Total synthesis of (±)-Marinopyrrole a and its library as potential antibiotic and anticancer agents

Article abstract of DOI:10.1021/cc100052j

The first total synthesis of marine natural product, (±)- marinopyrrole A, has been accomplished via a nine-step synthesis in an overall yield of 30%. A small focused library based on marinopyrrole has been designed and synthesized. The scope of chemistry was investigated, and a robust chemistry suitable for library synthesis has been developed in the current study. The method that we have developed has made it possible to generate diverse analogues based on structurally novel marinopyrroles for study of potential antibiotic and anticancer activities.

Full text of DOI:10.1021/cc100052j

J. Comb. Chem. 2010, 12, 541–547
541
Total Synthesis of (()-Marinopyrrole A and Its Library as Potential
Antibiotic and Anticancer Agents
Chunwei Cheng,† Lili Pan,† Yi Chen,† Hao Song,† Yong Qin,† and Rongshi Li*,‡
Key Laboratory of Drug Targeting & Drug DeliVery Systems of the Ministry of Education, West China
School of Pharmacy, State Key Laboratory of Biotherapy, Sichuan UniVersity, Chengdu 610041, and
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Shanghai 200032, P.R. China, and Department of Drug DiscoVery, H. Lee Moffitt Cancer
Center and Research Institute, and Oncological Sciences, UniVersity of South Florida, 12902 Magnolia
DriVe, MRC-4072B, Tampa, Florida 33612
ReceiVed March 26, 2010
The first total synthesis of marine natural product, (()-marinopyrrole A, has been accomplished via a nine-
step synthesis in an overall yield of 30%. A small focused library based on marinopyrrole has been designed
and synthesized. The scope of chemistry was investigated, and a robust chemistry suitable for library synthesis
has been developed in the current study. The method that we have developed has made it possible to generate
diverse analogues based on structurally novel marinopyrroles for study of potential antibiotic and anticancer
activities.
Introduction
Combinatorial chemistry or parallel medicinal chemistry
has been utilized successfully in different stages of drug
discovery and development. In particular, discovery and
optimization of “lead” compounds and “privileged structures”
have been demonstrated in many drug discovery and
development cases.5 Modern natural products chemistry has
been re-emerging to provide invaluable means for accessing
and exploring the diverse structures of natural products. A
combination of natural products chemistry and focused
library design and synthesis is expected to be a useful and
powerful tool for drug discovery and development. This
structurally novel natural product inspired us to develop its
chemistry and investigate the feasibility for library synthesis.
In this paper, we report the first total synthesis of the racemic
form of the marine natural product marinopyrrole A, and
show the robustness of the method for synthesis of libraries
of marinopyrrole analogues using the chemistry that we have
developed.
Historically, the majority of drugs have been discovered
and developed from natural products, as well as their
derivatives, metabolites, and mimics. Natural-products-based
drug discovery reached its peak during the 1970s and 1980s.1
Among the small molecule new chemical entities (NCEs)
introduced to the market over the past 20 years, 49%1b to
57.7%1c were natural products, synthetic or semisynthetic
natural product derivatives, or compounds based on natural
product “leads”. Marine natural products, even though limited
by technologies such as scuba diving for collecting samples,
became invaluable sources of “leads” for drug discovery.2
Because of advances in analytical technology, spectroscopy,
and high-throughput screening,3 research in the field has
again become more active from both industrial and academic
laboratories. The first drug from the sea, ziconotide (ω-
conotoxin MVIIA) was approved by the Food and Drug
Administration (FDA) in 2004 for the treatment of chronic
pain in spinal cord injury.2 Recently, the marinopyrroles A
(1a) and B (1b) (Figure 1) were reported to exhibit significant
antibiotic activity and cytotoxicity against a human cancer
cell line (HCT-116).4 Small samples in quantities of 15.7
mg of 1a and 1.0 mg of 1b were obtained by the cultivation
of Streptomyces strain CNQ-418 in 20 L of the culture broth
after purification, respectively.4a This unprecedented bispyr-
role structure was confirmed by X-ray crystallography to
adopt M-(-)- configuration (1a) which can be racemized at
elevated temperature after separation to yield the non-natural
P-(+)-atropo-enantiomer.4a
Results and Discussion
Chemistry for Synthesis of (()-Marinopyrroles. A nine-
step synthesis of the marine natural product marinopyrrole
A, (()-1a, has been developed for the first time. The
synthetic strategy has been established and is outlined in
Scheme 1. A bis-pyrrole skeleton 4 was formed in one-pot
in 82% yield via a TsOH-catalyzed condensation and
cyclization reactions of 2-ethoxycarbonyl-3-aminopyrrole 2
* To whom correspondence should be addressed. E-mail:
rongshi.li@moffitt.org. Phone: (813) 745-6485. Fax: (813) 745-7264.
† Sichuan University and Shanghai Institute of Organic Chemistry.
‡ Moffitt Cancer Center.
Figure 1. Structure of marinopyrroles.
10.1021/cc100052j  2010 American Chemical Society
Published on Web 04/29/2010

542 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Cheng et al.
