Synthesis and antimicrobial activity of brominated resorcinol dimers

Article abstract of DOI:10.1016/j.bmcl.2011.09.072

Dibrominated resorcinol dimers were synthesized by reaction of 4-bromoresorcinol with aldehydes under reflux in ethanol in the presence of HCl. Subsequent dehalogenation yielded the corresponding monobrominated compounds and a fully dehalogenated dimer. O

Full text of DOI:10.1016/j.bmcl.2011.09.072

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7142–7145
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antimicrobial activity of brominated resorcinol dimers
Elise Bouthenet a, Ki-Bong Oh b, Seungil Park c, Navjeet K. Nagi a, Hyi-Seung Lee c, , Susan E. Matthews a,
⇑
⇑
a School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom
b Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea
c Marine Natural Products Laboratory, Korea Ocean Research and Development Institute, Ansan, PO Box 29, Seoul 425-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Dibrominated resorcinol dimers were synthesized by reaction of 4-bromoresorcinol with aldehydes
under reflux in ethanol in the presence of HCl. Subsequent dehalogenation yielded the corresponding
monobrominated compounds and
phenyl)methylene)bis(4-bromobenzene-1,3-diol) (4) displayed potent antibacterial activity and inhibi-
tory activity against isocitrate lyase Candida albicans.
Received 25 August 2011
Revised 18 September 2011
Accepted 19 September 2011
Available online 24 September 2011
a
fully dehalogenated dimer. Of the dimers, 6,60-((4-hydroxy-
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bromophenol
Red alga
Antibacterial activity
Antifungal activity
Resorcinol
The isolation of bromophenolic dimers, of general structures 1
and 2 (Fig. 1) from marine red algae of the Rhodomelaceae family
such as Odonthalia corymbifera,1,2 Symphyocladia latiuscula,3,4 Rho-
domela confervoide,5–7 Rhodomela larix8,9 and Polysiphonia bro-
diaei10 and brown algae of the Leatesiaceae family including
Leathesia nana11 has been accompanied by their evaluation as al-
dose-reductase inhibitors,2 antibacterial and antifungal com-
pounds,1 feeding deterrent molecules and for their free-radical
scavenging ability.3
macrocyclic host molecules resorcin[4]arenes.20,21 Through choice
of reaction conditions, for example, by the use of an excess of resor-
cinol,22 a less reactive resorcinol derivative23 or by blocking the sec-
ond reactive position by introducing a substituent, generally a
halogen, at position 4,24 the cyclisation reaction can be halted at
the dimer stage. Such dimers have subsequently been exploited for
the formation of hybrid calixarene-resorcin[4]arene structures,24
resorcin[4]arenes with alternate bridging substituents,25 xanthene
dyes26,27 and visual sensors for saccharides.28 In light of the positive
results obtained with catechol dimers we now report the synthesis
of a family of halogenated and nonhalogenated resorcinol dimers
and their biological evaluation as inhibitors of isocitrate lyase
Building on the observed activity of 1a against isocitrate lyase1
a component of the glyoxylate cycle present in prokatyotes and
plants, we have investigated the synthesis of a range of haloge-
nated diphenolic compounds to determine the structure–activity
requirements for antifungal and antimicrobial activity.12–14 In con-
trast, Zhao et al.15 have considered similar molecules for their anti-
oxidant effects.
4-Bromoresorcinol
3
was prepared from dihydroxy-5-
bromobenzoic acid using a modification of a two step procedure
developed by Sandin and McKee29 in which bromination using bro-
mine is followed by a heat induced decarboxylation. Dimerisation
Whilst the natural products and previous synthetic derivatives
feature catechol motifs, early research, on alkyl resorcinol deriva-
tives16,17 and their halogenated derivatives18 has indicated that
this arrangement of phenolic units also shows significant antibac-
terial activity.
R2O
Br
Br
Br
Br
R3
Br
Br
Resorcinol dimers, formed from the reaction of aldehydes with
resorcinol under acid-catalysed conditions have been shown to be
reaction intermediates19 in the synthesis of the popular
R3
OH
R1
R1
OH
HO
HO
OH
OH
OH
OH
1a
1b
R2 = H or Me or Et
R1 = H
R
R3 = H or Br
1 = Br
⇑
Corresponding authors. Tel.: +82 31 400 6179; fax: +82 31 400 6170 (H.-S.L.);
tel.: +44 1603 593986; fax: +44 1603 592003 (S.E.M.).
