An efficient lactamization of fimbrolides to novel 1,5-dihydropyrrol-2-ones

Article abstract of DOI:10.1016/j.tetlet.2007.01.165

A new versatile method for the conversion of fimbrolides to the corresponding novel dihydropyrrol-2-ones is described. This new efficient lactamization protocol has the advantage of higher yields and can be used for the synthesis of a series of new dihydr

Full text of DOI:10.1016/j.tetlet.2007.01.165

Tetrahedron Letters 48 (2007) 2287–2290
An efficient lactamization of fimbrolides to novel
1,5-dihydropyrrol-2-ones
Wai Kean Goh, George Iskander, David StC Black and Naresh Kumar*
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
Received 8 December 2006; revised 22 January 2007; accepted 31 January 2007
Available online 3 February 2007
Abstract—A new versatile method for the conversion of fimbrolides to the corresponding novel dihydropyrrol-2-ones is described.
This new efficient lactamization protocol has the advantage of higher yields and can be used for the synthesis of a series of new
dihydropyrrol-2-ones with interesting anti-bacterial properties.
ꢀ 2007 Elsevier Ltd. All rights reserved.
R2
R1 R2 R3
Br
OAc H Br
With the emergence of multi-resistant strains of bacte-
ria, it is increasingly important to identify new therapeu-
tic compounds with novel mechanisms of action to
supplement existing anti-microbials. A key strategy is
to target the various regulatory systems in bacteria that
control the expression of virulence.
R3
a
b
c
d
e
H
H
Br
O
OH H Br
H
Br Br
R1
O
OAc H Cl
1
Bacteria utilize a rich lexicon of diffusible chemical sig-
nals to communicate both within and between species.1
These chemical cues are used as a Quorum Sensing
(QS) platform for a variety of signal detection and trans-
duction mechanisms that are vital for processes such as
bioluminescence, virulence factor expression and biofilm
development.2
growth. The potency of the fimbrolides has encouraged
an interest in developing synthetic analogues of the par-
ent fimbrolide as novel anti-bacterial agents.
In view of the important biological properties of the fim-
brolides, modifications on the basic scaffold of the ring
may also bring significant changes in the antagonist
activities, which have not been previously reported. A
related structure to the fimbrolides is 1,5-dihydropyr-
rol-2-ones 2.
It is well understood that pathogenic bacteria rely on
this system to control the expression of virulence.3–5
One such system, found in the Gram-negative bacteria
is the N-acylated homoserine lactone (AHL) system,
which controls phenotypes such as biofilm formation.2
R1
R2
R1 = alkyl
R2 = H, Br
R3 = H, Br
R4 = alkyl, aryl
R3
Br
It has been shown that fimbrolides 1, a novel class of
marine natural products isolated from Delisea pulchra,
act as antagonists that specifically inhibit the AHL-
dependent phenotypes (swarming and bioluminescence)
behaviour of Serratia liquefaciens.4,6
O
N
R4
2
Ecological studies have found fimbrolides 1 to be effec-
tive in reducing the bacterial phenotype expression while
having minimal effect on bacterial protein synthesis or
Numerous methods for the synthesis of the pyrrol-2-
ones have been reported;7–9 however, these methods lack
the halogenation pattern present in fimbrolides.
Recently, synthesis of 3-butyl-5-bromomethylene-1,5-
dihydropyrrol-2-one has been reported via halolactami-
zation of allenamides with copper halides, in moderate
*
Corresponding author. Tel.: +61 293854698; fax: +61 293856141;
e-mail: n.kumar@unsw.edu.au
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.165

