Homoarcyriaflavin: Synthesis of Ring-Expanded Arcyriaflavin Analogues

Article abstract of DOI:10.1021/jo981926g

The construction of the ring-expanded carbazole system, forming arcyriaflavin homologues, is efficiently accomplished by the reaction of 2,2′-bridged bis-indoles with 3,4-dibromo-2,5-dihydro-1H-2,5-pyrroledione derivatives under Grignard conditions. A ring size of up to nine members in the central ring is achievable. Substitutions either at the indole system or at the imide-N are also possible. The conformation of homoarcyriaflavins as a cross-link between the rigid arcyriaflavins and the flexible arcyriarubins was investigated by NMR, X-ray, and semiempiric quantum chemical calculation methods.

Full text of DOI:10.1021/jo981926g

8130
J . Org. Chem. 1999, 64, 8130-8137
Hom oa r cyr ia fla vin : Syn th esis of Rin g-Exp a n d ed Ar cyr ia fla vin
An a logu es†
Siavosh Mahboobi,* Thomas Burgemeister, Stefan Dove, Sabine Kuhr, and Alfred Popp
Faculty of Chemistry and Pharmacy, University Regensburg, D-93040 Regensburg, Germany
Received September 22, 1998
The construction of the ring-expanded carbazole system, forming arcyriaflavin homologues, is
efficiently accomplished by the reaction of 2,2′-bridged bis-indoles with 3,4-dibromo-2,5-dihydro-
1H-2,5-pyrroledione derivatives under Grignard conditions. A ring size of up to nine members in
the central ring is achievable. Substitutions either at the indole system or at the imide-N are also
possible. The conformation of homoarcyriaflavins as a cross-link between the rigid arcyriaflavins
and the flexible arcyriarubins was investigated by NMR, X-ray, and semiempiric quantum chemical
calculation methods.
In tr od u ction
The indole[2,3-a]carbazole alkaloid ring system is
present in several biologically active molecules, such as
the arcyriaflavins and the potent antitumor agent rebec-
camycin,1 isolated from Nocardia aerocoligenes in 1985.2,3
This structurally rare class of compounds represents,
together with the closely related arcyriarubins (Figure
1 and Table 1), new lead structures for the synthesis of
biologically active substances.
For example, arcyriaflavin derivatives have antimi-
crobacterial activity against Bacillus cereus,4 antitumor
activity against P388 leukemia cells,4 and inhibit protein
kinase A (PKA), protein kinase C (PKC),4-6 topoisomeras-
es I and II4 as well as tyrosine and serine kinases.5
Arcyriaflavin analogues are currently being evaluated in
human clinical trials as anticancer drugs.1
Arcyriarubins,7-10 isolated from the fruiting bodies of
the slime mould Arcyria denundata,11 and related com-
pounds also show highly potent biological effects. Inhibi-
tion of protein kinases A and C and of protein tyrosine
kinase (PTK) has been described, and emerging interest
F igu r e 1.
in these compounds can be noted in recent patent
literature.8,12-16 These bis-indolylimides are, in contrast
to indolo[2,3-a]carbazoles, not bridged at their indole-2-
positions. Therefore, they are also named secoindolocar-
bazoles.17
For compounds 1a -c a planar conformation with
undistorted indole rings can be assumed. In contrast,
computer calculations, NMR-studies and X-ray analysis
indicated that arcyriarubin (2a -c) can adopt three
different conformations due to the free rotation around
the maleinimide-indole single bond.12
† Dedicated to Prof. W. Wiegrebs on the occasion of his 67th birthday.
‡ Corresponding author. Fax: (0049)-0941-943-4809. E-mail:
siavosh.mahboobi@chemie.uni-regensburg.de.
(1) Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Vyas, D.
M. Tetrahedron Lett. 1995, 36, 7841-7844.
(2) Nettleton, D. E.; Doyle, T. W.; Krishnan, B.; Matsumoto, G. K.;
Clardy, J . Tetrahedron Lett. 1985, 26, 4011-4014.
(3) Pearce, C. J .; Doyle, T. W.; Forenza, S.; Lam, K. S.; Schroeder,
D. R. J . Nat. Prod. 1988, 51, 937-940.
Arcyriaflavin and arcyriarubin represent the border-
line cases of a completely rigid and a quite flexible
arrangement of the indole substituents at the malein-
imide ring.
(4) Pereira, E. R.; Belin, L.; Sancelme, M.; Prudhomme, M.; Ollier,
M. J . Med. Chem. 1996, 39, 4471-4477.
(5) Trinks, U.; Buchdunger, E.; Furet, P.; Kump, W.; Mett, H. J .
Med. Chem. 1994, 37, 1015-1027.
(12) Hartenstein, J . H.; Aranda, J .; Barth, H.; Betche, H. J .;
Kleinschroth, J .; Rudolph, C.; Reck, R.; Trostmann, U.; Scha¨chtele, C.
In Perspectives in Medicinal Chemistry; Testa, B., Fuhrer, W., Kyburz,
E., Giger, R., Eds.; Verlag Helvetica Chimica Acta und VCH: Wein-
heim, New York, Basel, Cambridge, 1993; pp 99-118.
(13) Gillig, J . R.; J irousek, M. R. (Eli Lilly and Co.) US Patent Appl.
413,311, 1996; Chem. Abstr. 1996, 125, P 247615f.
(14) Heath, W. F.; J irousek, M. R.; Mcdonald, J . H.; Rito, C. J . (Eli
Lilly and Co.), Eur. Pat. Appl. 657, 458 A1, 1995; Chem. Abstr. 1996,
123, P 314033p.
(6) Sancelme, M.; Fabre, S.; Prudhomme, M. J . Antibiot. 1994, 47,
792-798.
(7) Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.; Hurst, S. A.;
Keech, E.; Kumar, M. K. H.; Lawton, G.; Nixon, J . S.; Wilkinson, S. E.
J . Med. Chem. 1992, 35, 994-1001.
(8) Toullec, D.; Pianetti, P.; Coste, H.; Bellevergue, P.; Grand-Perret,
T.; Ajakane, M.; Baudet, V.; Boissin, P.; Boursier, E.; Loriolle, F.;
Duhamel, L.; Charon, D.; Kirilovsky, J . J . Biol. Chem. 1991, 266,
15771-15781.
(9) Davis, P. D.; Hill, C. H.; Lawron, G.; Nixon, J . S.; Wilkinson, S.
E.; Hurst, S. A.; Keech, E.; Turner, S. E. J . Med. Chem. 1992, 35, 177-
184.
(15) Heath, W. F.; J irousek, M. R.; Mcdonald, J . H.; Rito, C. J .;
Winneroski, L. L. (Eli Lilly and Company), Eur. Patent Appl. 657,411
A1, 1995; Chem. Abstr. 1996, 125, P 328740v.
(10) Davis, P. D.; Hill, C. H.; Keech, E.; Lawton, G.; Nixon, J . S.;
Sedgwick, A. D.; Wadsworth, J .; Westmacott, D.; Wilkinson, S. E. FEBS
Lett. 1989, 259, 61-63.
(11) Steglich, W.; Steffan, B.; Kopanski, L.; Eckhardt, G. Angew.
Chem. 1980, 92, 463-464.
(16) Heath, W. F.; McDonald, J . H.; Paal, M.; Ru¨hter, G.; Schotten,
T.; Stenzel, W. (Eli Lilly and Co.), US Patent Appl. 324,948, 1996;
Chem. Abstr. 1996, 123, P 339733d.
(17) Link, J . T.; Raghavan, S.; Danishefsky, S. J . J . Am. Chem. Soc.
1995, 117, 552-553.
10.1021/jo981926g CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/06/1999

Homoarcyriaflavin
J . Org. Chem., Vol. 64, No. 22, 1999 8131
Sch em e 2
F igu r e 2.
