An efficient synthesis of brominated 4-alkyl-2(5H)-furanones

Article abstract of DOI:10.1016/j.tetlet.2009.05.105

A versatile method for the synthesis of novel brominated 4-alkyl-2(5H)-furanones under mild reaction conditions is described. This synthetic strategy requires only one chromatographic separation over six steps and employs the cyclodehydration of brominate

Full text of DOI:10.1016/j.tetlet.2009.05.105

Tetrahedron Letters 50 (2009) 4613–4615
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of brominated 4-alkyl-2(5H)-furanones
George Iskander, Ruonan Zhang, Daniel Shiu-Hin Chan, David StC Black,
*
Mahiuddin Alamgir, Naresh Kumar
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A versatile method for the synthesis of novel brominated 4-alkyl-2(5H)-furanones under mild reaction
conditions is described. This synthetic strategy requires only one chromatographic separation over six
steps and employs the cyclodehydration of brominated levulinic acid as the key transformation.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 4 April 2009
Revised 21 May 2009
Accepted 26 May 2009
Available online 30 May 2009
Keywords:
Furanone
Fimbrolide
Cyclodehydration
Quorum sensing inhibitor
R1
R1 R2
The indiscriminate overuse of conventional antibiotics to com-
bat bacterial infection has resulted in the evolution of multidrug-
resistant bacterial ‘superbugs’.1 New therapeutic compounds with
novel modes of action are urgently needed to complement existing
anti-microbial treatments.2
A new key strategy is to target the various intercellular chemical
communication systems in bacteria known as ‘quorum sensing’.3
This regulatory platform mediates critical bacterial behaviour such
as biofilm formation, swarming motility and the expression of viru-
lence factors.4
Naturally occurring halogenated furanones or fimbrolides 1
isolated from the marine alga Delisea pulchra were found to inhi-
bit the N-acylhomoserine lactone (AHL)-mediated quorum sens-
ing system employed by many pathogenic gram-negative
bacterial species.5 Synthetic fimbrolides such as 2 are potent
antagonists of Pseudomonas aeruginosa virulence in vitro and in
vivo.6
Br
Br
a
b
c
d
H
H
R2
Br
OAc H
O
O
O
O
H
Br
OH
H
Br
1
2
In continuation of our efforts to develop novel quorum sensing
inhibitors based on fimbrolides,8 we decided to target 4-substituted
2(5H)-furanones 3,4 to investigate their potential biological activi-
ties. Furanones 4 (R = alkyl) are close analogues of the natural fim-
brolide 1a, but with the 3-alkyl and 4-bromo substituents
interchanged.
R
Br
R
Importantly, these furanones were efficacious at non-bacterici-
dal concentrations and therefore should not impose the same
selective pressure as conventional antibiotics on bacteria to de-
velop resistance. To date, over 200 analogues of furanones with
different bromination patterns and alkyl chain lengths have been
generated and evaluated for quorum sensing inhibitory
activities.7
O
O
O
O
Br
Br
4
3
R = alkyl, phenyl, benzyl
Although various methodologies exist for the synthesis of 3-alkylf-
uranones similar to fimbrolide 1a,9,10 an equivalent method to
furanones 3,4 has not previously been reported. 4-Alkyl-3-bromo-
2(5H)-furanones unsubstituted at C5 have been prepared via
bromination–dehydrobromination of 4-alkyl-2(5H)-furanones,11 or
* Corresponding author. Tel.: +61 2 9385 4698; fax: +61 2 9385 6141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.105

