Efficient relay syntheses and assessment of the DNA-cleaving properties of the pyrrole alkaloid derivatives permethyl storniamide A, lycogalic acid A dimethyl ester, and the halitulin core

Article abstract of DOI:10.1016/S0040-4020(02)00637-3

Palladium catalyzed Suzuki- and Negishi cross coupling reactions are used to convert the now readily available 3,4-dibromopyrrole derivatives 13 and 26 into the core structures of different pyrrole alkaloids. Several compounds of this series exhibit respe

Full text of DOI:10.1016/S0040-4020(02)00637-3

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6373±6380
Ef®cient relay syntheses and assessment of the DNA-cleaving
properties of the pyrrole alkaloid derivatives permethyl
storniamide A, lycogalic acid A dimethyl ester, and the
halitulin core
p
Alois Furstner, Helga Krause and Oliver R. Thiel
È
È
È
Max-Planck-Institut fur Kohlenforschung, Kaiser Wilhelm-Platz 1, D-45470Mu lheim/Ruhr, Germany
This paper is dedicated to Professor Yoshito Kishi in recognition of his outstanding contributions to modern organic chemistryand natural product s ynthesis
Received 11 April 2002; accepted 9 May2002
AbstractÐPalladium catalyzed Suzuki- and Negishi cross coupling reactions are used to convert the now readily available 3,4-dibromo-
pyrrole derivatives 13 and 26 into the core structures of different pyrrole alkaloids. Several compounds of this series exhibit respectable
cytotoxicity and resensitize multidrug resistant (MDR) cancer cell lines at non-toxic concentrations. Cytotoxicity and MDR reversal can be
ef®cientlyuncoupled byper- O-methylation of the peripheral hydroxyl groups. For the storniamide core structure 9 it is demonstrated that this
chemical modi®cation goes hand in hand with a complete loss of the DNA-cleaving capacityof the alkaloid. q 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
The abilityof malignant cell lines to develop resistance
against approved anticancer agents constitutes a major
problem for ef®cient chemotherapy. This phenotype of
multidrug resistance (MDR) is frequentlycaused bythe
overexpression of the plasma membrane glycoprotein
P-gp which functions as an ATP-dependent pump able to
export a wide varietyof drugs out of mammalian cells, thus
lowering their intramolecular concentration below the cyto-
toxic threshold.1 Agents that either retain activityon MDR
cells or resensitize them byspeci®callyinterfering with the
P-gp mediated ef¯ux are needed to improve prognosis for
patients failing to respond to conventional chemotherapy.
In this context, a series of marine alkaloids consisting of a
pyrrole core surrounded by a periphery of polyoxygenated
phenyl rings such as 1±8 (and manycongeners) has recently
attracted considerable attention.2,3 Theyhave been isolated
from widelyvarying locations and organisms (ascidians,
molluscs, sponges) and apparentlyderive from tyrosine or
Keywords: cross coupling; DNA; natural products; palladium; pyrrole.
Corresponding author. Fax: 149-208-306-2994;
e-mail: fuerstner@mpi-muelheim.mpg.de
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00637-3

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A. Furstner et al. / Tetrahedron 58 (2002) 6373±6380
6374
DOPA metabolism. Interestingly, exhaustive O-methylation
of the lateral hydroxyl groups signi®cantly reduces the cyto-
toxicityof these compounds but leaves the capacityfor
3
MDR reversal virtuallyunchanged.
Thus, permethyl
storniamide 8 (RˆMe) as a prototype example exhibits
essentiallyno cytotoxic activityagainst four different cancer
cell lines (IC50.100 mM) but completelyreverses MDR at
1 mM concentration, thus being more potent than the
reference compound verapamil. Even more strikingly, the
resistant human colon cancer cell line HTC116/VM46
becomes hypersensitive to doxorubicin and vincristine on
treatment with 7.5 mM solutions of compound 9 represent-
ing the permethylated storniamide core region.3
Insights into the molecular mechanism of action of such
pyrrole alkaloids, however, are still missing and no
explanation as to whysimple ether formation uncouples
their cytotoxicity and MDR reversing capacity has been
reported to date. Described below is a preliminarystudy
showing that the nature of the peripheral ±OR groups deter-
mines the abilityof such alkaloids to interact with double
stranded DNA. Whereas the storniamide core 10 containing
free ±OH groups at the rim constitutes a verypotent strand
cleaving agent, its ±OMe congener 9 causes no damage
under otherwise identical conditions.
Scheme 1. (a) NBS, THF, 278!08C, 70%; (b) (i) tert-BuLi, THF, 2788C;
(ii) ClC(O)OMe, 2788C, 83%; (c) Br2, H2O, 08C, 91%; (d) 3,4,5-
trimethoxybenzeneboronic acid, Pd(PPh3)4 cat., K2CO3, DME/H2O,
1108C, 88%; (e) 2-(4-methoxyphenyl)ethyl bromide, K2CO3, DMF,
1108C, 90%; (f) BBr3, CH2Cl2, 2788C, 57%; (g) BBr3, CH2Cl2, 2788C,
39%; (h) phenylboronic acid, Pd(PPh3)4 cat., K2CO3, DME/H2O, 1108C,
60% (16), or 4-methoxyphenylboronic acid, Pd(PPh3)4 cat., K2CO3, DME/
H2O, 1008C, 99% (17); (i) BBr3, CH2Cl2, 2788C, 54%.