2288
W. K. Goh et al. / Tetrahedron Letters 48 (2007) 2287–2290
yields.10 The uniqueness of the bromination pattern on
the ring and the presence of the bromomethylene group
make this molecule more elusive to the common lacta-
mization reactions that have been reported in the litera-
ture. Thus, the real challenge in synthesis lies in
preserving the bromination pattern, critical for biologi-
cal activity.
on compound 4b showed a correlation of H3 with the
nitrogen, thus confirming the presence of the lactam
ring.
Reactions with aniline required heating at 80 ꢁC for
24–48 h for completion and afforded two products in
equal ratios (Scheme 2). The first product with the
higher Rf value was phenyl-amino-methylene furanone
6 formed by a Michael-type addition across the
methylene side chain of the fimbrolide.
Here, we report a direct route to the 5-bromomethylene-
dihydropyrrol-2-one ring system via an efficient lactone–
lactam conversion. Significantly, this new approach
maintains the unique bromination pattern of the mole-
cule (Table 1).
The second eluted compound was the desired hydroxy-
lactam 4a. The structure of the former was established
by an X-ray crystallographic analysis. Reaction of the
natural fimbrolide 1b (R1 = OAc) with diethylamine
has been previously reported to yield the similar 5-
amino-methylene compound.12
Fimbrolides 3 (where R1 is restricted to H, n-C4H9 or n-
C6H13) were obtained via the sulfuric acid catalyzed
cyclization of brominated 2-alkyl-levulinic acids.11
5-Hydroxy-1,5-dihydropyrrol-2-ones 4 were synthesized
by dissolving fimbrolides 3 in CH2Cl2, cooling to 0 ꢁC,
and treating with excess amine (Scheme 1). Because of
the many potential reactive sites on the fimbrolide mole-
cules, the reaction temperature had to be closely
regulated as alkylamine reactions must be performed
in ice-cold conditions to control the regiospecificity of
the amine reaction at C2. The reactions were completed
within 2–3 h resulting in hydroxy-lactams 4a–i as the
only products (TLC monitoring) in good yields.
The dehydration of 5-hydroxy-1,5-dihydropyrrol-2-ones
4 could be accomplished by several dehydrating agents
such as sulfuric acid, phosphorus pentoxide or p-tolu-
enesulfonic acid (p-TsOH).13 It was found that p-TsOH
gave the cleanest reactions and products 5a–i were easily
purified by chromatography and obtained in high yields
(Scheme 1). The Z-isomer of the lactam was isolated
from all reactions as shown by a comparison of the
chemical shift of the methylene proton with that of the
corresponding parent fimbrolide.
The 1H NMR spectra of hydroxy-lactams 4a–i exhibit a
characteristic AB doublet for the CH2Br protons at d
3.30–3.60 ppm. A further 1H–15N HMBC experiment
The formation of the hydroxy-lactam analogues could
be explained by the reaction sequence presented in
Scheme 3.
A molecule of amine could react at the carbonyl group
followed by ring opening to form the amide intermediate
7. Subsequent keto–enol tautomerism would yield the
Table 1. Lactone–lactam conversion reaction of fimbrolides
R1
R2
4 Yielda (%)
5 Yielda (%)
a
b
c
d
e
f
H
H
H
Ph
20
57
39
26
73
80
69
85
82
92
80
43
95
98
82
91
89
79
CH2Ph
n-C4H9
Ph
CH2Ph
n-C4H9
Ph
Br
Br
Br
CH2Br
OH
n-C4H9
n-C4H9
n-C4H9
n-C6H13
n-C6H13
n-C6H13
Ph-NH2
+
H
H
O
O
O
O
O
N
Br
NH
Ph
g
h
i
Ph
CH2Ph
n-C4H9
6
4a
a Yield of isolated pure product.
Scheme 2.
Br
H
Br
R1
Br
R1
Br
H
R2-NH2
O
O
CH2Br
OH
H
O
Br
O
NH HO
O
O
O
N
Br
R
Br
R2
7
3
4a-i
R-NH2
O
R1
Br
Br
Br
P2O5
p-TsOH
H
H
Br
H
CH2Br
OH
O
N
R2
or
N
R
NH
R
O
Br
5a-i
8
Scheme 1.
Scheme 3.

