Synthesis of the marine alkaloids rhopaladins A, B, C and D

Article abstract of DOI:10.1016/S0040-4020(02)00171-0

The total synthesis of all four known rhopaladins, A-D, isolated from the Okinawan marine tunicate Rhopalaea sp., in two synthetic steps is described, involving an imidate based cyclization with tryptophan esters as the key step to afford the appropriately substituted imidazolinone unit. A short and efficient new synthesis of indol-3-yl-carbonyl nitriles from indol-3-yl-carboxaldehydes and trimethylsilyl cyanide, followed by oxidation with DDQ is also described.

Full text of DOI:10.1016/S0040-4020(02)00171-0

TETRAHEDRON
Pergamon
Tetrahedron 58 42002) 2813±2819
Synthesis of the marine alkaloids rhopaladins A, B, C and D
Tomasz Janosik,a,b Ann-Louise Johnsona,b and Jan Bergmana,b,p
aUnit for Organic Chemistry, Department of Biosciences, Karolinska Institute, Novum Research Park, SE-141 57 Huddinge, Sweden
b
È È
Sodertorn University College, SE-141 04 Huddinge, Sweden
Received 23 November 2001; revised 17January 2002; accepted 14 February 2002
AbstractÐThe total synthesis of all four known rhopaladins, A±D, isolated from the Okinawan marine tunicate Rhopalaea sp., in two
synthetic steps is described, involving an imidate based cyclization with tryptophan esters as the key step to afford the appropriately
substituted imidazolinone unit. A short and ef®cient new synthesis of indol-3-yl-carbonyl nitriles from indol-3-yl-carboxaldehydes and
trimethylsilyl cyanide, followed by oxidation with DDQ is also described. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Marine environments are a rich source of indole and bis-
4indole) alkaloids of great structural variety. Numerous
compounds belonging to these classes have been isolated
from, e.g. tunicates, sponges and algae, and display a wide
spectrum of biological activities.1±4 Recently four bis-
4indole) alkaloids rhopaladins A±D 41±4) 4Fig. 1) were
isolated from the Okinawan marine tunicate Rhopalaea
sp. and the structures were elucidated on the basis of
spectroscopic data. These bis4indole) alkaloids are the ®rst
tunicate metabolites possessing the interesting structural
feature of an imidazolinone ring, and have also been demon-
strated to show antibacterial activity against Sarcina lutea
and Corynebacterium xerosis and inhibitory activity against
cyclin dependent kinase 4 and c-erbB-2 kinase.5
Here we wish to disclose the total synthesis of all four
known rhopaladins A±D 41±4) in two synthetic steps. As
it has been suggested that the compounds 1±4 may be
biosynthetically derived from two molecules of tryptophan,5
the idea was to form the central imidazolinone ring through
a reaction between an amino acid ester and an imidate, a
well known reaction for the construction of 445)-imidazo-
linones 4Scheme 1).15±18 The tryptophan esters 15 would
provide one indole unit, with the possibility of dehydro-
genation to form the exo-cyclic double bond at the
4-position of the imidazolinone, while the imidates 16
4obtained from an indolyl carbonyl nitrile 17) would intro-
duce the indolyl carbonyl group. Preparation of rhopaladins
A 41) and B 42) would require the use of 6-methoxytrypto-
phan, which would allow for a ®nal transformation of the
6-OMe group to the desired 6-OH group by using boron
tribromide19 or a Prey demethylation20 4i.e. heating with
pyridine hydrochloride).
A complex total synthesis of rhopaladin D 44) has been
reported recently by Fresneda and Molina in six steps
based on the aza-Wittig reaction of the iminophosphorane
derived from the a-azido-b-43-indolyl)propenamide with
indol-3-yl-glyoxylyl chloride in the presence of a polymer
supported base.6
The most common method to synthesize indol-3-yl-carbo-
nyl nitriles, developed by Sainsbury, involves indol-3-yl-
glyoxylyl chloride and cuprous cyanide 453% yield for
Compounds structurally related to the rhopaladins 1±4
such as the topsentins 45±10)7±12 and nortopsentins A±D
411±14)13,14 4Fig. 2) possessing an imidazole instead of an
imidazolinone ring, have been isolated from Topsentia
genitrix and Spongosorites ruetzleri, and exhibit cytotoxic,
antiviral and antifungal properties.
Keywords: alkaloids; imidates; rhopaladins.
