Professional Documents
Culture Documents
Structures, Reactivities, and Antibiotic Properties of The Marinopyrroles A - F
Structures, Reactivities, and Antibiotic Properties of The Marinopyrroles A - F
org/joc
wfenical@ucsd.edu
Received February 9, 2010
Cultivation of actinomycete strain CNQ-418, retrieved from a deep ocean sediment sample off the
coast of La Jolla, CA, has provided marinopyrroles A-F. Sharing just 98% 16S rRNA gene sequence
identity with S. sannurensis, the strain likely represents a new Streptomyces species. The metabolites
contain an unusual 1,30 -bipyrrole core decorated with several chlorine and bromine substituents and
possess marked antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).
The congested N,C-biaryl bond establishes an axis of chirality that, for marinopyrroles A-E, is
configurationally stable at room temperature. Moreover, the natural products are fashioned strictly
in the M-configuration. The Paal-Knorr condensation was adapted for the synthesis of the 1,30 -
bipyrrole core. Halogenation of this material with N-bromosuccinimide cleanly furnished the
4,40 ,5,50 -tetrahalogenated core that characterizes this class of marine-derived metabolites.
3240 J. Org. Chem. 2010, 75, 32403250 Published on Web 04/20/2010 DOI: 10.1021/jo1002054
r 2010 American Chemical Society
Hughes et al.
JOC Article
CHART 1. Marinopyrroles A-F (1-6) in nature.7 As such, the marinopyrroles represent the first
naturally occurring 1,30 -bipyrroles. Perhaps for this reason,
reports that describe the synthesis of 1,30 -bipyrroles are few.8
1
TABLE 1. H and 13C NMR Spectral Data for Marinopyrroles A-F (1-6)
C22H12Cl4N2O4 C22H11BrCl4N2O4 C22H11Cl5N2O4 C22H11Cl5N2O4 C22H11BrCl4N2O4 C22H11Cl3N2O4
A (1) in CDCl3 B (2) in CDCl3 C (3) in CDCl3 D (4) in CDCl3 E (5) in CDCl3 F (6) in DMSO-d6
position Ca H, mult (J, Hz)b Ca H, mult (J, Hz)b Cc H, mult (J, Hz)b Cc H, mult (J, Hz)b Cc H, mult (J, Hz)b Ca H, mult (J, Hz)b
6 185.9 185.3 184.5 185.1 185.1 175.8
8 161.1 161.4 159.4 161.0 161.0 157.0
9 117.8 6.92, md 118.1 6.96, d (8.2) 118.9 6.87, d (9.0) 118.0 6.94, m f 118.4 6.96, d (7.8) 123.1 7.78, mh
10 136.2 7.35, t (7.8) 136.4 7.42, m 135.5 7.27, m 136.3 7.40, t (7.8) 136.0 7.40, t (7.8) 135.9 7.83, mh
11 118.7 6.52, t (7.8) 118.6 6.58, m 123.8 118.8 6.55, t (7.8) 119.1 6.55, t (7.8) 127.7 7.55, t (7.8)
12 130.3 7.48, d (7.8) 130.0 7.51, me 129.6 7.58, d (2.4) 129.9 7.33, mg 129.7 7.32, d (7.8) 132.7 8.06, d (7.8)
30 120.3 6.72, s j 120.9 6.81, s 120.4 6.69, s 120.6 6.68, s 120.4 6.95, s
60 186.8 188.5 186.7 185.3 185.3 183.8
80 162.5 162.5 162.4 160.7 161.2 158.2
90 118.4 7.03, d (7.8) 117.9 7.00, d (8.2) 118.3 7.03, d (7.8) 120.1 6.96, m f 120.4 6.91, d (9.0) 117.0 6.91, mi
100 136.3 7.51, t (7.8) 137.3 7.51, me 136.1 7.52, t (7.8) 136.3 7.44, d (9.0) 139.0 7.56, d (9.0) 134.0 7.44, t (7.8)
110 119.1 6.90, md 119.2 6.85, m 118.9 6.92, t (7.8) 123.7 120.0 118.8 6.94, mi
120 131.9 7.58, d (7.8) 134.2 131.1 7.66, d (7.8) 130.3 7.32, mg 133.4 7.44, d (2.6) 130.9 7.67, d (7.8)
-NH, OH 9.73, br s 9.55, br s 9.51, br s 9.58, br s 9.55, br s 10.27, s
10.42, s 10.39, s 10.26, s 10.31, s 10.31, s 13.77, s
11.18, s 11.10, s 11.06, s 11.03, s 11.05, s
a
75 MHz. b500 MHz. cCarbon chemical shifts were based on HSQC and HMBC data (500 MHz). d-iOverlapping signals. jSignal could not be assigned.
