The application of formyl group activation of bromopyrrole esters to formal syntheses of lycogarubin C, permethyl storniamide A and lamellarin G trimethyl ether

Article abstract of DOI:10.1016/j.tet.2014.11.035

Lycogarubin C, permethyl storniamide A, and lamellarin G trimethyl ether are pyrrole containing, natural products, which exhibit interesting biological properties. Such properties include anti-tumor activity on a variety of cancer cell lines including those that confer drug resistance, inhibition of HIV integrase, and vascular disrupting activity. We now describe the use of methyl and ethyl 3-bromo-2-formylpyrrole-5-carboxylate as building blocks for the formal synthesis of these three highly functionalized, bioactive pyrroles. These new building blocks will now provide ready access to the natural products and many novel analogs due to the ability to easily modify positions 2,3,4, and 5 of the pyrrole core.

Full text of DOI:10.1016/j.tet.2014.11.035

Tetrahedron 70 (2014) 9759e9767
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The application of formyl group activation of bromopyrrole esters to
formal syntheses of lycogarubin C, permethyl storniamide A and
lamellarin G trimethyl ether
*
John T. Gupton , Nakul Telang, Jon Patteson, Kristin Lescalleet, Scott Yeudall,
John Sobieski, Andrew Harrison, Will Curry
Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2014
Received in revised form 10 November 2014
Accepted 11 November 2014
Available online 15 November 2014
Lycogarubin C, permethyl storniamide A, and lamellarin G trimethyl ether are pyrrole containing, natural
products, which exhibit interesting biological properties. Such properties include anti-tumor activity on
a variety of cancer cell lines including those that confer drug resistance, inhibition of HIV integrase, and
vascular disrupting activity. We now describe the use of methyl and ethyl 3-bromo-2-formylpyrrole-5-
carboxylate as building blocks for the formal synthesis of these three highly functionalized, bioactive
pyrroles. These new building blocks will now provide ready access to the natural products and many
novel analogs due to the ability to easily modify positions 2,3,4, and 5 of the pyrrole core.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Suzuki cross-coupling
Pyrrole
Marine natural products
1. Introduction
products from slime molds in 1994. It is interesting to note that
11
Sherman (2005) and Walsh12 (2007) have suggested that lyco-
We have recently reported1 the use of ethyl 3-bromo-2-
formylpyrrole-5-carboxylate (1) as a very flexible and efficient
pyrrole building block, which allows for Suzuki cross-coupling re-
actions. This becomes important, since various non-activated bro-
mopyrroles have been reported2e8 to be problematic in such cross-
coupling reactions. In addition to the formyl group activating these
transformations, a versatile carbonyl function is also introduced at
the 2-position of the pyrrole and this is common to many pyrrole
containing natural products. In our recent report, we described the
utilization of this strategy for the formal synthesis of the natural
products polycitone A and B and polycitrin A (Scheme 1).
Lycogarubin C, permethyl storniamide A, and lamellarin G tri-
methyl ether (Fig. 1) also represent novel and biologically signifi-
cant, pyrrole containing natural products and we now describe our
use of the formyl group activation strategy for the completion of
formal syntheses of these substances.
gallic acid is a biosynthetic precursor to the important naturally
occurring, antitumor agents rebeccamycin and staurosporin. Pre-
vious syntheses of members of the lycogarubin/lycogallic acid
family of natural products have been accomplished by Steglich9
(1994), Furstner2 (2002), Onaka13 (2006), Boger14 (2010), Gribble15
(2010), and more recently by Xie16 (2014). The Boger and Gribble
syntheses both rely on the Kornfeld-Boger ring contraction meth-
odology to generate the pyrrole core. In the Gribble synthesis of
lycogarubin C, the final precursor to the natural product was a bis-
N,N-sulfonylated derivative of lycogarubin C and this material sub-
sequently became our synthetic target. We initiated our synthetic
strategy by preparing methyl 3-bromo-2-formylpyrrole-5-
carboxylate (8) in a three step process analogous to ethyl 3-
bromo-2-formylpyrrole-5-carboxylate, which we previously re-
ported.1 Such transformations proceed in very high yield with little
if any purification required of the intermediate products and very
significant amounts of the pyrrole building block (8) can be obtained
very rapidly. It is fortunate that 1-(phenylsulfonyl)-3-indolylboronic
acid pinacol ester (9) is commercially available and it was employed
in our Suzuki cross-coupling reaction (Scheme 2) with our pyrrole
building block (8) using reaction conditions described in our pre-
vious report.1 The resulting cross-coupled product (10) was then
oxidized with sodium chlorite in water/DMSO to produce the cor-
responding acid (11) in goodyield. Subsequent treatmentof this acid
2. Results and discussions
Steglich9 and Asakawa10 simultaneously reported the isolation of
various members of the lycogarubin/lycogallic acid family of natural
* Corresponding author. Tel.: þ1 804 287 6498; fax: þ1 804 287 1897; e-mail
address: jgupton@richmond.edu (J.T. Gupton).
http://dx.doi.org/10.1016/j.tet.2014.11.035
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

9760
J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
Br
Br
OH
Br
HO
Br
MeO
OMe
Br
Several Steps
Several Steps
H
O
O
O
HO
OH
N
H
N
N
H
O
O
O
O
1, Pyrrole Building Block
2, Key Steglich Precursor
Several Steps
OH
4, Polycitrin A
Br
Br
HO
Br
OH
Br
Br
Br
Br
HO
OH
N
X
O
O
Br
3a, X = 4-Hydroxyphenethyl: Polycitone A
3b, X = H: Polycitone B
Scheme 1. Formyl group activation in the formal synthesis of polycitone A and B and polycitrin A.
Me
Me
O
O
O
Me
O
O
Me
MeO
MeO
MeO
MeO
MeO
H
N
H
N
OMe
O
Me
Me
H
N
H
N
N
O
O
MeO
O
OMe
MeO2C
CO2Me
N
N
H
O
5, Lycogarubin C
6, Lamellarin G trimethyl ether
OMe
7, Permethyl Storniamide A
Fig. 1. Pyrrole containing natural products.
(11) with dicabonylimidazole and methanol generated the corre-
sponding bis-methyl ester (12) also in good yield. This diester (12)
was then brominated with KOH/NBS in DMF producing the corre-
sponding 4-bromo compound (13) and this material was cross-
coupled with 1-(phenylsulfonyl)-3-indolylboronic acid pinacol es-
ter (9) under previously detailed conditions. The resulting product
(14) was the Gribble lycogarubin C precursor, which was previously
bis de-sulfonylated with magnesium/ammonium chloride in
methanol by the Gribble group to yield the natural product (5). The
overall yield of the Gribble precursor (14) in five steps from our
pyrrole building block (8) was 37%. The proton and carbon NMR
spectra for compound 14 were identical to the values reported by
Gribble and co-workers.