Sch em e 1
In our group a strategy for synthesizing semirigid, ring-
expanded homoarcyriaflavins has been elaborated. New
arcyriaflavin derivatives with progressively increasing
ring size up to nine ring members are accessible. Due to
entropic reasons, larger ring systems could not be syn-
thesized.
Syn th esis
The methods for the synthesis of indolo[2,3-a]carba-
zoles are divided into two categories based on the ring-
formation in the last step, i.e., either the rings B and/ or
E18 or the central ring C18-20 (for the ring description,
see Figure 1).
ylsulfonylindole-2-carbaldehyde (4)24 in the presence of
LDA. The reduction of the hydroxyl group with tri-
phenylsilane and trifluoracetate (TFA) afforded 87% of
compound 8 and 56% of compound 14. Attempts to
remove the phenylsulfonyl protecting group of compound
8 with potassium tert-butoxide or 10% NaOH in EtOH
failed, but hydrolysis with K2CO3 in MeOH afforded the
deprotected product 10. Alternatively compounds 6 and
12 were oxidized with pyridinium dichromate (PDC), and
the sulfonamide moiety was cleft with 10% NaOH in
EtOH. The reduction of the keto group of compound 9
and 15 by Wolff-Kishner reaction under Huang-Minlon
conditions afforded good yields of the bis-indolyles 10 and
16 (Scheme 2).
The synthesis of the new class of indole-2,2′-alkyl
bridged bis-indolylmaleinimides was designed following
a retrosynthetic analysis of the target compounds, which
led to two possible synthetic equivalents, the 2,2′-bis-
indoles and dibromomaleinimide derivatives (Figure 2).
We intended to synthesize methylene-2,2′-bis-indole (X
) CH2) (10), the most simple derivative of the 2,2′-bis-
indole series, by the Madelung reaction. This method uses
the corresponding N,N′-o-toluidine bis-amides, which are
cyclized under the influence of strong bases at 200-400
°C. Compound 3 was obtained in moderate yield accord-
ing to J ulia et al.21 by reacting malonic acid dichloride
with o-toluidine. However, heating to 250 °C in the
presence of NaNH2 afforded no cyclized product (degra-
dation) (Scheme 1).
The dimethylene- and trimethylene-bridged bis-indoles
1,2-bis(1H-2-indolyl)ethane (17) and 1,3-bis(1H-2-indolyl)-
propane (18) were prepared according to the method of
Smith et al.,26 reacting N-deprotonated N-trimethylsilyl-
o-toluidine with the corresponding diethyl ester. The bis-
An alternative strategy led to compound 10 and its
5-methoxy derivative 16 in good overall yields. The
5-methoxy derivatives of these indole alkaloids were
synthesized because this substituent increases their
biological activity.12,22,23 N-Phenylsulfonylindole (5)24 and
the 5-methoxy derivative 1125 were coupled with N-phen-
(22) Kleinschroth, J .; Hartenstein, J .; Rudolph, C.; Scha¨chtele, C.
Bioorg. Med. Chem. Lett. 1995, 5, 55-60.
(23) Gribble, G. W.; Berthel, S. J . In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam, Lon-
don, New York, Tokyo, 1993; Vol. 12 (Part H), pp 365-409.
(24) Gribble, G. W.; Saulnier, M. G.; Sibi, M. P.; Obaza-Nutaitis, J .
A. J . Org. Chem. 1984, 49, 4518-4523.
(25) Leon, P.; Garbay-J aureuiberry, C.; LePecq, J .-B.; Roques, B.
P. Tetrahedron Lett. 1985, 27, 4923-4929.
(26) Smith, A. B. I.; Visnick, M. Tetrahedron Lett. 1985, 26, 3757-
3760.
(18) Bergman, J .; Pelcman, B. J . Org. Chem. 1989, 54, 824-828.
(19) Ohkubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M.; Morishima,
H. Tetrahedron 1997, 53, 585-592.
(20) Moody, C. J .; Rahimtoola, K. F.; Porter, B.; Ross, B. C. J . Org.
Chem. 1992, 57, 2105-2114.
(21) J ulia, M.; Manoury, P. Bull. Soc. Chim. France 1964, 1953-
1956.

8132 J . Org. Chem., Vol. 64, No. 22, 1999
Mahboobi et al.
Sch em e 3
Sch em e 5
Sch em e 4
Sch em e 6
indole derivatives 17 and 18 were obtained in good yields
(Scheme 3). The same reaction was carried out for the
synthesis of compound 10, but it was not practicable
because the desired product could only be isolated with
1% yield besides a great variety of unidentified products.
For the synthesis of the asymmetrically substituted bis-
indole 16, this reaction does not seem to be the method
of choice because of the low yield mentioned above.
The basic skeleton of the homoarcyriaflavins was
formed by reaction of the 2,2′-bis-indoles with ethylmag-
nesium bromide and the pertinent maleinimide deriva-
tives (Schemes 4 and 5).
isolated. For compound 21 neither the use of EtMgBr nor
n-BuLi to deprotonate the indole-NH yielded the 10-
membered central ring, but produced product 29 consist-
ing of one bisindolylalkane and two maleinimide moieties.
Formation of mono- and disubstituted products, already
observed for the 8- and 9-membered ring-forming reaction
(Scheme 5), here becomes predominant.
As the synthesized imides are scarcely soluble in water,
and the corresponding HCl salts are too acidic for
pharmacological or medicinal application, we introduced
the strongly basic 2-(N,N-dimethylamino)ethyl group into
With this approach, the products 22-26a and 27a
could be obtained in low to moderate yields, indicating
the wide range of this strategy. In addition, the bis-
indoles with n ) 2, 3 led to the noncyclized byproducts
26b, 26c, and 27b.
The reaction of 1,4-bis(1H-2-indolyl)butane (28),21 how-
ever, with the 3,4-dibromo-2,5-dihydro-1H-2,5-pyrrole-
diones 1927 and 2128 afforded no cyclized products (Scheme
6). For compound 19 no well-defined products could be
(27) Schmidt, E. K. G. Chem. Ber. 1974, 107, 2440-2452.
(28) Scharf, H. D.; Korte, F.; Seidler, H.; Dittner, R. Chem. Ber. 1965,
98, 8, 764-780.

Homoarcyriaflavin
J . Org. Chem., Vol. 64, No. 22, 1999 8133
F igu r e 4. Energy minimum conformation of compound 22 (CS
point group) calculated with MOPAC (AM1 Hamiltonian).
tributed to boat inversion. The 7-membered ring of
compound 31 adopts, according to the X-ray analysis, a
1
boatlike conformation. Low-temperature H NMR experi-
ments at 400 MHz with 22 and 27a as exemplary
compounds in THF-d8 as a solvent (solubility at low
temperature was sufficient) showed decoalescence at 175
( 3 K for 22, but cooling compound 27a to 175 K did not
change its spectrum. Using the Eyring equation the
corresponding free energy of activation for 22 amounts
F igu r e 3. X-ray structure of compound 31 showing the
crystallographic numbering scheme.
homoarcyriaflavin 22. As a direct substitution of the
indole-NH of 22 was not possible, the imide-N-protected
derivatives 24 and 25 were used, which were synthesized
by reacting the bis-indolylmagnesium bromide of meth-
ylene-2,2′-bis-indole (10) with the benzyloxymethyl- and
methyl-substituted dibromomaleinimides 20 and 21.
Finally the amines 30 and 31 were synthesized. The
benzyloxymethyl group of compound 30 was removed
hydrogenolytically, followed by ammonolysis29,30 to com-
plete the deprotection, affording imide 33. The methyl
group of compound 31 was removed by reaction with 5
N KOH in EtOH, yielding the anhydride 32, and subse-
quent melting of 32 with NH4OAc gives 33 (Scheme 4).
to ∆G* ) 9.0 ( 0.2 kcal mol-1 33,34
.
