The application of vinylogous iminium salt derivatives to an efficient relay synthesis of the pyrrole containing alkaloids polycitone A and B

Article abstract of DOI:10.1016/j.tet.2004.12.015

A new and efficient relay synthesis of the marine natural products polycitone A and B is described. The new strategy relies on the formation of 2,4-disubstituted pyrroles from a vinamidinium salt followed by electrophilic substitution at the 5-position of

Full text of DOI:10.1016/j.tet.2004.12.015

Tetrahedron 61 (2005) 1845–1854
The application of vinylogous iminium salt derivatives to an
efficient relay synthesis of the pyrrole containing alkaloids
polycitone A and B
a
b
a
a
John T. Gupton,a, Robert B. Miller, Keith E. Krumpe, Stuart C. Clough, Edith J. Banner,
*
Rene P. F. Kanters,a Karen X. Du,c Kartik M. Keertikar,c Nicholas E. Lauerman,a
John M. Solano,a Bret R. Adams,a Daniel W. Callahan,a Barrett A. Little,a Austin B. Scharfa
and James A. Sikorskid
aDepartment of Chemistry, University of Richmond, Gottwald Science Center, Richmond, VA 23173, USA
bDepartment of Chemistry, University of North Carolina at Asheville, Asheville, NC 28804, USA
cDepartment of Chemistry, University of Central Florida, Orlando, FL 32816, USA
dAtheroGenics Inc., 8995 Westside Parkway, Alpharetta, GA 30004, USA
Received 1 October 2004; revised 5 December 2004; accepted 7 December 2004
Available online 22 December 2004
Abstract—A new and efficient relay synthesis of the marine natural products polycitone A and B is described. The new strategy relies on the
formation of 2,4-disubstituted pyrroles from a vinamidinium salt followed by electrophilic substitution at the 5-position of the pyrrole and
Suzuki coupling at the 4-position to produce the tetrasubstituted heterocycle efficiently and with complete control of regiochemistry.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
DNA polymerases. These substances were first isolated and
reported by Kashman2 and co-workers and the first total
synthesis was recently accomplished by Steglich3 and
co-workers. The Steglich synthesis (Scheme 1) employs a
very elegant biomimetic approach involving the ammonia
promoted cyclodehydration of an appropriate 1,4-diketone 2
Polycitone A (1a) and B (1b) (Fig. 1) represent novel
members of a growing class of pyrrole-containing marine
natural products, which exhibit significant bioactivity1 as
inhibitors of retroviral reverse transcriptases and cellular
Figure 1.
Keywords: Vinamidinium salt; Pyrrole; Marine natural product.
* Corresponding author. Tel.: C1 804 287 6498: fax: C1 804 287 1897; e-mail: jgupton@richmond.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.015

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J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
Scheme 1.
to form a 3,4-diarylpyrrole-2,5-dicarboxylic acid 3. This
3,4-diarylpyrrole-2,5-dicarboxylic acid is then reacted
with anisole under Friedel–Crafts conditions to produce
the corresponding 2,5-dibenzoyl derivative 4, which is
O-dealkylated and brominated to produce polycitone B (1b)
in 55% overall yield. By subsequent O-protection, N-alkyl-
ation and O-deprotection, polycitone B (1b) was converted
to polycitone A (1a) in three steps and 39% yield.
somewhat different approach, which allows for the incor-
poration of much greater structural diversity. This new
strategy begins with the initial reaction of a 2-arylvinami-
dinium hexafluorophosphate with an a-aminoacetophenone
in order to construct a 2-aroyl-4-arylpyrrole. Our initial
studies of such a reaction are reported in Table 1.
2. Results and discussion
It is clear from the work of Steglich and co-workers that
symmetrical diketone 4 is a key synthetic intermediate for
the polycitone natural products and also for analogs. Since
SAR studies have yet to be accomplished for this class of
alkaloids, new synthetic approaches, which provide sub-
stantial structural and functional group diversity, are
required. We have previously reported the preparation of
diaryl substituted chloropropeniminium salts and their
corresponding b-chloroenals. Reacting either of these
materials with glycinate esters efficiently produced 2,3,4-tri-
substituted pyrroles4 and these substances served as key
synthons for the preparation of the pyrrole containing
alkaloids lukianol A, lamellarin O5 and ningalin B.6 For the
synthesis of polycitone A and B we have opted for a
a-Aminoketones are considerably less well behaved for
pyrrole formation as compared to a-aminoesters due to self-
condensation reactions. However, treatment of a series of
2-arylvinamidinium hexafluorophosphates 5, which are
readily available from the corresponding aryl acetic acids,
with a-aminoacetophenone hydrochloride in refluxing DMF
in the presence of sodium hydride (Table 1) results in
quite reasonable yields of the desired 4-aryl-2-benzoylpyr-
roles 6. The a-aminoketones can be easily and efficiently
prepared according to Scheme 2 by conversion of an
a-bromoketone 7 to the a-azidoketone 8 followed by
reduction to the amine by triphenylphosphine and crystal-
lization as the PTSA salt 9. Consequently, reaction of
Table 1. Reaction of aminoacetohenone with 2-arylvinamidinium salts
Compound
R
% Yield
a
b
c
d
e
f
4-MeOPh
3,4-(MeO)2Ph
4-MePh
Ph
4-BrPh
4-ClPh
4-FPh
81
55
77
85
79
73
63
g

J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
1847
Scheme 2.
aminoketone 9 (Scheme 3) with the 4-methoxyphenyl
vinamidinium salt 11 (obtained from aryl acetic acid 10)
under base mediated conditions produced the desired
polycitone precursor 12 in 77% yield. This substance was
then acylated with 4-methoxybenzoic acid in the presence
of trifluoroacetic anhydride/trifluoroacetic acid (TFAA/
TFA) according to the conditions of Edstrom7 and co-
workers in which case the 5-(4-methoxybenzoyl)-4-(4-
methoxyphenyl)-2-carbethoxypyrrole (13) was obtained in
97% yield.
this pyrrole 13 with NaOH/I2 in DMF yielded the 3-iodo
derivative 14a in 91% yield and this compound was also
subjected to a NOESY NMR experiment, which confirmed
the indicated regiochemical assignments (Table 2). The
3-iodopyrrole 14a was then subjected to standard Suzuki
cross-coupling conditions8 with conventional heating
(Method A) in which case a 21% yield of the ‘Steglich
synthon’ 4 was obtained. A substantial amount of starting
material was observed in this experiment thereby suggesting
this transformation to be rather sluggish, which may be due
to the steric congestion surrounding the iodine bearing
carbon.