In order to further demonstrate the utility of this synthetic
strategy as it relates to rapidly generating analogs, which might be
required in a biologically directed SAR study, we decided to utilize
the mono cross-coupled aldehyde (10) as a precursor to such
compounds. We selected boronic acids (16a, 16b, and 16c), which
contain highly oxygenated phenyl groups given that many of
the related pyrrole containing natural products possess such
functionality. The resulting synthetic process is presented in
Scheme 3. The presence of the aldehyde group in the final products
(17) allows great flexibility for further synthetic manipulations.
Another very significant natural product derived compound is
permethyl storniamide A (7, Fig. 1). The storniamide marine alka-
loids were first isolated in 1996 by Seldes and co-workers17 and
subsequently Takamura18 (2009), Iwao19 (2003), Furstner2 (2002),
Boger20 (1999), Steglich21 (1998), and our group22 (2008) reported
either total or formal syntheses of permethyl storniamide A (7,
Fig. 1).
Scheme 4 represents our bromoformylpyrrole methyl ester
building block approach to the synthesis of the Boger storniamide
intermediate20 (23). We have previously prepared22 this same
compound via a vinamidinium salt based approach and compounds
21, 22, and 23 in Scheme 4 have been previously synthesized and
fully characterized. The synthetic steps used in our approach are
analogous to those used in our formal synthesis of lycogarubin C
(Scheme 2). After an initial cross-coupling reaction of the bromo-
formylpyrrole ester (8) with 3,4,5-trimethoxyphenylboronic acid
(18), the resulting pyrrole (19) was oxidized to the corresponding
acid (20) and subsequently esterified (21) with iodomethane and
base. Iodination of the pyrrole diester (21) generated the 3-

J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
9761
SO2
N
O
B
SO2
N
O
9
Br
O
OMe
H
OMe
N
H
H
O
N
H
PdDPPF in Toluene/EtOH
with DABCO and Microwave
Heating at 110 0C for 2 hrs.
O
O
8, Pyrrole
Building Block
10, 90% yield
NaClO2, H2O in DMSO
SO2
N
SO2
N
Dicarbonylimidazole,
MeOH and DMF
OMe
OMe
HO
N
H
MeO
N
H
O
O
O
O
11, 93% yield
12, 87% yield
KOH, NBS
in DMF
SO2
N
O
B
O
SO2
N
SO2
N
SO2
N
9
Br
OMe
PdDPPF in Toluene/EtOH
with DABCO and Microwave
Heating at 110 0C for 2 hrs.
MeO2C
CO2Me
N
H
MeO
N
H
O
O
14, 63% yield, Gribble,
Lycogarubin C precursor
13, 81% yield
Scheme 2. Gupton Group Synthesis of Gribble Precursor to Lycogarubin C.
ArB(OH)2
16a Ar = 4-Methoxyphenyl
16b Ar = 3,4-Dimethoxyphenyl
16c Ar = 3,4,5-Trimethoxyphenyl
SO2
N
SO2
N
SO2
N
KOH, NBS in DMF
Ar
Br
PdDPPF in Toluene/EtOH
with DABCO and
OMe
OMe
H
H
OMe
N
N
H
N
H
H
Microwave Heating
O
O
O
O
O
at 110 0C for 2 hrs.
O
H
15, 89 % yield
17a, 96% yield
17b, 39% yield
17c, 91% yield
10
Scheme 3. Synthesis of Lycogarubin C analogs.

9762
J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
MeO
MeO
MeO
B(OH)2
OMe
MeO
MeO
Br
O
18
OMe
H
OMe
N
H
H
O
N
H
PdDPPF in Toluene/EtOH
with DABCO and Microwave
Heating at 110 0C for 2 hrs.
O
O
8, Pyrrole
Building Block
19, 56% yield
NaClO2, H2O
in DMSO
OMe
OMe
MeO
MeO
MeO
MeO
MeO
Ethyldiisopropyl amine,
Iodomethane in DCM
OMe
HO
OMe
N
H
O
N
H
O
O
O
20, 99% yield
21, 71% yield
KOH, I2
in DMF
Me
O
MeO
Me
OMe
OMe
OMe
O
MeO
MeO
MeO
MeO
MeO
B(OH)2
OMe
MeO
MeO
MeO
18
I
N
O
O
OMe
H
PdDPPF in Toluene/EtOH
with DABCO and Microwave
Heating at 110 0C for 2 hrs.
N
H
O
O
23, 65% yield
Boger Storniamide
Intermediate
22, 62% yield
Scheme 4. Gupton group synthesis of boger intermediate to permethyl storniamide A.
iodopyrrole (22), which was then cross-coupled with 3,4,5-
trimethoxyphenylboronic acid (18) using our standard conditions
for this transformation. The resulting product (23) from the cross-
coupling reaction exhibited spectral properties identical to those
reported for the Boger storniamide intermediate20 and also to
a sample of the compound, which we previously prepared by the
alternate route.22
(25) under our optimized conditions. The resulting product is io-
dinated at C-3 (27) and this material undergoes cross-coupling to
produce a tetrasubstituted pyrrole (28), which we previously pre-
pared24 via the vinamidinium salt route and was fully character-
ized. The spectral properties for the product (28) of our new
methodology were identical to those we reported earlier.
The lamellarin class of pyrrole-containing marine alkaloids has
been studied in some detail23 as a result of potent antitumor ac-
tivity. Lamellarin G trimethyl ether (6) is the substance often used
as a synthetic target for proof of concept for new synthetic methods
and approaches. We have previously reported24 a vinamidinium
salt based approach to this important target and we decided to use
our new synthetic methodology (Scheme 5) for the preparation of
a key pyrrole intermediate (28), which we previously described24 in
our formal synthesis of lamellarin G trimethyl ether (6).
3. Conclusions
Herein we have reported formal syntheses of lycogarubin C and
permethyl storniamde A via our bromoformylpyrrole methyl ester
building block (8). The products (14 and 23) from both reaction
schemes (Schemes 2 and 4) were obtained in five steps from the
pyrrole building block (8) in a very efficient manner. In addition,
a key lamellarin G trimethyl ether intermediate (28) was prepared
from a similar pyrrole building block (24) in 3 synthetic steps.
Regarding the lycogarubin C strategy, three analogs were easily
prepared (Scheme 3) demonstrating that this methodology should
prove very useful for the synthesis of libraries of highly
The synthetic process (Scheme 5) begins with an ethyl ester
analog (24) of our pyrrole methyl ester building block (8), which is
cross-coupled with potassium 3,4-dimethoxyphenyltrifluoroborate

J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
9763
MeO
OMe
MeO
MeO
BF3
K
Br
25
H
O
H
N
H
O
O
N
H
O
PdDPPF in Toluene/EtOH
with DABCO and Microwave
Heating at 110 0C for 2 hrs.
O
O
24
26, 70% Yield
KOH, I2
in DMF
MeO
MeO
OMe
MeO
MeO
MeO
BF3
K
OMe
25
OMe
I
H
H
O
PdDPPF in Toluene/EtOH
with DABCO and Microwave
Heating at 110 0C for 2 hrs.