E-mail addresses: hslee@kordi.re.kr (H.-S. Lee), susan.matthews@uea.ac.uk
(S.E. Matthews).
2
Figure 1. Natural bromophenolic dimers.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.072

E. Bouthenet et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7142–7145
7143
Br
Br
Br
O
HO
HO
OH
cat HCl
R
H
EtO H
OH
Br
OH
H
R
OH
X
Scheme 1. Synthesis of resorcinol dimers.
Br
HO
OH
HO
OH
H , Pd/Al O
3
2
2
MeOH
OH
R
OH
OH
R
OH
X = Br or H
Scheme 2. Catalytic hydrogenations of bromophenols.
X1
X2
X
Br
HO
OH
HO
OH
OH
OH
OH
OH
OH
4
9
. X = X = Br
1
2
5. X = Br
. X = Br, X = H
1
2
10. X = H
14. X = X = H
1
2
X
Br
X
Br
X
Br
HO
OH
HO
OH
HO
OH
OH
Cl
OH
Cl
OH
OH
OH
OH
NO2
NO2
6. X = Br
11. X = H
7. X = Br
12. X = H
8. X = Br
13. X = H
Figure 2. Synthesised resorcinol dimers.
was achieved simply by reaction of 2 equiv of 3 with the desired
aldehyde under reflux in ethanol in the presence of HCl.30 Purifica-
tion by column chromatography gave the five dibrominated dimers
4–8 in moderate to good yields of up to 75% (Scheme 1). The choice
of aldehydes was based on both synthetic and structure–activity
objectives, allowing exploration of the constraints of the condensa-
tion reaction and an insight into the effect of substituent at the
bridging position on inhibitory activity.
Although nonhalogenated resorcinol dimers could be accessed
through using a large excess of resorcinol we instead used sequen-
tial catalytic hydrogenation reactions to allow the isolation of both
the mono brominated derivatives 9–1331 and a fully dehalogenat-
ed dimer 1431 for comparison. The dibromoresorcinol dimers 4–8
were debrominated using H2 in the presence of 10% Pd/Al2O3 in
methanol at room temperature for 4 h12 (Scheme 2). The
debrominated phenolic compounds 9–14 were obtained from the
corresponding reaction mixture by HPLC techniques in satisfactory
yields.
All compounds (Fig. 2) were fully characterised using 1H NMR,
13C NMR, IR and mass spectra.
The in vitro antibacterial activity of the new dimers 4–14 and
compound 1a13 were assessed against three representative Gram
positive bacteria (Staphylococcus aureus, Bacillus subtilis and Micro-
coccus luteus) and three representive Gram negative bacteria (Sal-
monella typhimurium, Proteus vulgaris and Escherichia coli) using
our previously described method (Table 1).14 In all cases activity
against E. coli was low, however, no general selectivity between
Gram positive and negative bacteria was observed. The most effec-
tive compounds featured two bromo substituents with compound
5 showing particularly high activity comparable with ampicillin. It
is interesting to note that low activities were observed with 8 and
13 featuring a para-NO2 substituent. Compared with previously

7144
E. Bouthenet et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7142–7145
Table 1
Antibacterial activity
Compounds
Antibacterial activity (MIC, lg/ml)
S. aureus
B. subtilis
M. luteus
S. typhimurium
P. vulgaris
E. coli
1a13
25
25
25
25
25
50
4
5
6
7
8
9
10
11
3.12
0.78
6.25
3.12
25
6.25
6.25
12.5
12.5
100
12.5
0.39
1.56
0.78
1.56
1.56
12.5
3.12
3.12
6.25
6.25
50
1.56
0.78
1.56
1.56
12.5
3.12
3.12
12.5
12.5
50
3.12
1.56
6.25
3.12
25
3.12
6.25
12.5
6.25
100
12.5
0.78
1.56
0.78
1.56
1.56
25
3.12
3.12
12.5
6.25
100
12.5
0.78
50
>100
100
>100
>100
100
>100
>100
>100
>100
100
12
13
14
6.25
0.39
12.5
1.56
Ampicillin
6.25
Microorganisms: Staphylococcus aureus ATCC6538p; Bacillus subtilis ATCC6633; Micrococcus luteus IFC12708; Salmonella typhimurium ATCC14028; Proteus vulgaris ATCC3851;
Escherichia coli ATCC25922.