The regiochemistry of this trisubstituted pyrrole 13 was
determined by NOESY, DQF-COSY and HMBC experi-
ments, which allowed for the assignment of all signals in
the proton and carbon NMR spectra (Table 2). Iodination of
Microwave accelerated heating has become an important
tool9 to facilitate many types of organic reactions and we
Table 2. NMR Chemical shift assignments for compounds 13 and 14a via NOESY, HMBC and DQF-COSY studiesa
Label
RZH 13
1H NMR
RZI 14a
1H NMR
13C NMR
13C NMR
p1
p2
p3
p4
p5
kO
k1
k2
k3
k4
km
k0O
k01
k02
k03
k04
k0m
m1
m2
m3
m4
mm
10.103
10.150
132.65
131.61
118.24
130.51
186.31
129.67
132.04
113.31
163.11
55.40
183.80
130.27
131.45
113.89
163.88
55.53
132.21
135.30
130.76
133.70
185.56
128.95
131.73
113.04
162.87
55.37
185.70
129.43
132.41
114.00
163.79
55.57
6.958
7.640
6.701
7.478
6.602
3.801
3.769
8.031
7.033
7.923
7.032
3.927
3.928
127.02
130.53
113.65
158.77
55.29
126.50
132.33
113.36
159.12
55.22
7.139
6.720
7.083
6.721
3.771
3.767
a Carbon NMR shifts are reported to 2 decimal places and proton NMR shifts are reported to 3 decimal places so as to differentiate signals, which were
extremely close to one another. NMR spectra were obtained in CDCl3 solutions at room temperature.

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J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
Scheme 3.
opted to repeat the cross-coupling process with the aid of a
Personal Chemistry Emrys Liberator US microwave reac-
tion system (Method B) for 2 h at 110 8C and 50 W in which
case a 64% yield of the Steglich synthon was obtained. The
product 4 of both reaction sequences (Methods A and B)
exhibited mass spectra, proton and carbon NMR chemical
shifts and NMR coupling constants identical to the values
reported by Steglich3,10 and co-workers (Scheme 1).
synthon 4 could be observed. Although the bromo analog
14b failed to cross-couple, the five step synthesis of the
Steglich synthon 4 via the 3-iodopyrrole 14a proved to be
highly efficient (43% overall yield from the vinamidinium
salt), convenient and very amenable to creating a variety of
analogs late in the synthetic sequence.
We have previously reported11 the preparation of 2-carb-
ethoxy-4-(4-methoxyphenyl)pyrrole (15) (87% yield) by the
base mediated condensation of glycine ethyl ester with the
4-methoxyphenyl vinamidinium salt (11). We anticipated
applying a series of reactions (Scheme 4) analogous to those
represented in Scheme 3 to this compound 15 and this would
allow for the formation of tetrasubstituted pyrrole 18, which
could also be an appropriate precursor to the Steglich
synthon 4 albeit via a few additional steps. Consequently,
reaction of 2-carbethoxy-4-(4-methoxyphenyl)pyrrole (15)
with 4-methoxybenzoic acid and TFA/TFAA produced a
94% yield of 2-carbethoxy-5-(4-methoxybenzoyl)-4-(4-
methoxyphenyl)pyrrole (16), which was subjected
In addition, the symmetrical nature of 4 greatly facilitates
the unambiguous assignment of its structure. It is of interest
to note that the material 4 prepared in our laboratory had a
melting point of 163–164 8C while the compound prepared
by the Steglich group10 had a melting point of 131–132 8C.
In addition to studying the Suzuki cross-coupling reaction of
the 3-iodopyrrole 14a, the 3-bromo analog 14b was
prepared in 68% yield by reaction of 13 with NBS in
DMF. When the 3-bromo analog (14b) was subjected to
Suzuki cross-coupling conditions (both conventional and
microwave accelerated), none of the desired Steglich

J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
1849
Scheme 4.
to NOEDIF NMR analysis thereby confirming the
2,3,5-trisubstitution pattern. This pyrrole 16 was subjected
to both iodination and bromination conditions as previously
described in which case the 3-iodo analog 17a and 3-bromo
analog 17b were obtained in 89 and 99% yields,
respectively. Exposure of the 3-bromopyrrole or the
3-iodopyrrole to Suzuki cross-coupling conditions with
4-methoxyphenyl boronic acid yielded the corresponding
pyrrole ester 18 in 89 and 79% yields, respectively. It is of
interest to note that both reactions were accomplished using
conventional heating methods as opposed to microwave
acceleration thereby suggesting a greater reactivity of the
pyrrole ester 17a and 17b over the pyrrolo ketone 14a and
14b under Suzuki cross-coupling conditions. The resulting
pyrrole ester 18 was then converted to the corresponding
carboxylic acid 19 in 77% yield by base mediated
hydrolysis. Conversion of the carboxylic acid to the acid
chloride and subsequent acylation with anisole to yield the
Steglich synthon 4 was accomplished in 75% yield. The
overall yield for the preparation of 4 by this method from the
2,4-disubstituted pyrrole 15 was 42%.
3. Conclusions
In summary, we have demonstrated a new synthetic
approach to an important family of bioactive, pyrrole
containing marine natural products. This is accomplished by
constructing 2,4-disubstituted pyrroles from vinamidinium
salts, electrophilically substituting the 5-position of the
pyrrole followed by halogenation and a microwave
accelerated Suzuki coupling at the 3-position and ultimately

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J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
yielding the tetrasubstituted heterocycle. It is important to
note that each pyrrole substitutent (e.g. compound 18) is
introduced independently and can be easily varied so as to
accommodate in depth SAR studies for polycitone A and B
analogs. We are currently in the process of applying this
same strategy to other important pyrrole containing marine
natural products.
magnesium sulfate, filtered and concentrated. The residue
was dissolved in ethyl acetate (50 mL) and passed through a
4 g plug of 200 mesh silica gel. The silica gel was washed
with a mixture of 80:20 hexane/ethyl acetate and the solvent
was removed in vacuo from the filtrate. The product was
purified by radial chromatography using a mixture of 80:20
hexane/ethyl acetate as eluent. After removal of solvent
from the chromatography fractions, 0.594 g (81% yield) of a
light yellow solid was obtained, which exhibited the
1
following properties: mp 200–201 8C; H NMR (CDCl3) d
4. Experimental
4.1. General
3.83 (s, 3H), 6.92 (d, JZ8.7 Hz, 2H), 7.09 (m, 1H), 7.38 (m,
1H), 7.40–7.65 (m, 5H), 7.95 (d, JZ8.3 Hz, 2H) and 9.78
(broad s, 1H) ppm; 13C NMR (CDCl3) d 57.4, 116.3, 118.1,
123.5, 128.5, 129.0, 129.2, 130.4, 131.0, 133.6, 134.0,
140.3, 160.4 and 186.9 ppm; IR (CCl4) 3260, 1613 and
1247 cmK1; HRMS (EI, MC) m/z for C18H15NO2 calcd
277.1103, found 277.1106.