O
N
H
N
O
O
O
O
H
28, 56% Yield
Gupton Group
27, 70% Yield
Lamellarin Intermediate
Scheme 5. Synthesis of Gupton group lamellarin G trimethyl ether intermediate.
functionalized pyrroles. The examples depicted in Scheme 3 also
demonstrate the regiocontolled nature of introducing different
groups at positions 3 and 4 of the pyrrole core in a sequential
fashion. In addition, it should be noted that the aldehyde group at
C-2 of the various pyrroles (compounds 10,19 and 28) will allow for
a variety of functional group manipulations necessary for SAR
guided synthesis of analogs, which may possess enhanced bi-
ological properties. The vast number of boronic acid derivatives,
which are now commercially available, suggests that the formyl
group activation strategy may have wide ranging utility for the
preparation of highly functionalized pyrroles with complete control
of regiochemistry.
products gave TLC results, flash chromatograms, and 13C NMR
spectra consistent with a sample purity of >95%.
4.1.1. Methyl 3-bromo-2-formylpyrrole-5-carboxylate (8). Into a 100
mL round bottom flask equipped with magnetic stirring and
a rubber septum cap was placed 10 mL of anhydrous dichloro-
methane, 1.61 g (0.022 mol) of dry DMF, 2.90 g (0.019 mol) of
phosphorus oxychloride and the resulting mixture was stirred in an
ice bath for 10 min. To this flask was then added 1.28 g (0.0063 mol)
of methyl 4-bromopyrrole-2-carboxylate in 10 mL of anhydrous
dichloromethane and the resulting mixture was stirred overnight
at room temperature. The reaction was worked up by the addition
of 50 mL of water and separation of the two phases. The aqueous
phase was extracted with additional dichloromethane (3ꢀ15 mL)
and the combined dichloromethane phases were washed with
brine (1ꢀ15 mL), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo to yield 1.20 g (82% yield) of a light brown
solid. This material was of sufficient purity to be used in subsequent
experiments but an analytical sample was prepared by purification
via flash chromatography on a Biotage Isolera system in which case
a light colored solid was obtained, which exhibited the following
4. Experimental
4.1. General
All chemicals were used as received from the manufacturer
(Aldrich Chemicals and Fisher Scientific). All solvents were dried
ꢀ
over 4 A molecular sieves prior to their use. NMR spectra were
obtained on either a Bruker 300 MHz spectrometer, or a Bruker
500 MHz spectrometer in either CDCl3, DMSO-d6 or d6-acetone
solutions. IR spectra were recorded on a Nicolet Avatar 320 FT-IR
spectrometer with an HATR attachment. High resolution mass
spectra were obtained on a Shimadzu IT-TOF mass spectrometer at
the University of Richmond. Low resolution GCeMS spectra were
obtained on a Shimadzu QP 5050 instrument. Melting points and
boiling points are uncorrected. Chromatographic purifications were
carried out on a Biotage SP-1 instrument or a Biotage Isolera in-
strument (both equipped with a silica cartridge). Gradient elution
with ethyl acetate/hexane was accomplished in both instances. The
reaction products were normally eluted within the range of 4e8
column volumes of eluant with a gradient mixture of 60e80% ethyl
acetate in hexane. TLC analyses were conducted on silica plates
with hexane/ethyl acetate as the eluant. All purified reaction
physical properties: mp 169e172 ꢁC; 1H NMR (CDCl3)
d
9.75 (s, 1H),
179.3,
6.97 (d, J¼3.0 Hz, 1H), and 3.94 (s, 3H); 13C NMR (CDCl3)
d
159.9, 130.7, 127.5, 117.9, 107.8, and 52.5; IR (neat) 1704 and
1663 cmꢂ1; HRMS (ES, MþH) m/z calcd for C7H7BrNO3 231.9609,
found 231.9609.
4.1.2. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-5-formyl-1H-pyrrole-2-
carboxylic acid methyl ester (10). Into a 20 mL microwave reaction
tube containing
a stir bar was placed methyl 3-bromo-2-
formylpyrrole-5-carboxylate (0.250 g, 1.22 mmol), 1-(phenyl-
sulfonyl)-3-indolylboronic acid pinacol ester (0.468 g, 1.22 mmol),
DABCO (0.160 g, 1.43 mmol) along with 9 mL of toluene and 3 mL of
ethanol. After stirring the resulting mixture for several minutes,
dichloro[1,10-bis-(diphenyl-phosphino)ferrocene]palladium(II) dic

9764
J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
hloromethane adduct (0.037 g, 0.031 mmol) was added to the
microwave reaction tube followed by the addition of 20 drops of
water and the tube was capped and sealed with a crimping tool. The
reaction mixture was heated in a Biotage Initiator microwave sys-
tem for 2 h at 110 ꢁC. After cooling to room temperature, the re-
action mixture was filtered through a short plug of silica gel and the
silica was subsequently washed with 3ꢀ20 mL of ethyl acetate and
the combined organic materials were concentrated in vacuo to give
a dark solid (0.598 g). The solid was subjected to flash chromato-
graphic purification on a Biotage Isolera system with a SNAP 25 g
silica column in which case an orange-red solid was obtained
(0.374 g, 90% yield). This material exhibited the following physical
a Biotage Isolera system in which case the resulting solid exhibited
the following physical properties: mp 130e132 ꢁC; 1H NMR (ace-
tone-d6)
3H), 7.40 (t, J¼7.8 Hz, 1H), 7.31 (t, J¼7.8 Hz, 1H), 7.14 (s, 1H), 3.88 (s,
3H), and 3.77 (s, 3H); 13C NMR (acetone-d6)
160.2, 160.8, 138.1,
d
8.06e8.09 (m, 4H), 7.68 (t, J¼7.2 Hz, 1H), 7.61e7.64 (m,
d
134.8,134.2,130.5,129.5,126.9,126.1,125.6,124.7,123.6,122.8,121.5,
120.5, 116.3, 115.7, 113.5, 51.2, and 51.0; IR (neat) 1695 cmꢂ1; HRMS
(ES, MþNa) m/z calcd for C22H18N2NaO6S 461.0783 found 461.0777.
