Two-step synthesis of the bipyrrole precursor of prodigiosins

Article abstract of DOI:10.1016/j.tetlet.2006.02.035

The key intermediate in the synthesis of prodigiosins, 4-methoxy-2, 2′-bipyrrole-5-carboxaldehyde, has been prepared in two steps and 65% overall yield from the commercially available 4-methoxy-3-pyrrolin-2-one.

Full text of DOI:10.1016/j.tetlet.2006.02.035

Tetrahedron Letters 47 (2006) 2605–2606
Two-step synthesis of the bipyrrole precursor of prodigiosins
Kenza Dairi, Sasmita Tripathy, Giorgio Attardo and Jean-Fran c¸ ois Lavall e´ e*
*
Department of Medicinal Chemistry, Gemin X Biotechnologies Inc., 3576 Avenue du Parc, Suite 4310,
Montr e´ al, Canada QC H2X 2H7
Received 19 January 2006; revised 3 February 2006; accepted 6 February 2006
Available online 23 February 2006
0
Abstract—The key intermediate in the synthesis of prodigiosins, 4-methoxy-2,2 -bipyrrole-5-carboxaldehyde, has been prepared in
two steps and 65% overall yield from the commercially available 4-methoxy-3-pyrrolin-2-one.
ꢀ
2006 Elsevier Ltd. All rights reserved.
0
4
-Methoxy-2,2 -bipyrrole-5-carboxaldehyde is the key
O
B
intermediate in the biosynthesis of many polypyrrole
natural products such as the prodigiosins and tambja-
mines. Although its chemical structure is relatively simple
NH
1
OMe
and known for more than 40 years, only three groups
have reported its total synthesis with modest overall
yields. In 1996, a new alternative approach for the syn-
H
N
MeO
R
B
N
2
C
TfO
thesis of prodigiosins was reported by D’Alessio and
3
Rossi. In contrast with biomimetic routes in which
H
N
C
the B ring was first coupled to the A ring, they have first
condensed the C ring to B ring (Scheme 1) and com-
pleted the synthesis through a Suzuki cross-coupling
reaction with ring A. Although the synthesis is very
short, efficient, and scalable, it does not give access to
the natural bipyrrole aldehyde precursor of pro-
digiosins.
R
Boc
N
A
B(OH)2
OMe
In this present letter, we wish to report a two-step syn-
A
B
N
0
thesis of 4-methoxy-2,2 -bipyrrole-5-carboxaldehyde
N
H
4
(
3). Using the same building blocks as D’Alessio and
Rossi, we have reorganized the reaction sequence in
order to get access to the natural biomimetic precursor.
The commercially available 4-methoxy-3-pyrolin-2-one
H
N
C
R = C H
23
1
1
(
1) (Scheme 2) was treated with the Vislmeier–Haack
R
reagent (3 equiv) derived from diethylformamide to
produce the bromo pyrrole enamine 2 in 70% yield.
Scheme 1.
5
,6
Using the original procedure with dimethylformamide,
proceeded in only 30% yield despite the use of various
experimental conditions. This key haloformylation reac-
tion has been previously reported by Von Dobeneck and
Schnierler in 1966 on a dialkylpyrrolinone derivative
7
but to our knowledge, it has never been applied to the
synthesis of prodigiosins. The Suzuki cross-coupling
Keywords: Natural product; Prodigiosins; Tambjamines; Haloformyla-
tion; Bipyrrole; Suzuki coupling.
3
,8
*
Corresponding authors. Tel.: +1 514 281 8989; fax: +1 514 281 1065
J.-F.L); e-mail addresses: jflavallee@geminx.com; stripathy@geminx.
reaction between 2 and the Boc-pyrrole boronic acid
led to the desired natural bipyrrole aldehyde 3 in 95%
(
9
1
com
yield. The H NMR, FT-IR, HRMS and TLC were
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.035