3243
JOC Article Hughes et al.
14 (X = O) 15 (X = S) 16 (X = N)
position C a
H, mult b
C a
H, mult b
Ca H, multc
30 122.4 6.66, s 119.9 6.82, s 122.0 6.69, s
a 50 146.7 131.6 143.8
Reagents and conditions: (a) Ac2O, DMAP, pyr, rt, 62%; (b) Me2SO4,
60 186.3 187.6 186.6
K2CO3, Me2CO, rt, quant; (c) CH2N2, ether, 0 C, 86%. DMAP =
140 60.9 3.79, s 35.4 2.37, m 41.5 2.30, s
4-(dimethylamino)pyridine.
2.67, m
a
75 MHz. b500 MHz. c600 MHz.
0a
SCHEME 2. Nucleophilic Aromatic Substitution at C-5
SCHEME 4. Proposed Ullman Coupling for the Synthesis of SCHEME 5. Synthesis of Monodeoxypyoluteorin (10) and 3-
(()-1 Halo Analoguesa
Conclusion
Herein, we report the full composition and final structure
a
Reagents and conditions: (a) 1. 27, THF, -78 C, 90%; 2. O3, -78 C, assignments and reactivity of a family of densely haloge-
then Me2S; (b) 29, THF, PTSA, 23% (two steps); (c) NBS, DCE, 90 C, nated, axially chiral metabolites from a marine actinomycete
86%. PTSA = p-toluenesulfonic acid, NBS = N-bromosuccinimide,
DCE = 1,2-dichloroethane strain identified as a member of the genus Streptomyces
(strain CNQ-418). The marinopyrroles are antibiotics of an
unprecedented structure class, containing the first naturally
TABLE 3. Antimicrobial and Cytotoxic Properties of Selected occurring 1,30 -bipyrrole. Except for (()-marinopyrrole F
Marinopyrroles and Derivatives (g mL-1)27,28 (6), the metabolites are M-configured and configurationally
compd MRSAa (MIC90) HCT-116b (IC50) stable at room temperature. Given the difficulty associated
(-)-1 0.31 4.5 with the transition metal-catalyzed formation of tetra-ortho-
(-)-2 0.63 5.3 substituted biaryls in chemical synthesis, the biosynthetic
(-)-3 0.16 0.21 mechanism by which this coupling occurs for the marino-
(()-6 3.1 2.9
11 1.6 0.42 pyrroles is of considerable interest. That the N,C-biaryl bond
12 NSA NSA is formed in a completely atropo-selective manner is, like-
13 NSA NSA wise, an appealing biosynthetic concept. As such, elucidation
14 0.78 1.1 of the biosynthetic gene cluster responsible for marinopyr-
15 6.3 7.2
16 1.6 4.4
role production may set the stage for a biomimetic total
a synthesis and even elicit the development of novel biaryl
MRSA = methicillin-resistant Staphylococcus aureus. Positive con-
trol: vancomycin (MIC90 = 0.20-0.39 g mL-1) and penicillin G coupling reactions with larger scope.
(MIC90 = 6.3-12 g mL-1). bHCT-116 is a human colon cancer cell
line. Positive control: etoposide (IC50 = 0.29-2.9 g mL-1). NSA = no
Experimental Section
significant activity (>8 g mL-1).
Cultivation of CNQ-418. The strain was cultured in 2.8 L
exist as a racemic mixture of two configurationally stable Fernbach flasks (20 1 L) in a seawater-based medium (per 1 L
atropo-enantiomers at room temperature, but this could not seawater: 10 g of starch, 4 g of yeast extract, 2 g of peptone, 1 g of
be strictly confirmed by chiral chromatography. CaCO3, 40 mg of Fe2(SO4)3 3 4H2O, 100 mg of KBr) and shaken
Antibiotic Properties. The marinopyrroles A-C (1-3), at 230 rpm at 27 C.