4.1.5. 3-(1-Benzenesulfonyl-1H-indol-3-yl)-4-bromo-1H-pyrrole-
2,5-dicarboxylic acid dimethyl ester (13). Into a 100 mL round bot-
tomed flask equipped with a magnetic stir bar was placed 3-(1-
benzenesulfonyl-1H-indol-3-yl)-1H-pyrrole-2,5-dicarboxylic acid
dimethyl ester (0.090 g, 0.205 mmol), KOH (0.023 g, 0.410 mmol)
and 10 mL of DMF. The resulting mixture was stirred for 15 min and
N-bromosuccinimide (0.037 g, 0.205 mmol) was added in one
portion. The flask was covered with aluminum foil and the reaction
mixture was stirred overnight at room temperature. The reaction
was subsequently worked up by dilution with water (20 mL) and
a 10% aqueous solution of sodium thiosulfate (20 mL) followed by
extraction with ethyl acetate (3ꢀ15 mL). The combined organic
phases were washed with water (1ꢀ20 mL), brine (1ꢀ15 mL) and
dried over anhydrous sodium sulfate. After removal of the drying
agent by filtration, the organic phase was concentrated in vacuo to
yield a light yellow solid (0.086 mg, 81% yield). This material
exhibited the following physical properties: mp 182e184 ꢁC; 1H
properties: mp 160e162 ꢁC; 1H NMR (acetone-d6)
d 9.85 (s, 1H),
8.10e8.14 (m, 4H), 7.68e7.73 (m, 2H), 7.62 (t, J¼6.3 Hz, 2H), 7.45 (t,
J¼6.9 Hz, 1H), 7.36 (t, J¼6.9 Hz, 1H), 7.20 (s, 1H), and 3.91 (s, 3H); 13
C
NMR (CDCl3)
d 185.0, 165.4, 143.1, 140.3, 139.6, 136.9, 135.2, 134.9,
133.1, 132.2, 130.8, 130.4, 129.3, 129.2, 125.5, 120.9, 120.2, 118.9, and
56.6; IR (neat) 1720 and 1658 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C
21H16N2NaO5S 431.0678 found 431.0641.
4.1.3. 3-(1-Benzenesulfonyl-1H-indol-3-yl)-1H-pyrrole-2,5-
dicarboxylic acid 5-methyl ester (11). Into a 100 mL round bottomed
flask equipped with
a magnetic stir bar was placed 4-(1-
benzenesulfonyl-1H-indol-3-yl)-5-formyl-1H-pyrrole-2-carboxylic
acid methyl ester (0.120 g, 0.376 mmol) along with 35 mL of DMSO. The
flask was placed in an ice bath and sodium dihydrogen phosphate
(0.204 g, 2.25 mmol), which had been dissolved in 10 mL of water, was
added followed by the dropwise addition of sodium chlorite (0.080 g,
0.881 mmol) in 10 mL of water. The mixture was allowed to stir
overnight. The same reaction conditions were repeated exactly for
a second time and both reaction mixtures were combined and worked
up together. The combined reaction mixtures were adjusted to pH 2
with 6M hydrochloric acid and then diluted with 200 mL of water and
then extracted with ethyl acetate (3ꢀ25 mL). The combined organic
phases were extracted with brine (2ꢀ50 mL), dried over anhydrous
sodium sulfate, filtered and concentrated invacuo to yield 0.270 g (93%
yield) of a yellow solid. This material was of sufficient purity to be used
in subsequent experiments but an analytical sample was prepared by
purification via flash chromatography on a Biotage Isolera system in
which case the resulting solid exhibited the following physical prop-
NMR (acetone-d6)
d
8.04e8.08 (m, 3H), 7.79 (s,1H), 7.69 (t, J¼7.8 Hz,
1H), 7.62 (t, J¼7.8 Hz, 2H), 7.37 (t, J¼6.9 Hz, 1H), 7.32 (d, J¼6.9 Hz,
1H), 7.28 (t, J¼6.9 Hz, 1H), 3.91 (s, 3H), and 3.56 (s, 3H); 13C NMR
(acetone-d6)
d 159.3, 159.1, 138.1, 134.8, 134.2, 130.7, 129.5, 126.9,
126.6, 124.6, 123.9, 123.3, 123.2, 122.0, 121.0, 115.0, 113.5, 105.7, 51.3,
and 51.1; IR (neat) 1699 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C22H17BrN2NaO6S 538.9888 found 538.9895.
4.1.6. 3,4-Bis-(1-benzenesulfonyl-1H-indol-3-yl)-1H-pyrrole-2,5-
dicarboxylic acid dimethyl ester (14). Into a 20 mL microwave re-
action tube containing a stir bar was placed 3-(1-benzenesulfonyl-
1H-indol-3-yl)-4-bromo-1H-pyrrole-2,5-dicarboxylic
acid
di-
methyl ester (0.100 g, 0.190 mmol), 1-(phenylsulfonyl)-3-
indolylboronic acid pinacol ester (0.145 g, 0.380 mmol), and
DABCO (0.031 g, 0.270 mmol) along with 9 mL of toluene and 3 mL
of ethanol. After stirring the resulting mixture for several minutes,
dichloro[1,10-bis-(diphenylphosphino)ferrocene]palladium(II) dic
hloromethane adduct (0.007 g, 0.009 mmol) was added to the
microwave reaction tube followed by the addition of 20 drops of
water and the tube was capped and sealed with a crimping tool. The
reaction mixture was then heated in a Biotage Initiator microwave
system for 2 h at 110 ꢁC. After cooling to room temperature, the
reaction mixture was filtered through a short plug of silica gel and
the silica was subsequently washed with ethyl acetate (2ꢀ20 mL)
and the combined organic phases were concentrated in vacuo to
yield a yellow-orange solid (0.210 g). This material was purified via
flash chromatography on a Biotage Isolera system in which case
a yellow-orange solid (0.082 g, 63% yield) resulted. This material
exhibited spectral properties identical with those reported by
Gribble and co-workers for bis-N-Benzenesulfonyllycogarubin C:
erties: mp 205e207 ꢁC; 1H NMR (acetone-d6)
d 8.19 (s,1H), 8.03e8.06
(m, 3H), 7.67 (d, J¼7.8 Hz, 1H), 7.52e7.59 (m, 3H), 7.34 (t, J¼7.8 Hz, 1H),
7.30 (t, J¼7.8 Hz, 1H), 7.14 (s, 1H), and 3.88 (s, 3H); 13C NMR (acetone-
d6)
d 160.2, 138.0, 134.8, 134.1, 130.7, 129.5, 127.0, 126.4, 124.5, 124.4,
123.5, 120.6, 120.4, 116.2, 116.1, 113.5, and 51.1; IR (neat) 1717 and
1677 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C21H16N2NaO6S 447.0627
found 447.0605.
4.1.4. 3-(1-Benzenesulfonyl-1H-indol-3-yl)-1H-pyrrole-2,5-
dicarboxylic acid dimethyl ester (12). Into a 100 mL round bottomed
flask equipped with a magnetic stir bar, reflux condenser, heating
mantel and under a nitrogen atmosphere was placed carbonyl dii-
midazole (0.077 g, 0.470 mmol) and 3-(1-benzenesulfonyl-1H-
indol-3-yl)-1H-pyrrole-2,5-dicarboxylic acid 5-methyl ester
(0.200 g, 0.470 mmol) in 2 mL of DMF. The reaction mixture was
stirred at 40 ꢁC for 1 h. Methanol (0.003 mL, 0.94 mmol) was then
added to the reaction mixture and the subsequent mixture was
maintained at 40 ꢁC for 24 h. After the reaction mixture had cooled
to room temperature it was diluted with ethyl acetate (20 mL) and
the resulting solution was extracted with 10% hydrochloric acid
(1ꢀ20 mL), saturated aqueous bicarbonate (1ꢀ20 mL) and water
(1ꢀ20 mL). The resuitng organic phase was dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to yield a light
yellow solid (0.180 g, 87% yield). This material was of sufficient
purity to be used in subsequent experiments but an analytical
sample was prepared by purification via flash chromatography on
mp 204e206 ꢁC (lit. 205e207 ꢁC); 1H NMR (acetone-d6)
d 7.85 (d,
J¼8.1 Hz, 2H), 7.66e7.71 (m, 6H), 7.58 (t, J¼7.5 Hz, 2H), 7.46 (t,
J¼7.5 Hz, 4H), 7.16e7.24 (m, 4H), 7.01 (t, J¼7.5 Hz, 2H), and 3.56 (s,
6H); 13C NMR (acetone-d6)
d 160.0, 138.0, 134.3, 134.0, 131.0, 129.5,
126.4, 126.2, 124.4,123.8, 123.1, 121.7, 120.5, 115.5, 113.1, and 50.9; IR
(neat) 1701 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C36H27N3NaO8S2
716.1137 found 716.1129.