A Suzuki cross coupling reaction12,16 of 13 with commercial
3,4,5-trimethoxybenzene boronic acid delivers diaryl-
pyrrole 14 in 88% yield. An X-ray structure of this
compound shows the orthogonal arrayof its benzene rings
in the solid state (Fig. 1). Subsequent N-alkylation under
2. Results and discussion
2.1. Syntheses
Following the ®rst total syntheses of lukianol A and
lamellarin O dimethyl ether based on a titanium-mediated
oxo-amide coupling reaction,4,5 various imaginative
approaches to alkaloids belonging to the lukianol-,6
lamellarin-,7 storniamide-,8 ningalin-9 and related families10
have been reported in the literature.11 Herein we describe a
streamlined synthesis of the particularly promising
compound 9 which is ¯exible enough to provide analogues
as well. In view of its symmetrical core structure, we
elaborated on established cross coupling methodology12,13
which allows to use dimethyl 3,4-dibromopyrrole-2,5-di-
carboxylate 13 as the starting material (Scheme 1).
Compound 13 is readilyprepared from N-Boc pyrrole by
reaction with NBS in THF at low temperature to give di-
bromide 1114 followed bymetal±halogen exchange with
tert-BuLi and quenching of the resulting dilithio species
with methyl chloroformate;15 thereby, it is essential to add
the cold solution of the organometallic reagent to an excess
of the electrophile to ensure good results. Reaction of diester
12 with Br2 provides product 13 in excellent overall yield.
Figure 1. Molecular structure of 14. Anisotropic displacement parameters
are shown at 50% probabilitylevel.

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A. Furstner et al. / Tetrahedron 58 (2002) 6373±6380
6375
This methodologycan be extended to provide 3,4-diaryl-
pyrrole alkaloids devoid of the carboxylic acid esters at
C-2 and C-5. A particularlyinteresting member of this series
is halitulin 6, a strongly cytotoxic bisquinolinyl pyrrole
derivative isolated from the Indo-Paci®c sponge Haliclona
tulearensis.19 Our synthesis of its core segment is depicted
in Scheme 3. Starting from commercial bromoxine 21, a
sequence of O-methylation (!22), directed metal±bromine
exchange followed bybolraytion/oxidation furnished
phenol 23, which is treated with MeI in the presence of
K2CO3 to give product 24 in good overall yield.20 While
several attempts to effect metal±bromine exchange at the
5-position with tert-BuLi, PhLi, i-PrMgBr, or i-PrBu2MgLi
Scheme 2. (i) Boronic acid 19, Pd(PPh3)4 cat., Na2CO3, DMF, 1508C;
(ii) TBAF´3H2O, 81%.
21
met with failure, it was found that highlyactivated zinc
oxidativelyinserts into the C±Br bond leading to the forma-
tion of the corresponding organozinc reagent 25 which
reacts with the known dibromide 2622 in the presence of
Pd(dppf)Cl2 in THF.23 Under these conditions, the Negishi
reaction12 gave access to the halitulin core 27 in reasonable
yield. Interestingly, the use of either Pd(PPh3)4 or Pd2(dba)3/
dppf as the catalyst led to no productive C±C-bond forma-
tion.
2.2. Investigation of the DNA-cleaving properties
Various ascidians and related marine organisms are known
to accumulate large quantities of transition metals from sea
water. DOPA derived metabolites are likelyresponsible for
this phenomenon because their polyhydroxylated phenyl
rings confer potent chelating properties towards metal
cations if the pH of the medium is greater than 4.24
Scheme 3. (a) MeI, (n-Bu)4NI, NaOH, THF/H2O, 408C, 78%; (b) (i) PhLi,
Et2O, 2788C; (ii) B(OMe)3, 2788C; (iii) peracetic acid, 08C, 77%; (c) MeI,
K2CO3, acetone, r.t., 83%; (d) Rieke-Zn, THF, 808C; (e) (i) dibromide 26,
Pd(dppf)Cl2 cat., THF, 808C; (ii) TBAF´3H2O, THF, room temperature,
44% (over both steps).
Previous studies from this and other laboratories25,26 suggest
that the speci®c abilityto sequester metal cations might also
be relevant with regard to the cytotoxicity of such
compounds. It is well precedented in the literature that
certain metal±catechol or metal±pyrogallol complexes,
particularlythose incorporating Cu II, are immediately
further oxidized to the corresponding o-quinones with
concomitant release of H2O2. Its subsequent cleavage by
the metal cation then produces diffusible oxygen radicals27
and therebytriggers massive DNA-damage.
standard conditions leads to the desired target 9 which can
be converted into permethyl storniamide A 8 (RˆMe)
according to literature procedures.3a,17 Demethylation of
compounds 14 or 9 on treatment with BBr3 furnishes the
corresponding phenol derivatives 15 and 10, respectively.
As expected, the Suzuki cross coupling step is rather general
and can be used to prepare related 3,4-diarylated pyrrole
derivatives as well. In addition to products 16±18, this
refers to lycogalic acid dimethyl ester 20 (Scheme 2), an
alkaloid isolated from the mycomycete Lycogala
epidendrum exhibiting some anti-HIV I activity.18
To studywhether this mechanism accountsÐat least in
partÐfor the cytotoxicity exerted by the polyarylated pyr-
role alkaloids described above, representative compounds
have been assayed for their capacity to induce DNA strand
Figure 2. Result of an agarose gel electrophoresis showing the extent of DNA cleavage produced bydifferent pyrrole alkaloids (50 mM) in the presence of
Cu(OAc)2 after an incubation time of 1.5 h at 378C. Lane 1: DNA marker (500 base pairs molecular weight difference); lane 2: DNA alone; lane 3: DNA
enriched in linear form (partial cleavage of parent DNA byrestriction endonuclease Xho I); lane 4: DNA1compound 161CuII; lane 5: DNA1compound
201CuII; lane 6: DNA1compound 171CuII; lane 7: DNA1compound 181CuII; lane 8: DNA1compound 141CuII; lane 9: DNA1compound 151CuII.