W. K. Goh et al. / Tetrahedron Letters 48 (2007) 2287–2290
2289
more stable keto tautomer 8, and this intermediate
of the pendant hydroxyl group of compound 10 on the
would cyclize to generate the lactam ring.
C5 position of a second molecule.
In an attempt to prepare 1-(2-hydroxyethyl)-dihydro-
pyrrol-2-one 9 by the reaction of ethanolamine with fim-
brolide 1d, formation of a dimeric structure containing a
ten-membered heterocyclic ring 11, was observed
instead of the expected dibromomethylene lactam 10
(Scheme 4).
All reported products were characterized by 1H and 13
C
NMR, IR spectra, mass spectra and elemental analyses,
and several by X-ray crystallographic analysis.
In conclusion, an efficient sequential lactamization of
fimbrolides to the corresponding dihydropyrrol-2-ones
has been developed. This reaction scheme generates a
new series of N-substituted dihydropyrrol-2-one deriva-
tives, which show potent Quorum Sensing antagonist
activity in Gram-negative bacteria.
The structure of dimer 11 was consistent with NMR and
mass spectroscopic data and confirmed by X-ray crystal-
lographic analysis14 (Fig. 1). It is likely that compound
11 was formed by the intermolecular nucleophilic attack
Acknowledgements
C4H9
O
C4H9
O
We thank the University of New South Wales and
the Australian Research Council for their financial
support.
a
CHBr2
OH
Br
Br
O
N
1d
OH
9
References and notes
b
1. Bassler, B. L.; Winans, S. C. J. Bacteriol. 2002, 184, 873–
883.
2. Chen, X.; Schauder, S.; Potier, N.; Dorsselear, A. V.;
Pelczer, I.; Bassler, B. L.; Hughson, F. M. Nature 2002,
415, 545–549.
3. Manefield, M.; De Nys, R.; Kumar, N.; Read, R.;
Givskov, M.; Steinberg, P.; Kjelleberg, S. Microbiology
1999, 145, 283–291.
4. Zhang, R.; Pappas, T.; Brace, J. L.; Miller, P. C.;
Oulmassov, T.; Molyneaux, J. M.; Anderson, J. C.;
Bashkin, J. K.; Winans, S. C.; Joachimiak, A. Nature
2002, 417, 971–974.
C4H9
O
CHBr2
O
Br
O
N
N
Br
N
O
O
OH
10
Br2HC
11
Scheme 4. Reagents: (a) Ethanolamine/CH2Cl2, (b) treatment with
P2O5.
5. Geske, G. D.; Wezeman, R. J.; Siegel, A. P.; Blackwell, H.
E. J. Am. Chem. Soc. 2005, 127, 12762–12763.
6. Hentzer, M.; Riedel, K.; Rasmessenl, T.; Heydorn, A.;
Anderson, J. B.; Parsek, M. B.; Rice, S. A.; Eberl, L.;
Molin, S.; Hoiby, N.; Kjelleberg, S.; Givskov, M. Micro-
biology 2002, 148, 87–102.
7. Ghelfi, F.; Stevens, C. V.; Laureyn, I.; Van Meenen, E.;
Rogge, T. M.; De Buyck, L.; Nikitin, K. V.; Grandi, R.;
Libertini, E.; Pagoni, U. M.; Schenetti, L. Tetrahedron
2003, 59, 1147–1157.
8. Mase, N.; Nishi, T.; Takamori, Y.; Yoda, H.; Takabe, K.
Tetrahedron: Asymmetry 1999, 10, 4469–4471.
9. Egorova, A. Y.; Sedavkina, V. A.; Timofeeva, Z. Y. Chem.
Heterocycl. Comp. 2001, 37, 694–697.
10. Ma, S.; Xie, H. Tetrahedron 2004, 61, 251–258.
11. Manny, A. J.; Kjelleberg, S.; Kumar, N.; de Nys, R.;
Read, R. W.; Steinberg, P. Tetrahedron 1997, 53, 15813–
15826.
12. Kazlauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J.
Tetrahedron Lett. 1977, 1, 37–40.
13. Representative procedure for 5: Fimbrolides 3 (2.0 mmol)
were dissolved in CH2Cl2 (10 mL) and the solution was
cooled to 0 ꢁC. The amine (10.0 mmol, 5 equiv) in CH2Cl2
(10 mL) was added dropwise to the solution and the
reaction mixture was maintained at 0 ꢁC for 3 h. The
reaction mixture was quenched with hydrochloric acid
(2 M) and the dichloromethane layer washed with a
saturated aqueous sodium bicarbonate solution followed
by brine. The organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Flash
Figure 1. ORTEP diagram of 11.

2290
W. K. Goh et al. / Tetrahedron Letters 48 (2007) 2287–2290
column chromatography provided intermediate 4, which 449.985299 (M+Na; calcd for C18H21Br2NONa, m/z
together with p-TsOH (0.3 mmol equiv) was dissolved in
dry CHCl3 and refluxed for 2 h. The mixture was
concentrated in vacuo and purified by flash chromatogra-
phy to give dihydropyrrol-2-one derivatives 5a–i. Com-
pound 5h: Yellow oil; 1H NMR: d 0.87 (m, 3H, CH3), 1.31
(m, 6H, 3 · CH2), 1.56 (m, 2H, CH2), 2.43 (m, 2H, CH2),
5.27 (s, 2H, NCH2), 6.21 (s, 1H, CHBr), 7.13–7.32 (m, 5H,
449.986188).
14. Crystal data for 11: C22H30Br4N2O4, colourless, crystal
dimension 0.34 · 0.14 · 0.14 mm, triclinic, space group
˚
˚
˚
ꢀ
P1, a = 6.731(4) A, b = 10.461(5) A, c = 11.759(6) A,
a = 83.27(3)ꢁ,
b = 75.38(3)ꢁ,
c = 82.24(3)ꢁ,
V =
3
790.9(5) A , Mr = 788.2, Z = 1, Dc = 1.65 Mg/m3,
˚
k = 0.71073 A, l(MoKa) = 5.077 mmÀ1
, F(000) = 392,
˚
H
aryl); 13C NMR: 13.9 (CH3), 22.4 (CH2), 25.4 (CH2), 27.2
2ꢁ < h < 23ꢁ, R = 0.047, wR = 0.057, S = 1.74, largest
3
˚
(CH2), 28.9 (CH2), 31.3 (CH2), 43.9 (NCH2), 90.5 (CHBr),
126.2 (2C) (CHaryl), 126.6 (C), 127.0 (CHaryl), 128.4 (2C)
(CHaryl), 135.6 (C), 137.5 (C), 138.6 (C), 169.2 (C@O); IR:
(Nujol, m, cmÀ1): 3081, 3029, 1705, 1624, 1453, 1432, 1354,
1152, 882, 721, 695; HRMS (M+Na in ESI): m/z
difference in peak and hole: 0.71 and À1.13 e/A . Crys-
tallographic data for the structure of 11 reported in this
paper have been deposited with the Cambridge Crystal-
lograpic Data Centre as Supplementary Publication No.
CCDC-629740.