4.1.7. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-3-bromo-5-formyl-1H-
pyrrole-2-carboxylic acid methyl ester (15). Into a 100 mL round

J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
9765
bottomed flask equipped with a magnetic stir bar was placed 4-(1-
benzenesulfonyl-1H-indol-3-yl)-5-formyl-1H-pyrrole-2-carboxylic
acid methyl ester (0.100 g, 0.245 mmol), KOH (0.014 g, 0.245 mmol)
and 10 mL of DMF. The resulting mixture was stirred for 45 min and
N-bromosuccinimide (0.087 g, 0.45 mmol), which had been dis-
solved in 5 mL of DMF, was added in one portion. The flask was
covered with aluminum foil and the reaction mixture was stirred
overnight at room temperature. The reaction was subsequently
worked up by dilution with water (40 mL) and a 10% aqueous so-
lution of sodium thiosulfate (20 mL) followed by extraction with
ethyl acetate (3ꢀ15 mL). The combined organic phases were
washed with brine (1ꢀ30 mL) and dried over anhydrous magne-
sium sulfate. After removal of the drying agent by filtration, the
organic phase was concentrated in vacuo to yield a solid (0.340 g).
This material was purified via flash chromatography on a Biotage
Isolera system in which case a white solid (0.105 g, 89% yield)
resulted. This material exhibited the following physical properties:
phases were concentrated in vacuo to yield a solid. The crude
product was purified via flash chromatography on a Biotage Isolera
system in which case 0.161 g (91% yield) of an orange solid was
obtained and exhibited the following properties: mp 71e74 ꢁC; 1H
NMR (acetone-d6)
d
9.66 (s, 1H), 7.98 (d, J¼8.4 Hz, 1H), 7.93 (d,
J¼7.2 Hz, 2H), 7.84 (s, 1H), 7.71 (t, J¼7.5 Hz, 1H), 7.60 (t, J¼7.2 Hz,
2H), 7.30 (t, J¼8.4 Hz, 1H), 7.07e7.14 (m, 2H), 6.55 (s, 2H), 3.81 (s,
3H), 3.67 (s, 3H), and 3.39 (s, 6H); 13C NMR (acetone-d6)
d 180.2,
160.4, 152,5, 137.6, 134.5, 131.3, 131.1, 130.9, 129.7, 128.1, 126.8, 126.6,
124.9, 124.1, 123.9, 123.5, 120.6, 114.2, 113.2, 108.3, 93.0, 59.7, 55.3,
and 51.3; IR (neat) 1714 and 1666 cmꢂ1; HRMS (ES, MþNa) m/z
calcd for C30H26N2NaO8S 597.1302 found 597.1237.
4.1.10. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-3-(3,4-dimethoxy-
phenyl)-5-formyl-1H-pyrrole-2-carboxylic acid methyl ester (17c). Into
a 20 mL microwave reaction tube containing a stir bar was placed 4-
(1-benzenesulfonyl-1H-indol-3-yl)-3-bromo-5-formyl-1H-pyrrole-
2-carboxylic acid ethyl ester (0.100 g, 0.205 mmol), 3,4-
dimethoxyphenylboronic acid (0.045 g, 0.246 mmol), DABCO
(0.032 g, 0.287 mmol), dichloro[1,10-bis-(diphenyl-phosphino)ferro-
cene]palladium(II) dichloro-methane adduct (0.008 g, 0.010 mmol),
toluene (9 mL), methanol (3 mL) and water (5 drops). The resulting
mixture was stirred and heated in a Biotage Initiator microwave
system for 2 h at 110 ꢁC. After cooling to room temperature, the re-
action mixture was filtered through a short plug of silica gel and the
silica was subsequently washed with ethyl acetate (25 mL) and the
combined organic phases were concentrated in vacuo to yield a solid.
The crude product was purified via flash chromatography on a Biot-
age Isolera system in which case 0.043 g (39% yield) of a red solid was
obtained and exhibited the following properties: mp 68e71 ꢁC; 1H
mp 211e213 ꢁC; 1H NMR (acetone-d6)
d 9.57 (1H), 8.10e8.12 (m,
3H), 8.02 (s, 1H), 7.71 (t, J¼7.2 Hz, 1H), 7.63 (t, J¼7.2 Hz, 2H),
7.40e7.48 (m, 2H), 7.31 (t, J¼8.7 Hz, 1H), and 3.92 (s, 3H); 13C NMR
(acetone-d6)
d 179.7, 158.3, 137.7, 134.9, 134.5, 131.5, 130.4, 129.7,
129.6, 127.1, 127.0, 125.2, 125.1, 125.0, 123.8, 121.0, 113.6, 113.0, and
51.5; IR (neat) 1713 1672 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C
21H15N2NaO5SBr 508.9777 found 508.9729.
4.1.8. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-5-formyl-3-(4-metho-
xyphenyl)-1H-pyrrole-2-carboxylic acid methyl ester (17a). Into
a 20 mL microwave reaction tube containing a stir bar was placed 4-
(1-benzenesulfonyl-1H-indol-3-yl)-3-bromo-5-formyl-1H-pyrrole-
2-carboxylic acid ethyl ester (0.080 g, 0.164 mmol), 4-
methoxyphenylboronic acid (0.030 g, 0.197 mmol), DABCO
(0.026 g, 0.230 mmol), dichloro[1,10-bis-(diphenyl-phosphino)fer-
NMR (acetone-d6)
d
9.60 (s, 1H), 7.98 (d, J¼8.4 Hz, 1H), 7.90 (d,
J¼8.4 Hz, 2H), 7.78 (s,1H), 7.72 (t, J¼7.8 Hz, 1H), 7.59 (t, J¼7.2 Hz, 2H),
7.30 (t, J¼8.4 Hz, 1H), 7.17 (d, J¼8.7 Hz, 1H), 7.13 (t, J¼8.1 Hz, 1H),
6.70e6.80 (m, 3H), 3.78 (s, 3H), 3.76 (s, 3H), and 3.35 (s, 3H); 13C NMR
rocene]palladium(II)
dichloromethane
adduct
(0.006
g,
0.008 mmol), toluene (9 mL), methanol (3 mL), and water (5 drops).
