Open analogues of arcyriaflavin A. Synthesis through Diels-Alder reaction between maleimides and 1-aryl-3-tert-butyldimethylsiloxy-1,3- butadienes

Article abstract of DOI:10.1021/jo991815x

The preparation of a range of open analogues of arcyriaflavin A is described. The synthetic approach is based on the use of perhydroisoindole- 1,3,5-triones as key intermediates, which were obtained via Diels-Alder methodology using 1-aryl-3-siloxy-1,3-butadienes as starting materials. Fischer indolization and aromatization processes afforded different methoxy- substituted arylpyrrolocarbazoles. The stereochemistry and conformation of the Diels-Alder products and the regiochemistry of the indolization reactions are supported by NMR and molecular modeling studies.

Full text of DOI:10.1021/jo991815x

J . Org. Chem. 2000, 65, 3387-3394
3387
Op en An a logu es of Ar cyr ia fla vin A. Syn th esis th r ou gh Diels-Ald er
Rea ction betw een Ma leim id es a n d
1-Ar yl-3-ter t-bu tyld im eth ylsiloxy-1,3-bu ta d ien es
Marta Adeva, Heidi Sahagu´n, Esther Caballero, Rafael Pela´ez-Lamamie´ de Clairac,
Manuel Medarde,* and Fernando Tome´*
Laboratorio de Quı´mica Orga´nica y Farmace´utica, Universidad de Salamanca, Facultad de Farmacia,
Campus Miguel de Unamuno, E-37007 Salamanca, Spain
Received November 23, 1999
The preparation of a range of open analogues of arcyriaflavin A is described. The synthetic approach
is based on the use of perhydroisoindole-1,3,5-triones as key intermediates, which were obtained
via Diels-Alder methodology using 1-aryl-3-siloxy-1,3-butadienes as starting materials. Fischer
indolization and aromatization processes afforded different methoxy-substituted arylpyrrolocar-
bazoles. The stereochemistry and conformation of the Diels-Alder products and the regiochemistry
of the indolization reactions are supported by NMR and molecular modeling studies.
In tr od u ction
There is a growing interest in the preparation of
analogues of indolocarbazole alkaloids, aimed at modu-
lating the biological properties of these natural products.
Staurosporine and rebeccamycin, isolated from Strepto-
myces staurosporeus1 and Saccharotrix aerocolonigenes,
respectively,2 are representative members of this family
and display noteworthy cytotoxicity due to the inhibition
of protein kinase C (PKC)3 or mammalian topoisomerase
I.4 A broad variety of related compounds has been
obtained from broth cultures and either by semisynthesis
or total synthesis,5 taking the natural products arcyri-
aflavin A6 and staurosporine aglycon as the simplest
models. At first sight, slight structural variations change
the molecular mechanism of their biological activities7
(mainly PKC or topoisomerase I inhibition and DNA
intercalation). Among them, NB-506, a topoisomerase I
inhibitor, is currently undergoing clinical trials as an
antitumor agent.8
With a view to synthesizing new analogues of the
aforementioned molecules, we recently began a research
line aimed at the preparation of open analogues of
rebeccamycin or staurosporine aglycons, leading to the
final compound shown in Scheme 1, which exhibits