Corresponding author. Address: Unit for Organic Chemistry, Department
p
of Biosciences, Karolinska Institute, Novum Research Park, SE-141
57Huddinge, Sweden. Tel.: 146-8-608-9204; fax: 146-8-608-1501;
e-mail: jabe@cnt.ki.se
Figure 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020402)00171-0

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T. Janosik et al. / Tetrahedron 58 32002) 2813±2819
Figure 2.
41H-indol-3-yl)carbonyl nitrile).21 We observed that the
presence of a bromine in 5-position of the indole ring
severely decreased the yield giving only 17±34% of the
desired product, hence in order to prepare the necessary
imidates, a reliable route to indol-3-yl-carbonyl nitriles
had to be developed. Synthesis of acyl cyanides through
O-silylated cyanohydrins and subsequent oxidation is a
well described topic.22±25 An ef®cient synthesis of the parent
indolyl-3-carbonyl nitrile 420a) was thus developed via a
masked cyanohydrin silylether as the intermediate followed
by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone 4DDQ). The method was also shown to be appli-
cable to indoles with various substituents, e.g. 5-Br, 6-OMe,
2-Ph as outlined in Scheme 2. Treatment of the 3-formyl-
indoles 18a±d26±28 4prepared via the standard Vilsmeier
procedure) with trimethylsilyl cyanide 4TMSCN) in re¯ux-
ing 1,2-dimethoxyethane 4DME) or acetonitrile afforded the
cyanohydrin silylethers 19a±d in good yields. The reaction
works well in both solvents with only minor differences in
yields. During the development of the method it was noticed
that aldehydes of high purity were essential for satisfactory
results. The stability of the silylethers 19a±d at room
temperature was found to be rather low and hence these
products were used immediately or stored in a refrigerator
for a short period of time. Compounds 19a±d were oxidized
smoothly with DDQ in dioxane to the corresponding
carbonyl nitriles 20a±d, in good yields. The method is
applicable to a number of substituted indoles, but strongly
Scheme 1.
Scheme 2. Reagents and conditions: 4a) TMSCN, DME or acetonitrile, re¯ux 1.5±3 h; 4b) DDQ, dioxane, rt 0.5±8 h.

T. Janosik et al. / Tetrahedron 58 32002) 2813±2819
2815
Scheme 3. Reagents and conditions: 4a) HCl 4g), EtOH, Et2O, 08C, 8 h; 4b) TrpOMe´HCl, Et3N, dioxane, ,608C, 3 days.
electron-withdrawing substituents 4e.g. 4-NO2) or N-pro-
tecting groups 4e.g. SO2Ph) on the cyanohydrin silylether
prevent the DDQ-oxidation. In conclusion, this method-
ology to prepare indol-3-yl-carbonyl nitriles is a good
complement to the already existing one, with advantages
of good overall yields, shorter reaction times, and tolerance
towards a variety of substituents.
presence of triethylamine resulted in the formation of
rhopaladins C 43) and D 44) in moderate yields 438 and
35%, respectively). The reaction may as well be performed
at re¯ux, run for various periods of time 41±4.5 days) or be
performed in acetonitrile without notable differences in yield.
Interestingly, the outcome of this reaction is the result of a
coupling followed by a cyclization and a ®nal spontaneous
dehydrogenation. The reaction speci®cally produces the
4Z)-isomers of the rhopaladins, which appears to be the
most stable arrangement. The presence of the 4E)-isomers
could not be detected. The 4Z)-orientation of the exo-cyclic
double bond was elucidated using difference-NOE experi-
ments, as irradiation of the 2-hydrogen resonance of the
carbonyl bridged indole unit produced enhancement of the
signals corresponding to the 2- and 4-protons of the second
indole, thus also establishing the presence of rotamers as
indicated previously.5
Imidates are often prepared in a Pinner reaction where a
nitrile and an alcohol are reacted under anhydrous con-
ditions in the presence of hydrogen chloride.15±18 To the
best of our knowledge no heterocyclic acyl imidates have
been previously reported, and only few cyclic acyl imidates
are known.29,30 In our application of the Pinner protocol,
carbonyl nitriles 20a, b underwent transformation in
respectable yields into the imidates 21a, b when exposed
to gaseous hydrogen chloride and ethanol in dry ether
4Scheme 3). The imidates 21a, b were found to be rather
labile and moisture sensitive when isolated, but can be
stored under dry conditions in a refrigerator for a short
period of time. Reliable NMR data for the imidates 21a, b
could not be obtained since a rapid hydrolysis of the imine
functionality into a carbonyl takes place in the presence of
even minute amounts of moisture in, e.g. DMSO-d6, thus
producing the corresponding dicarbonyl compounds.31
Nevertheless, FAB- and electrospray-MS data, as well as
the IR spectra strongly support the assigned structures
21a, b. The coupling of the imidates 21a, b with tryptophan
methyl ester hydrochloride 4TrpOMe´HCl) in dioxane in
The precursors of rhopaladins A and B 423a, b) were
prepared from 6-methoxytryptophan ethyl ester32
46-MeOTrpOEt) 422) using the same imidate based cycli-
zation as described above. The geometry of the double bond
was also in these cases shown as 4Z) on the basis of
NOE-experiments. The ®nal O-demethylation was accom-
plished by treatment of 23a or 23b with BBr3 in dichloro-
methane to afford rhopaladins A 41) and B 42) in yields of 81
and 62%, respectively, after puri®cation by column chroma-
tography 4Scheme 4).