This experimental approximation of the barrier to ring
inversion of compound 22 has been compared with a
semiempirical quantum chemical approach to the activa-
tion enthalpy, which additionally should lead to conclu-
sions about the geometry of the transition state. All
calculations were performed with the QCPE program
MOPAC 6.0 (AM1 Hamiltonian), implemented within the
molecular modeling software SYBYL 6.4 (Tripos Assoc.)
on a Silicon Graphics Indigo2 Solid Impact workstation.
One of the two global energy minima of 22 with CS
symmetry (see Figure 4, heat of formation 77.16 kcal
mol-1) essentially corresponds to the X-ray structure of
31. The angle between the indole planes amounts to
128.2°.
Molecu la r Str u ctu r e
Ring inversion was first simulated by a MOPAC
SADDLE approach, starting from both minima. The
resulting state was fully planar with an enthalpy of 13.5
kcal mol-1 above the minimum. However, the FORCE
calculation indicated that this structure represents a
third-order transition state. It is therefore likely that the
real inversion pathway is neither forced with all possible
symmetry relations nor crossing a fully planar conforma-
tion. Further work was based on a careful gridsearch
with variation of the torsion angles τ1 (C10-C17-C18-
C19; see Figure 3) from -60° to 60° and τ2 (C19-C7-
C8-C24) from 160° to -160°, each with an increment of
5°. All other internal coordinates were optimized without
symmetry conditions. Results are illustrated by the
isocontour plot in Figure 5. It becomes obvious that the
inversion pathway does not proceed along the diagonal
of the xy plane, but that τ2 passes 180° before τ1 arrives
at 0° and before both indole moieties and the C18 atom
of the cycloheptatriene ring are nearly coplanar. An
inspection of the geometries shows that the pyrroledione
oxygens do successively, not jointly, cross the neighboring
indole rings without significant repulsion. The highest
Compound 31 nicely crystallized from MeOH so that
a X-ray structure analysis could be performed.31 Figure
3 (ORTEP Plot, thermal ellipsoids for 50% probability32)
shows the structure of compound 31 (MeOH in the crystal
lattice was omitted); the central ring C (Figure 1) adopts
a boatlike conformation, and the plane angle between the
indole rings amounts to 116.5°.
In contrast to the X-ray analysis, NMR spectroscopy
gives information about the average population of con-
formations in solution. The X-ray analysis shows a
different chemical environment for the two methylene
protons of the bridge, which should result in different
1
chemical NMR shifts. With H NMR spectroscopy, how-
ever, diastereotopic protons of the bridge could not be
distinguished because of their fast interconversion in
relation to the NMR time scale.
The singlet of the methylene protons of the bridge
between the two indole rings at 4.25 ppm can be at-
(29) Kaneko, T.; Wong, H.; Okamoto, K. T.; Clardy, J . Tetrahedron
Lett. 1985, 26, 4015-4018.
(30) Gallant, M.; Link, J . T.; Danishefsky, S. J . J . Org. Chem. 1993,
58, 343-349.
(31) Crystallographic data for the reported structure have been
deposited at the Cambridge Crystallographic Data Centre, no. CCDC
116076.
(33) Gu¨nther, H. NMR-Spektroskopie; 3rd ed.; Georg Thieme
Verlag: Stuttgart, New York, 1992.
(32) Burnett, M. N.; J ohnson, C. K. ORTEP-III: Oak Ridge
Thermal Ellipsoid Plot Program for Crystal Structure Illustrations,
Oak Ridge National Laboratory Report ORNL-6895, 1996.
(34) Oki, M. In Methods in Stereochemical Analysis; Merchand, A.
P., Ed.; VCH Publishers Inc.: Deerfield Beach, 1985; Vol. 4, pp 287-
324.

8134 J . Org. Chem., Vol. 64, No. 22, 1999
Mahboobi et al.
F igu r e 6. Transition state of the inversion of compound 22
(C2 point group) as suggested from MOPAC calculations (AM1
Hamiltonian). Additionally, the bisindolylcycloheptatriene and
the pyrroledione planes are drawn.
Exp er im en ta l Section
Gen er a l In for m a tion . Melting points were recorded on a
microscope heating stage and are not corrected. 1H and 13C
nuclear magnetic resonance spectra, mass spectra, and mi-
croanalyses were performed by Zentrale Analytik, University
of Regensburg. IR spectroscopy was performed on a FT-IR
spectrometer. Thin-layer chromatography (TLC) was carried
out on Al sheets coated with 60F245 silica. Compounds were
detected using sprays of 3% w/v vanillin in 96% ethanol, and
5% w/v H2SO4 in 96% ethanol, respectively. Column chroma-
tography was carried out using 70-230 mesh ASTM silica.
Solvents and commercially available reagents were dried and
purified before use according to standard procedures. All
reactions were carried out under dried N2 in flame- or oven-
dried vessels. A lot of maleimides crystallize with solvents,
which could not be removed despite vigorous heating of the
ground materials in vacuo. The presence of these solvents was
F igu r e 5. Isocontour plot resulting from grid searches of
compound 22 (MOPAC, AM1 Hamiltonian). The x axis is the
torsion angle τ1 (C10-C17-C18-C19, see Figure 3), and the
y axis is the torsion angle τ2 (C19-C7-C8-C24). The isocon-
tour lines are 4HF (4.5-11 kcal mol-1, interval 0.5 kcal mol-1),
as the energy difference to the minimum energy conformation.
(b): transition state (τ1 ) -0.6°, τ2 ) 190.2°). Two continuous
“linewise” approaches (preceding conformation ) starting
conformation of next grid point) with constant values of τ1 and
τ2, respectively, and increasing values of the other angle were
applied in order to simulate inversion. Both approaches lead
to the same result.
1
assured by H NMR spectra.
Bis(1-p h en ylsu lfon yl-1H-2-in d olyl)m eth a n ol (6). To a
solution of dry diisopropylamine (30.4 mL, 0.22 mol) in dry
THF (200 mL) was added n-BuLi (125 mL, 0.20 mol, 1.6 M in
n-hexane) at - 78 °C within 30 min. After stirring at 0 °C for
30 min 1-phenylsulfonyl-1H-indole (5)24 (49.1 g, 0.19 mol),
dissolved in dry THF (300 mL), was added within 10 min. The
resulting mixture was stirred for 30 min at 0 °C and subse-
quently cooled to - 78 °C. At this temperature, 1-phenylsul-
fonyl-1H-2-indolcarbaldehyde (4)24 (60.0 g, 0.21 mol), dissolved
in dry THF (200 mL), was added. The resulting mixture was
stirred overnight and allowed to warm to room temperature.
A 1% HCl solution (500 mL) was added in one portion. After
the addition of diethyl ether (500 mL) the organic layer was
separated, and the aqueous phase was extracted with diethyl
ether. The combined organic layers were washed with satu-
rated NaHCO3 solution and brine and dried over Na2SO4. The
solvent was evaporated. Purification of the residue by column
chromatography (CH2Cl2) yielded the alcohol 6 as colorless
crystals (86.5 g, 0.16 mol, 84%): mp 185 °C (MeOH); IR (KBr)
3535, 3180-2950, 1455, 1370, 1175 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 8.03 (d, J ) 7.9 Hz, 6H), 7.58-7.67 (m, 2H), 7.46-
7.57 (m, 6H), 7.19-7.38 (m, 5H), 6.76 (d, J ) 6.76 Hz, 1H,
exchangeable), 6.46 (s, 2H); 13C NMR (63 MHz, DMSO-d6) δ
143.39, 137.96, 136.24, 134.32, 129.42, 128.56, 126.62, 124.77,
energy of the minimum energy pathway results after the
first crossing.