Scheme 1. Synthesis of (()-Marinopyrrole A, Reagents and Conditionsa
a (a) TsOH, toluene, reflux, 82%; (b) TsCl, DMAP, NEt(iPr)2, CH2Cl2, rt, 95%; (c) DIBAL-H, CH2Cl2, rt, 92%; (d) IBX, DMSO, 60 °C, 90%; (e)
2-MeOPhMgBr, THF, 0 °C; (f) AcOH or SiO2, 80%; (g) CrO3, pyridine, rt, 69% from 7; (h) KOH, MeOH/THF (1:1), rt, 95%; (i) BBr3, CH2Cl2, -78 °C,
98%; (j) NCS, MeCN, rt, 75%; (k) BBr3, CH2Cl2, -78 °C, 95%; (l) NBS, MeCN. DMAP: 4-N,N-dimethyl pyridine; DIBAL-H: diisobutyl-aluminum hydride;
IBX: 2-iodoxybenzoic acid; PCC: pyridinium chlorochromate; NCS: N-chlorosuccinimide; NBS: N-bromosuccinimide.
with R-ketone ester 3 in toluene under reflux condition.6
After protecting the nitrogen on the pyrrole ring in 4, the
two ester groups were reduced with DIBAL-H at room
temperature in CH2Cl2 to afford diol 6 in 87% yield in two
steps. The hydroxyl groups in 6 were oxidized with IBX in
dimethyl sulfoxide (DMSO) to give dialdehyde 7 in 90%
yield. Although addition of 2-methoxyphenylmagnesium
bromide to 7 in tetrahydrofuran (THF) or toluene at 0 °C
provided diol 8 with high conversion, initial attempts to
isolate the unstable 8 by chromatography on silica gel or
under a weak acid condition (AcOH) exclusively afforded
oxazepine 9 as byproduct with the two phenyl rings in a cis
relationship. The relative configuration of 9 was confirmed
by the X-ray analysis of a single crystal.7 To avoid the
formation of 9, the crude 8 was directly subjected to
oxidation by CrO3 in anhydrous pyridine at room temperature
to furnish diketone 10 in 69% yield and byproduct 9 in 10%
yield in two steps. This operation not only supressed the
byproduct formation but also saved an additional purification
step. After deprotection of the Ts group in 10 in MeOH/
THF (1:1), the resulting 11 was reacted with 4.4 equiv of
N-chlorosuccinimide (NCS) in anhydrous acetonitrile to give
tetrachloro-substituted 1c in 75% yield. Demethylation of
11 was achieved using BBr3 in CH2Cl2 at -78 °C to give
phenol 12 in 98% yield. Compound 12 lacking the tetrachloro
substituents present in 1a was interesting for three reasons:
(i) to test the importance of those tetrachloro substituents
on pyrrole rings for biological activities; (ii) to explore the
effects of substituents other than chlorine; (iii) to provide a
site for further elaboration for Structure-Activity-Relation-
ships (SAR). The racemic form of natural product marinopy-
rrole A was obtained in 95% yield in the final step by
demethylation of 1c with BBr3. Unfortunately, attempts to
prepare marinopyrrole B, (()-1b, by bromination of (()-1a
with N-bromosuccinimide (NBS) under various conditions
were unsuccessful. This is probably due to the electron-
deficient characteristics of the pyrrole ring when it contains
three electron-withdrawing groups.
Chemistry for Synthesis of a Focused Library of
Marinopyrrole. Having developed a practical and robust
synthetic method to racemic marinopyrrole A, analogues of
marinopyrrole A shown in Figure 2 were designed and
synthesized to demonstrate the suitability of the chemistry
for the synthesis of libraries of marinopyrrole analogues. To
investigate the scope of chemistry and feasibility that library
compounds can be synthesized, we chose electron-donating,

Total Synthesis of (()-Marinopyrrole A and Its Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 543
Figure 2. Focused library of marinopyrroles.
Scheme 2. Synthesis of a Focused Library of Marinopyrroles
electron-withdrawing and non-substitued phenyl rings to be
installed as the phenyl-ketone moiety on bis-pyrrole system.
Variation on ortho, meta, and para substitution on phenyl
rings to the ketone functional group as well as mono- or
disubstitutions were also incorporated. The design served the
purpose of investigating the scope of the chemistry and its
robustness for library synthesis, as well as the effect of
substituents on the phenyl rings for future optimization and
SAR studies. As outlined in Scheme 2, synthesis of a small
library of marinopyrrole 1c-1l with different substituents
on the phenyl rings was accomplished in yields of 5-49%
in a four-step synthesis. It has been demonstrated that the
chemistry can accommodate substituents on phenyl rings
from strong electron donating groups (bis-methoxy, 1l, 1m)
to electron withdrawing groups (trifluoromethyl, 1j, 1k) by
addition of a variety of Grignard’s reagents or organic lithium
reagents to dialdehyde 7. The alcohol intermediates were
subjected to oxidation with CrO3, followed by deprotection
of the Ts group, and chlorination with NCS to furnish the
desired product 1c-1m. The chloro atom on the electron-
rich phenyl rings in 1l and 1m was introduced unintentionally
during chlorination of the corresponding precursor, but the
outcome paves the avenue to access diversity of both phenyl
rings with trisubstituents. Compound 1n was not made
because chlorination can not be avoided on the electron-
rich bis-methoxyphenyl rings. Compound 1m was obtained
from 1l by selective demethylation with BBr3 in CH2Cl2 in
high yield using a similar procedure for preparation of (()-

544 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Cheng et al.
1a from 1c. Chlorination on the electron-rich phenyl rings
also established a route for potential substitutions replacing
chlorines if needed.
(26 mg, 0.14 mmol). Ethyl 3-amino-1H-pyrrole-2-carboxy-
late hydrochloride (2)8 and ethyl 4-(1,3-dioxan-2-yl)-2-
oxobutanoate (3)6 were prepared according to literature
procedure. The mixture was then heated to reflux for 10 h.
After cooling to room temperature, the mixture was adjusted
to pH 7.0 with saturated aqueous NaHCO3 and extracted with
EtOAc (20 mL × 3). The combined organic layers were dried
over anhydrous Na2SO4, filtered and concentrated in vacuum.
The residue was purified by column chromatography (10%
EtOAc/petroleum ether) to give 4 (2.40 g, 82% yield) as a
Although our current method has been limited to the
generation of symmetrical compounds in terms of constitu-
tion and substituents on the two halves of the molecule as
racemic materials, the convergent synthesis of intermediate
4 may allow de-symmetrization of the final target. Our efforts
toward de-symmetrization of the final target and enantio-
merically pure materials are ongoing, and the accomplish-
ment of novel chemical entities based on marine natural
product marinopyrrole will be realized if successful.