4614
G. Iskander et al. / Tetrahedron Letters 50 (2009) 4613–4615
the regioselective Suzuki–Miyaura reaction of 3,4-dibromo-2(5H)-
furanones.12 The presence of the additional exocyclic bromomethyl-
ene moiety at C5 in furanones 3,4 makes these syntheses
unsuitable. Here we describe a versatile and efficient method for
the synthesis of novel fimbrolide analogues 3,4 employing the
cyclodehydration of brominated levulinic acid as the key step.
The intermediate 4-oxoalkenoic acids 6a–h were obtained from
the acid-catalysed condensation of 2-alkanones 5 with glyoxylic
acid (Scheme 1). In order to assess the generality of our methodol-
ogy, and to provide potential SAR data on the 4-alkyl-substituted
series of furanones, we used 2-alkanones with aliphatic side chains
of different lengths ranging from methyl to n-decyl, as well as phe-
nyl and benzyl-substituted alkanones.
H
H
R
H
H
OH
O
O
6a-h
Figure 1. Key NOE correlation for (E)-alkenoic acids 6.
O
Br
O
H
Br2, CH2Cl
2
OH
OH
-78 °C to rt, 15 h
Br
R
O
R
O
The condensation reaction of 2-alkanones 5 occurs regioselec-
tively at C3, and 4-oxoalkenoic acids 6a–h are formed as the major
products.13 The minor products 7 resulting from condensation at
C1 and pseudoacids 8 were also sometimes observed in low yields.
In contrast, branched 2-alkanones react preferentially at the less
hindered C1 position,14 presumably due to kinetic factors. The E-
stereochemistry for alkenoic acids 6 was established on the basis
of NOE correlations of the olefinic proton to the terminal methyl
group (Fig. 1).
6a-h
9a-h
p-TsOH, toluene
reflux, 24 h
75-87%
P2O5, CH2Cl2
reflux, 2 h
58-89%
Br R
R
H
Br
O
O
O
O
The key 3-alkyl-2,3-dibromolevulinic acids 9a–h were prepared
via bromination of 4-oxoalkenoic acids 6. A range of dehydrating
agents were investigated for the cyclodehydration of 4-oxoalke-
noic acids 6 and brominated levulinic acids 9, including phospho-
rus pentoxide, p-toluenesulfonic acid, silica gel, alumina,
polyphosphoric acid, phosphoryl chloride, acetic anhydride, triflu-
oroacetic anhydride and triflic anhydride. Of these, p-toluenesul-
fonic acid was found to be the most efficient for the cyclisation
of 4-oxoalkenoic acids 6 into the corresponding 5-methylene-4-
alkylfuranones 10a–h, while phosphorus pentoxide in dichloro-
methane gave the highest yields for the cyclisation of brominated
acids 9 to dihydrofuranones 11a–h (Scheme 2). In the latter case, a
simple filtration sufficed to afford the corresponding dihydrofura-
nones 11a–h in moderate to high yields and sufficient purity for
use in the next step. This cyclodehydration reaction appears to
be quite general and was repeated on a gram scale. Interestingly,
during the bromination of alkenoic acids 6, partial cyclisation of
the alkenoic acids to the 5-hydroxy-5-methyl-4-alkylfuranones 8
was also observed. This product does not undergo bromination
as the double bond is now in the ring. This compound can be dehy-
drated under acidic conditions to yield 5-methylene-4-alkylfura-
nones 10a–h.
10a-h
11a-h
Scheme 2. Cyclodehydration reactions of acids 6a–h and 9a–h.15
containing the 5-bromomethylene moiety by a standard bromina-
tion–dehydrobromination sequence (Scheme 3).
While the bromination of the 2(5H)-furanones 12 to the trib-
romo intermediates 13 proceeded smoothly, unexpected difficul-
ties were encountered in the dehydrobromination step
employing the previously used reagent such as DBU or DABCO.
Fortunately, this was overcome by the use of N,N-diisopropylethyl-
amine (Hünig’s base) in dichloromethane to yield the target 4-al-
kyl-3-bromo-5-bromomethylene-2(5H)-furanones 4a–h.16 Similar
bromination and dehydrobromination of the desbromo furanones
10 gave 4-alkyl-5-bromomethylene-2(5H)-furanones 3a–f.17 How-
ever, in this case dehydrobromination could be carried out with
DBU in dichloromethane.
It is known that the chemical shift value for the exocyclic
olefinic proton in 5-bromomethylene-2(5H)-furanones is charac-
teristic for either the (Z)-isomer (typically d 6.24 ppm) or the (E)-
isomer (typically d 6.57 ppm).18 Thus the (Z)-stereochemistry of
the products was confirmed by the chemical shifts of that proton,
which occurred in the range d 6.22–6.25 ppm for furanones 4a–h.
The preference for the (Z)-isomer is expected because the alkyl
chain at C4 discourages the formation of the transition state lead-
The dihydrofuranones 11 were dehydrobrominated by treat-
ment with DBU to yield 5-methylene-2(5H)-furanones 12a–h, as
desbromo analogues of the target furanones 4. We anticipated that
these could be readily converted into the fimbrolide analogues 4
Br R
O
Br
R
H
Br
O
DBU, CH2Cl2
OH
O
O
O
H
-78 °C to rt, 1.5 h
50-82%
O
O
OH
O
R
12a-h
11a-h
H3PO4, 80 °C, 4 h
60-90%
R
O
5a-h
6a-h
Br2, CH2Cl2
-78 °C to rt, 15 h
40-85%
a: R = Me
R
b: R =
c: R =
n
n
n
n
-Pr
O
-Bu
Br
R
Br
R
R
OH
d
: R =
: R =
: R =
-Hex
-Hep
O
OH
EtN(i-Pr)2, CH2Cl2
O
e
O
Br
f
7a-h
8a-h
n
-Dec
O
O
0 °C to rt, 72 h
28-64%
Br
O
O
g
h
: R = Ph
Br
: R = CH2Ph
4a-h
13a-h
Scheme 1. Synthesis of 4-oxoalkenoic acids 6a–h.
Scheme 3. Synthesis of furanones 4a–h.