Therefore, in the transition state the pyrroledione
plane should be intersected with the coplanar rest of the
molecule (C2 point group). This suggestion was verified
by a further SADDLE calculation, starting from grid
search conformations closer to the postulated state, but
still with CS symmetry. The resulting saddle geometry
was optimized with the TS keyword (eigenvector follow-
ing routine toward transition states). The final geometry
meets all conditions of a transition state: A FORCE
calculation yielded one complex eigenvalue of the Hess
matrix, and the eigenvalues of the rotational and trans-
lational vibrations are sufficiently close to zero. The heat
of formation amounts to 87.61 kcal mol-1, corresponding
to an activation enthalpy of 10.44 kcal mol-1. Since
entropy contributions to ring inversion are mostly in the
range of (1-2 kcal mol-1, this calculated value does well
correspond to the measured barrier of ring inversion of
22. The postulated transition state is drawn in Figure 6.
The bisindolylcycloheptatriene and the pyrroledione planes
become obvious, which are angled by 21.5°. At room
temperature, the molecule flutters such as a hum-
mingbird.
123.60, 121.38, 114.09, 110.52, 62.26. Anal. Calcd for C29H22
-
N2O5S2 (542.62): C, 64.19; H, 4.09; N, 5.16. Found: C, 64.06;
H, 4.02; N, 5.08.
Bis(1-p h en ylsu lfon yl-1H-2-in d olyl) Keton e (7). The so-
lution of 6 (20.0 g, 36.9 mmol) in dry DMF (200 mL) was cooled
to 0 °C. After the addition of pyridinium dichromate (PDC)
(90.4 g) the mixture was stirred for 20 h at room temperature.
Then H2O (700 mL) and CH2Cl2 (700 mL) were added, the
layers were separated, and the aqueous phase was extracted
with CH2Cl2 (2 × 200 mL). The combined organic extracts were
washed with H2O (500 mL) and dried over Na2SO4, and the
solvent was evaporated. After addition of CH2Cl2 the ketone
7 crystallizes as colorless crystals (15.0 g, 27.7 mmol, 75%):
mp 244 °C (MeOH/diethyl ether); IR (KBr) 3100-2950, 1665,
1450, 1375, 1175 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 8.20-
Con clu sion
With the synthesis of the homoarcyriaflavins the
successful bridging of the gap between the rigid arcyri-
aflavins and the flexible arcyriarubins has been achieved.
A wide variety of homoarcyriaflavin derivatives can now
be synthesized with our method, so that structure-
activity relationship (SAR) studies of these bis-indole
alkaloids can be performed.

Homoarcyriaflavin
J . Org. Chem., Vol. 64, No. 22, 1999 8135
8.15 (m, 2H), 8.12-8.07 (m, 4H), 7.84-7.57 (m, 12H), 7.45-
7.37 (m, 2H). Anal. Calcd for C29H20N2O5S2 (540.61): C, 64.43;
H, 3.73; N, 5.18. Found: C, 64.14; H, 4.01; N, 5.10.
7.39 (m, 1H), 7.17-7.29 (m, 2H), 7.04-7.11 (m, 1H), 6.90-
6.99 (m; 1H), 6.69-6.80 (m, 1H, exchangeable), 6.60 (s, 2H),
3.73 (s, 3H); 13C NMR (63 MHz, DMSO-d6) δ 156.21, 143.98,
143.42, 137.97, 137.91, 136.22, 134.31, 134.23, 130.79, 129.72,
129.41, 129.39, 128.55, 126.64, 126.52, 124.76, 123.59, 121.37,
114.99, 114.09, 113.51, 110.86, 110.51, 104.00, 62.29, 55.38.
Anal. Calcd for C30H24N2O6S2 (572.65): C, 62.92; H, 4.22; N,
4.89. Found: C, 62.81; H, 4.38; N, 4.99.
Bis(1-p h en ylsu lfon yl-1H-2-in d olyl)m eth a n e (8). After
stirring of a solution of 6 (26.7 g, 49.2 mmol) and triphenyl-
silane (15.0 g, 57.8 mmol) in dry CH2Cl2 (400 mL) for 30 min,
TFA (22.4 mL) was added. The solution was stirred for 1 h at
room temperature, H2O was added, and the solution was
carefully neutralized with solid Na2CO3 with ice cooling. The
organic phase was separated, dried over Na2SO4, and evapo-
rated. Purification of the residue by column chromatography
(CH2Cl2/hexane 6:4) yielded compound 8 as colorless crystals
(22.5 g, 40.0 mmol, 87%): mp 144-145 °C (diethyl ether); IR
(KBr) 3150-2900, 1450, 1370, 1175 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 8.08 (d, J ) 7.9 Hz, 2H), 7.83-7.92 (m, 4H), 7.60-
7.69 (m, 2H), 7.42-7.60 (m, 8H), 7.33 (t, J ) 7.1 Hz, 2H), 7.23
(t, J ) 6.5 Hz, 2H), 6.46 (s, 2H); 13C NMR (63 MHz, DMSO-
d6) δ 138.06, 137.67, 136.30, 134.48, 129.71, 129.09, 126.23,
124.44, 123.73, 120.88, 114.18, 111.36, 28.62. Anal. Calcd for
C29H22N2O4S2 (526.62): C, 66.14; H, 4.21; N, 5.32. Found: C,
65.99; H, 4.21; N, 5.18.
Bis(1H-2-in d olyl) Keton e (9). To a solution of 7 (10.0 g,
18.5 mmol) in 99% ethanol (380 mL) was added a 10% solution
of NaOH (210 mL), and the mixture was refluxed for 20 h.
Then ethanol was evaporated, brine (500 mL) and CH2Cl2 (500
mL) were added, and the organic phase was separated. The
aqueous phase was extracted with CH2Cl2 (2 × 200 mL), and
the combined organic extracts were dried over Na2SO4 and
evaporated. The crude product crystallizes during the evapora-
tion of CH2Cl2 and was recrystallized from CH2Cl2, affording
yellow crystals (4.50 g, 17.3 mmol, 93%): mp 272-273 °C; IR
(KBr) 3335, 3100-2950, 1665, 1445 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 12.00 (s, 2H), 7.78 (d, J ) 7.9 Hz, 2H), 7.60-7.66
(m, 2H), 7.54 (d, J ) 7.9 Hz, 2H), 7.33 (t, J ) 7.9 Hz, 2H),
7.13 (d, J ) 7.9 Hz, 2H); 13C NMR (63 MHz, DMSO-d6) δ
176.75, 137.75, 134.58, 127.29, 125.27, 122.68, 120.32, 112.65,
109.51. Anal. Calcd for C17H12N2O (260.30): C, 78.44; H, 4.65;
N, 10.76. Found: C, 78.22; H, 5.05; N, 10.78.
(5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-
su lfon yl-1H-2-in d olyl) k eton e (13). Oxidation of alcohol 12
(3.10 g, 5.40 mmol) with PDC (12.2 g) was performed as
described for alcohol 6. The crude product was purified by
column chromatography (CH2Cl2), affording ketone 13 as pale
yellow crystals (1.20 g, 2.10 mmol, 39%): mp 205 °C (MeOH);
1
IR (KBr) 3100-2900, 2840, 1650, 1360, 1175 cm-1; H NMR
(250 MHz, DMSO-d6) δ 7.19-8.19 (m, 19H), 3.80 (s, 3H). Anal.
Calcd for C30H22N2O6S2 (570.64): C, 63.15; H, 3.89; N, 4.91.
Found: C, 62.85; H, 4.16; N, 4.87.