All chemicals were used as received from the manufacturer
(Aldrich Chemicals and Fisher Scientific) and all reactions
were carried out under a nitrogen or argon atmosphere. All
˚
solvents were dried over 4 A molecular sieves prior to their
use. NMR spectra were obtained on either a GE Omega
300 MHz spectrometer, a Bruker 500 MHz spectrometer or
a Varian Gemini 200 MHz spectrometer in either CDCl3 or
d6-DMSO solutions. IR spectra were recorded on a Nicolet
Avatar 320 FT-IR spectrometer with an HATR attachment
or a Perkin–Elmer 1600 series FT-IR spectrometer. High-
resolution mass spectra were provided by the Midwest
Center for Mass Spectrometry at the University of Nebraska
at Lincoln. Low resolution GC–MS spectra were obtained
on a Shimadzu QP 5050 instrument. Melting points and
boiling points are uncorrected. Radial chromatographic
separations were carried out on a Harrison Chromatotron
using silica gel plates of 2 mm thickness with a fluorescent
backing using ethyl acetate/hexane as the eluant. Flash
chromatographic separations were carried out on a Biotage
Horizon HFC instrument, which had been equipped with a
#1542-2 silica cartridge, and ethyl acetate/hexane was used
as the eluant. TLC analyses were conducted on silica plates
with hexane/ethyl acetate as the eluant. Vinamidinium salts
utilized for pyrrole formation were prepared according to
standard procedures.12 All purified reaction products gave
TLC results, GC–MS spectra, flash chromatograms and 13C
NMR spectra consistent with a sample purity of O95%.
4.1.2. 2-Benzoyl-4-(3,4-dimethoxyphenyl)pyrrole (6b).
This compound was prepared from 5b by the same
procedure as previously described affording a 55% purified
yield of a light yellow solid, which exhibited the following
1
properties: mp 163–164 8C; H NMR (CDCl3) d 3.90 (s,
3H), 3.94 (s, 3H), 6.89 (d, JZ8.2 Hz, 1H), 6.98–7.12 (m,
3H), 7.37 (m, 1H), 7.46–7.66 (m, 3H), 7.95 (d, JZ8.2 Hz,
2H) and 9.58 (broad s, 1H) ppm; 13C NMR (CDCl3) d 58.0,
111.0, 113.6, 118.1, 119.8, 123.6, 129.4, 129.5, 130.5,
131.0, 133.6, 134.0, 140.2, 150.0, 151.2 and 186.8 ppm; IR
(CCl4) 3212 and 1612 cmK1; HRMS (EI, MC) m/z for
C19H17NO3 calcd 307.1208, found 307.1208.
4.1.3. 2-Benzoyl-4-(4-methylphenyl)pyrrole (6c). This
compound was prepared from 5c by the above procedure
affording a 77% purified yield of a light yellow solid, which
exhibited the following properties: mp 190–191 8C; 1H
NMR (CDCl3) d 2.36 (s, 3H), 7.12 (m, 1H), 7.18 (d, JZ
8.0 Hz, 2H), 7.40–7.65 (m, 6H), 7.95 (d, JZ8.2 Hz, 2H) and
9.80 (broad s, 1H) ppm; 13C NMR (CDCl3) d 23.1, 118.3,
123.8, 127.3, 129.5, 130.4, 131.0, 131.5, 133.4, 133.6,
134.0, 138.2, 140.3 and 186.9 ppm; IR (CCl4) 3256 and
1610 cmK1; HRMS (EI, MC) m/z for C18H15NO calcd
261.1154, found 261.1163.
4.1.1. 2-Benzoyl-4-(4-methoxyphenyl)pyrrole (6a). Into a
250 mL, round bottom flask was placed 1.0 g (2.64 mmol)
of vinamidinium salt (5a) and 0.454 g (2.64 mmol) of
a-aminoacetophenone hydrochloride. After a magnetic stir
bar and dry DMF (60 mL) were added to the flask, the
mixture was stirred at room temperature for 3 h. Another
250 mL, round-bottom flask was equipped with a magnetic
stir bar, a reflux condenser, and placed under a nitrogen
atmosphere. To this flask was added 0.158 g (0.66 mmol) of
a 60% mineral oil dispersion of sodium hydride. The sodium
hydride was washed twice with dry hexane and the washings
were removed via cannula. Dry DMF (20 mL) was slowly
added to the flask and the resulting mixture was allowed to
stir for several minutes. The vinamidinium salt solution was
added dropwise to the sodium hydride solution and the
resultant mixture was stirred for 1 h at room temperature
followed by refluxing for 2 h. The reaction was quenched
with methanol and the solvent was removed in vacuo and
the residue was partitioned between water (50 mL) and
chloroform (50 mL) and the aqueous phase was extracted
with additional portions of chloroform (2!50 mL). The
combined chloroform extracts were dried over anhydrous
4.1.4. 2-Benzoyl-4-phenylpyrrole (6d). This compound
was prepared from 5d by the above procedure affording a
85% purified yield of a light yellow solid, which exhibited
the following properties: mp 191–192 8C; 1H NMR (CDCl3)
d 7.15 (m, 1H), 7.20–7.61 (m, 9H), 7.95 (d, JZ8.3 Hz, 2H)
and 9.80 (broad s, 1H) ppm; 13C NMR (CDCl3) d 118.4,
124.1, 127.4, 128.5, 129.4, 130.5, 130.8, 131.0, 133.7,
134.0, 136.3, 140.2 and 187.0 ppm; IR (CCl4) 3256 and
1614 cmK1; HRMS (EI, MC) m/z for C17H13NO calcd
247.0997, found 247.1001.
