in the
CAN-mediated reaction that would also lead to the formation of
spirobenzofuran type compounds as we believed that these would
show, in particular, good antifungal activity. Hence, as a result of
our previous experience with the CAN reaction,5 we prepared the
MeO
21
Scheme 3. Reagents and conditions: (i) 5% Pd/C, EtOAc, H2, 24 h, 1 atm, 70%; (ii) CAN,
H2O/MeCN/CHCl3, rt, 10 min 19 18%, and 20, 22%; (iii) DME, microwave, 10 min,
150 °C, 120 W, 33%.

J. J. Omolo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7085–7088
7087
Table 1
Antimicrobial and antifungal activity of selected compounds
Compound
Bacillus cereus
Staphylococcus aureus
Escherichia coli
Moraxella catarrhalis
Cryptococcus neoformans
Candida albicans
ATCC 11778
ATCC 2587
ATCC 8739
ATCC 232446
ATCC 90112
ATCC 10231
Pathogen (MIC lg/mL)
10
11
15
16
19
20
21
22a
22b
22c
22d
22e
22f
23
24
25
31.3
31.3
31.3
31.3
31.3
31.3
31.3
46.9
15.6
31.3
31.3
31.3
31.3
19.5
78.1
156.2
312.5
312.5
39.0
625.0
156.2
46.9
0.08
NA
93.7
125.0
62.5
250.0
62.5
62.5
62.5
62.5
15.6
62.5
62.5
62.5
62.5
78.1
19.5
156.2
117.1
156.2
39.0
234.3
156.2
62.5
1.25
NA
125.0
125.0
62.5
125.0
187.5
62.5
125.0
125.0
62.5
62.5
62.5
62.5
62.5
156.2
468.7
312.5
312.5
312.5
156.2
625.0
312.0
125.0
0.12
125.0
125.0
125.0
>250
125.0
125.0
125.0
>250
125.0
125.0
125.0
125.0
125.0
78.1
312.5
312.5
625.0
625.0
156.2
1250.0
156.2
125.0
1.25
3.6
3.6
31.3
7.8
15.6
15.6
11.7
15.6
15.6
15.6
23.4
15.6
15.6
15.6
15.6
15.6
19.5
29.2
39.0
78.1
78.1
15.6
156.2
7.8
31.3
31.3
31.3
31.3
31.3
31.3
62.5
23.4
62.5
23.4
78.1
468.7
156.2
156.2
156.2
20.8
234.3
156.2
31.3
NA
26
27
28
29
30
31
31.3
NA
2.5
Ciprofloxacin
Amphotericin B
NA
NA
3.0
NA = Not appropriate control; media control (not presented) demonstrated sterility and solvent control (not presented) had no additional antimicrobial effects.
trimethoxy derivative 17. Removal of the O-benzyl substituent
afforded the phenol 18 in good yield. Treatment of 18 with CAN
yielded the dione 19 as well as the expected spirobenzofuran
20.9 Subsequently, the dione 19 was subjected to microwave con-
ditions developed previously to yield the desired xanthone 21 in a
mediocre yield of 33% (Scheme 3).
As we had prepared the spirobenzofuran 20 with a aromatic
bromine substituent in place, we were now in a position to attempt
Suzuki–Miyaura reactions on this substrate. Treatment of 20 with a
range of boronic acids under Suzuki–Miyaura microwave condi-
tions, as shown in Scheme 4, resulted in the formation of com-
pounds 22a–f in fair to good yields.10
The collection of xanthones, xanthenediones, and spirobenzofu-
rans both from the work reported in this Letter, as well as that
published previously,5 (Fig. 2) were subjected to antibacterial and
antifungal testing. Two pathogenically important yeasts (C. albicans
and C. neoformans) were selected for representation of the fungal
group. The in vitro antimicrobial MIC screening results for selected
compounds are given in Table 1. Compounds with antimicrobial
Acknowledgments
This work was supported by SABINA (Southern African Bio-
chemistry and Informatics for Natural Products Network), the Na-
tional Research Foundation (NRF, GUN 2053652 and IRDP of the
NRF (South Africa) for financial support provided by the Research
Niche Areas programme), Pretoria, and the University of the Wit-
watersrand (Science Faculty Research Council). We also gratefully
acknowledge the NRF scarce skills programme for generous fund-
ing to M.M.J. Mr. R. Mampa (University of the Witwatersrand)
and Mr. B. Moolman and Dr. M. Stander (University of Stel-
lenbosch) are thanked for providing the NMR and HRMS MS spec-
troscopy services, respectively.