G. Iskander et al. / Tetrahedron Letters 50 (2009) 4613–4615
4615
8. Goh, W. K.; Iskander, G.; Black, D. StC.; Kumar, N. Tetrahedron Lett. 2007, 48,
2287–2290.
9. Manny, A. J.; Kjelleberg, S.; Kumar, N.; de Nys, R.; Read, R. W.; Steinberg, P.
Tetrahedron 1997, 53, 15813–15826.
10. Caine, D.; Ukachukwu, V. C. J. Org. Chem. 1985, 50, 2195–2198.
11. Grossmann, G.; Poncioni, M.; Bornand, M.; Jolivet, B.; Neuburger, M.; Séquin, U.
Tetrahedron 2003, 59, 3237–3251.
12. Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett. 2001, 42, 3851–3854.
13. Scheffold, R.; Dubs, P. Helv. Chim. Acta 1967, 50, 798–808.
14. Zhang, R.; Chan, D.; Jessica, S.; Iskander, G.; Black, D. StC.; Kumar, N. ARKIVOC
2009, 5, 102–115.
ing to the (E)-isomer, due to steric clashes with the exocyclic bro-
mine atom.
The levulinic acids and the 4-alkyl-2(5H)-furanones were
mostly obtained as colourless, pale yellow or pale brown oils. An
aqueous work-up or filtration was sufficient for all intermediate
reactions and column chromatography was only used after the
final step to isolate furanone products 4a–h. The final products
have a tendency to polymerise while standing, even in cold stor-
age, however they were stable enough to be purified and fully
characterised. All products gave satisfactory 1H and 13C NMR spec-
tra and HRMS values.
15. Representative procedure for compound 11d: To a solution of acid 9d (0.052 mol)
in dry dichloromethane (25 mL) were added phosphorus pentoxide
(0.156 mol) and
a few crystals of hydroquinone, and the mixture was
refluxed for 2 h. The solution was cooled, filtered through a bed of Celite–
In summary, we have described a versatile and efficient method
for the synthesis of novel brominated 4-alkyl-2(5H)-furanones.
This methodology utilises simple starting materials and reagents,
mild reaction conditions and requires only one chromatographic
purification over six steps. Further studies on the chemistry and
biological activity of these fimbrolide derivatives are being con-
ducted in our laboratory.
silica and evaporated under reduced pressure to afford
a mixture of
diastereomers of furanone 11d as a pale yellow oil (89%). 1H NMR (CDCl3): d
0.92 (3H, t, J = 7.1 Hz, CH3), 1.33–1.35 (6H, m, CH2), 1.76 (2H, m, CH2), 2.23–
2.25 (2H, m, CH2), 4.62 and 4.66 (1H, each s, H3), 4.87 and 5.03 (1H, each d,
J = 3.2 Hz, @CHa), 4.88 and 5.05 (1H, each d, J = 3.2 Hz, @CHb); IR (KBr): mmax
2956, 2930, 2859, 1787, 1767, 1650, 1605, 1460, 1378, 1268, 1239, 1166, 1109,
969, 931, 890 cmÀ1. UV–vis (MeOH): kmax 258 nm ( 14,800 cmÀ1MÀ1).
e
16. Representative procedure for compound 4d: To a stirred solution of furanone 13d
(0.05 mol) in dry dichloromethane (100 mL) at 0 °C was added a solution of
N,N-diisopropylethylamine (0.17 mol) in dry dichloromethane (20 mL). The
mixture was allowed to warm to room temperature and was further stirred for
72 h. The reaction mixture was washed successively with 2 M HCl (30 mL) and
brine (30 mL), and the organic extract was dried over Na2SO4 and evaporated
under reduced pressure. Purification by column chromatography on silica gel
(25% dichloromethane/light petroleum) gave furanone 4d (Rf 0.90) as a pale
yellow oil (55%). 1H NMR (CDCl3): d 0.90 (3H, t, J = 7.2 Hz, CH3), 1.33 (6H, m,
CH2), 1.61 (2H, m, CH2), 2.52 (2H, t, J = 7.9 Hz, CH2), 6.22 (1H, s, CHBr). 13C NMR
(75 MHz, CDCl3): d 13.9 (CH3), 22.3, 26.1, 28.2, 29.0, 31.2 (5CH2), 90.5 (CHBr),
117.7, 151.4, 153.5, 163.5 (C@O). IR (KBr): mmax 3092, 2955, 2928, 2857, 1786,
1679, 1636, 1595, 1465, 1364, 1301, 1219, 1183, 1050, 982, 914, 840, 765,
Acknowledgements
We thank the University of New South Wales and the Australian
Research Council for their financial support.
References and notes
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e
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2.11 (3H, s, CH3), 5.98 (1H, s, H3), 6.02 (1H, s, CHBr). 13C NMR (75 MHz, CDCl3):
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