4.1.5. 2-Benzoyl-4-(4-bromophenyl)pyrrole (6e). This
compound was prepared from 5e by the above procedure
affording a 79% purified yield of a light yellow solid, which
exhibited the following properties: mp 226–227 8C; 1H
NMR (CDCl3) d 7.10 (m, 1H), 7.37–7.7 (m, 8H), 7.94 (d,
JZ8.2 Hz, 2H) and 9.88 (broad s, 1H) ppm; 13C NMR
(CDCl3) d 122.9, 125.8, 131.1, 131.7, 134.2, 135.7, 135.9,
138.6, 138.7, 139.1, 140.9, 145.4 and 191.0 ppm; IR (CCl4)

J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
1851
3250 and 1616 cmK1; HRMS (EI, MC) m/z for
C17H12BrNO calcd 325.0102, found 325.0118.
temperature and subsequently added over a 1 h period to a
250 mL 3-neck round bottom flask containing 0.381 g
(15.8 mmol) of sodium hydride (60% by wt. mineral oil
dispersion) in 75 mL of DMF. The reaction mixture was
heated at reflux for 18 h, cooled to room temperature,
quenched with saturated aqueous ammonium chloride and
extracted with ethyl acetate (3!50 mL). The organic layers
were combined, washed with brine (50 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated in
vacuo to give 1.24 g (77% yield) of a dark solid which was
suitable for further transformations. An analytical sample
was prepared by purification of a 0.500 g sample by
automated flash chromatography on silica gel using a
gradient elution of hexane/ethyl acetate to give 0.213 g of a
yellow solid, which exhibited the following properties: mp
153–154 8C; 1H NMR (CDCl3) d 3.85 (s, 3H), 3.92 (s, 3H),
6.94 (d, JZ9.0 Hz, 2H), 7.03 (d, JZ9.0 Hz, 2H), 7.10 (m,
1H), 7.36 (m, 1H), 7.48 (d, JZ9.0 Hz, 2H), 8.00 (d, JZ
9.0 Hz, 2H) and 9.88 (broad s, 1H) ppm; 13C NMR (CDCl3)
d 55.3, 55.5, 113.7, 114.3, 115.4, 121.0, 126.5, 127.0, 127.2,
130.9, 131.2, 131.7, 158.4, 162.9 and 183.7 ppm; FTIR
(neat) 3250 and 1588 cmK1; HRMS (EI, MC) m/z calcd for
C19H17NO3 307.1208, found 307.1207.
4.1.6. 2-Benzoyl-4-(4-chlorophenyl)pyrrole (6f). This
compound was prepared from 5f by the above procedure
affording a 73% purified yield of a light yellow solid, which
exhibited the following properties: mp 208–209 8C; 1H
NMR (CDCl3) d 7.11 (m, 1H), 7.28–7.65 (m, 8H), 7.95 (d,
JZ8.1 Hz, 2H) and 9.88 (broad s, 1H) ppm; 13C NMR
(CDCl3) d 118.2, 124.1, 128.2, 128.6, 130.5, 130.9, 133.9,
134.1, 134.2, 134.8, 140.1 and 187.0 ppm; IR (CCl4) 3259
and 1617 cmK1; HRMS (EI, MC) m/z for C17H12ClNO
calcd 281.0607, found 281.0606.
4.1.7. 2-Benzoyl-4-(4-flurophenyl)pyrrole (6g). This com-
pound was prepared from 5g by the above procedure
followed by recrystallization with a mixture of 70:30
hexane/ethyl acetate and affording a 63% purified yield of
a light yellow solid, which exhibited the following proper-
1
ties: mp 177–178 8C; H NMR (CDCl3) d 6.98–7.15 (m,
3H), 7.37 (m, 1H), 7.40–7.65 (m, 5H), 7.94 (d, JZ8.3 Hz,
2H) and 9.65 (broad s, 1H) ppm; 13C NMR (CDCl3) d 122.6
(d, JZ20.6 Hz), 123.0, 130.7, 132.0, 134.0 (d, JZ7.8 Hz),
135.7, 136.0, 138.1 (d, JZ3.0 Hz), 138.5, 139.0, 145.5,
167.9 (d, JZ245.6 Hz) and 190.9 ppm; IR (CCl4) 3266 and
1613 cmK1; HRMS (EI, MC) m/z for C17H12FNO calcd
265.0903, found 265.0904.
4.1.10. 2,5-Bis(4-methoxybenzoyl)-3-(4-methoxyphenyl)-
pyrrole (13). Into a 250 mL 3-neck flask was placed 5.22 g
(34.4 mmol) of 4-methoxybenzoic acid and methylene
chloride (35 mL). To the stirring suspension was added
7.22 g (34.4 mmol) of trifluroacetic anhydride. After 5 min
the solution became homogeneous and 9.16 g (80.4 mmol)
of trifluroacetic acid was added in one portion. To the
stirring solution was added 2.35 g (7.65 mmol) of 2-(4-
methoxybenzoyl)-4-(4-methoxyphenyl)pyrrole and the
reaction mixture was allowed to stir overnight. After 17 h
the reaction mixture was carefully quenched with saturated,
aqueous sodium bicarbonate, diluted with ethyl acetate
(200 mL), washed with 10% aqueous sodium hydroxide
(3!50 mL), brine (50 mL), dried over anhydrous mag-
nesium sulfate, filtered and concentrated in vacuo to give
3.26 g (97% yield) of a black solid. An analytical sample
was prepared by automated flash chromatography of a
0.500 g sample of crude material on silica gel using a
gradient elution of hexane/ethyl acetate to give 0.325 g of
a yellow solid which exhibited the following properties:
4.1.8. 20-Amino-4-methoxyacetophenone p-toluenesul-
fonic acid salt (9). Into a 3000 mL flask was placed
20.0 g (87.3 mmol) of 20-bromo-4-methoxyacetophenone
along with dry ethanol (500 mL). Once the solution became
homogeneous, 5.70 g (87.3 mmol) of sodium azide was
added in one portion. The reaction mixture was allowed to
stir at room temperature for 24 h and the ethanol was
removed in vacuo to give a yellow, oily solid. The solid
was dissolved in chloroform (150 mL) and the organic layer
was washed with water (3!100 mL), brine (100 mL), dried
over anhydrous magnesium sulfate, filtered and concen-
trated in vacuo to give an amber oil. This oil was dissolved
in THF (400 mL) and to the solution was added 22.9 g
(87.3 mmol) of triphenylphosphine. Once the solution was
homogeneous, 49.6 g (261 mmol) of PTSA was added in
small portions and the reaction mixture was allowed to stir
for 24 h. The resulting product was filtered and allowed to
dry under vacuum to give 24.7 g (80%) of a white solid,
which was suitable for further reactions and exhibited the
following properties: mp 188–189 8C; 1H NMR (d6-DMSO)
d 2.27 (s, 3H), 3.85 (s, 3H), 4.52 (s, 2H), 7.10 (d, JZ8.0 Hz,
4H), 7.46 (d, JZ8.0 Hz, 2H), 7.98 (d, JZ8.0 Hz, 2H) and
8.08 (broad s, 3H) ppm; 13C NMR (d6-DMSO) d 20.7, 44.9,
55.7, 114.3, 125.6, 126.7, 128.1, 130.7, 137.7, 145.9, 164.3
and 191.4 ppm; IR (KBr) 3100 (broad absorption) and
1690 cmK1; HRMS (EI, MC) m/z calcd for C9H12NO2
166.0868, found 166.0875.