our previously described method32 (Table 3). All new dimers
Table 2
Antifungal activity
showed inhibition of the glyoxalate pathway enzyme. The impor-
tance of halogen substitution in achieving high inhibitory values
for isocitrate lyase is clear, with the dibrominated compounds
4–8 being more active than the monobrominated 9–13 or the non-
halogenated control molecule 14. This is particularly apparent in
the case of 6, which features additional chlorine atoms. It is inter-
esting to note that the inhibitory activity of the dibrominated com-
pounds is comparable with the natural lead bromophenol 1a,
demonstrating that resorcinol derivatives bind well to isocitrate
lyase. Unlike the natural products and catechol dimers all of the
compounds under study also incorporate a bridging substituent,
however, the excellent IC50 values show that such a substituent,
whether aromatic or aliphatic, can be accommodated easily in
the binding site allowing the possibility of further structural diver-
sification and optimisation of binding.
Compounds
Antifungal activity (MIC, lg/ml)
A. fumigatus
T. rubrum
T. mentagrophytes
C. albicans
1a13
4
5
6
7
8
9
10
11
12
13
14
12.5
12.5
50
100
100
12.5
12.5
100
1.56
25
100
25
25
50
100
50
>100
100
100
100
>100
50
>100
50
>100
50
>100
50
>100
>100
>100
>100
>100
1.56
>100
>100
>100
>100
>100
1.56
>100
>100
>100
>100
>100
1.56
>100
>100
100
>100
>100
0.78
Ampicillin
Microorganisms: Aspergillus fumigates HIC6094; Trichophyton rubrum IFO9185;
Trichrophton mentagrophytes IFO40996; Candida albicans ATCC10231
In conclusion, a new series of brominated resorcinol dimers was
synthesized and their antimicrobial activities were investigated.
Among the synthesized resorcinol dimers, 6,60-((4-hydroxy-
phenyl)methylene)bis(4-bromobenzene-1,3-diol) (4) displayed po-
tent antibacterial activity and inhibitory activity against isocitrate
lyase (ICL) of C. albicans. Since the enzymes of the glyoxylate cycle
are not present in mammals, the readily prepared brominated resor-
cinol dimers tested in this study are good starting candidates for
antimicrobial drug design. Future work will investigate further the
constraints surrounding substituents at the bridging position and
the effect of higher levels of halogenations on activity.
Table 3
Inhibitory effect of 4–14 on the activity of isocitrate
lyase (ICL)
Compounds
ICL IC50 lg/ml (lM)
1a13
4
5
6
10.1 (18.4)
12.9 (28.0)
12.5 (25.9)
9.6 (17.9)
7
8
9
10
11
12
13
14
13.7 (26.8)
10.6 (20.7)
17.8 (46.6)
36.5 (90.5)
35.9 (78.7)
30.2 (69.9)
17.8 (41.2)
50.5 (167.0)
4.7 (6.0)
Acknowledgments
The authors thank the University of East Anglia for funding a
Ph.D. studentship (E.B.) and the Ministry of Land, Transport and
Maritime Affairs, Republic of Korea (H.-S.L.).
References and notes
3-Nitropropionate
1. Lee, H.-S.; Lee, T.-H.; Lee, J. H.; Chae, C.-S.; Chung, S.-C.; Shin, D.-S.; Shin, J.; Oh,
K.-B. J. Agric. Food. Chem. 2007, 55, 6923.
2. Kurata, K.; Taniguchi, K.; Takashima, K.; Hyashi, I.; Suzuki, M. Phytochemistry
1997, 45, 485.
synthesised catechol dimers12–14 and the natural product 1a activ-
ity is high.