1
light yellow solid. mp 70-71 °C; H NMR (400 MHz,
CDCl3) δ 1.11 (t, J ) 7.2 Hz, 3H), 1.23 (t, J ) 7.2 Hz, 3H),
4.10-4.19 (m, 4H), 6.26 (dd, J ) 4.0, 2.8 Hz, 1H), 6.31 (t,
J ) 2.8 Hz, 1H), 6.89 (t, J ) 1.6 Hz, 1H), 6.91 (t, J ) 3.2
Hz, 1H), 7.07 (dd, J ) 4.0, 2.0 Hz, 1H), 9.32 (br, s, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 13.8, 14.2, 59.6, 60.2,
108.5, 109.6, 117.4, 117.7, 120.6, 124.5, 129.7, 130.1, 160.1,
160.6 ppm; HRMS (M+Na)+ calcd for C14H16N2NaO4
299.1008, found 299.0987; IR (KBr) 3300, 2987, 1713, 1672,
1421, 1282, 1138, 733, 608 cm-1.
Conclusions
In summary, the first total synthesis of antibiotic natural
product (()-marinopyrrole A has been achieved via a nine-
step synthesis in an overall yield of 30%. Spectroscopic data
of (()-marinopyrrole A synthesized in this study are
consistent with those of 1a, the naturally isolated product.4a
The synthesis avails the natural product in good quantities
as compared to an earlier biosynthetic effort that provided
the material in only very limited amounts. Using this method,
a focused library of (()-marinopyrrole A derivatives was
designed and synthesized to study the scope of chemistry
and the feasibility for library synthesis. Since the parent
compound (-)-marinopyrrole A displayed antibitotic and
cytotoxicity, the chemistry developed in this report makes
access to the natural product derivatives possible for SAR
studies and further development. All compounds synthesized
Diethyl 1′-Tosyl-1′H-1,3′-bipyrrole-2,2′-dicarboxylate
(5). To a solution of 4 (2.00 g, 7.25 mmol) in anhydrous
CH2Cl2 (20 mL) were added 4-dimethylaminopyridine
(DMAP, 4.40 g, 36.07 mmol) and N,N-diisopropylethyl-
amine (DIPEA, 4.70 g, 36.43 mmol) at 0 °C. After being
stirred for 10 min, TsCl (11.50 g, 72.33 mmol) was added
to the mixture and allowed to stir for 8 h at room temperature.
The mixture was extracted with CH2Cl2 (25 mL × 3). The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuum. The residue was
purified by column chromatography (5% EtOAc/petroleum
ether) to give 5 (2.96 g, 95% yield) as a light yellow solid.
1
were fully characterized using H and 13C NMR, and high
resolution mass spectrometry. The purity of the library
compounds ranges from 95.0% to 99.4% and confirmed by
high-performance liquid chromatography (HPLC). Design
and synthesis of the next generation of marinopyrrole
analogues have been ongoing. The use of combinatorial
chemistry as a powerful tool to elaborate and speed up
evaluation of marinopyrrole derivatives for both antibiotic
and anticancer activities will be reported in due course.
1
mp 87-89 °C; H NMR (400 MHz, CDCl3) δ 0.91 (t, J )
7.2 Hz, 3H), 0.94 (t, J ) 7.2 Hz, 3H), 2.44 (s, 3H), 3.97 (q,
J ) 7.2 Hz, 2H), 4.07 (q, J ) 7.2 Hz, 2H), 6.22 (dd, J ) 4,
2.8 Hz, 1H), 6.37 (d, J ) 3.6 Hz, 1H), 6.81 (dd, J ) 2.8,
2.0 Hz, 1H), 7.03 (q, J ) 2.0 Hz, 1H), 7.35 (d, J ) 8.4 Hz,
2H), 7.65 (d, J ) 3.2 Hz, 1H), 7.93 (d, J ) 8.4 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ 13.4, 13.9, 21.6, 59.8,
60.9, 109.0, 111.1, 118.1, 120.7, 124.7, 125.3, 128.2, 128.2,
129.5, 129.5, 129.7, 134.3, 135.7, 145.1, 158.2, 160.1 ppm;
HRMS (M+Na)+ calcd for C21H22N2NaO6S 453.1096, found
453.1097; IR (KBr) 3436, 3141, 2982, 1727, 1579, 1441,
1374, 1179, 1101, 1024, 748, 671, 591 cm-1.
Experimental Section
All chemicals were purchased from commercial suppliers
and used without further purification. All solvents were dried
and distilled before use. THF was distilled from sodium/
benzophenone. Dichloromethane and acetonitrile were dis-
tilled over calcium hydride. Flash column chromatography
(1′-Tosyl-1′H-1,3′-bipyrrole-2,2′-diyl)dimethanol (6). To
a solution of 5 (500 mg, 1.16 mmol) in anhydrous CH2Cl2
(15 mL) was slowly added DIBAL-H (4.67 mL, 1 M solution
in toluene, 4.70 mmol) by syringe under N2 at 0 °C. After
being stirred for 6 h at room temperature, the mixture was
quenched by addition of saturated aqueous Na2SO4. The
resulting suspension was filtered. The filtrate was concen-
trated in vacuum, and then purified by column chromatog-
raphy (33% EtOAc/petroleum ether) to give 6 (370 mg, 92%
yield) as a white solid. mp 103-106 °C; 1H NMR (400 MHz,
CDCl3) δ 2.44 (s, 3H), 2.63 (br, s, 1H), 3.48 (br, s, 1H),
4.31 (s, 2H), 4.42 (s, 2H), 6.19 (t, J ) 3.6 Hz, 1H), 6.29
(dd, J ) 3.6, 1.6 Hz, 1H), 6.33 (d, J ) 3.6 Hz, 1H), 6.63 (q,
J ) 1.6 Hz, 1H), 7.30 (d, J ) 3.2 Hz, 1H), 7.35 (d, J ) 8.4
Hz, 2H), 7.85 (d, J ) 8.4 Hz, 2H) ppm; 13C NMR (100 MHz,
1
was performed with silica gel (200-300 mesh). H NMR
spectra were recorded at 400 MHz at ambient temperature.