1
mp 148–150 8C; for detailed H and 13C NMR analysis
of compound 13 see Table 2; FTIR (neat) 3242 and
1592 cmK1; HRMS (EI, MC) m/z calcd for C27H23NO5
441.1576, found 441.1578.
4.1.11. 2,5-Bis(4-methoxybenzoyl)-3-iodo-4-(4-methoxy-
phenyl)pyrrole (14a). Into a 100 mL flask was placed
0.750 g (1.70 mmol) of 2,5-bis(4-methoxybenzoyl)-3-(4-
methoxyphenyl)pyrrole along with DMF (40 mL). To the
stirring solution was added 0.285 g (5.07 mmol) of
potassium hydroxide and after 5 min 0.560 g (2.21 mmol)
of iodine was added. The reaction mixture was allowed to
stir overnight (18 h) and was then quenched with 20%
aqueous sodium thiosulfate (50 mL) with stirring. The
reaction mixture was extracted with ethyl acetate (3!
50 mL). The organic layers were combined and washed
once with brine (50 mL), dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give 0.880 g
(91% yield) of a dark oil. An analytical sample (0.500 g
4.1.9. 2-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)pyr-
role (12). Into a 250 mL erylenmyer flask was placed
2.00 g (5.29 mmol) of 4-methoxyphenyl vinamidiniun
hexafluorophosphate (11), 2.07 g (5.82 mmol) of
20-amino-4-methoxyacetophenone p-toluenesulfonic acid
salt (9), 0.593 g (5.29 mmol) of DABCO and DMF
(50 mL). The mixture was allowed to stir for 1 h at room

1852
J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
sample of crude material) was prepared by automated flash
chromatography of a on silica using a gradient elution of
hexane/ethyl acetate to give 0.350 mg of yellow solid,
which exhibited the following properties: mp 77–79 8C; For
4.1.14. 2,5-Bis(4-methoxybenzoyl)-3,4-bis(4-methoxy-
phenyl)pyrrole (4) (Method B). Into a 7 mL test tube
(microwave reaction vessel) was placed 0.100 g
(0.176 mmol) of 2,5-bis(4-methoxybenzoyl)-3-iodo-4-(4-
methoxyphenyl)pyrrole along with 5 mL of 3:1 toluene/
ethanol and a stir bar. To the solution was added 0.079 g
(0.529 mmol) of 4-methoxyphenylboronic acid 0.082 g
(0.598 mmol) of potassium carbonate and 0.002 g
(0.00176 mmol) of Pd(PPh3)4. The reaction mixture was
subjected to the following microwave conditions: 5 min
initial stir time; 100 W power setting; 110 8C; 2 h run time.
After 2 h the reaction mixture was filtered through a plug of
sand/silica/celite and the cake was washed with ethyl
acetate (50 mL). The organic filtrate was washed with 10%
aqueous sodium hydroxide (3!25 mL), with brine
(50 mL), dried over anhydrous magnesium sulfate, filtered
and concentrated in vacuo to give 0.250 g of a brown-
yellow semi-solid. The crude mixture was purified by
automated flash chromatography on silica gel using a
gradient elution of hexane/ethyl acetate to give 0.061 g
(64% yield) of a yellow solid, which exhibited 1H NMR and
13C NMR spectra and TLC behavior identical to the
compound prepared by Method A.
1
detailed H and 13C NMR analysis of compound 14a see
Table 2; FTIR (neat) 3215 and 1596 cmK1; HRMS (EI, MC)
m/z calcd for C27H22NO5I 567.0543, found 567.0564.
4.1.12. 2,5-Bis(4-methoxybenzoyl)-3-bromo-4-(4-meth-
oxyphenyl)pyrrole (14b). Into a 50 mL flask was placed
0.430 g (1.21 mmol) of 2,5-bis(4-methoxybenzoyl)-3-(4-
methoxyphenyl)pyrrole along with DMF (30 mL). To the
stirring solution was added 0.324 g (1.82 mmol) of NBS in
one portion and the resulting reaction mixture was allowed
to stir at room temperature overnight. Subsequently, the
DMF was removed in vacuo and the resulting residue was
dissolved in ethyl acetate (100 mL) and the organic layer
was washed with water (3!50 mL), with brine (50 mL),
dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo to give 0.430 g (68% yield) of a
brown solid. An analytical sample was prepared by
automated flash chromatography on silica gel using a
gradient elution of hexane/ethyl acetate to give a yellow
solid, which exhibited the following properties: mp 147–
149 8C (recrystallized from MeOH/H2O); 1H NMR (CDCl3)
d 3.77 (s, 3H), 3.78 (s, 3H), 3.93 (s, 3H), 6.62 (d, JZ9.0 Hz,
2H), 6.72 (d, JZ9.0 Hz, 2H), 7.03 (d, JZ9.0 Hz, 2H), 7.11
(d, JZ9.0 Hz, 2H), 7.51 (d, JZ9.0 2H), 7.94 (d, JZ9.0 Hz,
2H) and 9.97 (broad s, 1H) ppm; 13C NMR (CDCl3) d 55.2,
55.4, 55.5, 113.1, 113.4, 113.8, 124.8, 128.9, 129.5, 130.1,
131.0, 131.3, 131.6, 131.8, 132.2, 132.3, 159.1, 162.9,
163.7, 185.1 and 185.5 ppm; FTIR (neat) 3231 and
1584 cmK1; HRMS (EI, MC) m/z calcd for C27H22NO5Br
calcd for 519.0681, found 519.0674.