(5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-
su lfon yl-1H-2-in d olyl)m eth a n e (14). The reduction of al-
cohol 12 (2.00 g, 3.49 mmol) with triphenylsilane (1.07 g, 4.11
mmol) was effected as described for alcohol 6. Column chro-
matography (CH2Cl2) of the crude product yielded compound
14 as colorless crystals (1.10 g, 1.98 mmol, 56%): mp 98-100
°C (CH2Cl2/hexane); IR (KBr) 3100-2870, 2840, 1610, 1365,
1175 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 8.02-8.06 (m, 1H),
7.93 (d, J ) 9.1 Hz, 1H), 7.84-7.89 (m, 2H), 7.79-7.84 (m,
2H), 7.63-7.70 (m, 2H), 7.51-7.59 (m, 4H), 7.47-7.50 (m, 1H),
7.30-7.35 (m, 1H), 7.21-7.26 (m, 1H), 7.02 (d, J ) 2.6 Hz,
1H), 6.92 (dd, J ) 9.1, 2.6 Hz, 1H), 6.43 (s, 1H), 6.39 (s, 1H),
4.84 (s, 2H), 3.73 (s, 3H). Anal. Calcd for C30H24N2O5S2
(556.66): C, 64.73; H, 4.35; N, 5.03. Found: C, 64.65; H, 4.70;
N, 5.09.
1H-2-In d olyl (5-Meth oxy-1H-2-in d olyl) Keton e (15). The
phenylsulfonyl groups of 13 (1.00 g, 1.75 mmol) were removed
as described for compound 7. Column chromatography (CH2-
Cl2) afforded yellow crystals (0.38 g, 1.31 mmol, 75%): mp
233-235 °C (MeOH); IR (KBr) 3395, 3100-2900, 2840, 1665,
1
Bis(1H-2-in d olyl)m eth a n e (10). Meth od A. A solution of
8 (15.0 g, 28.5 mmol) and K2CO3 (20.0 g) in methanol (800
mL) and H2O (200 mL) was heated to reflux for 14 d. Then
brine (500 mL) and CH2Cl2 (500 mL) were added, and the
organic phase was separated. The aqueous phase was ex-
tracted with CH2Cl2 (2 × 200 mL). After drying of the organic
phase over Na2SO4, the solvent was removed. The crude
product was purified by column chromatography (CH2Cl2/ethyl
acetate 1:1), yielding 10 as colorless crystals (5.40 g, 21.9 mmol,
76%): mp 168 °C (diethyl ether/petroleum ether); IR (KBr)
1440 cm-1; H NMR (250 MHz, DMSO-d6) δ 9.30 (br s, 1H),
9.23 (br s, 1H), 7.04-7.56 (m, 9H), 3.88 (s, 3H). Anal. Calcd
for C18H14N2O2 (290.32): C, 74.47; H, 4.86; N, 9.95. Found:
C, 74.29; H, 4.90; N, 10.06.
1H -2-In d olyl-(5-m et h oxy-1H -2-in d olyl)m et h a n e (16).
Compound 16 was obtained from ketone 15 (0.35 g, 1.21 mmol)
using method B (cf. reduction of ketone 9). The crude product
was purified by column chromatography (CH2Cl2), yielding 16
as colorless crystals (0.28 g, 1.01 mmol, 84%): mp 112 °C
(MeOH); IR (KBr) 3400, 3150-2950, 2840, 1620, 1450 cm-1
;
1
3375, 3150-2950, 1455 cm-1; H NMR (250 MHz, DMSO-d6)
1H NMR (90 MHz, CDCl3) δ 7.68 (br s, 2H, exchangeable),
6.50-7.27 (m, 7H), 6.36 (s, 1H), 6.32 (s, 1H), 4.17 (s, 2H), 3.80
(s, 3H). Anal. Calcd for C18H16N2O (276.34): C, 74.47; H, 4.86;
N, 9.95. Found: C, 74.37; H, 4.95; N, 9.77.
δ 10.99 (s, 2H), 7.42 (d, J ) 7.5 Hz, 2H), 7.30 (d, J ) 7.5 Hz,
2H), 6.97-7.05 (m, 2H), 6.89-6.97 (m, 2H), 6.22 (s, 2H), 4.22
(s, 2H); 13C NMR (63 MHz, DMSO-d6) δ 136.98, 136.21, 128.23,
120.29, 119.27, 118.67, 110.81, 99.50, 27.11. Anal. Calcd for
1,2-Bis(1H-2-in d olyl)eth a n e (17). To a solution of N-
trimethylsilyl-o-toluidine (2.00 g, 11.2 mmol) in dry hexane
(100 mL) was added n-BuLi (14.0 mL, 22.4 mmol, 1.6 M in
n-hexane) drop by drop at room temperature. The mixture was
refluxed overnight and then cooled to - 78 °C. At this
temperature diethyl succinate (0.97 g, 5.57 mmol), dissolved
in THF (40 mL), was added slowly. Then the mixture was
warmed to room temperature and poured into ice water (100
mL). The organic layer was separated, and the aqueous phase
was extracted with ethyl acetate (3 × 30 mL). The combined
organic extracts were dried over Na2SO4, the solvent was
evaporated, and the residue was purified by column chroma-
tography (CH2Cl2/hexane 4:1), yielding the bis-indole 17 as
colorless crystals (0.26 g, 0.99 mmol, 18%): mp 264-267 °C;
C
17H14N2 (246.31): C, 82.90; H, 5.73; N, 11.37. Found: C,
82.65; H, 5.81; N, 11.36.
Meth od B. A solution of 9 (5.00 g, 19.2 mmol), KOH (4.80
g), and hydrazine hydrate (3.50 mL) in 2-(2-hydroxyethyloxy)-
1-ethanol (50 mL) was slowly heated to 190 °C, and after 2 h
the excess hydrazine hydrate and H2O were removed by
distillation. After cooling to room temperature, H2O (50 mL)
was added, and the mixture was extracted with CH2Cl2 (2 ×
50 mL). The combined extracts were dried over Na2SO4, the
solvent was removed, and the crude product was purified by
column chromatography (see above), affording 10 (4.30 g, 17.5
mmol, 91%). See method A for characterization data.
(5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-
su lfon yl-1H-2-in dolyl)m eth an ol (12). The reaction of 1-phen-
ylsulfonyl-1H-2-indolcarbaldehyde (4)24 (2.00 g, 6.98 mmol)
with 5-methoxy-1-phenylsulfonyl-1H-indole (11)25 (1.82 g, 6.32
mmol) was effected as described for the alcohol 6. Purification
by column chromatography (CH2Cl2) yielded the alcohol 12 as
orange-yellow crystals (2.30 g, 4.03 mmol, 64%): mp 104-105
°C (CH2Cl2/hexane); IR (KBr) 3550-3240, 3130-2870, 2840,
1620, 1360, 1160 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 7.88-
8.09 (m, 6H), 7.58-7.69 (m, 2H), 7.45-7.58 (m, 5H), 7.29-
1
IR (KBr) 3394, 3048, 2911 cm-1; H NMR (250 MHz, DMSO-
d6) δ 11.00 (s, 2H), 7.40 (d, J ) 7.6 Hz, 2H), 7.29 (d, J ) 7.4
Hz, 2H), 6.91-6.99 (m, 4H), 6.19 (s, 2H), 3.16 (s, 4H); MS m/z
(%) 260 (42) [M+•]. Anal. Calcd for C18H16N2 (260.34): C, 83.04;
H, 6.19; N, 10.76. Found: C, 82.77; H, 6.31; N, 10.67.