References and notes
1. Ei-Seedi, H. R.; El-Barbary, M. A.; El-Ghorab, D. M. H.; Bohlin, L.; Borg-Karlson,
A.-K.; Goransson, U.; Verpoorte, R. Curr. Med. Chem. 2010, 17, 854.
2. Ngeneving, J. R.; Azehuze, A. G. B.; Kuete, V.; Carly, N. N. E.; Beng, V. P.; Meyer,
M.; Blond, A.; Bodo, B.; Nkengfack, A. E. Phytochemistry 2006, 67, 1341.
3. Fukai, T.; Yonekawa, M.; Hou, A.-J.; Nomura, T.; Sun, H.-D.; Uno, J. J. Nat. Prod.
2003, 66, 1118.
4. Rukachaisirikul, V.; Kamkaew, M.; Sukavisit, D.; Phongpaichit, S.; Sawangchote,
P.; Taylor, W. C. J. Nat. Prod. 2003, 66, 1531.
5. 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.
6. (a) Ruge, E.; Korting, H. C.; Borelli, C. Int. J. Antimicrob. Agents 2005, 26, 427; (b)
Pirrung, M. C.; Brown, W. L.; Rege, S.; Laughton, P. J. Am. Chem. Soc. 1991, 113,
8561; (c) Wildfeuer, A.; Seidl, H. P.; Paule, I.; Haberreiter, A. Mycosis 1998, 41,
309.
7. (a) Dahiya, R.; Gautam, H. Afr. J. Pharm. Pharmacol. 2011, 5, 447; (b) Gadakh, A.
V.; Pandit, C.; Rindhe, S. S.; Karale, B. K. Bioorg. Med. Chem. Lett. 2010, 20, 5572;
(c) Kavitha, A.; Prabhakar, P.; Narasimhulu, M.; Vijayalakshmi, M.;
Venkateswarlu, Y.; Rao, K. V.; Raju, V. B. S. Microbiol. Res. 2010, 165, 199.
8. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
activities of 64–100 lg/mL were accepted as having clinical rele-
vance11 and compounds with activities 10
lg/mL or less were con-
sidered significant.12 All compounds showing significant
antimicrobial activity are highlighted in bold (Table 1).13
Examination of these biological results shows that a sizable
number of the spirobenzofurans 19–21 and 22b–f showed very
good activity against the yeast, C. neoformans. In addition, xan-
thone 11 was also very active against C. neoformans. The same or-
der of activity was noted with diones 15, 16, 23, 28, and 30. Slightly
less activity was generally observed against C. albicans, however,
the majority of compounds tested still presented with activities
being clinically significant. Dione 10 displayed the most significant
activity against both yeasts having mean MIC values of 3.6 lg/mL.
This noteworthy activity observed has potential for further devel-
opment as an antifungal, as activities expressed are close to that
of the commercial antifungal controls (2.5–3.0 lg/mL). As griseo-
9. Synthesis of 7-bromo-3,4a-dimethoxy-2H-xanthene-2,9(4aH)-dione 19 and 5-
bromo-20,50-dimethoxy-3H-spiro[benzofuran-2,10-cyclohexa[2,5]diene]-3,40-
dione 20.
Ceric ammonium nitrate (1.2880 g, 2.35 mmol) in water (20 mL) was added
dropwise to
a
stirring mixture of (5-bromo-2-hydroxyphenyl)(2,4,5-
trimethoxyphenyl)methanone 18 (200 mg, 0.55 mmol) in acetonitrile (25 mL)
and chloroform (5 mL). The mixture was stirred at room temperature for
10 min. The reaction mixture was filtered through celite and washed with
EtOAc (3 ꢀ 25 mL). The organic layer was washed consecutively with
fulvin 4 is particularly active against filamentous fungi, this will
be the focus of future biological testing.
a

7088
J. J. Omolo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7085–7088
saturated aqueous NaHCO3 solution (25 mL), brine (25 mL), and water (25 mL).