Scheme 4. Reagents and conditions: 4a) 21a or 21b, Et3N, dioxane, ,608C, 2.5 days; 4b) BBr3, CH2Cl2, 2788C to rt, 4.5 days.

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T. Janosik et al. / Tetrahedron 58 32002) 2813±2819
A rather large excess of BBr3 4,30 equiv.) and long reac-
tion times 44.5 days) were needed to ensure deprotection as
the precursors 23a, b have limited solubility in CH2Cl2. The
spectroscopic data for all rhopaladins were in excellent
agreement to those reported for the natural products.
However, we found that all rhopaladins were insuf®ciently
soluble in MeOH-d4 4dark red crystals quickly separated
from the solution), thus all NMR data were recorded in
DMSO-d6. In the publication describing the isolation of
the rhopaladins A±D,5 MeOH-d4 was used as the NMR
solvent for 2±4 and DMSO-d6 for 1.
time 1.5 h. IR 4CHCl3) 3471, 2961, 1551, 1457, 1257, 1091,
1
868 cm21; H NMR 4DMSO-d6) d 11.53 4s, 1H), 7.80 4d,
Jˆ1.9 Hz, 1H), 7.59 4s, 1H), 7.43 4d, Jˆ8.7Hz, 1H), 7.30
4dd, Jˆ8.7, 1.9 Hz, 1H), 6.19 4s, 1H), 0.13 4s, 9H); 13C NMR
4DMSO-d6) d 135.2 4s), 126.5 4d) 126.4 4s), 124.5 4d), 120.7
4d), 119.9 4s), 114.1 4d), 112.14s), 110.4 4s), 56.8 4d), 20.3
4q); MS 4ESI) m/z 321 and 323 4M2H)2.
3.1.3. ,6-Methoxy-1H-indol-3-yl)-,trimethylsiloxy)aceto-
nitrile ,19c). The procedure above was used with
6-methoxy-1H-indol-3-yl-carboxaldehyde 418c)27 4350 mg,
2.0 mmol) and TMSCN 40.35 mL, 2.6 mmol) in acetonitrile
410 mL) to give 19c 4364 mg, 66%) as a yellow oil. Reaction
time 2 h. IR 4CHCl3) 3474, 3013, 2960, 2838, 1555, 1458,
In conclusion we have devised a two step synthesis of the
marine alkaloids rhopaladins A±D 41±4), starting from
indol-3-yl-carbonyl nitriles 20a, b in overall yields of
13±26%. Furthermore, the central imidate based cyclization
may be considered as a possible tool for creating other
imidazolinone or imidazole containing indole alkaloids.
1
1258, 1084, 852 cm21; H NMR 4DMSO-d6) d 11.09 4s,
1H), 7.53 4d, Jˆ8.7Hz, 1H), 7.374d, Jˆ2.5 Hz, 1H), 6.92
4d, Jˆ2.2 Hz, 1H), 6.77 4dd, Jˆ8.7, 2.2 Hz, 1H), 6.11 4s,
1H), 3.79 4s, 3H), 0.11 4s, 9H); 13C NMR 4DMSO-d6) d
156.0 4s), 137.3 4s), 123.6 4d), 120.1 4s), 119.2 4d), 119.0
4s), 110.6 4s), 109.8 4d), 94.9 4d), 57.1 4d), 55.2 4q), 20.2 4q);
MS 4ESI) m/z 273 4M2H)2.
3. Experimental
3.1. General
3.1.4. ,2-Phenyl-1H-indol-3-yl)-,trimethylsiloxy)aceto-
nitrile ,19d). The procedure above was used with 2-phenyl-
1H-indol-3-yl-carboxaldehyde 418d)28 4442 mg, 2.0 mmol)
and TMSCN 40.35 mL, 2.6 mmol) in acetonitrile 410 mL) to
give 19d 4585 mg, 91%) as a yellow oil. Reaction time 3 h.