obtained in sufficient quantity and purity for testing, dis- Isolation and Purification of the Marinopyrroles. After 17 days
played significant activity against methicillin-resistant S. of cultivation, sterilized XAD-18 resin (20 g L-1) was added,
aureus (MRSA) with MIC90 values of less than 1 g mL-1 and the resin was collected 24 h later by filtration, washed with
(Table 3). Marinopyrrole F (6) and derivatives 11-16, deionized water, and eluted with acetone. The acetone was
removed under reduced pressure, and the resulting aqueous
encompassing modifications of 1 either at a polar functional
layer was extracted with ethyl acetate (3 600 mL). The
group on the periphery or at core halogen substituents, were combined extracts were dried, filtered, and concentrated. The
much less active against MRSA. The loss in activity of 11-13 crude extract was loaded onto silica gel (20 g) and fractionated
reflects the importance of the hydrogen-bonding capacity of on a silica column (80 60 mm, h w) using a stepwise gradient
the salicyloyl hydroxyl groups and the N-H functionality. (0.5% EtOAc in hexanes, 30% EtOAc in hexanes, EtOAc, 10%
Methylation of the latter functionality proved particularly MeOH in EtOAc, MeOH). The fractions were concentrated to
detrimental to activity. The requirement of a free N-H group give F1 (81.6 mg), F2 (1.34 g), F3 (199.8 mg), F4 (144.8 mg), and
for activity against MRSA may point toward a crucial F5 (422.4 mg). A portion of F2 (134 mg) was dissolved in MeOH
hydrogen-bonding interaction between the molecule and its (3.0 mL), and the marinopyrroles were purified by reversed-
bacterial target. The loss in antimicrobial activity of 6, 15, phase HPLC (80% MeOH in H2O, 0.2% TFA). Pure marino-
pyrrole A (1) (92.1 mg) was thus obtained. Further purification
and 16 may reflect the central role that the C-50 chlorine
by reversed-phase HPLC (65-68% CH3CN in H2O, 0.2%
substituent plays in the mechanism of antibiotic action. TFA) provided, in order of elution, marinopyrrole F (6) (2.7
Ether 14 retained much of the activity characteristic of mg), C (3) (1.2 mg), B (2) (2.0 mg), D (4) (1.8 mg), E (5) (0.5 mg).
metabolites 1-3, presumably, since the C-50 methoxy sub- Marinopyrrole A (1): UV/vis (CH3CN/H2O) max = 270, 324,
stituent can also function as an effective leaving group in 348 nm; [R]D -69 (c 0.39, MeOH); IR (film) ~ = 1623, 1595 cm-1;
1
nucleophilic aromatic substitution reactions. Remarkably, H NMR see Table 1; 13C NMR 186.8, 185.9, 162.5, 161.1,
136.3, 136.2, 131.9, 130.3, 128.8, 124.1, 123.8, 123.1, 120.4, 1.1 mmol) dropwise via syringe. The mixture was heated at 40 C
120.3, 119.1, 118.9, 118.9, 118.7, 118.4, 117.8, 112.7, 110.7; overnight, allowed to cool, filtered through Celite with acetone
HRMS (ESI-TOF) m/z (M - H)- calcd for C22H1135Cl4N2O4 washings, and concentrated. The product was purified by
506.9473, found 506.9447; m/z (M Na) calcd for C22H12- reversed-phase C-18 HPLC (73% CH3CN in H2O, 0.2%
35
Cl4N2O4Na 530.9449, found 530.9439. TFA, tR = 23 min) to furnish 27.3 mg (100%) of 12 as a white
Marinopyrrole B (2): UV/vis (CH3CN/H2O) max = 274, 322, solid: [R]D -92 (c 0.42, MeOH); IR (film) ~ = 1647, 1597 cm-1;
348 nm; [R]D -72 (c 0.20, MeOH); IR (film) ~ = 1622, 1599 cm-1; 1
H NMR 7.40 (t, J = 7.8 Hz, 1H), 7.24-7.18 (m, 3H), 6.98-
1
H NMR see Table 1; 13C NMR 188.5, 185.3, 162.5, 161.4, 137.3, 6.93 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.67 (t, J = 7.8 Hz, 1H),
136.4, 134.2, 133.7, 130.0, 124.4, 121.9, 121.7, 120.0, 119.2, 118.8, 6.25 (s, 1H), 4.05 (s, 3H), 3.80 (s, 3H), 3.75 (s, 3H); 13C NMR
118.6, 118.5, 118.1, 117.9, 114.7, 104.7 (one quaternary carbon 184.2, 182.9, 157.3, 157.0, 131.9, 131.9, 130.7, 129.4, 129.1,
signal was not detected); HRMS (ESI-TOF) m/z (M - H)- calcd 127.5, 127.4, 126.4, 125.6, 125.0, 123.6, 121.2, 119.8, 119.6,
for C22H1079Br35Cl4N2O4 584.8578, found 584.8588; m/z 111.7, 111.5, 110.5, 109.6, 55.6, 55.5, 34.7; HRMS (ESI-TOF)
(M Na) calcd for C22H1179Br35Cl4N2O4Na 608.8554, found m/z (M H) calcd for C25H1935Cl4N2O4 551.0099, found
608.8570. 551.0100.