4.1.15. 2-Carbethoxy-5-(4-methoxybenzoyl)-4-(4-meth-
oxyphenyl)pyrrole (16). To a solution of 3.13 g
(20.57 mmol) of 4-methoxybenzoic acid in dry methylene
chloride (25 mL) was added 4.32 g (20.5 mmol) of
trifluoroacetic anhydride and the resulting solution was
stirred for 15–20 min at room temperature. This was
followed by the addition of 5.48 g (48.0 mmol) of
trifluoroacetic acid and the resulting mixture was stirred
for an additional 5 min. Subsequently, 1.68 g (6.86 mmol)
of 2-carbethoxy-4-(4-methoxyphenyl)pyrrole11 was added
to the reaction mixture in which case the solution darkened
immediately. The resulting solution was then stirred at room
temperature for 3 days and the reaction was carefully
quenched with saturated, aqueous sodium bicarbonate. The
reaction mixture was then diluted with ethyl acetate
(100 mL), washed with 10% aqueous sodium hydroxide
(3!50 mL), brine (50 mL), dried over anhydrous mag-
nesium sulfate, filtered, and concentrated in vacuo. The
crude residue was subjected to radial chromatography using
hexane/ethyl acetate as the eluant in which case 2.45 g (94%
yield) of brown solid was obtained, which exhibited the
4.1.13. 2,5-Bis(4-methoxybenzoyl)-3,4-bis(4-methoxy-
phenyl)pyrrole (4) (Method A). Into a 250 mL, 3-neck
flask was placed 0.225 g (0.396 mmol) of 2,5-bis(4-
methoxybenzoyl)-3-iodo-4-(4-methoxy-phenyl)pyrrole and
50 mL of a 3:1 mixture, respectively, of toluene/ethanol.
The solution was allowed to become homogeneous and
then 0.072 g (0.475 mmol) of 4-methoxyphenylboronic acid
and 0.076 g (0.554 mmol) of potassium carbonate were
added. The system was purged with Ar and to the stirring
suspension was added 0.004 g (0.0039 mmol) of Pd(PPh3)4.
The reaction mixture was heated at 80 8C overnight. After
18 h the reaction mixture was allowed to cool and was
filtered through a plug of sand/silica/celite. The cake was
washed with ethyl acetate (50 mL) and the resulting organic
layer was washed with 10% aqueous sodium hydroxide (3!
50 mL), with brine (50 mL), dried over anhydrous mag-
nesium sulfate, filtered, and concentrated in vacuo to give
0.280 g of a brown solid. The crude material was subjected
to automated flash chromatography on silica gel using a
gradient elution of hexane/ethyl acetate to give 0.048 g
(21% yield) of a yellow solid,12 which exhibited the
following properties: mp 163–164 8C (lit.3 131–132 8C);
1H NMR (CDCl3) d 3.69 (s, 6H), 3.76 (s, 6H), 6.53 (d, JZ
8.8 Hz, 4H), 6.60 (d, JZ9.0 Hz, 4H), 6.78 (d, JZ8.8 Hz,
4H), 7.53 (d, JZ9.0 Hz, 4H) and 10.03 (broad s, 1H) ppm;
13C NMR (CDCl3) d 55.1, 55.3, 113.0, 113.2, 125.8, 129.7,
129.9, 130.5, 131.8, 132.2, 158.3, 162.7 and 186.7 ppm;
FTIR (neat) 3289 and 1596 cmK1; MS (EI, MC) m/z 547.
1
following properties: mp 145–147 8C; H NMR (CDCl3) d
1.39 (t, JZ7.1 Hz, 3H), 3.73 (s, 3H), 3.75 (s, 3H), 4.39 (q,
JZ7.1 Hz, 2H), 6.63 (d, JZ8.9 Hz, 2H), 6.66 (d, JZ
8.9 Hz, 2H), 6.99 (d, JZ2.9 Hz, 1H), 7.06 (d, JZ8.9 Hz,
2H), 7.54 (d, JZ8.9 Hz, 2H) and 9.86 (broad s, 1H) ppm;
13C NMR (CDCl3) d 16.4, 31.7, 57.2, 57.3, 63.1, 115.1,
115.5, 118.1, 127.5, 129.1, 131.5, 131.6, 132.5, 133.7,
134.1, 160.6, 162.4, 164.9 and 188.1 ppm; IR (KBr) 3309,
1711 and 1597 cmK1; HRMS (EI, MC) m/z for C22H21NO5
calcd 379.1420, found 379.1421.
4.1.16. 2-Carbethoxy-3-iodo-5-(4-methoxybenzoyl)-4-(4-
methoxyphenyl)pyrrole (17a). To a stirred solution of 2-
carbethoxy-5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-
pyrrole (1.00 g, 2.64 mmol) in DMF (60 mL) was added
potassium hydroxide (0.44 g, 7.90 mmol). After 10 min,
iodine (0.87 g, 3.43 mmol) was added in one portion and the
reaction mixture was stirred for 18 h while protecting it

J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
1853
from light. The reaction mixture was quenched with 20%
aqueous sodium thiosulfate (70 mL) and extracted with
ethyl acetate (3!100 mL). The combined organic layers
were washed with brine (100 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo to
give 1.18 g (89% yield) of a brown oil. An analytical sample
was prepared by automated flash chromatography on silica
gel using a gradient elution of hexane/ethyl acetate to give a
dark yellow solid, which exhibited the following properties:
which exhibited the following properties: mp 151–153 8C;
1H NMR (CDCl3) d 1.26 (t, JZ7.2 Hz, 3H), 3.68 (s, 3H),
3.75 (s, 3H), 3.80 (s, 3H), 4.28 (q, JZ7.2 Hz, 2H), 6.50 (d,
JZ9.0 Hz, 2H), 6.59 (d, JZ9.0 Hz, 2H), 6.73 (d, JZ
9.0 Hz, 2H), 6.80 (d, JZ9.0 Hz, 2H), 7.10 (d, JZ9.0 Hz,
2H), 7.50 (d, JZ9.0 Hz, 2H) and 9.93 (broad s, 1H) ppm;
13C NMR (CDCl3) d 14.2, 55.0, 55.1, 55.3, 60.8, 112.9,
113.0, 113.1, 122.1, 125.4, 125.7, 129.6, 129.7, 130.7,
131.7, 131.8, 132.0, 132.2, 158.3, 158.6, 160.4, 162.7 and
186.5 ppm; FTIR (neat) 2963, 1693 and 1600 cmK1; HRMS
(EI, MC) m/z calcd for C29H27NO6 485.1838, found
485.1833.