3. Wang, W.; Okada, Y.; Shi, H.; Wang, Y.; Okuyama, T. J. Nat. Prod. 2005, 68, 620.
4. Duan, X.-Y.; Li, X.-M.; Wang, B.-G. J. Nat. Prod. 2007, 70, 1210.
5. Fan, X.; Xu, N.-J.; Shi, J.-G. J. Nat. Prod. 2003, 66, 455.
In contrast, antifungal activity, against a panel of fungi (Aspergil-
lus fumigates, Trichophyton rubrum, Trichrophton mentagrophytes
and Candida albicans) of the new brominated resorcinol dimers is
generally lower than the natural product 1a and comparable with
brominated catechol dimers,12,13 with good activity only being ob-
served in the case of 4 (Table 2).
6. Pedersen, M. Phytochemistry 1978, 17, 291.
7. Xu, N.; Fan, X.; Yan, X.; Li, X.; Niu, R.; Tseng, C. K. Phytochemistry 2003, 62, 1221.
8. Suzuki, M.; Kowata, N.; Kurosawa, E. Bull. Chem. Soc. Jpn. 1980, 53, 2099.
9. Kurata, K.; Amiya, T. Chem. Lett. 1977, 1435.
10. Lundgren, L.; Olsson, K.; Theander, O. Acta Chem. Scand. B 1979, 333, 105.
11. Xu, X.; Song, F.; Wang, S.; Li, S.; Xiao, F.; Zhao, J.; Yang, Y.; Shang, S.; Yang, L.;
Shi, J. J. Nat. Prod. 2004, 67, 1661.
Inhibition of isocitrate lyase, from C. albicans, was assessed, in
comparison with the known inhibitor 3-nitropropionate, using

E. Bouthenet et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7142–7145
7145
12. Oh, K.-B.; Lee, J. H.; Chung, S.-C.; Shin, J.; Shin, H. J.; Kim, H.-K.; Lee, H.-S. Bioorg.
Med. Chem. Lett. 2008, 18, 104.
13. Oh, K.-B.; Lee, J. H.; Lee, J. W.; Yoon, K.-M.; Chung, S.-C.; Jeon, H. B.; Shin, J.; Lee,
H.-S. Bioorg. Med. Chem. Lett. 2009, 19, 945.
14. Oh, K.-B.; Jeon, H. B.; Han, Y.-R.; Lee, Y.-J.; Park, J.; Lee, S. H.; Yang, D.; Kwon, M.;
Shin, J.; Lee, H.-S. Bioorg. Med. Chem. Lett. 2010, 20, 6644.
15. Zhao, W.; Feng, X.; Ban, S.; Lin, W.; Li, Q. Bioorg. Med. Chem. Lett. 2010, 20, 4132.
16. Klarmann, E. J. Am. Chem. Soc. 1926, 48, 791.
6.48 (s, 2H, Ar), 5.94 (s, 1H, CHbridging); 13C NMR (500 MHz, CD3OD-d4) d 156.7,
154.9, 149.8, 148.3, 136.6, 134.4, 130.3, 124.5, 123.9, 122.1, 104.8, 100.0, 44.0;
IR 3348, 2973, 1617, 1524, 1426, 1350, 1201, 1123, 1055 cmꢀ1; Mpt 218–
220 °C; MS (LRESI) 509.92 (MꢀH). Compound 8: column chromatography
DCM/MeOH 9:1 yield = 72% 1H NMR (500 MHz, CD3OD-d4) d 8.14 (d, J = 9.0 Hz,
2H, Ar) 7.24 (d, J = 8.5 Hz, 2H, Ar), 6.67 (s, 2H, Ar), 6.47 (s, 2H, Ar), 5.95 (s, 1H,
CHbridging); 13C NMR (500 MHz, CD3OD-d4) d 156.7, 154.8, 154.0, 147.8, 134.4,
131.1, 124.3, 123.9, 104.7, 99.9, 44.1; IR 3437 2921, 1735, 1606, 1512, 1428,
1346, 1201, 1120, 1054 cmꢀ1; Mpt 226–227 °C; MS (LRESI): 509.89 (MꢀH).