13C NMR spectra were recorded at either 50 or 100 MHz at
ambient temperature. Infrared spectra were recorded on a
spectrophotometer (Perkin-Elmer Spectrum 100)). Melting
points were determined with melting point apparatus (Fukai
X-4)). High resolution mass spectra were performed by FAB
method. The specifications of HPLC analysis are as follows:
flow rate, 1 mL/min; column, Inertsil SIL, 5 µm, 4.6 × 250
mm; wavelength 254 nm; mobile phase, n-hexane/iso-
propanol.
Diethyl 1′H-1,3′-bipyrrole-2,2′-dicarboxylate (4). To a
solution of 2 (2.00 g, 10.50 mmol) in toluene (20 mL) were
added R-ketone ester 3 (3.40 g, 15.74 mmol) and p-TSA

Total Synthesis of (()-Marinopyrrole A and Its Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 545
1367, 1176, 1020, 754 cm-1. Oxazepine 9: Yellow solid,
mp 193-195 °C; H NMR (400 MHz, CDCl3) δ 2.35 (s,
CDCl3) δ 21.6, 52.3, 55.3, 108.6, 109.9, 111.4, 121.4, 124.2,
127.2, 127.7, 127.7, 130.1, 130.1, 130.1, 134.3, 135.5, 145.7
ppm; HRMS (M+Na)+ calcd for C17H18N2NaO4S 369.0885,
found 369.0881; IR (KBr) 3324, 2928, 1646, 1592, 1453,
1375, 1148, 1087, 1006, 670, 602 cm-1.
1
3H), 3.75 (s, 3H), 3.79 (s, 3H), 5.31 (d, J ) 1.6 Hz, 1H),
5.87 (s, 1H), 6.04 (t, J ) 3.2 Hz, 1H), 6.54 (d, J ) 3.6 Hz,
1H), 6.57 (td, J ) 7.6, 0.8 Hz, 1H), 6.71 (dd, J ) 7.6, 2.0
Hz, 1H), 6.83-6.89 (m, 3H), 6.95 (t, J ) 7.6 Hz, 1H), 7.09
(t, J ) 8.0 Hz, 2H), 7.16 (td, J ) 8.4, 1.6 Hz, 1H), 7.27 (td,
J ) 8.4, 1.6 Hz, 1H), 7.31 (d, J ) 8.0 Hz, 3H), 7.38 (d, J )
3.6 Hz, 1H), 7.49 (dd, J ) 3.6, 1.6 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 21.4, 55.3, 56.2, 68.8, 74.4, 107.0,
107.6, 108.5, 109.7, 111.6, 119.4, 120.4, 120.4, 122.9, 123.7,
126.6, 126.6, 127.8, 128.3, 128.4, 128.9, 129.2, 129.6, 129.6,
129.7, 129.9, 135.4, 136.9, 144.3, 155.7, 157.8 ppm; HRMS
(M+H)+ calcd for C31H29N2O5S 541.1797, found 541.1800;
IR (KBr) 3448, 2921, 2842, 1601, 1493, 1462, 1369, 1248,
1136, 1058, 745, 672 cm-1.
1′-Tosyl-1′H-1,3′-bipyrrole-2,2′-dicarbaldehyde (7). To
a solution of diol 6 (2.90 g, 8.38 mmol) in anhydrous DMSO
(20 mL) was added 2-iodoxybenzoic acid (IBX, 7.04 g, 25.14
mmol). After being stirred for 6 h at 70 °C, the mixture was
allowed to cool to room temperature. The suspension was
filtered, and the filtrate was extracted with EtOAc (50 mL
× 3). The combined organic layers were dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuum. The
residue was purified by column chromatography (12%
EtOAc/petroleum ether) to give 7 (2.58 g, 90% yield) as a
1
light yellow solid. mp 138-140 °C; H NMR (400 MHz,
CDCl3) δ 2.44 (s, 3H), 6.41 (dd, J ) 4.0, 2.4 Hz, 1H), 6.45
(d, J ) 3.2 Hz, 1H), 7.02-7.03 (m, 1H), 7.10 (dd, J ) 4.0,
1.6 Hz, 1H), 7.37 (d, J ) 8.8 Hz, 2H), 7.70 (d, J ) 3.6 Hz,
1H), 7.87 (d, J ) 8.4 Hz, 2H), 9.49 (s, 1H), 9.71 (s, 1H)
ppm;13C NMR (50 MHz, CDCl3) δ 21.7, 111.3, 111.6, 124.1,
125.7, 127.5, 127.9, 127.9, 130.1, 130.1, 132.3, 133.0, 134.7,
136.6, 146.3, 177.2, 179.4 ppm; HRMS (M+Na)+ calcd for
C17H14N2NaO4S 365.0572, found 365.0530; IR (KBr) 3444,
3137, 2923, 1668, 1562, 1447, 1361, 1180, 1014, 752, 668
cm-1.