The resulting mixture was stirred and heated in a Biotage Initiator
microwave system for 2 h at 110 ꢁC. After cooling to room temper-
ature, the reaction mixture was filtered through a short plug of silica
gel and the silica was subsequently washed with ethyl acetate
(25 mL) and the combined organic phases were concentrated in
vacuo to yield an orange solid. The crude product was purified via
flash chromatography on a Biotage Isolera system in which case
a yellow-orange solid (0.081 g, 96% yield) was obtained and
exhibited the following physical properties: mp 75e78 ꢁC; 1H NMR
(acetone-d6)
d 180.1, 160.4, 148.6, 148.3, 137.7, 134.6, 134.3, 131.3,
131.0, 129.6, 126.7, 126.6, 125.3, 124.9, 124.2, 123.9, 123.6, 122.9, 120.6,
114.5, 114.4, 113.3, 110.8, 55.0, 54.5, and 51.1; IR (neat) 1708 and
1663 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C29H24N2O7S 567.1196
found 567.1135.
4.1.11. 5-Formyl-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole-2-carboxy-
lic acid methyl ester (19). Into a 20 mL microwave reaction tube
containing a stir bar was placed 4-bromo-5-formyl-1H-pyrrole-2-
carboxylic acid methyl ester (0.400 g, 1.72 mmol), potassium
3,4,5-trimethoxyphenyltrifluoroborate (0.570 g, 2.07 mmol),
DABCO (0.270 g, 2.41 mmol) and dichloro[1,10-bis-(diphenylphos-
phino)ferrocene]palladium(II) dichloromethane adduct (0.063 g,
0.086 mmol). To this mixture was added 9 mL of toluene, 3 mL of
ethanol and 20 drops of water and the resulting mixture was stirred
and heated in a Biotage Initiator microwave system for 2 h at 110 ꢁC.
After cooling to room temperature, the reaction mixture was fil-
tered through a short plug of silica gel and the silica was sub-
sequently washed with ethyl acetate (25 mL) and the combined
organic phases were concentrated in vacuo to yield a dark solid
(0.500 g). The crude product was purified via flash chromatography
on a Biotage Isolera system in which case a yellow-orange solid
(0.31 g, 56% yield) was obtained. This material exhibited the fol-
(acetone-d6)
d
9.61 (s, 1H), 7.98 (d, J¼6.0 Hz, 1H), 7.90 (d, J¼8.4 Hz,
2H), 7.75 (s, 1H), 7.72 (t, J¼7.5 Hz, 1H), 7.59 (t, J¼6.9 Hz, 2H), 7.28 (t,
J¼8.1 Hz 1H), 7.07e7.16 (m, 4H), 6.68 (d, J¼8.7 Hz, 2H), 3.77 (s, 3H),
and 3.74 (s, 3H); 13C NMR (acetone-d6)
d 180.5, 160.4, 158.8, 137.7,
134.8, 134.3, 131.4, 131.3, 131.0, 129.7, 129.6, 127.0, 126.8, 126.7, 125.0,
124.5, 123.9, 123.6, 120.5, 114.6, 113.4, 112.8, 54.5, and 51.1; IR (neat)
1714 and 1666 cmꢂ1
;
HRMS (ES, MþNa) m/z calcd for
C28H22N2NaO6S 537.1091 found 537.1054.
4.1.9. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-5-formyl-3-(3,4,5-
trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid methyl ester
(17b). Into a 20 mL microwave reaction tube containing a stir bar
was
placed
4-(1-benzenesulfonyl-1H-indol-3-yl)-3-bromo-5-
formyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.150 g,
0.307 mmol), 3,4,5-trimethoxyphenylboronic acid (0.080 g,
0.369 mmol), DABCO (0.048 g, 0.430 mmol), dichloro[1,10-bis-
lowing physical properties: mp 150e152 ꢁC; 1H NMR (CDCl3)
(s, 1H), 7.02 (d, J¼2.4 Hz, 1H), 6.89 (s, 2H), 3.96 (s, 3H), and 3.92 (s,
9H); 13C NMR (CDCl3)
180.6, 160.6, 153.6, 138.5, 138.0, 130.3, 128.1,
d 9.83
(diphenyl-phosphino)ferrocene]palladium(II)
dichloro-methane
d
adduct (0.011 g, 0.015 mmol), toluene (9 mL), methanol (3 mL),
and water (5 drops). The resulting mixture was stirred and heated
in a Biotage Initiator microwave system for 2 h at 110 ꢁC. After
cooling to room temperature, the reaction mixture was filtered
through a short plug of silica gel and the silica was subsequently
washed with ethyl acetate (25 mL) and the combined organic
127.2, 115.3, 106.5, 61.0, 56.3, and 52.3; IR (neat) 1695 and
1648 cmꢂ1; HRMS (ES, MþH) m/z calcd for C16H18NO6 320.1134
found 320.1144.
4.1.12. 3-(3,4,5-Trimethoxyphenyl)-1H-pyrrole-2,5-dicarboxylic acid
5-methyl ester (20). Into a 100 mL round bottomed flask equipped

9766
J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
with
a
magnetic stir bar was placed 5-formyl-4-(3,4,5-
ethanol and 20 drops of water. The resulting mixture was stirred and
heated in a Biotage Initiator microwave system for 2 h at 110 ꢁC. After
cooling to room temperature, the reaction mixture was filtered
through a short plug of silica gel and subsequently washed with ethyl
acetate (25 mL) and the combined organic phases were concentrated
in vacuo to yield a dark solid. The crude material was purified via
flash chromatography on a Biotage Isolera system in which case
a yellow solid (0.070 g, 65% yield) was obtained, which we have
previously prepared22 and characterized via a different route: 1H
trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid methyl ester
(0.280 g, 0.870 mmol), 35 mL of DMSO and sodium dihydrogen
phosphate (0.120 g, 0.870 mmol), which had been dissolved in
10 mL of water. The resulting solution was cooled in an ice bath for
5 min and a solution of sodium chlorite (0.236 g, 2.61 mmol) in
10 mL of water was added dropwise and the reaction mixture was
allowed to stir overnight at room temperature. The cooled reaction
mixture was worked up by acidification with 6 M hydrochloric acid
and was then diluted with 150 mL of water. Extraction of the
aqueous mixture with ethyl acetate (3ꢀ25 mL) followed by drying
over anhydrous sodium sulfate, filtration and concentration in
vacuo produced a light yellow solid (0.290 g, 99% yield). This ma-
terial was of sufficient purity to be used in subsequent experiments
but an analytical sample was prepared by purification via flash
chromatography on a Biotage Isolera system in which case the
resulting solid exhibited the following physical properties: mp
NMR (CDCl3) d 6.40 (s, 4 H), 3.85 (s, 12H), and 3.67 (s, 12H). We have
previously reported22 that this material was identical to a key syn-
thon used by Boger and co-workers to prepare per-
methylstorniamide A.