1
mp 123–125 8C; H NMR (CDCl3) d 1.46 (t, JZ6.9 Hz,
3H), 3.75 (s, 3H), 3.76 (s, 3H), 4.46 (q, JZ6.9 Hz, 2H), 6.59
(d, JZ9.0 Hz, 2H), 6.71 (d, JZ9.0 Hz, 2H), 7.04 (d, JZ
9.0 Hz, 2H), 7.45 (d, JZ9.0 Hz, 2H) and 10.15 (broad s,
1H) ppm; 13C NMR (CDCl3) d 14.4, 55.2, 55.4, 61.5, 75.1,
113.0, 113.3, 125.8, 126.4, 128.4, 130.8, 131.7, 132.3,
135.1, 159.1, 159.5, 162.9 and 185.5 ppm; FTIR (neat)
3310, 1714 and 1594 cmK1; HRMS (EI, MC) m/z calcd for
C22H20NO5I 505.0386, found 505.0395.
4.1.19. 3,4-Bis-(4-methoxyphenyl)-2-carbethoxy-5-(4-
methoxybenzoyl)pyrrole (18) (Method D). Into a nitrogen
purged round bottom flask was placed 4-methoxyphenyl
boronic acid (0.896 g, 5.9 mmol), potassium carbonate
(0.816 g, 5.9 mmol), 200 mL of a toluene/ethanol solution
(3:1) and a stir bar. To the stirred suspension was added
2-carbethoxy-3-iodo-5-(4-methoxybenzoyl)-4-(4-methoxy-
phenyl)pyrrole (1.93 g, 3.8 mmol). Once the pyrrole
became dissolved in solution, Pd(PPh3)4 (0.066 g,
0.057 mmol) was added and the reaction mixture was
heated to reflux. Upon reflux, 8 drops of water were added to
the reaction mixture. Reflux was continued and after 24 h
additional boronic acid (0.40 g, 2.6 mmol) and Pd catalyst
(0.04 g, 0.034 mmol) were added and reflux was continued
for another 24 h. The reaction mixture was cooled to room
temperature, filtered through a plug of sand/silica gel/celite
and the plug was washed with ethyl acetate (100 mL). The
filtrate was extracted with 10% aqueous sodium hydroxide
(3!50 mL), with brine (50 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo, to
yield 1.45 g of a dark yellow solid (79% yield), which
exhibited physical properties identical to the product
described in the above reaction. This material was
sufficiently pure by spectroscopic characterization and
TLC for direct use in subsequent reactions.
4.1.17. 3-Bromo-2-carbethoxy-5-(4-methoxybenzoyl)-4-
(4-methoxyphenyl)pyrrole (17b). Into a 100 mL round
bottom flask was placed 0.250 g (0.660 mmol) of 2-carb-
ethoxy-5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)pyrrole
along with DMF (50 mL). To the reaction mixture was
added 0.176 g (0.990 mmol) of NBS and the resulting
solution was stirred for 23 h at room temperature. The
solvent was removed in vacuo and the remaining residue
was dissolved in ethyl acetate (100 mL), washed with water
(3!50 mL), brine (50 mL), dried over anhydrous mag-
nesium sulfate, filtered and concentrated in vacuo to give
0.300 g (99% yield) of a brown solid. An analytical sample
was prepared by automated flash chromatography on silica
using a gradient elution of hexane/ethyl acetate to give a
solid, which exhibited the following properties: mp 128–
130 8C; 1H NMR (CDCl3) d 1.43 (t, JZ7.2 Hz, 3H), 3.78 (s,
6H), 4.44 (q, JZ7.2 Hz, 2H), 6.58 (d, JZ9.0 Hz, 2H), 6.70
(d, JZ9.0 Hz, 2H), 7.06 (d, JZ9.0 Hz, 2H), 7.46 (d, JZ
9.0 Hz, 2H) and 10.10 (broad s, 1H) ppm; 13C NMR
(CDCl3) d 14.3, 55.2, 55.3, 61.4, 104.9, 113.0, 113.4, 123.0,
124.7, 128.9, 129.9, 131.1, 131.8, 132.1, 159.0, 159.5, 162.9
and 185.5 ppm; FTIR (neat) 3256, 1678 and 1592 cmK1
;
HRMS (EI, MC) m/z calcd for C22H20NO5Br 457.0525,
found 457.0529.
4.1.20. 3,4-Bis-(4-methoxyphenyl)-5-(4-methoxyben-
zoyl)-2-pyrrolecarboxylic acid (19). Into a 100 mL flask
was placed 0.300 g of 3,4-bis-(4-methoxyphenyl)-2-carb-
ethoxy-5-(4-methoxybenzoyl)pyrrole and 50 mL of a 50/50
mixture of ethanol/water. To the stirring suspension was
added 0.100 g (2.47 mmol) of aqueous sodium hydroxide
and the reaction mixture was heated at reflux for 22 h.
Subsequently, the reaction mixture was allowed to cool to
room temperature and was acidified with 6 M hydrochloric
acid. An appropriate amount of water was added to induce
crystallization and the resulting solid was collected by
vacuum filtration and dried in vacuo to give 0.217 g (77%
yield) of a brown solid, which exhibited the following
properties: mp 212–215 8C (dec.); 1H NMR (CDCl3) d 3.68
(s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 6.51 (d, JZ9.0 Hz, 2H),
6.60 (d, JZ9.0 Hz, 2H), 6.74 (d, JZ9.0 Hz, 2H), 6.81 (d,
JZ9.0 Hz, 2H), 7.12 (d, JZ9.0 Hz, 2H), 7.52 (d, JZ
9.0 Hz, 2H) and 10.13 (broad s, 1H) ppm; 13C NMR
(CDCl3) d 55.1, 55.3, 113.1, 113.2, 120.9, 124.9, 125.5,
129.4, 130.7, 130.8, 131.6, 131.9, 132.0, 132.2, 158.3,
158.7, 162.9, 164.1 and 186.5 ppm; FTIR (neat) 3231, 1681
and 1588 cmK1; HRMS (EI, MC) m/z calcd for C27H23NO6
457.1525, found 457.1521.