1′H-1,3′-Bipyrrole-2,2′-diylbis(2-methoxyphenyl)metha-
none (11). To a solution of 10 (58 mg, 0.10 mmol) in a 1:1
mixture of MeOH/THF (2 mL) was added KOH (24 mg,
0.42 mmol) at room temperature. After being stirred for 1 h,
the mixture was adjusted to pH 7.0 with 0.5 N HCl and
extracted with EtOAc (10 mL × 3). The combined organic
layers were dried over anhydrous Na2SO4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography (14% EtOAc/petroleum ether) to give 11
(40 mg, 95% yield) as a light yellow solid. mp 175-176
1
°C; H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.80 (s,
(()-4,6-Bis(2-methoxyphenyl)-3-tosyl-4,6-dihydro-3H-
dipyrrolo[2,1-c:3′,2′-e][1,4]oxazepine (9) and 1′-Tosyl-
1′H-1,3′-bipyrrole-2,2′-diyl)bis((2-methoxyphenyl)meth-
anone (10). Under N2, the freshly prepared 2-methoxy
phenylmagnesium bromide (4.94 g, 23.39 mmol) was added
dropwise to a stirred solution of 7 (1.00 g, 2.92 mmol) in
anhydrous THF (25 mL) at 0 °C. After being stirred for 5 h,
the mixture was quenched by addition of a saturated aqueous
solution of Na2SO4 (5 mL) and extracted with EtOAc (20
mL × 3). The combined organic layers were dried over
Na2SO4 and evaporated to give a yellow residue. Without
purification, the residue was directly subjected to the
oxidation by CrO3 (1.17 g, 11.70 mmol) in anhydrous
pyridine (15 mL) at room temperature. The reaction mixture
was stirred for 4 h and then concentrated in vacuum. The
residue was dissolved in EtOAc and filtered. The filter cake
was washed by EtOAc (30 mL × 3). The combined organic
layers were concentrated to give a residue, which was
purified by column chromatography (12% EtOAc/petroleum
ether) to give 10 (1.12 g, 69% yield) and 9 (157 mg, 10%
yield). 1′-Tosyl diketone 10: Light yellow solid, mp
3H), 5.81 (dd, J ) 4.0, 2.8 Hz, 1H), 6.33-6.35 (m, 2H),
6.65 (dd, J ) 2.8, 2.0 Hz, 1H), 6.69-6.72 (m, 2H),
6.93-6.97 (m, 2H), 7.07 (t, J ) 3.2 Hz, 1H), 7.17-7.23
(m, 3H), 7.39 (td, J ) 7.2, 1.6 Hz, 1H), 9.43 (br, s, 1H)
ppm; 13C NMR (CDCl3, 50 MHz) δ 55.3, 55.6, 108.4, 110.6,
110.6, 111.4, 119.5, 119.9, 122.9, 123.2, 125.9, 128.0, 128.7,
129.0, 129.4, 129.7, 130.8, 130.9, 131.2, 132.3, 156.5, 157.1,
183.4, 183.8 ppm; HRMS (M+Na)+ calcd for C24H20N2NaO4
423.1321, found 423.1310; IR (KBr) 3363, 3069, 2934, 2841,
1625, 1491, 1437, 1407, 1250, 1164, 1027, 726 cm-1.
1′H-1,3′-Bipyrrole-2,2′-diylbis(2-hydroxyphenyl)metha-
none (12). To a solution of 11 (50 mg, 0.13 mmol) in
anhydrous CH2Cl2 (2 mL) was slowly added BBr3 (124 mg,
0.52 mmol) via a syringe under N2 at -78 °C. After being
stirred for 0.5 h, the mixture was quenched by addition of
MeOH (0.5 mL) and extracted with CH2Cl2 (10 mL × 3).
The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated in vacuum. The residue
was purified by column chromatography (12% EtOAc/
petroleum ether) to give 12 (47 mg, 98% yield) as a yellow
solid. mp 150-154 °C; 1H NMR (400 MHz, CDCl3) δ 6.17
(t, J ) 2.8 Hz, 1H), 6.34 (t, J ) 2.8 Hz, 1H), 6.46 (t, J )
8.0 Hz, 1H), 6.71 (dd, J ) 4.0, 1.6 Hz, 1H), 6.77-6.80 (m,
2H), 6.91 (t, J ) 2.8 Hz, 1H), 6.96 (d, J ) 8.0 Hz, 1H),
7.10 (t, J ) 2.8 Hz, 1H), 7.24-7.28 (m, 1H), 7.35 (dd, J )
8.0, 1.2 Hz, 1H), 7.40-7.45 (m, 2H), 9.73 (br, s, 1H), 11.03
(s, 1H), 11.56 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ
109.4, 110.2, 117.5, 117.8, 118.5, 118.6, 119.0, 119.8, 123.2,
123.4, 123.5, 130.1, 130.4, 130.8, 131.5, 132.3, 135.3, 135.4,
161.5, 162.3, 187.7, 188.2 ppm; HRMS (M+H)+ calcd for
C22H17N2O4 373.1188, found 373.1224; IR (KBr) 3345, 2962,
2923, 2855, 1623, 1584, 1555, 1409, 1256, 1096, 1028, 805
1
113-115 °C; H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H),
3.68 (s, 3H), 3.75 (s, 3H), 5.83 (t, J ) 3.2 Hz, 1H), 6.27 (d,
J ) 2.4 Hz, 1H), 6.43 (d, J ) 3.6 Hz, 1H), 6.66-6.75 (m,
3H), 6.90 (d, J ) 8.4 Hz, 2H), 7.10 (d, J ) 7.2 Hz, 1H),
7.23-7.26 (m, 1H), 7.33-7.36 (m, 4H), 7.57 (d, J ) 3.6
Hz, 1H), 7.96 (d, J ) 8.0 Hz, 2H) ppm; 13C NMR (50 MHz,
CDCl3) δ 21.3, 55.5, 55.5, 109.3, 111.7, 111.9, 112.0, 119.7,
119.7, 119.7, 122.8, 125.4, 126.8, 128.0, 128.0, 128.7, 129.2,
129.9, 129.9, 130.6, 131.2, 132.0, 132.4, 132.5, 133.6, 135.7,
145.4, 156.5, 157.8, 182.6, 182.9 ppm; HRMS (M+Na)+
calcd for C31H26N2NaO6S 577.1409, found 577.1386; IR
(KBr) 3451, 3139, 2926, 3843, 1646, 1596, 1487, 1412,

546 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Cheng et al.
cm-1. Purity was determined to be 97.1% by HPLC analysis
using n-hexane/iso-propanol (95:5) as mobile phase.