promising cytotoxicity against nonsmall cell lung and
breast cancer cell lines.9 Our approach to the synthesis
of that compound was based on the retrosynthetic
analysis depicted below (Scheme 1), through the prepara-
tion of 7-phenylperhydroisoindole-1,3,5-triones as key
intermediates en route to pyrrolocarbazoles,10 which were
subsequently obtained by Fischer indolization. Consider-
able efforts have been devoted to synthesizing arcyri-
aflavin A,11 staurosporine,12 rebeccamycin,13 and other
indolocarbazoles,14 but there are few references concern-
ing the synthesis of analogues with structures similar
* To whom correspondence should be addressed. E-mail: medarde@
gugu.usal.es; frena@gugu.usal.es. Phone: 34-923-294528. Fax: 34-923-
294515.
(1) (a) O¨ mura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J .;
Tsuchiya, H.; Takahashi, Y.; Masuma, R. J . Antibiot. 1977, 30, 275.
(b) O¨ mura, S.; Sasaki, Y.; Iwai, Y.; Takeshima, H. J . Antibiot. 1995,
48, 535.
(2) Nettleton, D. E.; Doyle, T. W.; Kirshnan, B.; Matsumoto, G. K.;
Clardy, J . Tetrahedron Lett. 1985, 25, 4011.
(3) (a) Tamaoki, T. Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto,
M.; Tomita, F. Biochem. Biophys. Res. Commun. 1986, 135, 397. (b)
Ruegg, U. T.; Burgess, G. M. Trends Pharmacol. Sci. 1989, 10, 218.
(c) Takagi, A.; Yamada Mizutani, M.; Tomioka, N.; Itai, A. Chem.
Pharm. Bull. 1996, 44, 618.
(4) (a) Yamashita, Y.; Fujii, N.; Murkata, C.; Ashizawa, T.; Okabe,
M.; Nakano, H. Biochemistry 1992, 31, 12069. (b) Rodrigues-Pereira,
E.; Belin, L.; Sancelme, M.; Prudhomme, M.; Ollier, M.; Rapp, M.;
Serve`re, D.; Riou, J . F.; Fabbro, D.; Meyer, T. J . Med. Chem. 1996,
39, 4471.
(5) For a survey of this class of compounds, see: (a) Bergman, J .
Stud. Nat. Prod. Chem., Part A 1988, 1, 3. (b) Gribble, G. W.; Berthel,
S. J . Stud. Nat. Prod. Chem. 1993, 12, 365. (c) Steglich, W. Fortschs.
Chem. Org. Naturst. 1987, 51, 216.
(8) (a) Yoshinari, T.; Matsumoto, M.; Arakawa, H.; Okada, H.;
Noguchi, K.; Suda, H.; Okura, A.; Nishimura, S. Cancer Res. 1995,
55, 1310. (b) Arakawa, H.; Iguchi, T.; Morita, M.; Yoshinari, K.; Suda,
A.; Okura, A.; Nishimura, S. Cancer Res. 1995, 55, 1316. (c) Ohe, Y.;
Tanigawara, Y.; Fujii, H.; Ohtsu, T.; Wakita, H.; Igarashi, T.; Minami,
H.; Eguchi, K.; Shinkai, T.; Tamura, T.; Kunotoh, H.; Saijo, N.; Okada,
K.; Ogino, H.; Sasaki, Y. Proc. ACSO 1997, 16, 199a.
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Chem., Int. Ed. Engl. 1980, 19, 459.
(7) (a) Reference 4b. (b) Qatsha, K. A.; Rudolph, C.; Marme´, D.;
Scha¨chtele, C.; May, W. S. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 4674.
(c) Anizon, F.; Belin, L.; Moreau, P.; Sancelme, M.; Voldoire, A.;
Prudhomme, M.; Ollier, M.; Seve`re, D.; Riou, J . F.; Bailly, C.; Fabbro,
D.; Meyer, T. J . Med. Chem. 1997, 40, 3456.
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H.; Tome´, F. Bioorg. Med. Chem. Lett. 1996, 6, 2459.
(10) Bryan Reed, G. W.; Cheng, P. T. W.; McLean, S. Can. J . Chem.
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10.1021/jo991815x CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000