4.1.16. 4-(3,4-Dimethoxyphenyl)-5-formyl-1H-pyrrole-2-carboxylic
acid ethyl ester (26). Into a 20 mL microwave reaction tube con-
taining a stir bar was placed 4-bromo-5-formyl-1H-pyrrole-2-
carboxylic acid ethyl ester (0.250 g, 1.02 mmol), potassium 3,4-
dimethoxyphenyltrifluoroborate (0.316 g, 1.32 mmol), DABCO
(0.229 g, 2.04 mol) and a mixture of 3:1 toluene:ethanol (12 mL)
along with 20 drops of water. After stirring for several minutes,
dichloro[1,10bis(diphenyl-phosphino)ferrocene]palladium(II) dich
loromethane adduct (0.037 g, 0.051 mmol) was added and the
resulting mixture was stirred and heated in a Biotage Initiator
microwave system for 2 h at 110 ꢁC. After cooling to room tem-
perature, the reaction mixture was filtered through a short plug of
silica gel and was subsequently washed with ethyl acetate
(2ꢀ30 mL) and the combined organic phases were concentrated in
vacuo to yield a dark solid. The crude material was purified via flash
chromatography on a Biotage Isolera system in which case a light
colored solid (0.300 g, 70% yield) was obtained, which have pre-
viously prepared24 and characterized via a different route: 1H NMR
201e203 ꢁC; 1H NMR (CDCl3)
d
7.00 (d, J¼3.0 Hz, 1H), 6.84 (s, 2H),
3.95 (s, 3H), 3.92 (s, 3H), and 3.90 (s, 6H); 13C NMR (CDCl3)
d
164.1,
160.6, 152.8, 137.9, 133.8, 128.9, 125.5, 120.4, 116.9, 107.0, 60.9, 56.2,
and 52.2; IR (neat) 1717 and 1677 cmꢂ1; HRMS (ES, MþNa) m/z
calcd for C16H17NNaO7 358.0903 found 358.0913.
4.1.13. 3-(3,4,5-Trimethoxyphenyl)-1H-pyrrole-2,5-dicarboxylic acid
dimethyl ester (21). Into a 100 mL round bottomed flask equipped
with a magnetic stir bar was placed 3-(3,4,5-trimethoxyphenyl)-
1H-pyrrole-2,5-dicarboxylic acid 5-methyl ester (0.150 g,
0.447 mmol), ethyldiisopropylamine (0.170 g, 1.34 mmol), and
35 mL of anhydrous dichloromethane. The mixture was stirred for
30 min and iodomethane (0.25 g, 1.79 mmol) was added in one
portion. The resulting mixture was stirred overnight at room
temperature and concentrated in vacuo to yield a viscous orange
product. The material was subjected to flash chromatography on
a Biotage Isolera system in which case the resulting solid (0.110 g,
71% yield) exhibited spectral properties identical to material, which
we have previously prepared22 and characterized via a different
(CDCl3)
d
9.79 (s, 1H), 7.05 (dd, J¼3.0 Hz, J¼9.0 Hz, 1H), 7.02 (d,
J¼3.0 Hz, 1H), 7.00 (d, J¼1.5 Hz, 1H), 6.97 (d, J¼9.0 Hz, 1H), 4.42 (q,
J¼6.0 Hz, 2H), 3.95 (broad s, 6H), and 1.42 (t, J¼6.0 Hz, 3H).
route: 1H NMR (CDCl3)
3H), 3.91 (s, 3H), 3.90 (s, 6H), and 3.87 (s, 3H).
d
6.98 (d, J¼3.0 Hz, 1H), 6.83 (s, 2H), 3.95 (s,
4.1.17. 4-(3,4-Dimethoxyphenyl)-5-formyl-3-iodo-1H-pyrrole-2-
carboxylic acid ethyl ester (27). Into a 100 mL round bottomed flask
equipped with a magnetic stir bar was placed 4-(3,4-dimethoxy-
phenyl)-5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.340 g,
1.11 mmol), potassium hydroxide (0.250 g, 4.46 mmol), and 15 mL
of DMF. The mixture was stirred for 30 min and iodine (0.566 g,
2.23 mmol) was added in one portion. The reaction flask was
covered with aluminum foil and the resulting mixture was stirred
overnight at room temperature. The reaction mixture was
quenched with 45 mL of sodium thiosulfate and extracted with
ethyl acetate (3ꢀ30 mL). The combined organic phases were
washed with aqueous lithium chloride solution (3ꢀ15 mL) and
dried over anhydrous sodium sulfate. After removing the drying
agent by filtration and concentration in vacuo a dark solid product
was obtained. The crude material was purified via flash chroma-
tography on a Biotage Isolera system in which case an orange solid
(0.162 g, 70% yield) was obtained, which we have previously pre-
pared24 and characterized via a different route: 1H NMR (DMSO-d6)
4.1.14. 3-Iodo-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole-2,5-
dicarboxylic acid dimethyl ester (22). Into a 100 mL round bottomed
flask equipped with a magnetic stir bar was placed 3-(3,4,5-
trimethoxyphenyl)-1H-pyrrole-2,5-dicarboxylic acid dimethyl es-
ter (0.190 g, 0.543 mmol), potassium hydroxide (0.087 g,
1.63 mmol), and 20 mL of DMF. The reaction mixture was stirred at
room temperature for 30 min and iodine (0.207 g, 0.816 mmol) was
added, the reaction flask was covered with aluminum foil and the
resulting mixture was stirred overnight at room temperature. The
reaction mixture was quenched with 25 mL of sodium thiosulfate
and extracted with ethyl acetate (2ꢀ25 mL). The combined organic
phases were washed with water (2ꢀ25 mL) and brine (1ꢀ15 mL)
and dried over anhydrous sodium sulfate. After removing the
drying agent by filtration and concentration in vacuo a solid
product (0.160 g, 62% yield) was obtained, which we have pre-
viously prepared22 and characterized via a different route: 1H NMR
d
9.45 (s, 1H), 7.04 (d, J¼8.4 Hz, 1H), 6.99 (d, J¼2.1 Hz, 1H), 6.92 (dd,
(CDCl3)
(s, 3H).
d
6.55 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 3.89 (s, 6H), and 3.10
J¼2.1 Hz, J¼8.4 Hz, 1H), 4.32 (q, J¼7.2 Hz, 2H), 3.81 (s, 3H), 3.77 (s,
3H), and 1.33 (t, J¼7.2 Hz, 3H).