CDCl3) δ 110.6, 112.0, 120.6, 120.8, 123.7, 124.6, 124.7,
127.8, 127.8, 127.9, 127.9, 128.3, 128.3, 129.4, 129.4, 129.8,
131.8, 132.6, 136.9, 137.1, 183.5, 183.9 ppm; HRMS
(M+Na)+ calcd for C22H12Cl4N2NaO2 498.9551, found
498.9543; IR (KBr) 3442, 3211, 2930, 1637, 1399, 1240,
1013, 706 cm-1. Purity was determined to be 99.3% by
HPLC analysis using n-hexane/iso-propanol (95:5) as mobile
phase.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(3-
methoxyphenyl)methanone (1e). (24 mg, 56% yield). mp
56-59 °C; 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 3.86
(s, 3H), 6.89 (s, 1H), 7.11-7.14 (m, 1H), 7.23-7.25 (m,
1H), 7.31 (dd, J ) 2.0, 0.8 Hz, 1H), 7.36-7.47 (m, 5H)
ppm; 13C NMR (100 MHz, CDCl3) δ 55.4, 55.5, 111.9,
112.0, 113.1, 113.6, 113.7, 114.4, 118.4, 118.8, 120.8, 121.8,
122.6, 123.9, 124.9, 129.3, 130.1, 130.2, 132.8, 138.8, 159.5,
160.0, 164.9, 183.1 ppm; HRMS (M+K)+ calcd for
C24H16Cl4KN2O4 574.9501, found 574.9504; IR (KBr) 3431,
2960, 2925, 1729, 1642, 1582, 1435, 1266, 1207, 1041, 806
cm-1. Purity was determined to be 98.7% by HPLC analysis
using n-hexane/iso-propanol (95:5) as mobile phase.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(4-
methoxyphenyl)methanone (1f). (45 mg, 65% yield). mp
67-72 °C; 1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 3.91
(s, 3H), 6.83 (s, 1H), 6.95-7.02 (m, 4H), 7.81-7.84 (m,
4H) ppm; 13C NMR (100 MHz, CDCl3) δ 55.5, 55.7, 111.3,
111.7, 112.7, 113.5, 113.7, 113.7, 114.7, 114.7, 118.0, 120.0,
123.7, 130.2, 130.5, 131.6, 131.6, 132.2, 134.0, 134.0, 163.2,
164.0, 165.6, 182.4 ppm; HRMS (M+K)+ calcd for
C24H16Cl4KN2O4 574.9501, found 574.9650; IR (KBr) 3448,
2925, 2847, 1722, 1600, 1510, 1438, 1258, 1172, 1026, 845
cm-1. Purity was determined to be 99.2% by HPLC analysis
using n-hexane/iso-propanol (95:5) as mobile phase.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(2-
fluorophenyl)methanone (1g). (20 mg, 50% yield). mp
46-48 °C; 1H NMR (400 MHz, CDCl3) δ 6.78 (s, 1H), 7.16
(t, J ) 8.8 Hz, 1H), 7.20-7.25 (m, 2H), 7.33 (t, J ) 7.6 Hz,
1H), 7.48-7.54 (m, 2H), 7.65-7.75 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3) δ 116.3, 116.5, 116.9, 117.2, 121.2,
121.4, 124.0, 124.1, 125.0, 125.0, 130.4, 132.2, 133.0, 133.1,
136.7, 136.8, 158.5, 160.2, 161.0, 161.1, 162.8, 179.7 ppm;
HRMS (M+K)+ calcd for C22H10Cl4F2KN2O2 550.9102,
found 550.9101; IR (KBr) 3437, 2923, 2854, 1727, 1649,
1608, 1412, 1284, 1098, 925, 753 cm-1. Purity was
determined to be 96.0% by HPLC analysis using n-hexane/
iso-propanol (95:5) as mobile phase.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(2-
methoxyphenyl)methanone (1c). To a solution of 11 (400
mg, 1.00 mmol) in acetonitrile (5 mL) was added NCS (587
mg, 4.40 mmol) at 40 °C. After being stirred for 30 h, the
mixture was extracted with EtOAc (10 mL × 3). The
combined organic layers were dried over anhydrous Na2SO4,
filtered and concentrated in vacuum. The residue was purified
by column chromatography (11% EtOAc/petroleum ether)
to give 1c (401 mg, 75% yield) as a light yellow solid. mp
1
193-194 °C; H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H),
3.79 (s, 3H), 6.32 (s, 1H), 6.68 (t, J ) 7.2 Hz, 1H), 6.77 (d,
J ) 8.4 Hz, 1H), 6.96 (t, J ) 7.6 Hz, 2H), 7.18 (dt, J ) 7.2,
1.2 Hz, 2H), 7.25 (td, J ) 8.0, 1.6 Hz, 1H), 7.41 (td, J )
8.0, 1.6 Hz, 1H), 9.76 (br, s, 1H) ppm; 13C NMR (50 MHz,
CDCl3) δ 55.5, 55.7, 110.4, 110.0, 111.6, 111.6, 119.7, 119.8,
120.2, 120.7, 124.0, 125.0, 125.7, 126.5, 127.9, 128.7, 129.3,
130.9, 131.6, 131.7, 156.6, 157.2, 182.4, 182.4 ppm; HRMS
(M+H)+ calcd for C24H17Cl4N2O4 536.9942, found 536.9940;
IR (KBr) 3447, 2931, 2856, 1639, 1598, 1489, 1430, 1402,
1250, 1023, 929, 754, 646 cm-1. Purity was determined to
be 99.3% by HPLC analysis using n-hexane/iso-propanol (95:
5) as mobile phase.