Marinopyrrole C (3): UV/vis (CH3CN/H2O) max = 270, 324, (4,40 ,5,50 -Tetrachloro-10 -methyl-10 H-1,30 -bipyrrole-2,20 -diyl)-
346 nm; [R]D -100 (c 0.040, MeOH); IR (film) ~ = 1623, 1597 bis((2-hydroxyphenyl)methanone) (13). To a solution of meta-
cm-1; 1H NMR see Table 1; 13C NMR (HSQC and HMBC) bolite 1 (8.7 mg, 0.017 mmol) in ether (2.0 mL) at 0 C was added
186.7, 184.5, 162.4, 159.4, 136.1, 135.5, 131.1, 129.6, 128.9, an ethereal solution of diazomethane via pipet (torched to
123.8, 123.8, 120.9, 118.9, 118.9, 118.3; HRMS (ESI-TOF) m/z remove sharp edges). After 1 min, several drops of acetic acid
(M H) calcd for C22H1235Cl5N2O4 542.9240, found 542.9229. were added (until gas evolution ceased), and the solution was
Marinopyrrole D (4): UV/vis (CH3CN/H2O) max = 270, 320, concentrated. The product was purified by reversed-phase
352 nm; [R]D -55 (c 0.080, MeOH); IR (film) ~ = 1624, 1593 HPLC (72% CH3CN in H2O, 0.2% TFA, tR = 33 min) to
cm-1; 1H NMR see Table 1; 13C NMR (HSQC and HMBC) afford 7.7 mg (86%) of 13 as a pale yellow solid: [R]D -62 (c 0.35,
185.3, 185.1, 161.0, 160.7, 136.3, 136.3, 130.3, 129.9, 128.4, MeOH); IR (film) ~ = 1624, 1596 cm-1; 1H NMR 11.17 (s,
124.9, 123.7, 120.4, 120.1, 118.8, 118.0; HRMS (ESI-TOF) m/z 1H), 10.94 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz,
(M H) calcd for C22H1235Cl5N2O4 542.9240, found 542.9217. 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.01 (d,
Marinopyrrole E (5): UV/vis (CH3CN/H2O) max = 270, 320, J = 8.2 Hz, 1H), 6.91-6.87 (m, 2H), 6.59 (s, 1H), 6.55 (t, J = 7.8
350 nm; [R]D -100 (c 0.005, MeOH); IR (film) ~ = 1623, 1593 Hz, 1H), 3.89 (s, 3H); 13C NMR 187.9, 186.7, 162.4, 161.9,
cm-1; 1H NMR: see Table 1; 13C NMR (HSQC and HMBC) 136.4, 136.1, 131.9, 131.6, 129.0, 125.1, 124.6, 122.6, 122.5,
185.3, 185.1, 161.2, 161.0, 139.0, 136.0, 133.4, 129.7, 128.4, 120.3, 119.7, 119.1, 118.9, 118.5, 118.3, 117.6, 112.3, 108.7,
124.9, 120.6, 120.4, 120.0, 119.1, 118.4; HRMS (ESI-TOF) m/z 34.3; HRMS (ESI-TOF) m/z (M H) calcd for C23H1535Cl4-
(M H) calcd for C22H1279Br35Cl4N2O4 586.8735, found N2O4 522.9786, found 522.9778.