17. Harden, W. C.; Reid, E. E. J. Am. Chem. Soc. 1932, 54, 4325.
18. Klarmann, E.; Von Wowern, J. J. Am. Chem. Soc. 1929, 51, 605.
19. Weinelt, F.; Schneider, H.-J. J. Org. Chem. 1991, 56, 5527.
31. General debromination method of Dibromoresorcinol dimers 4–8. A stirred
mixture of the dibromoresorcinol dimers 4–8 (15–25 mg), and 10% Pd/Al2O3
(15 mg) in methanol (10 ml) was hydrogenated using H2 balloon at room
temperature for 4 h. The reaction mixture was filtered and the filtrate was
evaporated to dryness. The residue was partitioned between ethyl acetate and
H2O, and the organic layer was concentrated and purified by RP-18 HPLC with
a mixture of water and methanol as an eluent to afford corresponding phenolic
compounds 11–16, respectively. Compound 9: HPLC yield = 21%, 1H NMR
(500 MHz, CD3OD-d4) d 7.10 (s, 1H, Ar), 6.94 (d, J = 8.0 Hz. 1H, Ar), 6.38 (s, 1H,
Ar), 6.27 (d, J = 8.0 Hz, 1H, Ar), 6.26 (s, 1H, Ar), 4.34 (t, J = 7.5 Hz, 1H, CHbridging),
1.90 (m, 2H, 1CH2), 1.27 (m, 6H, 3CH2), 0.87 (t, J = 7.0 Hz, 3H, 1CH3); 13C NMR
(500 MHz, CD3OD-d4) d 157.3, 156.6, 156.2, 153.5, 132.4, 129.3, 127.2, 123.8,
107.9, 104.7, 103.7, 100.5, 36.3, 35.3, 33.1, 28.9, 23.8, 14.6; IR 3384, 2928, 1616,
1507, 1457, 1431, 1290, 1161 cmꢀ1; Mpt 105–107 °C; MS (LRESI) 381.17
(MꢀH). Compound 10: HPLC yield = 38%, 1H NMR (500 MHz, CD3OD-d4) d 6.82
(d, J = 8.5 Hz, 2H, Ar), 6.67 (s, 1H, Ar) 6.66 (d, J = 7.5 Hz, 2H, Ar), 6.47 (d,
J = 8.0 Hz, 1H, Ar), 6.41 (s, 1H, Ar), 6.28 (d, J = 2.0 Hz, 1H, Ar), 6.18 (d, J = 9.0 Hz,
1H, Ar), 5.78 (s, 1H, CHbridging); 13C NMR (500 MHz, CD3OD-d4) d 157.7, 156.9,
156.4, 156.4, 153.8, 136.7, 134.6, 131.7, 131.3, 126.8, 123.7, 115.8, 107.0, 104.6,
103.6, 99.7, 42.8; IR 3351, 2919, 1734, 1613, 1511, 1427, 1240, 1011 cmꢀ1; Mpt
124–126 °C; MS (LRESI) 403.11 (MꢀH). Compound 11: HPLC yield = 57% 1H
NMR (500 MHz, CD3OD-d4) d 7.26 (d, J = 7.5 Hz, 1H, Ar), 7.25 (s, 1H, Ar) 7.11 (t,
J = 8.0 Hz, 1H, Ar), 6.77 (s, 1H, Ar), 6.61 (d, J = 8.0 Hz, 1H, Ar), 6.38 (s, 1H,
CHbridging), 6.38 (d, J = 5.0 Hz, 1H, Ar), 6.30 (d, J = 2.5 Hz, 1H, Ar), 6.19 (dd,
J = 2.5, 8.0 Hz, 1H, Ar); 13C NMR (500 MHz, CD3OD-d4) d 158.1, 157.3, 156.8,
154.1, 141.0, 137.7, 135.2, 131.9, 130.3, 128.7, 123.2, 119.4, 107.1, 104.1, 103.4,
99.7, 43.1; IR 3246, 2916, 1609, 1510, 1430, 1206 cmꢀ1; Mpt 127–129 °C; MS