(()-(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)-
bis(2-hydroxyphenyl)methanone (()-1a. Compound (()-
1a was prepared according to the procedure for the prepa-
ration of 12 from 11 by using 1c (100 mg, 0.19 mmol) and
BBr3 (187 mg, 0.75 mmol) to give a yellow solid (90 mg,
95% yield), which was purified by column chromatography
1
(10% EtOAc/petroleum ether). mp 205-207 °C; H NMR
(400 MHz, CDCl3) δ 6.52 (t, J ) 7.2 Hz, 1H), 6.71 (s, 1H),
6.88-6.93 (m, 2H), 7.02 (d, J ) 8.4 Hz, 1H), 7.35 (td, J )
7.2, 1.2 Hz, 1H), 7.47-7.53 (m, 2H), 7.57 (dd, J ) 8.0, 1.6
Hz, 1H), 10.00 (s, 1H), 10.42 (s, 1H), 11.20 (s, 1H) ppm;
13C NMR (50 MHz, CDCl3) δ 110.6, 112.7, 117.7, 118.3,
118.6, 118.9, 118.9, 119.0, 120.3, 120.4, 123.2, 123.8, 124.1,
128.8, 130.3, 131.8, 136.1, 136.2, 161.0, 162.4, 185.9, 186.8
ppm; HRMS (M+Na)+ calcd for C22H12Cl4N2NaO4 530.9449,
found 530.9455; IR (KBr) 3302, 3247, 2923, 2854, 1622,
1592, 1441, 1406, 1257, 1026, 867, 764, 584 cm-1. Purity
was determined to be 97.8% by HPLC analysis using
n-hexane/iso-propanol (95:5) as mobile phase.
General Procedure for Synthesis of Compound 1c-1m.
Ketone (11) was prepared by addition of the corresponding
Grignard’s reagent or organic lithium reagent generated in
situ to dialdehyde 7 (1 equiv) in n-pentane (lithium reagent,
8 equiv) or THF (Grignard’s reagent, 8 equiv), followed by
oxidation using CrO3 (4 equiv) in pyridine. After purification
by flash column chromatography, removal of Ts protecting
group was carried out with KOH (4 equiv) in MeOH/THF
(1:1). The corresponding intermediate after purification by
flash column chromatography was chlorinated using NCS
(4 equiv) in acetonitrile to furnish the desired product.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(phe-
nyl)methanone (1d). (56 mg, 74% yield). mp 118-122 °C;
1H NMR (400 MHz, CDCl3) δ 5.30 (br, s, 1H), 6.44 (s, 1H),
7.10 (t, J ) 6.8 Hz, 2H), 7.32 (t, J ) 7.6 Hz, 1H), 7.37-7.43
(m, 4H), 7.47-7.55 (m, 3H) ppm; 13C NMR (100 MHz,
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(3-
fluorophenyl)methanone (1h). (26 mg, 65% yield). mp
38-41 °C; 1H NMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 7.30
(td, J ) 8.4, 2.0 Hz, 1H), 7.41-7.54 (m, 3H), 7.55 (dd, J )
8.4, 2.8 Hz, 1H), 7.58-7.62 (m, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 115.9, 116.1, 117.5, 117.7, 119.4, 119.6,
121.2, 122.6, 122.8, 124.9, 127.0, 129.6, 130.1, 130.2, 131.0,
131.1, 133.7, 139.5, 161.5, 163.7, 163.7, 181.9 ppm; HRMS
(M+K)+ calcd for C22H10Cl4F2KN2O2 550.9102, found
550.9216; IR (KBr) 3132, 2963, 2632, 1794, 1732, 1645,
1588, 1441 cm-1. Purity was determined to be 95.0% by
HPLC analysis using n-hexane/iso-propanol (95:5) as mobile
phase.

Total Synthesis of (()-Marinopyrrole A and Its Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 547
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(4-
fluorophenyl)methanone (1i). (27 mg, 67% yield). mp
48-52 °C; H NMR (400 MHz, CDCl3) δ 6.85 (s, 1H),
by HPLC analysis using n-hexane/iso-propanol (85:15) as
mobile phase.
1
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(5-
chloro-2-hydroxy-4-methoxyphenyl)methanone (1m). (46
7.17 (t, J ) 4.8 Hz, 2H), 7.24 (t, J ) 4.8 Hz, 2H),
7.83-7.92 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ
115.5, 115.8, 116.7, 116.9, 120.8, 121.1, 125.1, 127.9,
129.9, 131.7, 131.8, 132.0, 132.1, 133.8, 134.1, 134.2,
163.8, 164.1, 165.8, 166.6, 168.4, 182.1 ppm; HRMS
(M+K)+ calcd for C22H10Cl4F2KN2O2 550.9102, found
550.9116; IR (KBr) 3438, 3127, 2921, 1729, 1643, 1596,
1434, 1238, 1152, 850 cm-1. Purity was determined to
be 97.7% by HPLC analysis using n-hexane/iso-propanol
(95:5) as mobile phase.