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A. Furstner et al. / Tetrahedron 58 (2002) 6373±6380
6376
Figure 3. Agarose gel electrophoresis showing a comparison of the extent
of DNA cleavage produced bydifferent concentrations of compound 10 and
the parent trimethyl ether derivative 9, respectively, in the presence of
Cu(OAc)2 after an incubation time of 1.5 h at 378C. Lane 1: DNA marker
(500 base pairs molecular weight difference); lane 2: DNA alone; lane 3:
linear DNA produced bycleavage of parent DNA with restriction endo-
nuclease Xho I; lane 4: DNA1compound 10 (50 mM)1CuII; lane 5:
DNA1compound 10 (30 mM)1CuII; lane 6: DNA1compound 10
(10 mM)1CuII; lane 7: DNA1compound 9 (100 mM)1CuII; lane 8:
Figure 4. Result of an agarose gel electrophoresis showing the extent of
DNA cleavage produced bycompound 10 (10 mM) in the presence of
Cu(OAc)2 with increasing incubation time at 378C. Lane 1: DNA marker
(500 base pairs molecular weight difference); lane 2: DNA alone; lane 3:
linear DNA produced bycleavage of parent DNA with restriction endo-
nuclease Xho I; lane 4: 5 min; lane 5: 15 min; lane 6: 30 min; lane 7:
45 min; lane 8: 60 min; lane 9: 90 min; lane 10: 120 min.
DNA1compound
9
(50 mM)1CuII; lane 9: DNA1compound
9
experiments on a panel of tumor cell lines which have
shown that (i) an increase in the number of peripheral
methylations of such pyrrole alkaloids causes a sharp
decrease in their antitumoral activity, whereas (ii) no
distinct correlation between the structure and the cytotoxic
activityof diverse members of the lamellarin familywith
similar oxygenation patterns could be established.2,3
Although further experiments are necessaryto con®rm the
possible link between the observed DNA damage and the
cell culture assays, the results summarized above provide a
tentative explanation why similarly hydroxylated deriva-
tives of this series exert virtuallyidentical ctyotoxicity
that is lost on O-alkylation while MDR reversal activity
persists. Further studies on this and related aspects are
(10 mM)1CuII.
cleavage in the presence of Cu(OAc)2. As can be seen from
the agarose gel depicted in Fig. 2, onlycompound 15
containing two pyrrolgallol rings relaxes the supercoiled
plasmid DNA of the bacteriophage FX174 (form I) to the
nicked form II and even to the linear form III under these
conditions (lane 9), whereas all other derivatives have no
appreciable effect.28 This includes the corresponding
permethyl ether 14 (lane 8), as well as compounds 16, 17,
18 and 20 (lanes 4±7) in which the electron rich pyrogallol
units of 15 are replaced by either phenyl-, methoxyphenyl-,
phenol- or indole moieties, respectively.
29
currentlyunderway.
Fig. 3 illustrates the exceptional potencyof the intact storni-
amide core 10 and shows that strand cleavage is clearly
concentration dependent. After incubation with this
compound (50 mM) in the presence of Cu(OAc)2 for 1.5 h
at 378C, the double stranded plasmid DNA I has completely
disappeared and onlythe nicked form II and substantial
amounts of the linear DNA III formed bydouble strand
cleavage are observed (lane 4, compare with lane 3 showing
linear DNA obtained with the restriction endonuclease Xho
I). Reducing the concentration of 10 to 30 mM (lane 5) or
10 mM (lane 6) under otherwise identical conditions
diminishes the amount of the linear form III, whereas single
strand cleavage to the nicked form II remains essentially
complete. This effect is in striking contrast to the inabilityof
the permethylated analogue 9 to induce anystrand cleavage
even at 10-times higher concentration (lane 7) as evident by
comparison with the native DNA sample (lane 2).
3. Experimental
3.1. General
All reactions were carried out under Ar. The solvents used
were puri®ed bydistillation over the drying agents indicated
and were transferred under Ar: THF, Et2O, DME (Mg±an-
thracene), CH2Cl2 (P4O10), MeCN, Et3N, pyridine, DMF
(CaH2), MeOH (Mg), hexane, toluene (Na/K). Flash
chromatography: Merck silica gel 60 (230±400 mesh).
NMR: spectra were recorded on a Bruker DPX 300 spectro-
meter in the solvents indicated; chemical shifts (d) are given
in ppm relative to TMS, coupling constants (J) in Hz. IR:
Nicolet FT-7199 spectrometer, wavenumbers in cm21. MS
(EI): Finnigan MAT 8200 (70 eV), HRMS: Finnigan MAT
95. Melting points: BuÈchi melting point apparatus
(uncorrected). Elemental analyses: H. Kolbe, MuÈlheim/
Ruhr. All commerciallyavailable compounds (Lancaster,
Fluka, Aldrich) were used as received.