586.8740. (4,40 ,50 -Trichloro-5-methoxy-10 H-1,30 -bipyrrole-2,20 -diyl)bis-
Marinopyrrole F (6): UV/vis (CH3CN/H2O) max = 264, 336 ((2-hydroxyphenyl)methanone) (14). To metabolite 1 (10.0 mg,
nm; [R]D 0 [c 0.057, MeOH/Me2CO (2:1)]; IR (film) ~ = 1620, 0.0196 mmol) and potassium cabonate (100 mg, 0.72 mmol) was
1601 cm-1; 1H NMR (DMSO-d6) see Table 1; 13C NMR added MeOH (2.0 mL). The mixture was heated at 65 C for 2 d,
(DMSO-d6) 183.8, 175.8, 158.2, 157.0, 145.8, 135.9, 134.0, allowed to cool, diluted with a saturated NH4Cl solution (4 mL),
132.7, 130.9, 129.0, 127.7, 125.6, 123.2, 123.1, 121.6, 121.5, and extracted with EtOAc (2 2 mL). The combined extracts
120.9, 120.4, 118.8, 117.0, 105.7, 99.2; HRMS (ESI-TOF) m/z were washed with brine (1 mL), dried, filtered, and concen-
(M H) calcd for C22H1235Cl3N2O4 472.9863, found trated. The product was purified by reversed-phase HPLC (65%
472.9858. (()-Marinopyrrole F (6) was prepared from marino- CH3CN in H2O, 0.2% TFA, tR(14) = 25 min, tR(1) = 30 min) to
pyrrole A (1): A solution of metabolite 1 (4.5 mg, 0.0088 mmol) give 2.1 mg (21%) of 1 and 4.2 mg (42%) of 14 as a yellow
in DMA (1.0 mL) was heated at 145 C for 3 d. The mixture was residue: [R]D 5 (c 0.22, MeOH); IR (film) ~ = 1619, 1592 cm-1;
allowed to cool and concentrated under full vacuum. The 1
H NMR 11.30 (s, 1H), 10.61 (s, 1H), 9.58 (br s, 1H), 7.72 (d,
product was purified by reversed-phase HPLC (65% CH3CN J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.8 Hz,
in H2O, 0.2% TFA, tR = 27 min) to give 2.6 mg (62%) of (()-6 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H),
as a white solid. All analytical and spectroscopic data agreed 6.95-6.89 (m, 2H), 6.66 (s, 1H), 6.53 (t, J = 7.8 Hz, 1H),
with the natural product. 3.79 (s, 3H); 13C NMR 186.3, 186.1, 162.1, 161.1, 146.7,
4,40 ,5,50 -Tetrachloro-10 H-1,30 -bipyrrole-2,20 -diyl)bis((2-acetoxy- 136.0, 135.5, 131.7, 130.6, 123.3, 122.6, 122.4, 121.4, 119.9,
phenyl)methanone) (11). To a solution of metabolite 1 (18.0 mg, 119.3, 118.9, 118.8, 118.8, 118.2, 117.4, 110.2, 96.5, 60.9;
0.0353 mmol) and DMAP (1 mg) in pyridine (1.0 mL) was added HRMS (ESI-TOF) m/z (M H) calcd for C23H 16 35Cl 3N 2O 5
acetic anhydride (0.20 mL, 2.7 mmol) dropwise via syringe. The 505.0125, found 505.0118.
mixture was stirred at room temperature for 5 h and concentrated. N-(2-(3,40 ,50 -Trichloro-20 ,5-bis(2-hydroxybenzoyl)-10 H-1,30 -
The product was purified twice by reversed-phase HPLC (70% bipyrrol-2-ylthio)ethyl)acetamide (15). To a solution of metabo-
CH3CN in H2O, 0.2% TFA, tR = 18 min; then 80% MeOH in lite 1 (7.0 mg, 0.014 mmol) and potassium carbonate (100 mg,
H2O, 0.2% TFA, tR = 25 min) to yield 12.9 mg (62%) of 11 as a 0.72 mmol) in DMF (1.0 mL) was added N-acetylcysteamine
white solid: [R]D 20 (c 0.38, MeOH); IR (film): ~ = 1767, 1640 (20 L, 0.19 mmol) via syringe. The solution was heated at 80 C
cm-1; 1H NMR 9.66 (br s, 1H), 7.58-7.51 (m, 2H), 7.38 (t, J = for 20 h, allowed to cool, diluted with a saturated NH4Cl
7.8 Hz, 1H), 7.35-30 (m, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.12-7.08 solution (4 mL), and extracted with EtOAc (2 2 mL). The