4.1.15. 3,4-Bis-(3,4,5-trimethoxyphenyl)-1H-pyrrole-2,5-dicarboxylic
acid dimethyl ester (23). Into a 20 mL microwave reaction tube
containing a stir bar was placed 3-iodo-4-(3,4,5-trimethoxyphenyl)-
1H-pyrrole-2,5-dicarboxylic acid dimethyl ester (0.100 g,
0.210 mmol), potassium 3,4,5-trimethoxyphenyltrifluoroborate
(0.069 g, 0.25 mmol), DABCO (0.033 g, 0.29 mmol), dichloro[1,10-
bis-(diphenylphosphino)ferrocene]palladium(II) dichloromethane
adduct (0.00 7 g, 0.009 mmol) along with 9 mL of toluene, 3 mL of
4.1.18. 3,4-Bis-(3,4-dimethoxyphenyl)-5-formyl-1H-pyrrole-2-
carboxylic acid ethyl ester (28). Into a 20 mL microwave reaction
tube containing
a stir bar was placed potassium 4-(3,4-
dimethoxyphenyl)trifluoroborate (0.198 g, 0.811 mmol), 5-formyl-
3-iodo-1H-pyrrole-2-carboxylic acid ethyl ester (0.290 g,
0.676 mmol), DABCO (0.106 g, 0.946 mmol), dichloro[1,10-bis-
(diphenylphosphino)ferrocene]palladium(II) dichloromethane ad-
duct (0.025 g, 0.033 mmol) along with 9 mL of toluene, 3 mL of

J.T. Gupton et al. / Tetrahedron 70 (2014) 9759e9767
9767
ethanol, and 20 drops of water. The resulting mixture was stirred
References and notes
and heated in a Biotage Initiator microwave system for 2 h at 110 ꢁC.
This reaction was duplicated and both reaction mixtures were
combined after the microwave heating was completed. The com-
bined organic phases were filtered through a short plug of silica gel
and subsequently washed with ethyl acetate (3ꢀ20 mL) and con-
centrated in vacuo to yield a dark solid. The crude material was
purified via flash chromatography on a Biotage Isolera system in
which case a yellow-orange solid (0.33 g, 56% yield) was obtained,
which we have previously prepared24 and characterized via a dif-
1. Gupton, J.; Telang, N.; Wormald, M.; Lescalleet, K.; Patteson, J.; Curry, W.;
Harrison, A.; Hoerrner, M.; Sobieski, J.; Kimmel, M.; Kluball, E.; Perry, T. Tetra-
hedron 2014, 70, 2738.
2. Furstner, A.; Krause, H.; Thiel, O. Tetrahedron 2002, 58, 6373.
3. Pla, D.; Marchal, A.; Olsen, C.; Albericio, F.; Alavarez, M. J. Org. Chem. 2005, 70,
8231.
4. (a) Banwell, M.; Bray, A.; Edwards, A.; Wong, D. J. Chem. Soc. Perkin Trans. 1
2002, 1340; (b) Banwell, M.; Goodwin, T.; Ng, S.; Smith, J.; Wong, D. Eur. J. Org.
Chem. 2006, 14, 3043.
5. Handy, S.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004, 69, 2362.
6. Serge-Mitherand, T.; Fatunsin, O.; Villinger, A.; Langer, P. Tetrahedron. Lett. 2011,
52, 3732.
7. Fukuda, T.; Sudo, E.; Shimokawa, K.; Iwao, M. Tetrahedron 2008, 64, 328.
8. Handy, S.; Bregman, H.; Lewis, J.; Zhang, X.; Zhang, Y. Tetrahedron. Lett. 2003,
44, 427.
9. Frode, R.; Hinze, C.; Josten, I.; Schmidt, B.; Steffan, B.; Steglich, W. Tetrahedron.
Lett. 1994, 11, 1689.
ferent route: 1H NMR (DMSO-d6)
d
9.61 (s, 1H), 6.87 (d, J¼8.1 Hz,
1H), 6.83 (d, J¼8.1 Hz, 1H), 6.76 (dd, J¼2.1 Hz, J¼8.1 Hz, 1H), 6.73 (d,
J¼2.1 Hz, 1H), 6.70 (d, J¼2.1 Hz, 1H), 6.64 (dd, J¼2.1 Hz, J¼7.2 Hz,
1H), 4.14 (q, J¼6.9 Hz, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 3.58 (s, 3H), 3.53
(s, 3H), and 1.13 (t, J¼7.2 Hz, 3H). We have previously reported that
this material was identical to a key synthon used by our research
group in the formal synthesis of lamellarin G trimethyl ether.
10. Asakawa, Y.; Hashimoto, T.; Yasuda, A.; Akasawa, K.; Takaoka, S.; Tori, M. Tet-
rahedron. Lett. 1994, 35, 2559.
11. Sherman, D.; Nishizawa, T.; Gruschow, S.; Jayamaha, D.; Nishizawa-Harada, C. J.
Am. Chem. Soc. 2006, 128, 724.
12. Walsh, C.; Howard-Jones, A. J. Am. Chem. Soc. 2007, 129, 11016.
13. Asamizu, S.; Kato, Y.; Igarashi, Y.; Furumai, T.; Onaka, H. Tetrahedron. Lett. 2006,
47, 473.
Acknowledgements
14. Oakdale, J.; Boger, D. Org. Lett. 2010, 12, 1132.
15. Fu, L.; Gribble, G. Tetrahedron. Lett. 2010, 51, 537.
We gratefully thank the National Institutes of Health (grant no.
R15-CA67236) for support of this research project. Thanks also to
the Floyd D. and Elisabeth S. Gottwald endowment for support to
JTG. We are also very appreciative of Advion Inc. for the generous
donation of a CMS electrospray mass spectrometer. Previous grants
from the MRI program of the National Science Foundation for the
purchase of a 500 MHz NMR spectrometer (CHE-0116492) and
a high resolution electrospray mass spectrometer (CHE-0320669)
are also gratefully acknowledged. We are also very appreciative of
Professor Gordon Gribble for helpful discussions regarding the
spectral properties of the Gribble precursor to lycogarubin C (14).
16. Zhou, N.; Xie, T.; Liu, L.; Xie, Z. J. Org. Chem. 2014, 79, 6061.
17. Palermo, J. ,; Brasco, M.; Seldes, A. Tetrahedron. Lett. 1996, 52, 2727.
18. Yasui, E.; Wada, M.; Takamura, N. Tetrahedron. Lett. 2009, 50, 4762.
19. Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron. Lett.
2003, 44, 4443.
20. Boger, D.; Boyce, C.; Labroli, M.; Sehon, C.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54.
21. Ebel, H.; Terpin, A.; Steglich, W. Tetrahedron. Lett. 1998, 39, 9165.
22. Gupton, J.; Banner, E.; Sartin, M.; Fisher, D.; Giglio, B.; Smith, K.; Keough, M.;
Smith, T.; Kanters, R.; Dominey, R.; Sikorski, J. Tetrahedron 2008, 64, 5246.
23. Hasse, K.; Willis, A.; Banwell, M. Eur. J. Org. Chem. 2011, 88 and references
therein.
24. Gupton, J.; Giglio, B.; Eaton, J.; Rieck, E.; Smith, K.; Keough, M.; Barelli, P.; Firich,
L.; Hempel, J.; Smith, T.; Kanters. Tetrahedron 2009, 65, 4283.