NMR spectra were recorded at 300 MHz for 1H and 75 MHz
for 13C, respectively. Coupling constants are given in Hz.
The IR spectra were acquired using a FT-IR instrument.
Elemental analyses were performed by H. Kolbe Mikro-
analytisches Laboratorium, MuÈlheim an der Ruhr,
Germany. High-resolution mass spectroscopic 4HRMS)
analyses were performed by E. Nilsson, University of
Lund, Sweden, or Sveriges Lantbruksuniversitet 4SLU),
Uppsala, Sweden. Melting points were determined on a
capillary melting point apparatus or a Ko¯er hot stage and
are uncorrected. Chromatography was performed on Merck
Silica Gel 60. All reagents were purchased from Aldrich or
Lancaster and were used as received. All solvents were
puri®ed by distillation or were of analytical grade. Diethyl
ether was stored over sodium wire. The indolyltrimethyl-
siloxyacetonitriles 19a±d are unstable at room temperature
and should preferably be used within 24 h.
1
IR 4CHCl3) 3460, 2959, 1454, 1255, 1078, 870 cm21; H
NMR 4DMSO-d6) d 11.75 4s, 1H), 7.82 4d, Jˆ7.6 Hz, 1H)
7.67±7.44 4m, 6H), 7.22±7.15 4m, 2H), 6.05 4s, 1H), 0.01 4s,
9H); 13C NMR 4DMSO-d6) d 137.3 4s) 135.8 4s), 131.0 4s),
128.9 4d), 128.74d), 128.74d), 126.2 4s), 122.3 4d), 119.9
4d), 119.74s), 118.9 4d), 111.74d), 106.8 4s), 56.4 4d), 20.4
4q); MS 4ESI) m/z 319 4M2H)2.
3.1.5. ,1H-Indol-3-yl)carbonyl nitrile ,20a). A solution of
DDQ 42.05 g, 9.0 mmol) in dioxane 460 mL) was added
dropwise to compound 19a 42.0 g, 8.2 mmol) dissolved in
dioxane 410 mL) at room temperature. The mixture was
stirred for 2 h and the solid formed was thereafter ®ltered
off. The ®ltrate was evaporated, leaving a dark brown
residue which was puri®ed by column chromatography
4CH2Cl2) to afford 20a 41.27g, 91%) as an off-white
solid: mp 224±2268C [lit.20,1908C 4dec.)]; IR 4KBr)
3.1.1. ,1H-Indol-3-yl)-,trimethylsiloxy)acetonitrile ,19a).
To a solution of 1H-indol-3-yl-carboxaldehyde 418a)
41.16 g, 8.0 mmol) in acetonitrile 410 mL) was added
TMSCN 41.39 mL, 10.4 mmol). The mixture was heated
at re¯ux for 2 h and thereafter allowed to cool. The solvent
was evaporated, and the brown residue was subjected to
column chromatography 4hexane/ethyl acetate 80:20) to
afford 19a 41.30 g, 67%) as a yellow oil. IR 4CHCl3)
3474, 3013, 2961, 1554, 1456, 1254, 1085, 1047, 868
1
3230, 1622, 1514, 1435, 1234, 919, 744 cm21; H NMR
4DMSO-d6) d 12.89 4s, 1H), 8.63 4d, Jˆ3.4 Hz, 1H),
8.06±8.03 4m, 1H), 7.60±7.57 4m, 1H), 7.37±7.30 4m,
2H); 13C NMR 4DMSO-d6) d 158.5 4s), 141.3 4d), 137.5
4s), 124.9 4d), 124.14s), 123.8 4d), 121.0 4d), 116.2 4s),
114.3 4s), 113.3 4d); MS 4ESI) m/z 171 4M1H)1.
1
cm21; H NMR 4DMSO-d6) d 11.31 4s, 1H), 7.68 4d, Jˆ
3.1.6. ,5-Bromo-1H-indol-3-yl)carbonyl nitrile ,20b).