(LRESI) 455.01 (MꢀH). Compound 12: HPLC yield = 50%, 1H NMR (500 MHz,
CD3OD-d4) d 8.03 (d, J = 8.0 Hz, 1H, Ar), 7.84 (s, 1H, Ar), 7.47 (t, J = 7.5 Hz, 1H,
Ar), 7.43 (d, J = 7.5 Hz, 1H, Ar), 6.70 (s, 1H, Ar), 6.47 (d, J = 8.5 Hz, 1H, Ar), 6.46
(s, 1H, Ar), 6.33 (d, J = 2.0 Hz, 1H, Ar), 6.23 (dd, J = 2.5, 8.5 Hz, 1H, Ar), 5.99 (s,
1H, CHbridging); 13C NMR (500 MHz, CD3OD-d4) d 158.4, 157.1, 156.7, 154.6,
149.7, 149.1, 136.7, 134.6, 131.7, 130.1, 124.6, 121.8, 121.7, 107.4, 104.7, 104.7,
103.8, 99.9, 43.8; IR 3409, 2928, 1609, 1523, 1427, 1351, 1198, 1126,
1095 cmꢀ1; Mpt 123–125 °C; MS (LRESI) 430.01 (MꢀH). Compound 13: HPLC
yield = 23%, 1H NMR (500 MHz, CD3OD-d4) d 8.11 (d, J = 8.5 Hz, 2H, Ar), 7.24 (d,
J = 8.0 Hz, 2H, Ar), 6.70 (s, 1H, Ar), 6.47 (d, J = 8.5 Hz, 1H, Ar), 6.45 (s, 1H, Ar),
6.33 (d, J = 2.5 Hz, 1H, Ar), 6.22 (dd, J = 2.5, 8.0 Hz, 1H, Ar), 5.99 (s, 1H,
CHbridging); 13C NMR (500 MHz, CD3OD-d4) d 158.4, 157.1, 156.7, 154.9, 154.6,
147.6, 134.6, 131.8, 131.1, 124.6,124.2, 121.7, 107.3, 104.6, 103.8, 99.9, 44.0; IR
3400, 2917, 1606, 1512, 1427, 1345, 1199, 1125, 1013 cmꢀ1; Mpt 127–129 °C;
MS (LRESI) 430.04 (MꢀH). Compound 14: HPLC yield = 46%, 1H NMR (500 MHz,
CD3OD-d4) d 8.14 (d, J = 9.0 Hz, 2H, Ar) 7.24 (d, J = 8.5 Hz, 2H, Ar), 6.67 (s, 2H,
Ar), 6.47 (s, 2H, Ar), 5.95 (s, 1H, CHbridging); 13C NMR (500 MHz, CD3OD-d4) d
156.7, 154.8, 154.0, 147.8, 134.4, 131.1, 124.3, 123.9, 104.7, 99.9, 44.1; IR 3303,
2929, 1619, 1508, 1460, 1301, 1158 cmꢀ1; Mpt 169–171 °C, MS (LRESI) 301.17
(MꢀH).
20. Timmermann, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52, 2633.
21. Moore, D.; Matthews, S. E. J. Incl. Phenom. Macrocyl. Chem. 2009, 65, 137.
22. Sakhaii, P.; Verdier, L.; Ikegami, T.; Greisinger, C. Helv. Chim. Acta 2002, 85,
3895.
23. Tunstad, L. M.; Tucker, J. A.; Dalcanale, E.; Weiser, J.; Bryant, J. A.; Sherman, J.
C.; Helgeson, R. C.; Knobler, C. B.; Cram, D. J. J. Org. Chem. 1989, 54, 1305.
24. Tabatabai, M.; Vogt, W.; Böhmer, V. Tetrahedron Lett. 1990, 31, 3295.
25. Rumboldt, G.; Böhmer, V.; Botta, B.; Paulus, E. F. J. Org. Chem. 1998, 63, 9618.
26. He, Q.; Miller, E. W.; Wong, A. P.; Chang, C. J. J. Am. Chem. Soc. 2006, 128, 9316.
27. Fujikawa, Y.; Urano, Y.; Komatsu, T.; Hanaoka, K.; Kojima, H.; Terai, T.; Inoue,
H.; Nagano, T. J. Am. Chem. Soc. 2008, 130, 14533.