(m, 2H), 6.52 (s, 1H), 2.20 (s, 3H), 2.19 (s, 3H); 13C NMR (125 combined extracts were washed with brine (1 mL), dried,
MHz) 181.4, 180.2, 169.5, 169.3, 148.8, 148.4, 132.4, 132.2, 130.8, filtered, and concentrated. The product was purified by
130.1, 129.9, 129.2, 128.8, 125.4, 125.3, 125.3, 124.6, 123.8, 123.4, reversed-phase HPLC (50% CH3CN in H2O, 0.2% TFA, tR =
123.3, 121.6, 120.4, 112.2, 111.2, 20.9, 20.7; HRMS (ESI-TOF) m/z 24 min) to give 4.5 mg (55%) of 15 as a yellow residue: [R]D 29
(M H) calcd for C26H1735Cl4N2O6 592.9841, found 592.9840. (c 0.27, MeOH); IR (film) ~=1623, 1594 cm-1; 1H NMR 11.35
(4,40 ,5,50 -Tetrachloro-10 -methyl-10 H-1,30 -bipyrrole-2,20 -diyl)- (s, 1H), 10.58 (br s, 1H), 10.19 (br s, 1H), 7.88 (d, J = 7.8 Hz,
bis((2-methoxyphenyl)methanone) (12). To a solution of meta- 1H), 7.57-7.53 (m, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.06 (d,
bolite 1 (25.2 mg, 0.0494 mmol) and potassium carbonate (200 J = 8.2 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 8.2 Hz,
mg) in acetone (1.0 mL) was added dimethyl sulfate (0.10 mL, 1H), 6.82 (s, 1H), 6.43 (t, J = 7.8 Hz, 1H), 5.70 (br s, 1H), 3.14
allowed to cool, and concentrated. The product was purified by (q, J = 7.2 Hz, 2H), 4.13 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.08
column chromatography (30% EtOAc in hexanes) to furnish (t, J = 7.2 Hz, 3H); 13C NMR: 158.6, 158.2, 126.8, 125.9,
66.7 mg (23%) of bipyrrole 30 as a colorless oil. Analytically 120.5, 120.0, 114.3, 106.0, 102.2, 100.5, 61.3, 60.7, 14.1, 13.8;
pure 30 was obtained using reversed-phase HPLC (52% HRMS (ESI-TOF) m/z (M H) calcd for C14H1379Br4N2O4
CH3CN in H2O, tR = 16 min): IR (film) ~ = 1696 cm-1; 1H 588.7609, found 588.7607.
NMR (600 MHz) 9.42 (br s, 1H), 7.06 (m, 1H), 6.89 (m, 1H),
6.88 (m, 1H), 6.29 (m, 1H), 6.25 (m, 1H), 4.16 (q, J = 7.2 Hz, Acknowledgment. This work was supported by the Na-
2H), 4.12 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.10 (t, tional Institutes of Health, National Cancer Institute under
J = 7.2 Hz, 3H); 13C NMR 160.6, 160.0, 130.0, 129.7, 124.6,
Grant Nos. CA44848 and CA052955. We thank Drs. Arnold
120.4, 117.8, 117.5, 109.9, 108.5, 60.3, 59.6, 14.2, 13.9; HRMS
(ESI-TOF) m/z (M H) calcd for C14H17N2O4 277.1188, L. Rheingold and Antonio G. DPasquale (UCSD) for
found 277.1183. providing X-ray diffraction data and Sara Kelly (SIO) for
Diethyl 4,40 ,5,50 -Tetrabromo-10 H-1,30 -bipyrrole-2,20 -dicar- performing the MRSA and HCT-116 bioassays.
boxylate (31). To bipyrrole 30 (20.0 mg, 0.0724 mmol) and
N-bromosuccinimide (50 mg, 0.28 mmol) was added DCE (2.0 Supporting Information Available: Selected 1H, 13C, and 2D
mL). The mixture was heated at 80 C for 2 h, allowed to cool, NMR spectra and HRMS data for compounds 1-6, 11-17, 19,
and concentrated. The product was purified by reversed-phase 20, 22-25, 30, and 31. CD spectra for 1-6. Crystallographic
C-18 HPLC (65% CH3CN in H2O, tR = 25 min) to furnish 36.7 data for 6 (CCDC 764039), 19 (CCDC 764038), and 31 (CCDC
mg (86%) of tetrabromide 31 as a white solid: IR (film) ~ = 1699 764040) (CIF). This material is available free of charge via the
cm-1; 1H NMR (600 MHz) 10.45 (br s, 1H), 7.17 (s, 1H), 4.20 Internet at http://pubs.acs.org.