1
mg, 92% yield). mp 251-253 °C; H NMR (400 MHz,
CDCl3) δ 3.92 (s, 3H), 3.94 (s, 3H), 6.42 (s, 1H), 6.52 (s,
1H), 6.72 (s, 1H), 7.44 (s, 1H),7.46 (s, 1H), 9.77 (br, s, 1H),
11.13 (s, 1H), 11.77 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 56.5, 56.5, 100.4, 101.1, 110.5, 112.1, 112.5, 113.1,
113.2, 113.7, 119.8, 120.2, 122.7, 123.3, 123.7, 128.6, 131.1,
132.0, 161.1, 161.2, 163.2, 164.2, 183.6, 184.5 ppm; HRMS
(M+Na)+ calcd for C24H14Cl6N2NaO6 658.8881, found
658.8830; IR (KBr) 3305, 2920, 2851, 1624, 1582, 1443,
1276, 1060, 919, 783 cm-1. Purity was determined to be
96.1% by HPLC analysis using n-hexane/iso-propanol (95:
5) as mobile phase.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(2-
(trifluoromethyl)phenyl)methanone (1j). (11 mg, 58%
1
yield). mp 35-39 °C; H NMR (400 MHz, CDCl3) δ 6.54
(s, 1H), 7.48 (t, J ) 3.6 Hz, 1H), 7.47-7.49 (m, 3H), 7.71
(t, J ) 8.0 Hz, 1H), 7.74-7.77 (m, 2H), 7.88 (d, J ) 7.2
Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 112.7, 115.6,
119.8, 121.5, 122.4, 124.2, 126.8, 126.8, 127.6, 127.6, 128.0,
128.5, 129.6, 130.2, 130.6, 131.3, 132.1, 132.3, 133.1, 136.7,
136.7, 162.9, 162.9, 182.1 ppm; HRMS (M+K)+ calcd for
C24H10Cl4KN2O2 650.9038, found 650.8985; IR (KBr) 3449,
2924, 2855, 1738, 1649, 1421, 1316, 1277, 1126, 924, 770
cm-1. Purity was determined to be 99.4% by HPLC analysis
using n-hexane/iso-propanol (95:5) as mobile phase.
Acknowledgment. This work was supported by NSFC
(20772083, 20825207), PCSIRT (IRT0846), and the National
Basic Research Program of China (2010CB833200). We
thank H. Lee Moffitt Cancer Center and Research Institute
for Finacial support.
Supporting Information Available. Detailed 1H and 13
C
NMR spectra, HPLC spectra, and X-ray crystallographic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(4-
(trifluoromethyl)phenyl)methanone (1k). (18 mg, 48%
References and Notes
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(b) Abou-Gharbia, M. J. Med. Chem. 2009, 52, 2–9. (c) Ojima,
I. J. Med. Chem. 2008, 51, 2587–2588.
(2) Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes, J. P.
Nat. ReV. Drug DiscoVery 2009, 8, 69–85.
(3) (a) Koehn, F. E.; Carter, G. T. Nat. ReV. Drug DiscoVery 2004,
4, 206–220. (b) Bugni, T. S.; Richards, B.; Bhoite, L.; Cimbora,
D.; Harper, M. K.; Ireland, C. M. J. Nat. Prod. 2008, 71, 1095–
1098.
(4) (a) Hughes, C. C.; Prieto-Dave, A.; Jensen, P. R.; Fenical, W.
Org. Lett. 2008, 10, 629–631. (b) Hughes, C. C.; Yang, Y. L.;
Liu, W. T.; Dorrestein, P. C.; La Clair, J. L.; Fenical, W. J. Am.
Chem. Soc. 2009, 131, 12094–12096.
(5) (a) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales,
G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem. 2009, 11,
739–790. (b) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.;
Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem.
2008, 10, 753–802.
(6) Ragan, J. A.; Jones, B. P.; Castaldi, M. J.; Hill, P. D.;
Makowski, T. W. Org. Synth. 2004, 10, 418–422.
(7) A colorless crystal of 9 (C31H28N2O5S, mp 193-195 °C) for
the X-ray analysis was obtained by recrystallization from EtOH/
CH2Cl2 (20:1). The crystallographic data have been deposited
with the Cambride Crystallographic Data Centre, CCDC
747461.
1
yield). mp 39-43 °C; H NMR (400 MHz, CDCl3) δ 6.87
(s, 1H), 6.77 (d, J ) 8.0 Hz, 2H), 6.83 (d, J ) 8.0 Hz, 2H),
7.90 (d, J ) 8.0 Hz, 2H), 8.00 (d, J ) 8.0 Hz, 2H) ppm; 13
C
NMR (100 MHz, CDCl3) δ 112.6, 121.7, 121.7, 121.9, 124.4,
125.4, 125.5, 125.5, 125.5, 125.9, 126.3, 126.3, 126.3, 129.4,
129.4, 129.5, 129.6, 131.4, 131.4, 134.1, 136.3, 140.6, 164.1,
182.3 ppm; HRMS (M+K)+ calcd for C24H10Cl4KN2O2
650.9038, found 650.9099; IR (KBr) 2954, 2923, 2853, 1737,
1645, 1436, 1323, 1133, 1065, 856, 678 cm-1. Purity was
determined to be 97.2% by HPLC analysis using n-hexane/
iso-propanol (95:5) as mobile phase.
(4,4′,5,5′-Tetrachloro-1′H-1,3′-bipyrrole-2,2′-diyl)bis(5-
chloro-2,4-dimethoxyphenyl)methanone (1l). (50 mg, 75%
yield) mp 106-108 °C; 1H NMR (400 MHz, CDCl3) δ 3.78
(s, 3H), 3.81 (s, 3H), 3.90 (s, 3H), 3.96 (s, 3H), 6.38 (s,
1H), 6.44 (s, 1H), 6.50 (s, 1H), 7.18 (s, 1H), 7.30 (s, 1H),
8.26 (br, s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 56.0,
56.0, 56.3, 60.4, 95.8, 96.5, 111.6, 112.8, 112.9, 119.0, 120.0,
120.2, 120.7, 124.2, 125.2, 129.9, 130.7, 131.5, 157.6, 157.6,
158.0, 158.4, 178.1, 178.1, 180.2, 180.3 ppm; HRMS
(M+H)+ calcd for C26H19Cl6N2O6 664.9374, found 664.9387;
IR (KBr) 3415, 3215, 2939, 1638, 1600, 1432, 1402, 1288,
1211, 1026, 612 cm-1. Purity was determined to be 98.1%
(8) (a) Stowell, J. C.; Keith, D. R.; King, B. T. Org. Syn. 1990, 7,
59–62. (b) Schmidt, U.; Riedl, B. Synthesis 1993, 8, 809–814.
CC100052J