The procedure above was used with compound 19b
41.83 g, 5.7mmol) and DDQ 41.42 g, 6.2 mmol). Puri®-
cation by column chromatography hexane/ethyl acetate
460:40) afforded 20b 41.37g, 97%) as a yellow solid: mp
265±2668C; IR 4KBr) 3248, 3112, 2200 4w), 1612 4s), 1519,
7.7 Hz, 1H), 7.52 4d, Jˆ1.8 Hz, 1H) 7.45 4d, Jˆ8.0 Hz, 1H),
7.19±7.06 4m, 2H), 6.16 4s, 1H), 0.12 4s, 9H); 13C NMR
4DMSO-d6) d 136.5 4s), 125.0 4d), 124.74s), 121.9 4d),
120.1 4s), 119.5 4d), 118.6 4d), 112.0 4d), 110.6 4s), 57.0
4d), 20.2 4q); MS 4ESI) m/z 243 4M2H)2.
1
1436, 1225, 802 cm21; H NMR 4DMSO-d6) d 13.04 4s,
1H), 8.68 4s, 1H), 8.14 4d, Jˆ1.9 Hz, 1H), 7.58 4d, Jˆ
8.6 Hz, 1H), 7.53 4dd, Jˆ8.6, 1.9 Hz, 1H); 13C NMR
4DMSO-d6) d 158.74s), 142.0 4d), 136.3 4s), 127.6 4d),
125.9 4s), 123.0 4d), 116.4 4s), 115.5 4s), 115.4 4d), 114.1
4s); MS 4ESI) m/z 247and 249 4M 2H)2; Anal. calcd for
3.1.2. ,5-Bromo-1H-indol-3-yl)-,trimethylsiloxy)aceto-
nitrile ,19b). The procedure above was used with
5-bromo-1H-indol-3-yl-carboxaldehyde 418b)26 41.62 g,
7.2 mmol) and TMSCN 41.06 mL, 7.9 mmol) in DME
410 mL) to give 19b 42.05 g, 88 %) as a yellow oil. Reaction

T. Janosik et al. / Tetrahedron 58 32002) 2813±2819
2817
C10H5BrN2O: C, 48.22; H, 2.02; N, 11.25. Found: C, 48.29;
H, 1.98; N, 11.19.
triethylamine 40.10 mL, 0.76 mmol) in dioxane 42 mL) was
added 6-MeOTrpOEt 422) 4100 mg, 0.38 mmol) dissolved in
1,4-dioxane 48 mL). The mixture was kept at 608C for 2.5
days, a dark red color appeared with time. After cooling, the
solvent was evaporated and the residue subjected to column
chromatography using ethyl acetate as eluent to yield
compound 23a 442 mg, 29%) as a red solid. An analytically
pure sample was obtained by crystallization from MeOH,
which afforded 23a as dark red crystals: mp 302.5±
304.58C; IR 4KBr) 3231, 1673, 1613, 1593, 1513, 1490,
3.1.7. ,6-Methoxy-1H-indol-3-yl)carbonyl nitrile ,20c).
The procedure above was used with compound 19c
4164 mg, 0.60 mmol) and DDQ 4150 mg, 0.66 mmol).
Reaction time 0.5 h. Trituration of the crude product with
hexane/ethyl acetate 460:40) afforded 20c 470 mg, 58%) as
a yellow solid. An analytical sample was obtained by
recrystallization from 2-propanol: mp 236±2378C; IR
4KBr) 3212, 1614, 1523, 1446, 1431, 1382, 1232, 1162,
1
1441, 1411, 1362, 1228, 1156, 1119, 975 cm21; H NMR
1
1093, 824 cm21; H NMR 4DMSO-d6) d 12.69 4br s, 1H),
4DMSO-d6) d 12.32 4br s, 1H), 12.11 4br s, 1H), 11.72 4br
s, 1H), 9.02 4s, 1H), 8.49 4br, 1H), 8.34±8.31 4m, 2H), 7.60±
7.56 4m, 2H), 7.32±7.25 4m, 2H), 7.03 4d, Jˆ2.3 Hz, 1H),
6.91 4dd, Jˆ8.8, 2.3 Hz, 1H), 3.83 4s, 3H); 13C NMR
4DMSO-d6) d 177.1 4s), 169.6 4s), 156.8 4s), 153.9 4s),
138.2 4s), 137.1 4s), 136.3 4d), 135.4 4d), 134.7 4s), 127.1
4d), 126.3 4s), 123.5 4d), 122.5 4d), 121.8 4d), 121.4, 4d),
120.1 4s), 113.4 4s), 112.6 4s), 112.6 4d), 111.2 4d), 95.5
4d), 55.3 4q); MS 4ESI) m/z 383 4M2H)2; HRMS 4FAB1)
m/z calcd for C22H17N4O3 4M1H)1 385.1301, found
385.1300.