As expected, DNA cleavage induced by 10/Cu(OAc)2 is a
function of the incubation time (Fig. 4). The progress can be
nicelyfollowed bycomparing lanes 4±10, showing that
single strand cleavage is complete after ,60 min even if
the concentration of 10 is only10 mM (lane 8). After that
time, onlyband III representing the linear form of the DNA
slowlygains intensity. A virtuallyidentical concentration-
and time-dependent behavior was observed for compound
15 (gels not shown). Hence, we conclude that the presence
of at least two unprotected hydroxyl groups within one
arene ring constitutes a minimum structural requirement
for ef®cient DNA cleavage under oxidative conditions.
This structure/activitypro®le in the DNA assayis strongly
reminiscent of previous observations in various cytotoxicity
3.1.1. 2,5-Dibromo-pyrrole-1-carboxylic acid tert-butyl
ester (11). Freshlyrecrystallized NBS (10.6 g, 60.0 mmol)
is added in portions to a solution of 1-tert-butoxycarbonyl-
pyrrole (5.0 g, 29.9 mmol)14 in THF (200 mL) at 2788C.
After stirring for 1 h at 2788C, the resulting mixture is
allowed to warm to 08C and stirring is continued for 18 h
at that temperature. For work-up, Na2SO3 (3.9 g,
31.0 mmol) is added to the stirred solution, the solvent is
evaporated, the residue is dispersed in CCl4 (170 mL) and
the resulting suspension is ®ltered with suction. Evaporation

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6377
of the ®ltrate followed by¯ash chromatography(hexanes/
EtOAc, 40:1) provides dibromide 11 as a colorless syrup
which solidi®es on standing at room temperature (6.82 g,
70%). The analytical and spectroscopic data are in full
agreement with those reported in the literature.14
NMR (CD2Cl2, 75.5 MHz) d 160.9, 153.0, 137.7, 131.3,
128.8, 121.5, 109.0, 66.5, 56.4, 52.1; IR (KBr) 3445,
3385, 3273, 2999, 2942, 2836, 1729, 1717, 1701, 1603,
1586, 1558, 1506, 1482, 1461, 1435, 1411, 1342, 1282,
1262, 1239, 1193, 1126, 1074, 1054, 1006, 878, 839,
783 cm21; MS (EI) m/z (rel. intensity) 515 ([M1], 100),
483 (47), 468 (36), 452 (2), 378 (2), 350 (2), 292 (1), 218
(5); HR-MS (EI) (C26H29NO10) calcd 515.1791, found
515.1793.
3.1.2. Pyrrole-1,2,5-tricarboxylic acid 1-tert-butyl ester
2,5-dimethyl ester (12). A solution of tert-BuLi (1.7 M in
pentane, 15 mL, 25.5 mmol) is added over a period of 1 h to
a solution of dibromide 11 (2.20 g, 6.77 mmol) in THF
(35 mL) at 2788C and stirring is continued for 70 min
once the addition is complete. The chilled solution of the
resulting dilithium species is slowlyadded over 1 h to a
solution of methyl chloroformate (6.70 g, 71 mmol) in
THF (40 mL) at 2788C and the resulting mixture is stirred
at that temperature for 16 h. For work-up, aq. sat. NH4Cl is
introduced into the cold mixture, the aqueous phase is
extracted with CH2Cl2, the combined organic phases dried
over Na2SO4 and evaporated, and the residue is puri®ed by
¯ash chromatography(hexanes/EtOAc, 20:1) to afford
compound 12 as a colorless solid (1.60 g, 83%). Mp 124±
3.1.5. 3,4-Diphenyl-1H-pyrrole-2,5-dicarboxylic acid
dimethyl ester (16).
A solution of compound 13
(60.0 mg, 0.175 mmol), phenylboronic acid (64.3 mg,
0.527 mmol), Pd(PPh3)4 (10.1 mg, 0.0087 mmol) and
K2CO3 (97.3 mg, 0.7 mmol) in DME (6 mL) and water
(0.5 mL) is stirred at 1108C for 2.5 h. A standard extractive
work-up followed by¯ash chromatography(hexanes/
EtOAc, 1:1) affords product 16 as a colorless solid
1
(35.0 mg, 60%). H NMR (CD2Cl2, 300 MHz) d 10.10±
9.90 (1H, br s), 7.25±7.18 (6H, m), 7.16±7.10 (4H, m),
3.75 (6H, s); 13C NMR (CD2Cl2, 75.5 MHz) d 160.9,
133.5, 131.6, 131.2, 127.6, 127.3, 121.7, 52.0; IR (KBr)
3309, 3064, 3027, 2957, 2927, 2854, 1709, 1664, 1607,
1556, 1518, 1496, 1463, 1444, 1429, 1296, 1242, 1194,
1156, 1072, 1040, 1017, 1008, 952, 919, 842, 799, 787,
774, 702 cm21; MS (EI) m/z (rel. intensity) 335 ([M1],
100), 303 (63), 272 (16), 244 (26), 216 (27), 189 (17),
136 (3), 107 (5); HR-MS (EI) (C20H17NO4) calcd
335.1158, found 335.1161.