4.1.18. 3,4-Bis-(4-methoxyphenyl)-2-carbethoxy-5-(4-
methoxybenzoyl)pyrrole (18) (Method C). In an Ar
purged 100 mL flask was placed 0.427 g (0.280 mmol) of
4-methoxyphenylboronic acid, 0.452 g (0.327 mmol) of
potassium carbonate, and 50 mL of a 3:1 toluene/ethanol
mixture. To the stirring suspension was added 1.07 g
(2.34 mmol) of 3-bromo-2-carbethoxy-5-(4-methoxy-
benzoyl)-4-(4-methoxy-phenyl)pyrrole. Once the pyrrole
dissolved, 0.0270 g (0.0234 mmol) of Pd(PPh3)4 was added
and the reaction mixture was heated at reflux for 22 h. The
reaction mixture was allowed to cool to room temperature,
filtered through a plug of sand/silica/celite and the cake was
washed with ethyl acetate (100 mL). The filtrate was
washed with 10% aqueous sodium hydroxide (3!50 mL),
brine (50 mL), dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo to give 0.990 g (87%
yield) of a brown semi-solid. An analytical sample was
prepared by automated flash chromatography on silica using
a gradient elution of hexane/ethyl acetate to give a soild,

1854
J. T. Gupton et al. / Tetrahedron 61 (2005) 1845–1854
4.1.21. 2,5-Bis(4-methoxybenzoyl)-3,4-bis(4-methoxy-
phenyl)pyrrole (4) (Method E). To a stirred suspension
of 3,4-bis-(4-methoxyphenyl)-5-(4-methoxybenzoyl)pyr-
role-2-carboxylic acid (0.370 g, 0.800 mmol) in dichloro-
methane (20 mL) at 0 8C were added oxalyl chloride
(0.80 mL, 1.60 mmol) and a catalytic amount (3.0 mL) of
DMF. The reaction mixture was warmed to room tempera-
ture, stirred for 2 h and the volatile materials were removed
in vacuo. The residue was taken up in methylene chloride
(20 mL) and cooled to 0 8C. With stirring under a nitrogen
atmosphere, aluminum trichloride [2.80 mL (2.80 mmol) of
a 1 M solution in nitrobenzene] and anisole (4.0 mmol)
were added to the methylene chloride solution and the
resulting reaction mixture was stirred overnight at room
temperature. The reaction was quenched by pouring it into
ice water (100 mL) and this was followed by extraction with
aqueous sodium bicarbonate (3!50 mL), drying the
organic phase over anhydrous magnesium sulfate, filtering
and concentrating in vacuo to yield 0.597 g of a brown semi-
solid. This material was purified by automated flash
chromatography on silica using a gradient elution of
hexane/ethyl acetate to give 0.330 g (75% yield) of yellow
this paper. A recent grant from the MRI program of the
National Science Foundation for the purchase of a 500 MHz
NMR spectrometer is also greatly appreciated.
References and notes
1. Loya, S.; Rudi, A.; Kashman, Y.; Hizi, A. Biochem. J. 1999,
344, 85–92.
2. Rudi, A.; Goldberg, I.; Stein, Z.; Frolow, F.; Benayahu, Y.;
Schleyer, M.; Kashman, Y. J. Org. Chem. 1994, 59, 999–1003.
Rudi, A.; Evan, T.; Aknin, M.; Kashman, Y. J. Nat. Prod.
2000, 63, 832–833.
3. Kreipl, A.; Reid, C.; Steglich, W. Org. Lett. 2002, 4,
3287–3288.
4. Gupton, J.; Krumpe, K.; Burnham, B.; Dwornik, K.; Petrich,
S.; Du, K.; Bruce, M.; Vu, P.; Vargas, M.; Keertikar, K.;
Hosein, K.; Jones, C.; Sikorski, J. Tetrahedron 1998, 54,
5075–5088.
5. Gupton, J.; Krumpe, K.; Burnham, B.; Webb, T.; Shuford, J.;
Sikorski, J. Tetrahedron 1999, 55, 14515–14522.
6. Gupton, J.; Clough, S.; Miller, R.; Lukens, J.; Henry, C.;
Kanters, R.; Sikorski, J. Tetrahedron 2003, 59, 207–215.
7. Edstrom, E.; Wei, Y. J.Org. Chem. 1993, 58, 403–407.
8. Miyaura, N.; Suzuki, S. Chem. Rev. 1995, 95, 2457–2483.
9. Hayes, B. Aldrichimica Acta 2004, 37, 66–77.
10. We are very appreciative of the helpful communications from
Professor Wolfgang Steglich during the completion of this
work and the preparation of this manuscript. We also greatly
appreciate the receipt of proton and carbon NMR spectra,
which enabled direct comparisons to be made between
our synthetic 2,5-bis(4-methoxybenzoyl)-3,4-bis(4-methoxy-
phenyl)pyrrole (4) and Professor Steglich’s material. The
reason for a difference in melting points between our sample
and that reported by Steglich and co-workers is not clear.
Polymorphic behavior of 4 is certainly one possibility but,
since there is no remaining material from the Steglich
synthesis, a direct comparison of the two samples is not
possible.
1
solid (4), which exhibited H NMR and 13C NMR spectra
and TLC behavior identical to the material prepared by
methods A and B.
Acknowledgements
We thank the National Institutes of Health (grant no. R15-
CA67236), the Thomas F. and Kate M. Jeffress Memorial
Trust and the American Chemical Society’s Petroleum
Research Fund for support of this research. We also
acknowledge the Camille and Henry Dreyfus Foundation
for a Scholar/Fellow Award to John T. Gupton. We are
exceedingly grateful to Mr. Dave Patteson of Biotage Inc.
for the generous donation of a Horizon HFC flash
chromatography system (which was used in the majority
of sample purifications) and also for the generous donation
of a Personal Chemistry Emrys Liberator US microwave
reaction system (which was crucial to the Suzuki cross-
coupling reaction utilized in the final step of the relay
synthesis of Polycitone A and B). In addition, we would like
to thank the Midwest Center for Mass Spectrometry at the
University of Nebraska-Lincoln for providing high-resol-
ution mass spectral analysis on the compounds reported in
11. Gupton, J.; Yu, R.; Krolikowski, D.; Riesinger, S.; Sikorski, J.
J. Org. Chem. 1990, 55, 4735–4740.
12. Davies, I.; Marcoux, F.; Wu, J.; Palucki, M.; Corley, E.;
Robbins, M.; Tsou, N.; Ball, R.; Dormer, P.; Larsen, R.;
Reider, P. J. Org. Chem. 2000, 65, 4571–4574.