8.51 4s, 1H), 7.91 4d, Jˆ8.7Hz, 1H), 7.06 4d, Jˆ2.3 Hz,
1H), 6.98 4dd, Jˆ8.7, 2.3 Hz, 1H), 3.81 4s, 3H); 13C NMR
4DMSO-d6) d 158.2 4s), 157.7 4s), 140.9 4d), 138.8 4s), 121.6
4d), 117.9 4s), 116.4 4s), 114.4 4s), 113.2 4d), 96.5 4d),
55.4 4q); MS 4ESI) m/z 199 4M2H)2; Anal. calcd for
C11H8N2O2: C, 65.99; H, 4.03; N, 13.99. Found: C, 65.78;
H, 3.99; N, 13.84.
3.1.8. ,2-Phenyl-1H-indol-3-yl)carbonyl nitrile ,20d).
The procedure above was used with compound 19d 4920
mg, 2.87mmol) and DDQ 4724 mg, 3.19 mmol). Reaction
time 8 h. Trituration of the crude product with hexane/ethyl
acetate 460:40) afforded 20d 4640 mg, 90%) as a yellow
solid. An analytical sample was obtained by recrystalli-
zation from 2-propanol: mp 261±2628C; IR 4KBr) 3222,
3.1.12. 2-,5-Bromo-1H-indole-carbonyl)-5-[1-,6-methoxy-
1H-indol-3-yl)-meth-,Z)-ylidene]-3,5-dihydro-imidazol-
4-one ,23b). The procedure above was used with compound
21b 4218 mg, 0.66 mmol), triethylamine 40.18 mL, 1.32
mmol) and 6-MeOTrpOEt 422) 4173 mg, 0.66 mmol) to
give 23b 494 mg, 31%) as a red solid. An analytically
pure sample was obtained by crystallization from MeOH,
which afforded 23b as dark red crystals: mp 323.5±325.58C;
IR 4KBr) 3393, 3336, 3114, 1680, 1615, 1572, 1495, 1412,
1
1583, 1453, 1428, 1366, 1242, 1197, 949, 746 cm21; H
NMR 4DMSO-d6) d 13.03 4br s, 1H), 8.19±8.16 4m, 1H),
7.81±7.78 4m, 2H), 7.63±7.53 4m, 4H), 7.39±7.36 4m, 2H);
13C NMR 4DMSO-d6) d 159.5 4s), 151.5 4s), 135.8 4s), 130.8
4d), 130.74d), 129.1 4s), 128.3 4d), 126.2 4s), 124.8 4d),
123.8 4d), 128.8 4d), 114.5 4s), 112.74d), 112.1 4s); MS
4ESI) m/z 245 4M2H)2; Anal. calcd for C16H10N2O: C,
78.03; H, 4.09; N, 11.38. Found: C, 77.96; H, 4.03; N, 11.32.
1
1348, 1238, 1160, 979, 844 cm21; H NMR 4DMSO-d6) d
12.274br, 2H), 11.76 4br s, 1H), 9.04 4s, 1H), 8.45 4br, 1H),
8.45 4d, Jˆ1.9 Hz, 1H), 8.33 4s, 1H), 7.61 4s, 1H), 7.59 4d,
Jˆ8.6 Hz, 1H), 7.46 4dd, Jˆ8.6, 1.9 Hz, 1H), 7.03 4d, Jˆ
2.2 Hz, 1H), 6.90 4dd, Jˆ8.8, 2.2 Hz, 1H), 3.83 4s, 3H); 13C
NMR 4DMSO-d6) d 177.1 4s), 169.5 4s), 156.8 4s), 153.5 4s),
138.2 4s), 138.1 4d), 135.74d), 135.1 4s), 134.6 4s), 128.1 4s),
127.4 4d), 126.0 4d), 123.5 4d), 121.8 4d), 120.1 4s), 115.3
4s), 114.74d), 112.8 4s), 112.6 4s), 111.2 4d), 95.5 4d), 55.9
4q); MS 4ESI) m/z 461 and 463 4M2H)2; HRMS 4FAB1)
m/z calcd for C22H16N4O379Br 4M1H)1 463.0406, found
463.0423.
3.1.9. ,1H-Indol-3-yl-carbonyl)ethyl imidate hydro-
chloride ,21a). Compound 20a 4289 mg, 1.70 mmol) was
dissolved in dry ether 4150 mL) and ethanol 40.11 mL,
1.87mmol) was added. A continuous ¯ow of gaseous
hydrogen chloride was introduced into the solution at 08C
over approximately 6 h. The resulting mixture was stored at
2208C overnight and the precipitate was thereafter
collected by ®ltration, washed with dry ether and dried to
give 21a 4318 mg, 74%) as a yellow solid. This material was
used directly in the next step: mp 225±2278C 4dec.); IR
4KBr) 3155, 1628, 1507, 1437, 1236, 1159, 848, 751, 638
cm21; MS 4ESI) m/z 215 4M2H)2; HRMS 4FAB1) m/z
calcd for C12H13N2O2 4M1H)1 217.0977, found 217.0982.