1
1258C. H NMR (CDCl3, 300 MHz) d 6.81 (2H, s), 3.84
(6H, s), 1.64 (9H, s); 13C NMR (CDCl3, 75.5 MHz) d
159.8, 126.7, 115.8, 86.3, 52.0, 27.3; IR (KBr) 2999,
2957, 2936, 1777, 1733, 1707, 1536, 1475, 1457, 1439,
1419, 1377, 1262, 1212, 1199, 1168, 1100, 1024, 947,
847, 809, 771, 746 cm21; MS (EI) m/z (rel. intensity) 283
([M1], .1), 210 (23), 183 (100), 152 (42), 125 (3), 120 (31),
93 (9), 57 (90), 41 (19); HR-MS (CI) (C13H17NO61H) calcd
284.1134, found 284.1136; C13H17NO6 (283.28) calcd C
55.12, H 6.06, N 4.94, found C 54.97, H 5.93, N 5.02.
3.1.6. 3,4-Bis-(4-methoxy-phenyl)-1H-pyrrole-2,5-dicar-
boxylic acid dimethyl ester (17). A solution of compound
13 (47.0 mg, 0.137 mmol), 4-methoxyphenylboronic acid
(63.0 mg, 0.42 mmol), Pd(PPh3)4 (8.0 mg, 0.007 mmol)
and K2CO3 (80 mg, 0.58 mmol) in DME (6 mL) and water
(0.5 mL) is stirred at 1008C for 2.5 h. A standard extractive
work-up followed by¯ash chromatography(hexanes/
EtOAc, 10:1!2:1) affords product 17 as a colorless solid
(57.0 mg, 99%). Mp 192±1938C; 1H NMR (CD2Cl2,
300 MHz) d 9.82 (br s, 1H), 7.05 (d, 4H), 6.74 (d, 4H),
3.76 (s, 6H), 3.73 (s, 6H); 13C NMR (CD2Cl2, 75.5 MHz)
d 160.9, 159.2, 132.3, 131.3, 125.7, 121.5, 113.1, 55.4, 51.9;
IR (KBr) 3350, 3008, 2953, 2838, 1707, 1613, 1535, 1469,
1437, 1308, 1248, 1181, 1036, 854, 826, 785 cm21; MS (EI)
m/z (rel. intensity) 396 (18), 395 (76, [M1]), 364 (24), 363
(100), 305 (7), 276 (7), 233 (4), 190 (5), 166 (10).
3.1.3. 3,4-Dibromo-1H-pyrrole-2,5-dicarboxylic acid
dimethyl ester (13). Bromine (0.5 mL, 9.7 mmol) is
added at 08C to a suspension of compound 12 (251 mg,
0.886 mmol) in water (10 mL). The reaction mixture is stir-
red for 5 min. Sat. aq. Na2SO3 is then introduced and stirring
is continued until complete reduction of excess bromine is
achieved. Extraction with CH2Cl2, drying of the combined
organic phases over Na2SO4, evaporation of the solvent and
¯ash chromatography(hexanes/EtOAc, 2:1 !1:1) affords
dibromide 13 as a colorless solid (274 mg, 91%). Mp
1
220±2228C; H NMR (CDCl3, 300 MHz) d 3.83 (6H, s),
9.95 (1H, br s); 13C NMR (CDCl3, 75.5 MHz) d 159.3,
123.5, 107.8, 52.7; IR (KBr) 3266, 2957, 1716, 1699,
1530, 1440, 1273, 1050, 954, 738 cm21; MS (EI) m/z (rel.
intensity) 343 ([M1], 50), 341 ([M1], 100), 339 ([M1], 50),
309 (28), 278 (48), 251 (31), 222 (3), 198 (5), 172 (8), 115
(3), 91 (10); HR-MS (EI) (C8H7Br2NO4) calcd 338.8742,
found 338.8743; C8H7Br2NO4 (340.96) calcd C 28.18, H
2.07, N 4.11, found C 28.28, H 2.15, N 4.06.
3.1.7. Lycogalic acid A dimethyl ether (20). A suspension
of dibromopyrrole 13 (68.2 mg, 0.2 mmol), indole-3-
boronic acid 19 (330 mg, 1.20 mmol),30 Pd(PPh3)4
(11.4 mg, 0.01 mmol) and Na2CO3 (127.2 mg, 1.2 mmol,
dissolved in minimum amount of water) in DMF (5 mL)
is heated to 1508C for 1 h. The reaction mixture is then
allowed to cool to ambient temperature before TBAF´3H2O
(157 mg, 0.5 mmol) is added and the solution is stirred for
10 min. Addition of brine, extraction with Et2O, drying of
the combined organic phases over Na2SO4, evaporation of
the solvent and ¯ash chromatography(hexanes/EtOAc, 1:1)
affords product 20 as a colorless solid (66.9 mg, 81%). Mp
3.1.4. 3,4-Bis-(3,4,5-trimethoxy-phenyl)-1H-pyrrole-2,5-
dicarboxylic acid dimethyl ester (14). A solution of
compound 13 (51.9 mg, 0.15 mmol), 3,4,5-trimethoxy-
phenylboronic acid (96.0 mg, 0.45 mmol), Pd(PPh3)4
(8.7 mg, 0.0075 mmol) and K2CO3 (83 mg, 0.6 mmol) in
DME (6 mL) and water (0.5 mL) is stirred at 1108C for
2.5 h. A standard extractive work-up followed by¯ash chro-
matography(hexanes/EtOAc, 1:1 !1:2) affords product 14
1
122±1258C. H NMR (CD2Cl2, 300 MHz) d 10.10±9.90
1
as a colorless solid (68.0 mg, 88%). Mp 172±1748C; H
(1H, br s), 8.11 (2H, br s), 7.25 (2H, d, Jˆ8.1 Hz), 7.20
(2H, d, Jˆ7.9 Hz), 7.10±7.04 (2H, m), 6.95±6.87 (4H,
m), 3.70 (6H, m); 13C NMR (CD2Cl2, 75.5 MHz) d 161.0,
NMR (CD2Cl2, 300 MHz) d 10.10±9.90 (1H, br s), 6.38
(4H, s), 3.80 (6H, s), 3.75 (6H, s), 3.63 (12H, s); 13C

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135.8, 128.0, 125.3, 124.9, 122.9, 121.8, 120.3, 119.6,
111.3, 109.2, 51.9; IR (KBr) 3403, 3051, 2949, 1701,
1619, 1519, 1478, 1455, 1434, 1408, 1346, 1313, 1267,
1241, 1194, 1130, 1097, 1060, 1008, 971, 926, 783,
741 cm21; MS (EI) m/z (rel. intensity) 413 ([M1], 100),
381 (67), 349 (34), 320 (9), 294 (14), 266 (8), 240 (3),
175 (6), 133 (7); HR-MS (EI) (C24H19N3O4) calcd
413.1376, found 413.1374.