1,3-Bis(1H-2-in d olyl)p r op a n e (18). Compound 18 was
prepared as described for the bis-indole 17 with diethyl
pentandioate (20.5 mL, 0.11 mol) and N-trimethylsilyl-o-
toluidine (38.0 g, 0.21 mol). The residue was purified by column

8136 J . Org. Chem., Vol. 64, No. 22, 1999
Mahboobi et al.
chromatography (CH2Cl2/hexane 1:1), yielding the bis-indole
18 as colorless crystals (6.55 g, 23.9 mmol, 22%): mp 143-
145 °C (ethanol); IR (KBr) 3388, 3053, 2941, 2916, 2863, 1542,
1615, 1455 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 11.59 (br s,
2H), 8.07 (d, J ) 7.6 Hz, 2H), 7.42 (d, J ) 7.6 Hz, 2H), 7.04-
7.36 (m, 4H), 4.28 (s, 2H), 3.10 (s, 3H); UV (MeOH) λmax (log ꢀ)
486 (3.70), 385 (3.50), 276 (4.08), 220 (4.44), 209 nm (4.46).
Anal. Calcd for C22H15N3O2 (353.38): C, 74.77; H, 4.28; N,
11.89. Found: C, 74.68; H, 4.39; N, 11.82.
1
1457 cm-1; H NMR (250 MHz, DMSO-d6) δ 10.91 (br s, 2H),
7.37-7.43 (m, 2H), 7.24-7.31 (m, 2H), 6.87-7.03 (m, 4H), 6.18
(d, J ) 1.6 Hz, 2H), 2.78 (t, J ) 7.3 Hz, 4H), 2.12 (quint, J )
7.3 Hz, 2H). Anal. Calcd for C19H18N2 (274.37): C, 83.18; H,
6.61; N, 10.21. Found: C, 82.94; H, 6.87; N, 10.21.
2-Met h yl-2,3,8,9,10,11-h exa h yd r o-1H -in d olo[3′,2′:5,6]-
pyr r olo[3′,4′:3,4]cycloocta[b]in dole-1,3-dion e (26a). 3-Br o-
m o-4-(2-(2-(1H -2-in d olyl)et h yl)-1H -3-in d olyl)-1-m et h yl-
2,5-d ih yd r o-1H-2,5-p yr r oled ion e (26b) a n d 3-Br om o-4-(2-
(2-(3-(4-b r o m o -1-m e t h yl-2,5-d ioxo-2,5-d ih y d r o -1H -3-
p yr r olyl)-1H-2-in d olyl)eth yl)-1H-3-in d olyl)-1-m eth yl-2,5-
dih ydr o-1H-2,5-pyr r oledion e (26c). Compounds 26a-c were
obtained when 3,4-dibromo-1-methyl-2,5-dihydro-1H-2,5-pyr-
roledione (21)28 (0.26 g, 0.96 mmol) was reacted with compound
17 (0.25 g, 0.96 mmol) under the conditions used for compound
22. The mixture of products was separated (CH2Cl2/ethyl
acetate 9:1) and further purified by column chromatography
(26a , CH2Cl2/ethyl acetate 9:1; 26b, 26c, diethyl ether).
26a : red crystals (83.0 mg, 0.23 mmol, 24%): mp >350 °C;
1,2,3,8,9,10-Hexa h yd r oin d olo[3′,2′:5,6]p yr r olo[3′,4′:3,4]-
cycloh ep ta [b]in d ole-1,3-d ion e (22). Mg shavings (0.24 g,
9.75 mmol) and ethyl bromide (0.37 mL, 4.88 mmol) were
added to dry THF (6 mL). When the reaction has started,
further ethyl bromide (0.37 mL, 4.88 mmol) was added
dropwise so that the solution was refluxing gently. Then the
solution was heated to reflux until all Mg has dissolved (ca.
30 min). After cooling to room temperature compound 10 (1.00
g, 4.06 mmol), dissolved in a mixture of dry toluene (25 mL)
and THF (1 mL), was added slowly, and the mixture was
stirred for 45 min at 45 °C. After the mixture has cooled to
room temperature, a solution of 3,4-dibromo-2,5-dihydro-1H-
2,5-pyrroledione (19)27 (1.04 g, 4.06 mmol) in dry toluene (50
mL) and THF (2 mL) was added drop by drop during 1 h, and
the resulting dark solution was heated to reflux overnight.
Then ice (100 g) and 20% citric acid (50 mL) were added, the
organic layer was separated, and the aqueous phase was
extracted with ethyl acetate (2 × 50 mL). The combined
organic phases were washed with H2O and dried over Na2-
SO4, and the solvent was evaporated. The crude product was
separated from remaining starting material and byproducts
by column chromatography (1, CH2Cl2/ethyl acetate 4:1; 2,
CH2Cl2/ethyl acetate 7:1), affording product 22 as red crystals
(0.29 g, 0.68 mmol, 17%): mp >350 °C (ethyl acetate); IR (KBr)
IR (KBr) 3410, 3349, 2931, 1692, 1626 cm-1 1H NMR (250
;
MHz, DMSO-d6) δ 11.61 (s, 2H), 7.48 (d, J ) 7.8 Hz, 2H), 7.30
(d, J ) 7.9 Hz, 2H), 6.84-7.16 (m, 4H), 3.24 (br s, 4H), 3.09
(s, 3H); MS m/z (%) 367 (100) [M+•]. Anal. Calcd for C23H17N3O2
(367.41) C, 75.19; H, 4.66; N, 11.44. Found: C, 75.38; H, 4.53;
N, 11.35.
26b: orange crystals (2.0 mg, 0.005 mmol, 0.5%): mp 169
°C (dec); IR (KBr) 3391, 2933, 1709, 1623 cm-1; FD-MS m/z
447; 449 [M+•]. Anal. Calcd for C23H18BrN3O2 (448.32) C, 61.62;
H, 4.05; N, 9.37. Found: C, 61.78; H, 4.17; N, 9.42.
26c: orange crystals (30.0 mg, 0.05 mmol, 5%): mp 179 °C
(dec); IR (KBr) 3387, 2938, 1710, 1625 cm-1 1H NMR (250
;
3385, 3100-2900, 1750, 1455 cm-1
;
1H NMR (250 MHz,
MHz, DMSO-d6) δ 11.77 (br s, 2H), 7.31-7.49 (m, 4H), 6.97-
7.20 (m, 4H), 3.16 (br s, 4H), 3.00 (s, 6H); FD-MS m/z 634;
636; 638 [M+•]. Anal. Calcd for C28H20Br2N4O4 (636.30) C,
52.85; H, 3.17; N, 8.81. Found: C, 52.80; H, 3.23; N, 8.63.
1,2,3,8,9,10,11,12-Octah ydr oin dolo[3′,2′:5,6]pyr r olo[3′,4′:
3,4]-cyclon on a [b]in d ole-1,3-d ion e (27a ) a n d 3-Br om o-4-
(2-(3-(3-(4-b r om o-2,5-d ioxo-2,5-d ih yd r o-1H -3-p yr r olyl)-
1H-2-in dolyl)pr opyl)-1H-3-in dolyl)-2,5-dih ydr o-1H-pyr r ol-
2,5-d ion e (27b). Compounds 27a and 27b were obtained from
compounds 18 (11.0 g, 0.04 mol) and 19 (5.70 g, 0.02 mol),
according to the procedure used for compound 22. The mixture
of products was separated and purified by column chromatog-
raphy (CH2Cl2/ethyl acetate 2:1).
27a : red powder (0.21 g, 0.54 mmol, 2%): mp >350 °C; IR
(KBr) 3400, 3188, 3064, 2929, 2854, 1702 cm-1; 1H NMR (250
MHz, DMSO-d6) δ 11.25 (s, 2H), 11.00 (s, 1H), 7.15-7.27 (m,
4H), 6.82-7.03 (m, 4H), 2.73-2.92 (br m, 4H), 1.95-2.10 (br
m, 2H); MS m/z (%) 367 (100) [M+•]. Anal. Calcd for C23H17N3O2
(367.41): C, 75.19; H, 4.66; N, 11.44. Found: C, 75.33; H, 4.82;
N, 11.20.