3.1.13. Rhopaladin A ,1). To a suspension of compound
23b 410.0 mg, 0.021 mmol) in dichloromethane 410 mL) at
2788C under nitrogen atmosphere was added BBr3 in
dichloromethane 41 M, 0.65 mL, 0.65 mmol). The mixture
was allowed to reach room temperature over 4.5 days,
saturated aqueous NaHCO3 415 mL) was thereafter added,
followed by extraction with ethyl acetate 425 mL) con-
taining a small amount of MeOH 4,1%). The aqueous
layer was extracted once more with ethyl acetate 425 mL)
and the combined organic phases were washed with brine
440 mL), dried over Na2SO4 and ®nally evaporated. The
dark red residue was subjected to gradient column chroma-
tography starting with ethyl acetate/hexane 470:30) with
increasing amounts of ethyl acetate to yield rhopaladin A
41) 48.0 mg, 81%) as a red solid. An analytically pure
sample was obtained by crystallization from MeOH,
which afforded 1 as dark red crystals. The spectral data of
this material were identical with those reported previously:5
3.1.10. ,5-Bromo-1H-indol-3-yl-carbonyl)ethyl imidate
hydrochloride ,21b). The procedure above was used with
compound 20b 4249 mg, 1.00 mmol) and ethanol 40.06 mL,
1.10 mmol) to give 21 4197mg, 59%) as a yellow solid. This
material was used directly in the next step: mp 229.5±2318C
4dec.); IR 4KBr) 3226 4b), 1613, 1519, 1451, 1225, 886,
802 cm21; MS 4ESI) m/z 293 and 295 4M2H)2; HRMS
4FAB1) m/z calcd for C12H12N2O279Br 4M1H)1
295.0082, found 295.0083.
3.1.11. 2-,1H-Indole-carbonyl)-5-[1-,6-methoxy-1H-indol-
3-yl)-meth-,Z)-ylidene]-3,5-dihydro-imidazol-4-one ,23a).
To a stirred suspension of 21a 496 mg, 0.38 mmol) and

2818
T. Janosik et al. / Tetrahedron 58 32002) 2813±2819
1
mp 299.0±300.58C; IR 4KBr) 3356, 3218, 1683, 1623, 1494,
741 cm21; H NMR 4DMSO-d6) d 12.31 4br, 2H), 11.74
4br s, 1H), 9.05 4s, 1H), 8.48 4br, 2H), 8.35±8.32 4m, 1H),
7.66 4s, 1H), 7.61±7.53 4m, 2H), 7.32±7.22 4m, 4H); 13C
NMR 4DMSO-d6) d 177.2 4s), 169.6 4s), 154.3 4s), 137.3 4s),
137.0 4d), 136.4 4s), 135.6 4d), 134.9 4s), 126.6 4s), 126.5 4s),
126.3 4d), 123.5 4d), 123.2 4d), 122.6 4d), 121.5 4d), 121.4
4d), 120.5 4d), 113.4 4s), 112.6 4d), 112.6 4d), 112.1 4s); MS
4ESI) m/z 353 4M2H)2; HRMS 4EI) m/z calcd for
C21H14N4O2 4M1) 354.1117, found 354.1120.
1
1445, 1416, 1351, 1264, 1140, 976, 886 cm21; H NMR
4DMSO-d6) d 12.10 4br, 2H), 11.74 4br s, 1H), 9.32 4br s,
1H), 9.03 4s, 1H), 8.44 4d, Jˆ1.9 Hz, 1H), 8.33 4br, 1H),
8.274s, 1H), 7.58 4d, Jˆ8.6 Hz, 1H), 7.57 4s, 1H), 7.42 4dd,
Jˆ8.6, 1.9 Hz, 1H), 6.88 4d, Jˆ2.1 Hz, 1H), 6.75 4dd, Jˆ
8.6, 2.1 Hz, 1H); MS 4ESI) m/z 447and 449 4M 2H)2;
HRMS 4FAB1) m/z calcd for C21H14N4O379Br 4M1H)1
449.0249, found 449.0235.