portions to a solution of 1-triisopropylsilanyl-1H-pyrrole
(3.35 g, 15.0 mmol)22 in THF (50 mL) at 2788C. After stir-
ring for 15 min, the reaction is quenched with aq. sat.
NaHCO3, the organic layer is extracted with Et2O, the
combined organic phases are dried over Na2SO4 and evapo-
rated, and the residue is puri®ed byrecrystallization from
pentane affording the title compound as a colorless solid
(3.61 g, 63%). Mp 78±808C (lit.22b 78±808C). In contrast
to the published procedure, we noticed that anywarming of
the reaction mixture to temperatures .2788C results in
signi®cantlyreduced yields. 1H NMR (CD2Cl2, 300 MHz)
3.1.8. 3-Bis-(3,4,5-trimethoxyphenyl)-1-[2-(4-methoxy-
phenyl)ethyl]pyrrole-2,5-dicarboxylic acid dimethyl
ester (9). A solution of pyrrole 14 (179 mg, 0.347 mmol),
2-(4-methoxyphenyl)ethyl bromide (413 mg, 1.91 mmol)
and K2CO3 (265 mg, 1.91 mmol) in DMF (3 mL) is stirred
for 2 h at 1108C. Evaporation of the solvent followed by
¯ash chromatographyof the crude product (CH 2Cl2/
acetone, 98:2) affords product 9 as a yellow syrup which
solidi®es upon standing (204 mg, 90%). Mp 118±1198C
d 6.68 (s, 2H), 1.33 (m, 3H), 1.04 (s, 9H), 0.99 (s, 9H); 13
NMR (CD2Cl2, 75.5 MHz) d 124.3, 101.0, 17.8, 11.8.
C
3.2.4. Halitulin core (27). A suspension of lithium powder
(83 mg, 12.0 mmol) and naphthalene (1.589 g, 12.4 mmol)
in THF (10 mL) is stirred for 2 h at ambient temperature. A
solution of ZnCl2 (818 mg, 6.0 mmol) in THF (5 mL) is
added to the resulting dark green mixture and stirring is
continued for 15 min. To the suspension of the activated
Zn thus formed is added 5-bromo-7,8-dimethoxy-quinoline
24 (536 mg, 2.0 mmol)20 and the resulting mixture is stirred
for 2 h at 808C to complete the oxidative insertion process.
Excess Zn is allowed to settle before the supernatant liquid
is transferred via canula into a second ¯ask containing a
solution of dibromopyrrole 26 (229 mg, 0.6 mmol) and
Pd(dppf)Cl2 (44 mg, 0.06 mmol). The resulting mixture is
stirred at 808C for 2 h. After cooling to ambient temperature,
the reaction is quenched with brine, the aqueous layer is
extracted with CH2Cl2, the combined organic phases are
dried over Na2SO4, concentrated and rapidlypassed through
a plug of silica gel. The product containing fractions are
combined and evaporated, the crude product is dissolved
in THF (20 mL) and treated with a TBAF (1 M in THF,
0.6 mL) to complete the cleavage of the TIPS group. A
standard extractive work-up followed by¯ash chromato-
1
(lit.3a 118±1198C); H NMR (CD2Cl2, 300 MHz) d 7.18
(d, 2H), 6.87 (d, 2H), 6.27 (s, 4H), 4.85 (t, 2H, Jˆ6.2 Hz),
3.79 (s, 3H), 3.75 (s, 6H), 3.64 (s, 18H), 3.09 (t, 2H,
Jˆ6.2 Hz); 13C NMR (CD2Cl2, 75.5 MHz) d 162.5, 158.8,
152.7, 137.3, 130.7, 130.6, 130.3, 130.1, 124.2, 114.1,
108.5, 60.8, 56.3, 55.5, 51.7, 49.0, 37.6, 29.4; IR (KBr)
3438, 2995, 2935, 2835, 1712, 1693, 1584, 1512, 1463,
1436, 1407, 1339, 1237, 1125, 825, 702 cm21; MS (EI)
m/z (rel. intensity) 650 (43), 649 (100, [M1]), 528 (16),
483 (5), 135 (18).