DMSO-d6) δ 11.92 (br s, 2H), 10.79 (br s, 1H), 8.03 (d, J ) 7.5
Hz, 2H), 7.41 (d, J ) 7.5 Hz, 2H), 7.03-7.16 (m, 4H), 4.27 (s,
2H); MS m/z (%) 339 (84) [M+•], 338 (100) [M - H]+; UV
(MeOH) λmax (log ꢀ) 475 (3.94), 384 (3.69), 274 (4.21), 219 nm
(4.65). Anal. Calcd for C21H13N3O2 (339.35): C, 74.24; H, 3.86;
N, 12.38. Found: C, 74.12; H, 3.63; N, 12.45.
5-Meth oxy-1,2,3,8,9,10-h exah ydr oin dolo[3′,2′:5,6]pyr r olo-
[3′,4′:3,4]cycloh ep ta [b]in d ole-1,3-d ion e (23). Compound 23
was obtained from the bis-indole 16 (0.27 g, 0.98 mmol) and
compound 19 (0.25 g, 0.98 mmol) as described for compound
22. The crude product was purified by column chromatography
(CH2Cl2/ethyl acetate 4:1) affording the product as red crystals
(35.0 mg, 0.08 mmol, 8%): mp >350 °C (EtOH); IR (KBr) 3380,
3100-2950, 2840, 1705, 1450 cm-1 1H NMR (250 MHz,
;
DMSO-d6) δ 11.89 (br s, 1H), 11.78 (br s, 1H), 10.79 (br s, 1H),
8.04 (d, J ) 7.5 Hz, 1H), 7.61 (d, J ) 7.5 Hz, 1H), 6.68-7.46
(m, 5H), 4.24 (s, 2H), 3.75 (s, 3H); MS m/z (%) 369 (97) [M+•],
368 (100) [M - H]+. Anal. Calcd for C22H15N3O3 (369.38): C,
72.12; H, 4.09; N, 11.38. Found: C, 72.31; H, 3.95; N, 11.52.
2-Ben zyloxym eth yl-1,2,3,8,9,10-h exa h yd r oin d olo[3′,2′:
5,6]p yr r olo[3′,4′:3,4]cycloh ep ta [b]in d ole-1,3-d ion e (24).
Compound 24 was obtained from the indole derivative 10 (4.00
g, 16.2 mmol) and 1-benzyloxymethyl-3,4-dibromo-2,5-dihydro-
1H-2,5-pyrroledione (20)29 (6.12 g, 16.3 mmol) as described for
compound 22. The crude product was purified by column
chromatography (CH2Cl2/ethyl acetate 9:1), affording 24 as
dark red crystals (2.30 g, 5.00 mmol, 31%): mp 288-290 °C
(CH2Cl2/hexane); IR (KBr) 3385, 3100-2900, 1740, 1705, 1455
27b: orange powder (4.80 g, 7.72 mmol, 38%): mp >350
°C; IR (KBr) 3217, 3056, 2929, 1719 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 11.68 (s, 2H), 11.36 (s, 2H), 7.29-7.42 (m, 2H),
6.74-7.25 (m, 6H), 2.70-2.90 (br m, 4H), 1.99-2.17 (br m,
2H). Anal. Calcd for C27H18Br2N4O4 (622.28): C, 52.12; H, 2.92;
N, 9.00. Found: C, 51.89; H, 3.11; N, 8.87.
3-Br om o-4-(2-(4-(3-(4-br om o-1-m eth yl-2,5-d ioxo-2,5-d i-
h yd r o-1H-3-p yr r olyl)-1H-2-in d olyl)bu tyl)-1H-3-in d olyl)-
1-m eth yl-2,5-d ih yd r o-1H-2,5-p yr r oled ion e (29). A solution
of 1,2-bis(1H-2-indolyl)butane (28)21 (8.05 g, 28.0 mmol) in dry
THF (100 mL) was cooled to 0 °C, and n-BuLi (42.0 mL, 67.2
mmol, 1.6 M in n-hexane) was added drop by drop. The
solution was stirred for 1 h at this temperature, then 3,4-
dibromo-1-methyl-2,5-dihydro-1H-2,5-pyrroledione (21)28 in
THF (100 mL) was added. The mixture was stirred at room
temperature overnight, then 2 N HCl (250 mL) was added.
The aqueous phase was extracted with ethyl acetate (3 × 100
mL). The combined organic extracts were dried over Na2SO4,
the solvent was evaporated, and the residue was purified by
column chromatography (CH2Cl2/ethyl acetate 9:1), yielding
compound 29 as a red powder (9.37 g, 14.1 mmol, 50%): mp
1
cm-1; H NMR (250 MHz, DMSO-d6) δ 12.00 (br s, 2H), 8.09
(d, J ) 7.4 Hz, 2H), 7.07-7.56 (m, 11H), 5.15 (s, 2H), 4.69 (s,
2H), 4.29 (s, 2H); MS m/z (%) 459 (10) [M+•]; UV (MeOH) λmax
(log ꢀ) 481 (3.52), 339 (3.49), 277 (3.84), 223 (4.26), 208 nm
(4.32). Anal. Calcd for C29H21N3O3 (459.50): C, 75.80; H, 4.61;
N, 9.14. Found: C, 75.86; H, 4.76; N, 8.91.
2-Meth yl-1,2,3,8,9,10-h exah ydr oin dolo[3′,2′:5,6]pyr r olo-
[3′,4′:3,4]cycloh ep ta [b]in d ole-1,3-d ion e (25). Compound 25
was obtained from the indole derivative 10 (10.0 g, 28.3 mmol)
and 3,4-dibromo-1-methyl-2,5-dihydro-1H-2,5-pyrroledione (21)28
(10.98 g, 40.8 mmol) as described for compound 22. The crude
product was purified by column chromatography (CH2Cl2/ethyl
acetate 9:1), affording 25 as red crystals (4.50 g, 11.3 mmol,
40%): mp >350 °C (EtOH); IR (KBr) 3400, 3100-2900, 1760,
1
190 °C (dec); IR (KBr) 3398, 1769, 1709 cm-1; H NMR (250
MHz, DMSO-d6) δ 11.70 (s, 2H), 6.99-7.38 (m, 8H), 3.00 (s,

Homoarcyriaflavin
J . Org. Chem., Vol. 64, No. 22, 1999 8137
6H), 2.66-2.82 (m, 4H), 1.68-1.83 (m, 4H); MS m/z (%) 504
(20) [M - 2 Br]+•, 156 (100). Anal. Calcd for C30H24Br2N4O4
(664.4): C, 54.24; H, 3.64; N, 8.43. Found: C, 54.34; H, 3.76;
N, 8.39.
column chromatography (CH2Cl2/MeOH 9:1), affording 32 as
red crystals (0.90 g, 2.10 mmol, 89%): mp >350 °C (MeOH);
1
IR (KBr) 3430, 3100-2900, 1850, 1750, 1440, 1040 cm-1; H
NMR (250 MHz, DMSO-d6) δ 12.80 (br s, 1H), 8.00-8.05 (m,
2H), 7.82 (d, J ) 8.1 Hz, 1H), 7.48 (d, J ) 7.1 Hz, 1H), 7.11-
7.33 (m, 4H), 4.93 (t, J ) 7.7 Hz, 2H), 4.50 (s, 2H), 3.51 (t, J
) 7.8 Hz, 2H), 2.51 (s, 6H); MS m/z (%) 411 (8) [M+•]; UV
(MeOH) λmax (log ꢀ) 477 (4.44), 386 (3.26), 351 (3.49), 286 (3.70),
260 (3.54), 223 (4.07), 207 nm (4.05). Anal. Calcd for C25H21N3O3‚
H2O (429.48): C, 69.92; H, 5.40; N, 9.78. Found: C, 69.56; H,
5.68; N, 9.37.