28. Lewis, P. T.; Davis, C. J.; Cabell, L. A.; He, M.; Read, M. W.; McCarroll, M. E.;
Strongin, R. M. Org. Lett. 2000, 2, 589.
29. Sandin, R. B.; McKee, R. A. Org. Synth. 1937, 17, 23.
30. Experimental: All reagents for synthesis were commercial (highest purity
available for reagent grade compounds) and used without further purification.
All reactions were performed under an Argon atmosphere. NMR solvents were
purchased from Apollo. NMR spectra were recorded at 293 K, expect where
stated, using a 500 MHz or a 400 MHz spectrometer. Shifts are referenced
relative to deuterated solvent residual peaks. Melting points were determined
using MelTemp digital melting point apparatus and are uncorrected. General
method for the synthesis of dibromoresorcinol dimers 4–8: concentrated
hydrochloric acid (7.5 ml) was added to a solution of aldehyde (2.6 mM) and
4-bromo resorcinol (5.2 mM) in 15 cm3 of ethanol. The mixture was heated at
70 °C for 3 h and then cooled. The solution was neutralised by addition of
NaHCO3 and then extracted into ethylacetate. The product was purified by
column chromatography as shown. Compound 4: column chromatography
hexane/ethyl acetate 7:3 yield = 22%, 1H NMR (500 MHz, CD3OD-d4) d 7.10 (s,
2H, Ar), 6.40 (s, 2H, Ar), 4.33 (t, J = 8.0 Hz, 1H, CHbridging), 1.88 (q, J = 7.5 Hz, 2H,
1CH2), 1.28 (m, 6H, 3CH2), 0.88 (t, J = 6.5 Hz, 3H, CH3); 13C NMR (500 MHz,
CD3OD-d4) d 156.3, 153.7, 132.6, 126.3, 104.7, 100.4, 36.9, 35.1, 33.0, 28.8, 23.8,
14.6; IR 3350, 2928, 1614, 1487, 1429, 1260 cmꢀ1; Mpt 107–109 °C; MS (LRESI)
458.98 (MꢀH). Compound
yield = 63% 1H NMR (500 MHz, CD3OD-d4) d 6.81 (d, J = 8.5 Hz, 2H, Ar), 6.69
(d, J = 8 Hz, 2H, Ar), 6.64 (s, 2H, Ar), 6.42 (s, 2H, Ar), 5.75 (s, 1H, CHbridging); 13
5 column chromatography DCM/MeOH 9:1
C
NMR (500 MHz, CD3OD-d4) d 156.6, 156.4, 154.0, 136.0, 134.4, 131.2, 126.2,
116.0, 104.6, 99.8, 42.9; IR 3426, 2922, 1734, 1614, 1511, 1427, 1242,
1054 cmꢀ1
;
Mpt 201–202 °C; MS (LRESI) 480.95 (MꢀH). Compound 6:
column chromatography DCM/MeOH 9:1 yield 36%, 1H NMR (500 MHz,
CD3OD-d4) 7.29 (d, J = 8.0 Hz, 2H, Ar) d 7.14 (t, J = 8.0 Hz, 1H, Ar), 6.78 (s, 2H,
Ar), 6.42 (s, 2H, Ar), 6.36 (s, 1H, CHbridging); 13C NMR (500 MHz, CD3OD-d4) d
156.8, 154.4, 140.3, 137.6, 134.9, 130.4, 129.0, 122.1, 104.2, 99.7, 43.0; IR 3481,
2923, 1610, 1502, 1426, 1338, 1173, 1122, 1011 cmꢀ1; Mpt 162–164 °C; MS
(LRESI) 533.02 (MꢀH). Compound 7: column chromatography DCM/MeOH 9:1
yield 75%, 1H NMR (500 MHz, CD3OD-d4) d 8.07 (d, J = 8.5 Hz, 1H, Ar) 7.84 (s,
1H, Ar), 7.50 (t, J = 8.0 Hz, 1H, Ar), 7.43 (d, J = 7.5 Hz, 1H, Ar), 6.67 (s, 2H, Ar),
32. Shin, D. S.; Kim, S.; Yang, H. C.; Oh, K.-B. J. Microbiol. Biotecnol. 2005, 15, 652.