3.2. Representative procedure for the exhaustive
demethylation
3.2.1. 3,4-Bis-(4-hydroxy-phenyl)-1H-pyrrole-2,5-dicar-
boxylic acid dimethyl ester (18). BBr3 (1 M in CH2Cl2,
1.3 mL, 1.3 mmol) is added to a solution of compound 17
(50 mg, 0.126 mmol) in CH2Cl2 (2.5 mL) at 2788C and
stirring is continued for 4 h at that temperature. The reaction
is quenched with MeOH (2.5 mL), all volatiles are evapo-
rated in vacuo, the residue is suspended twice in MeOH
(2.5 mL) which is subsequentlystripped off. The remaining
solid is then puri®ed by¯ash chromatography(CH 2Cl2/
MeOH, 7:1) to afford compound 18 as a colorless air-
graphy(CH Cl2/MeOH, 20:1) affords the title compound
2
1
as a colorless air-sensitive solid (117 mg, 44%). H NMR
(CD2Cl2, 300 MHz) d 10.20±10.00 (1H, br s), 8.74 (2H, dd,
Jˆ4.1, 1.7 Hz), 8.28 (2H, dd, Jˆ8.5, 1.7 Hz), 7.16 (2H, d,
Jˆ2.7 Hz), 7.11 (2H, s), 7.04 (2H, dd, Jˆ8.5, 4.1 Hz), 3.95
(6H, s), 3.66 (6H, s); 13C NMR (CD2Cl2, 75.5 MHz) d
151.3, 150.0, 143.8, 141.9, 135.2, 130.4, 123.7, 121.5,
119.4, 119.0, 117.6, 61.7, 56.9; IR (KBr) 3416, 3076,
2995, 2933, 2847, 1715, 1600, 1496, 1474, 1431, 1399,
1385, 1344, 1333, 1281, 1251, 1212, 1193, 1155, 1126,
1109, 1078, 1037, 992, 925, 876, 790, 720 cm21; MS (EI)
m/z (rel. intensity) 441 ([M1], 100), 426 (61), 408 (51), 394
(26), 364 (8), 309 (6), 242 (4), 213 (5), 154 (5); HR-MS (EI)
(C26H23N3O4) calcd 441.1689, found 441.1687; C26H23N3O4
(441.49) calcd C 70.74, H 5.25, N 9.52, found C 70.66, H
5.35, N 9.44.
1
sensitive solid (25.0 mg, 54%). Mp 247±2498C. H NMR
(CD3OD, 300 MHz) d 6.86 (d, 4H), 6.59 (d, 4H), 3.71 (s,
6H), 3.33 (s, 2H); 13C NMR (CD3OD, 75.5 MHz) d 163.0,
157.6, 133.5, 133.1, 126.5, 123.1, 115.5, 52.3; IR (KBr)
3536, 3459, 3390, 3037, 2952, 2508, 1701, 1614, 1554,
1482, 1437, 1259, 1243, 1122, 999, 838, 783, 535. MS
(ESI): 406 ([M1K]1), 390 ([M1Na]1), 368 ([M1H]1).
3.2.2. 3,4-Bis-(3,4,5-trihydroxy-phenyl)-1H-pyrrole-2,5-
dicarboxylic acid dimethyl ester (15). Prepared as
described above from compound 14 (51.5 mg, 0.1 mmol)
and BBr3 (1 mL, 1 M in CH2Cl2, 1 mmol) as a colorless
air-sensitive solid (24.8 mg, 57%). 1H NMR (CD3OD,
300 MHz) d 6.08 (4H, s), 3.67 (6H, s); 13C NMR
(CD3OD, 75.5 MHz) d 162.8, 145.9, 133.3, 132.9, 126.0,
122.6, 111.3, 51.9; IR (KBr) 3423, 2954, 2925, 2852, 2517,
1699, 1616, 1559, 1489, 1436, 1325, 1267, 1235, 1192,
3.3. DNA cleavage assay. Representative procedure
A solution of puri®ed scDNA (2 mL of a stock solution
containing ca. 400 mg mL21) [FX174 RF1 DNA, purchased
from MBI Fermentas GmbH, St. Leon-Rot, Germany; the
EDTA contained in the commercial sample was removed
according to the Qiaex II protocol for desalting and con-
centrating DNA byusing a Qiaex II Gel Extraction Kit]
was incubated at 378C for the time given in the ®gures
with the respective pyrrole alkaloid derivative (for the
1105, 1079, 1025, 974, 888, 845, 782 cm21
.
3.2.3. 3,4-Dibromo-1-triisopropylsilanyl-1H-pyrrole (26).
Freshlyrecrystallized NBS (5.60 g, 31.5 mmol) is added in

È
A. Furstner et al. / Tetrahedron 58 (2002) 6373±6380
6379
5. FuÈrstner, A.; Bogdanovic, B. Angew. Chem. 1996, 108, 2583±
2609 Angew. Chem., Int. Ed. Engl. 1996, 35 2442±2469.
6. Yoshida, W. Y.; Lee, K. K.; Carroll, A. R.; Scheuer, P. J. Helv.
Chim. Acta 1992, 75, 1721±1725.
concentrations see Figs. 2±4), Cu(OAc)2 (2 mL of a 1 mM
stock solution) and aq. NaCl (3 mL of a 0.5 mM stock
solution) in water (complemented to give a total volume
of 20 mL). The mixture was quenched with loading buffer
(BioRad laboratories) and the DNA resolved byelectro-
phoresis (Powerpac 300, BioRad) (85 V, 1 h) on a 0.8%
agarose gel (containing ethidium bromide) in tris/boronic
acid buffer (BioRad). The bands detected byUV were
analyzed and processed using the Bio Doc II software
(Biometra).