3.1.14. Rhopaladin B ,2). The procedure above was used
with compound 23a 45.0 mg, 0.013 mmol) and BBr3 in
dichloromethane 41 M, 0.16 mL, 0.16 mmol) to give rhopa-
ladin B 42) 43.0 mg, 62%) after gradient column chroma-
tography starting with ethyl acetate/hexane 470:30) with
increasing amounts of ethyl acetate. An analytically pure
sample was obtained by crystallization from MeOH,
which afforded 2 as dark red crystals: mp 239.5±241.58C;
IR 4KBr) 3251, 2426, 2292, 1676, 1622, 1593, 1509, 1499,
1326, 1227, 921 cm21; 1H NMR 4DMSO-d6) d 12.36 4br s,
1H), 11.95 4br s, 1H), 11.69 4br s, 1H), 9.31 4br s, 1H), 9.01
4s, 1H), 8.36 4br, 1H), 8.34±8.31 4m, 1H), 8.26 4s, 1H),
7.59±7.55 4m, 2H), 7.33±7.26 4m, 2H), 6.88 4d, Jˆ
2.1 Hz, 1H) 6.72 4dd, Jˆ8.6, 2.1 Hz, 1H); 13C NMR
4DMSO-d6) d 177.1 4s), 169.6 4s), 154.6 4s), 153.5 4s),
138.5 4s), 137.1 4d), 136.3 4s), 135.1 4d), 134.3 4s), 127.2
4d), 126.3 4s), 123.4 4d), 122.5 4d), 121.74d), 121.4 4d),
119.1 4s), 113.4 4s), 112.74s), 112.5 4d), 111.6 4d), 97.6
4d); MS 4ESI) m/z 369 4M2H)2; HRMS 4FAB1) m/z
calcd for C21H15N4O3 4M1H)1 371.1144, found 371.1148.
References
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3.1.15. Rhopaladin C ,3). To a solution of 21b 4100 mg,
0.30 mmol) and triethylamine 40.08 mL, 0.60 mmol) in
dioxane 48 mL) was added Trp±OMeHCl 477 mg, 0.30
mmol). The mixture was kept at 608C for 3 days, during
that period a dark red color appeared. After cooling, the
solvent was evaporated and the residue subjected to column
chromatography using ethyl acetate as eluent to yield
rhopaladin C 43) 450 mg, 38%) as a red solid. An ana-
lytically pure sample was obtained by crystallization from
MeOH, which afforded 3 as dark red crystals: mp 332.5±
333.58C; IR 4KBr) 3266, 3101, 2933, 1666, 1589, 1490,
10. Morris, S. A.; Andersen, R. Tetrahedron 1990, 46, 715.
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1
1420, 1235, 1132, 975, 840, 747 cm21; H NMR 4DMSO-
d6) d 12.39 4br s, 1H), 12.39 4br s, 1H), 11.79 4br s, 1H), 9.07
4s, 1H), 8.49 4s, 1H), 8.49±8.45 4br s, 1H), 8.474d,
Jˆ1.9 Hz, 1H), 7.86 4s, 1H), 7.59±7.53 4m, 2H), 7.46 4dd,
Jˆ8.6, 1.9 Hz, 1H), 7.31±7.21 4m, 2H); 13C NMR 4DMSO-
d6) d 177.1 4s), 169.5 4s), 153.9 4s), 138.3 4d), 137.0 4s),
135.74d), 135.1 4s), 134.9 4s), 128.1 4s), 126.9 4d), 126.5 4s),
126.1 4d), 123.5 4d), 123.2 4d), 121.5 4d), 120.4 4d), 115.3
4s), 114.74d), 112.8 4s), 112.5 4d), 112.1 4s); MS 4ESI) m/z
431 and 433 4M2H)2; HRMS 4FAB1) m/z calcd for
C21H14N4O279Br 4M1H)1 433.0300, found 433.0292.
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3.1.16. Rhopaladin D ,4). The procedure above was used
with 21a 4105 mg, 0.42 mmol), triethylamine 40.12 mL,
0.83 mmol) and Trp±OMeHCl 4107mg, 0.42 mmol) to
give rhopaladin D 44) 452 mg, 35%) after column chroma-
tography using ethyl acetate as eluent. An analytically pure
sample was obtained by crystallization from MeOH, which
afforded 4 as dark red crystals: mp 315.5±317.58C 4lit.6
287±2908C); IR 4KBr) 3436, 3284, 2934, 1162, 1612,
1594, 1581, 1490, 1426, 1359, 1232, 1131, 981, 835,
È
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T. Janosik et al. / Tetrahedron 58 32002) 2813±2819
2819
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