2606
K. Dairi et al. / Tetrahedron Letters 47 (2006) 2605–2606
Boc
OMe
N
ii
OMe
OMe
B(OH)2
N
N
H
N
N
N
CHO
i
H
H
O
Br
1
2
3
Scheme 2. Reagents and conditions: (i) POBr (3 equiv), diethylformamide (3 equiv), chloroform, reflux, 5 h, 70%. (ii) Boc pyrrole boronic acid
3
1.5 equiv), Pd(PPh , dioxane, H O, Na CO , reflux, 2.5 h, 95%.
3
(
3
)
4
2
2
in perfect agreement with the reported spectroscopic
data and with those recorded from an authentic sample
obtained by fermentation.
ature, and then heated at 60 ꢁC for 5 h. The mixture was
poured onto ice (75 mL), and the pH of the aqueous
solution was adjusted to pH 7–8 by treatment with NaOH
1
0
2
N. EtOAc (40 mL) was added to the resulting precipitate
ꢂ
and the mixture was filtered over Celite to remove the
black solid containing phosphorus salts. The two layers
were separated and the aqueous layer was extracted with
EtOAc (3 · 100 mL). The organic layers were combined,
Using the final condensation step described by Rapo-
2
a
port and Holden with different pyrroles, compound 3
and also other dipyrrole derivatives were converted to
1
1
prodigiosin analogues. This new approach has been
adapted and used on kg scale to support the develop-
2 4
washed with brine (3 · 200 mL), dried over Na SO ,
filtered and the solvent was removed by rotary evapora-
tion to furnish the crude bromo enamine 2. The residue
was filtered over a pad of silica gel (50 mL) using a 10%
EtOAC/hexanes as eluent to obtain the enamine as an oil,
1
2
ment of GX15-070, the first prodigiosin derivative to
reach clinical trials in oncology.
which upon drying in vacuo led to a beige solid. Yield:
1
Acknowledgements
3
.20 g, 70%. Mp: 38–40 ꢁC. H NMR (300 MHz, CDCl ):
3
d (ppm) 1.24–1.37 (6H, m), 3.31–3.46 (2H, q, J = 7.1), 3.76
(3H, s), 4.03–4.18 (2H, q, J = 7.1), 5.58 (1H, s), 6.98 (1H,
s). HRMS; m/z: 259.0440 [M+1]. Found: 259.0443.
We would like to thank Professor Daniel Chapdelaine
from University of Quebec in Montreal (UQAM) for
access to their FT-IR instrument and Ms. Sonia Bourgeois
for the spectra recording. Finally, Dr. Terrence W.
Doyle for reviewing the manuscript.
´
7
8
9
. Von Dobeneck, H.; Schnierle, F. Tetrahedron Lett. 1966,
4
3, 5327–5330.
. Martina, S.; Enkelmann, V.; Schlueter, A. D.; Wegner, G.
Synth. Metals 1991, 41, 403–406.
. Preparation of compound 3: To a degassed solution of
References and notes
toluene (1.5 mL) were added Pd(OAc)
and PPh (0.45 equiv, 456 mg). The mixture immediately
became bright yellow and was stirred at 70 ꢁC for 20 min
under N . A solution of bromo pyrrole enamine 2 (1 g,
.86 mmol) and N-Boc-pyrroleboronic acid (1.5 equiv,
.22 g) in 10% water/dioxane (15 mL) was degassed and
2
(0.1 equiv, 86 mg)
3
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2
suspension of Pd(PPh
addition of Na CO (3.0 equiv, 1.23 g). The mixture was
stirred for 90 min at 100 ꢁC and then poured onto water
100 mL), the pH of the solution was lowered to pH 7 with
N HCl. The brown precipitate was recovered by filtra-
3 4
) in toluene followed by the
2
3
(
2
1
3
4
tion over a fritted disc funnel and washed with water then
acetone. The yellow solid was washed with 10 mL of
0
CHCl
3
then 2 · 10 mL Et
2
O. The desired 4-methoxy-2,2 -
5
bipyrrole-5-carboxaldehyde (3) is obtained as a yellow
solid and used without further purification. Yield: 700 mg,
ꢀ
1
9
1
5%. Mp: 224–227 ꢁC (dec.). IR (Neat, cm ): 3244, 3196,
1
6
607, 1360. H NMR (300 MHz, DMSO-d ): d (ppm) 3.82
(
3H, s), 6.10 (1H, t, J = 2.9), 6.26 (1H, s), 6.73 (1H, d,
6
. Preparation of compound 2: To a mixture of diethylform-
amide (3 equiv, 5.8 mL) and chloroform (5 mL) at 0 ꢁC
was added dropwise a solution of phosphorus oxybromide
J = 2.6), 6.89 (1H, br s), 9.27 (1H, s), 11.13–11.29 (1H, br
s), 11.32–11.49 (1H, br s). HRMS; m/z: 191.0815 [M+1].
Found: 191.0807.
(
2.5 equiv, 12.6 g) in chloroform (15 mL). The resulting
1
1
0. Produced by MDS Pharma Services, South Bothell WA,
USA.
1. For recent examples see: Baldino, C. M.; Parr, J.; Wilson,
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suspension was stirred at 0 ꢁC for 30 min, and the solvent
was removed by rotary evaporation to obtain the Vilsme-
ier complex as a white solid. After drying in vacuo for
0 min, chloroform (10 mL) was added to the solid and
cooled to 0 ꢁC. A solution of 4-methoxy-3-pyrrolin-2-one
1) (2 g, 17.7 mmol) in chloroform (20 mL) was added
dropwise and the mixture was warmed to room temper-
2
1
2. 2-[2-[(3,5-Dimethyl-1H-pyrrol-2-yl)methylene]-3-methoxy-
(
2H-pyrrol-5-yl]-1H-indole.