7. (a) Andersen, R. J.; Faulkner, D. J.; Cun-heng, H.; Van Duyne,
G. D.; Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492±5495.
(b) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J.
J. Org. Chem. 1988, 53, 4570±4574. (c) Reddy, M. V. R.;
Faulkner, D. J.; Venkateswarlu, Y.; Rao, M. R. Tetrahedron
1997, 53, 3457±3466. (d) Urban, S.; Capon, R. J. Aust. J.
Chem. 1996, 49, 711±713. (e) Carroll, A. R.; Bowden, B. F.;
Coll, J. C. Aust. J. Chem. 1993, 46, 489±501. (f) Urban, S.;
Hobbs, L.; Hooper, J. N. A.; Capon, R. J. Aust. J. Chem. 1995,
48, 1491±1494. (g) Urban, S.; Butler, M. S.; Capon, R. J. Aust.
J. Chem. 1994, 47, 1919±1924. (h) Reddy, M. V. R.; Rao,
M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.; Bushman,
F. D.; Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999,
42, 1901±1907.
3.4. X-Ray crystallographic study
Suitable crystals of compound 14 were obtained by
recrystallization from dichloromethane. Data were recorded
using an Enraf±Nonius Kappa CCD diffractometer with
Ê
graphite-monochromated Mo Ka-radiation (lˆ0.71073 A).
The crystal was mounted in a stream of cold nitrogen gas.
The structures were solved bydirect methods (SHELXS-
97)31 and re®ned byfull-matrix least-squares techniques
against F2 (SHELXL-97).32 Hydrogen atoms were inserted
from geometryconsideration using the HFIX option of the
program. Crystal and intensity data for 14: C26H29NO10,
Mrˆ515.50 g mol21, colorless, crystal size 0.20£0.08£
0.06 mm, monoclinic, P21/n [No. 14], aˆ6.8512 (3),
(i) Davis, R. A.; Carroll, A. R.; Pierens, G. K.; Quinn, R. J. J.
Nat. Prod. 1999, 62, 419±424.
8. Palermo, J. A.; Brasco, M. F. R.; Seldes, A. M. Tetrahedron
1996, 52, 2727±2734.
9. Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254±3262.
10. (a) Polycitone: Rudi, A.; Goldberg, I.; Stein, Z.; Frolow, F.;
Benayahu, Y.; Schleyer, M.; Kashman, Y. J. Org. Chem.
1994, 59, 999±1003. (b) Rudi, A.; Evan, T.; Aknin, M.;
Kashman, Y. J. Nat. Prod. 2000, 63, 832±833. (c) Purpurone:
Chan, G. W.; Francis, T.; Thureen, D. R.; Offen, P. H.; Pierce,
N. J.; WestleyJ. W.; Johnson, R. K.; Faulkner, D. J. J. Org.
Chem. 1993, 58, 2544±2546.
Ê
bˆ17.8082 (8), cˆ20.3371 (10) A, bˆ94.530 (2)8, Vˆ
Ê 3
2473.5
(2) A ,
Zˆ4,
Dcalcˆ1.384 mg m23
,
mˆ
0.107 mm21, Tˆ100 K, 12,220 re¯ections collected, 5239
independent re¯ections, 2364 re¯ections with I . 2sꢀI†;
umaxˆ27.108, 342 re®ned parameters, Rˆ0.092,
Rwˆ0.186, Sˆ1.025, largest diff. peak and holeˆ0.3/
11. See the following for leading references concerning the
synthesis of these and related alkaloids: (a) Banwell, M. G.;
Flynn, B. L.; Hamel, E.; Hockless, D. C. R. Chem. Commun.
(Cambridge) 1997, 207±208. (b) Banwell, M.; Flynn, B.;
Hockless, D. Chem. Commun. (Cambridge) 1997, 2259±
2260. (c) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem.
1997, 109, 158±159 Angew. Chem., Int. Ed. Engl. 1997, 36,
155±156. (d) Peschko, C.; Winklhofer, C.; Steglich, W.
Chem.-Eur. J. 2000, 6, 1147±1152. (e) Gupton, J. T.; Krumpe,
K. E.; Burnham, B. S.; Webb, T. M.; Shuford, J. S.; Sikorski,
J. A. Tetrahedron 1999, 55, 14515±14522. (f) Ishibashi, F.;
Miyazaki, Y.; Iwao, M. Tetrahedron 1997, 53, 5951±5962.
(g) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C.
J. Org. Chem. 2000, 65, 3587±3595. (h) Diaz, M.; Guitian, E.;
Castedo, L. Synlett 2001, 1164±1166. (i) Ruchirawat, S.;
Mutarapat, T. Tetrahedron Lett. 2001, 42, 1205±1208.
(j) Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995,
51, 9941±9946. (k) Peschko, C.; Steglich, W. Tetrahedron
Lett. 2000, 41, 9477±9481.
Ê 23
20.3 e A . Crystallographic data (excluding structure
factors) have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementarypublication number
CCDC 182533. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1 EZ, UK (fax: 144-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
Generous ®nancial support bythe Deutsche Forschungsge-
meinschaft (Leibniz award to A. F.) and bythe Fonds der
Chemischen Industrie is gratefullyacknowledged. We
thank Dr C. W. Lehmann for solving the X-raystructure
of compound 14.
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È
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 Â
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