(DME). Cesium fluoride (38 mg, 0.25 mmol); phenylboronic acid (14.6 mg,
0.12 mmol); and Pd(PPh3)4 (1.16 mg, 0.01 mmol) were added and the solution
was heated in the microwave (at 150 °C, 120 W) for 10 min. The reaction
mixture was filtered through filter paper and cotton wool. The solvent was
removed in vacuo and silica gel column chromatography (20% EtOAc/hexane)
afforded a yellow compound 22a (0.018 g, 60%). Mp: 158–160 °C; IR (solid):
The organic layer was dried over magnesium sulfate. The solvent was removed
in vacuo and silica column chromatography (20% EtOAc/hexane) afforded two
products as yellow grains 19 (35 mg, 18%) and 20 (42 mg, 22%). 19: Mp: 119–
125 °C; IR (solid): mmax (cmꢁ1): 1728, 1690, 1678, 1664, 1653, 1601, 1534,
1426; 1H NMR (300 MHz; CDCl3): d 8.09 (1H, d, J = 2.4), 7.66 (1H, dd, J = 2.4,
8.7), 6.98 (1H, d, J = 8.7), 6.85 (1H, s), 5.95 (1H, s), 3.81 (3H, s), 3.32 (3H, s); 13
C
m
max (cmꢁ1): 1690, 1642, 1596, 1488, 1462, 1418; 1H NMR (300 MHz; CDCl3): d
NMR (75 MHz; CDCl3): d 180.2, 179.8, 156.4, 152.4, 144.1, 139.4, 129.9, 128.0,
122.9, 120.4, 115.9, 106.7, 98.1, 55.7, 51.2; HRMS (m/z): calcd for C15H11BrO5
12.16 (1H, s, OH), 7.71 (1H, dd, J = 2.1, 8.4), 7.65 (1H. d, J = 2.4), 7.43–7.29 (4H,
m), 7.10 (1H, d, J = 8.7), 6.93 (1H, s), 6.67 (1H, s), 5.99 (1H, s), 3.87 (3H, s), 3.71
(3H, s); 13C NMR (75 MHz; CDCl3): d 200.9, 162.1, 152.5, 149.3, 140.5, 140.0,
134.8, 132.1, 131.7, 128.8 (2), 126.9, 126.4 (2), 120.4, 118.5, 118.4, 112.1, 99.3,
56.6, 56.2; HRMS (m/z): calcd for C21H16O5, [M++H] 351.1154 found: 351.1247.
11. Gibbons, S. Nat. Prod. Rep. 2004, 21, 263.
[M++H] 350.9790 found: 350.9668. 20: Mp 208–215 °C; IR (solid): max (cmꢁ1):
m
1729, 1632, 1593, 1492, 1433, 1422; 1H NMR (300 MHz; CDCl3): d 7.82–7.77
(2H, m), 7.14 (1H, d, J = 8.7), 5.75 (1H, s), 5.10 (1H, s), 3.68 (3H, s), 3.67 (3H, s);
13C NMR (75 MHz; CDCl3): d 194.1, 181.1, 171.2, 167.5, 153.3, 141.5, 127.9,
121.5, 115.5, 115.2, 104.0, 102.3, 86.8, 56.6, 55.6; HRMS (m/z): calcd for
12. Rios, J. L.; Recio, M. C. J. Ethnopharmacol. 2005, 100, 8084.
C
15H11BrO5 [M++H] 350.9790 found: 350.9855.
13. Positive controls (ciprofloxacin for bacteria and amphotericin B for yeasts)
were included to monitor susceptibility of test organisms. Negative controls
(media and solvent only) were included to monitor sterility and possible
antimicrobial efficacy of diluents (Table 1).
10. Synthesis of 40-hydroxy-20,50-dimethoxy-5-phenyl-3H-spiro[benzofuran-2,10-
cyclohexa[2,5]diene]-3-one 22a
5-Bromo-20,50-dimethoxy-3H-spiro[benzofuran-2,10-cyclohexa[2,5]diene]-
3,40-dione 20 (30 mg, 0.08 mmol) was dissolved in 2 mL of dimethoxyethane