2-Ben zyloxym et h yl-8-(2-(N,N-d im et h yla m in o)et h yl)-
1,2,3,8,9,10-h exa h yd r oin d olo[3′,2′:5,6]p yr r olo[3′,4′:3,4]cy-
cloh ep ta [b]in d ole-1,3-d ion e (30). NaH (80% in paraffin oil)
(0.42 g, 3.92 mmol) was suspended in dry DMF (15 mL),
compound 24 (0.60 g, 1.31 mmol) was added, and the resulting
mixture was stirred for 30 min at room temperature. Then a
solution of 1-chloro-2-(N,N-dimethylamino)ethane (80.7 mg,
0.75 mmol) (freshly prepared from 1-chloro-2-(N,N-dimethyl-
amino)ethane hydrochloride35) in DMF (5 mL) was added drop
by drop, and the mixture was stirred for 4.5 h at 40 °C. After
2 and 4 h, further 1-chloro-2-(N,N-dimethylamino)ethane (each
time 30.0 mg, 0.28 mmol, see above) was added. This addition
in portions increases the yield of compound 30. Then saturated
NaHCO3 solution (15 mL) was added, and the resulting
mixture was extracted with CH2Cl2 (3 × 50 mL). The combined
organic phases were washed with H2O (100 mL) and dried over
Na2SO4, and the solvent was evaporated. The crude product
was purified by column chromatography (toluene/isopropy-
lamine 4:1), affording pure 30 as red crystals (0.30 g, 0.53
mmol, 41%): mp 164-165 °C (MeOH); IR (KBr) 3560, 2939,
1698, 1459 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 11.88 (br s,
1H), 8.05 (d, J ) 8.9 Hz, 1H), 8.01 (d, J ) 8.2 Hz, 1H), 7.55 (d,
J ) 8.1 Hz, 1H), 7.47 (d, J ) 7.3 Hz, 1H), 7.07-7.41 (m, 9H),
5.16 (s, 2H), 4.69 (s, 2H), 4.50 (t, J ) 6.5 Hz, 2H), 4.26 (s, 2H),
2.57 (t, J ) 6.5 Hz, 2H), 2.26 (s, 6H); MS m/z (%) 530 (6) [M+•];
UV (MeOH) λmax (log ꢀ) 483 (3.65), 388 (3.49), 277 (3.95), 207
nm (4.49). Anal. Calcd for C33H30N4O3‚MeOH (562.67): C,
72.58; H, 6.09; N, 9.96. Found: C, 72.19; H, 6.17; N, 9.97.
8-(2-(N,N-Dim eth yla m in o)eth yl)-2-m eth yl-1,2,3,8,9,10-
h exa h yd r oin d olo[3′,2′:5,6]p yr r olo[3′,4′:3,4]cycloh ep ta [b]-
in d ole-1,3-d ion e (31). Compound 31 was obtained from
compound 25 (2.00 g, 5.66 mmol) as described for compound
30, affording the product as red crystals (1.30 g, 2.95 mmol,
52%): mp 185 °C (MeOH); IR (KBr) 3390, 3100-2900, 1750,
1610, 1460 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 11.84 (br s,
1H), 8.06 (d, J ) 7.7 Hz, 1H), 8.02 (d, J ) 7.8 Hz, 1H), 7.53 (d,
J ) 7.6 Hz, 1H), 7.46 (d, J ) 7.6 Hz, 1H), 7.01-7.24 (m, 4H),
4.48 (t, J ) 6.8 Hz, 2H), 4.25 (s, 2H), 3.11 (s, 3H), 2.62 (t, J )
6.8 Hz, 2H), 2.26 (s, 6H); MS m/z (%) 424 (4) [M+•]; UV (MeOH)
λmax (log ꢀ) 486 (3.68), 358 (3.49), 277 (4.05), 207 nm (4.51).
Anal. Calcd for C26H24N4O2‚MeOH (440.52): C, 72.25; H, 5.95;
N, 12.72. Found: C, 72.60; H, 6.08; N, 12.68.
8-(2-(N,N-Dim et h yla m in o)et h yl)-1,2,3,8,9,10-h exa h y-
d r oin d olo[3′,2′:5,6]p yr r olo[3′,4′:3,4]cycloh ep ta [b]in d ole-
1,3-d ion e (33). Meth od A. A suspension of compound 30 (0.30
g, 0.57 mmol) and 5% Pd/C (0.60 g) in dry ethanol (200 mL)
was stirred for 7 d at a H2 pressure of 20 bar. When the
reaction was complete (TLC control) the catalyst was filtered
off through Celite, the filter was washed with CH2Cl2 (100 mL),
and the solvent was removed. The crude product was dissolved
in THF (40 mL), the solution was cooled to 0 °C, and NH3 was
bubbled through the solution29,30 for 10 min. After stirring for
2 h at room temperature, the solvent was removed, and the
residual oil was purified by column chromatography (toluene/
ethyl acetate 4:1), yielding 33 as red crystals (9.0 mg, 0.02
mmol, 3%): mp 213-214 °C (EtOH); IR (KBr) 3203, 2964,
1750, 1699, 1463 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 11.84
(br s, 1H), 11.82 (br s, 1H), 8.04 (d, J ) 7.5 Hz, 1H), 8.01 (d,
J ) 7.7 Hz, 1H), 7.52 (d, J ) 8.1 Hz, 1H), 7.44 (d, J ) 8.1 Hz,
1H), 7.04-7.23 (m, 4H), 4.50 (t, J ) 6.7 Hz, 2H), 4.24 (s, 2H),
2.61 (t, J ) 6.7 Hz, 2H), 2.22 (s, 6H); MS m/z (%) 410 (6) [M+•];
UV (MeOH) λmax (log ꢀ) 474 (3.69), 385 (3.49), 285 (3.98), 277
(3.97), 223 (4.44), 208 nm (4.46). Anal. Calcd for C25H22N4O2‚
EtOH (456.54): C, 71.03; H, 6.18; N, 12.27. Found: C, 71.38;
H, 5.86; N, 12.40.
Meth od B. A mixture of 32 (0.90 g, 2.19 mmol) and
ammonium acetate (30.0 g) was melted and stirred at 140 °C
for 1 h. After cooling of the mixture to room temperature,
saturated NaHCO3 solution (50 mL) and CH2Cl2 (50 mL) were
added, the phases were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL). The combined extracts
were dried over Na2SO4, the solvent was removed, and the
crude product was purified as described above, affording 33
(0.10 g, 0.22 mmol, 10%).
Ack n ow led gm en t. The authors wish to thank Prof.
Dr. K.-J . Range and Dr. M. Zabel, University of Re-
gensburg, for the X-ray crystallographic analysis of
compound 31, and I. Dechant and H. Reindl for some
experimental support.
8-(2-(N,N-Dim et h yla m in o)et h yl)-3,8,9,10-t et r a h yd r o-
1H-in d olo[3′,2′:5,6]fu r o[3′,4′:3,4]-cycloh ep ta [b]in d ole-1,3-
d ion e (32). A solution of 31 (1.00 g, 2.36 mmol) in EtOH (340
mL) and 5 N KOH (60 mL) was stirred overnight at room
temperature. After acidifying the solution with 2 N HCl to pH
) 7, the mixture was extracted with CH2Cl2 (2 × 50 mL). The
combined organic phases were dried over Na2SO4, and the
solvent was evaporated. The crude product was purified by
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for 31. This material is available free of charge via the
Internet at http://pubs.acs.org.
(35) Hickmott, R. W.; Wood, S.; Murray-Rust, P. J . Chem. Soc.,
Perkin Trans. 1 1985, 2033-2038.
J O981926G