3388 J . Org. Chem., Vol. 65, No. 11, 2000
Adeva et al.
Sch em e 1
methoxy- and dimethoxyphenyldienes were chosen as
reagents for the Diels-Alder reaction because these
residues confer a lipophilic character to several antitumor
compounds, which act through different mechanisms:
topoisomerase inhibitors,20 antitubulin agents,21 and
antimetabolites.22 Thus, starting from dimethoxy- or
trimethoxybenzaldehydes, the unsaturated ketones 1
were prepared by Claisen-Schmidt condensation with
acetone (which also yields minor amounts, e10%, of
double condensation products 2), followed by treatment
with tert-butyldimethylsilyltriflate to produce, in good
yield (g80%, two steps), tert-butyldimethylsiloxydienes
3,23 bearing 3,4,5-trimethoxy-, 2,5-dimethoxy-, and 3,4-
dimethoxyphenyl moieties (Scheme 2).
The Diels-Alder reactions between dienes 3 and
maleimides (R ) Ph, Me, or H) were carried out at rt in
benzene, yielding reaction products 4a -i, which were
hydrolyzed by acidic treatment (HCl-CH2Cl2) to cyclo-
hexanones 5a -i and then purified by ether insolubiliza-
tion. As we reported in our preliminary communication
about the synthesis of our lead compound in Scheme 1,9
the Diels-Alder reaction mainly yields the endo products
4a -i. In some cases, a minor reaction product was
to these described in this paper. Three of these ap-
proaches also use Diels-Alder methodology. In Moody’s
synthesis of the staurosporine aglycon,15 an intramolecu-
lar cycloaddition between an alkyne and a pyranoin-
dolone yielded an open 4-phenylpyrrolo[3,4-c]carbazole
analogue, a synthetic precursor of the target substance
finally obtained via nitrene insertion. Starting from a C-4
ester of a pyridazino[4,5-b]indole, a similar approach to
the same target has recently been reported.16 Finally, the
Hoffman-La Roche group has developed a strategy based
on the use of maleimides as dienophiles and 2-vinyl-N-
alkyl-substituted indoles as dienes, for the final Diels-
Alder step in its synthesis, leading to 4-heteroarylpyrrolo-
[3,4-c]carbazoles17 (which show cytotoxicity through PKC
inhibition). Further examples of the design and synthesis
of this kind of analogues is a series of pyrrolo[3,4-c]-
carbazoles (some of them with thrombopoietic activity)18
and the formation of 4-(1-aminophenyl)pyrrolo[3,4-c]-
carbazoles by heating bisindolyl maleimides in toluene.19
Here we report the results obtained by application of
our synthetic methodology for the preparation of new
analogues of arcyriaflavin A and the rebeccamycin ag-
lycon. Different substitution patterns on the F ring, the
imide N-atom, and the A ring are readily introduced by
the use of different starting benzaldehydes, N-substituted
maleimides, or hydrazine derivatives, respectively.
1
observed in the H NMR spectra of the crude of reaction,
which was then assumed to be the exo product, although
it was never isolated as the silyl enol ether 4 or as the
cyclohexanone 5.
Due to the conformational flexibility of the cis-fused
1
systems, the H NMR spectra were difficult to interpret,
and further evidence of the stereochemical outcome of
the reaction was needed. Consequently, a theoretical
study and extensive NMR experiments were performed.
For this purpose, the transition states leading to the
diastereomeric endo and exo Diels Alder adducts were
modeled by means of a systematic Monte Carlo confor-
mational search, followed by energy minimization using
the MM2 force field with the parameter set for the Diels-
Alder reaction derived by Houk et al.24 The differences
in the heats of formation for the diastereomeric transition
state pairs (typically 2-9 kJ /mol in favor of the endo
transition state; e.g., 5.4 kJ /mol for the reaction leading
to 4d ) suggested that the proposed endo products are the
major kinetic reaction products, in good qualitative
agreement with the interpretation of the experimental
results. The stereochemical course of the reaction was
also confirmed by comparing the NMR data derived from
the minimal energy conformations of the hydrolysis
products with those observed experimentally (see below).
Resu lts a n d Discu ssion
We followed the general sequence depicted in Scheme
1 to prepare a broad variety of pyrrolocarbazoles. Tri-
(12) (a) Link, J . T.; Raghavan, S.; Danishefsky, S. J . J . Am. Chem.
Soc. 1995, 117, 552. (b) Wood, J . L.; Stoltz, B. M.; Goodman, S. N.;
Onwueme, K. J . Am. Chem. Soc. 1997, 119, 9652.
(13) Kaneko, T.; Wong, H.; Okamoto, K. T.; Clardy, J . Tetrahedron
Lett. 1985, 26, 4015. (b) Gallant, M.; Link, J . T.; Danishfesky, S. J . J .
Org. Chem. 1993, 58, 343. (c) Faul, M. M.; Winneroski, L. L.; Krumrich,
C. A. J . Org. Chem. 1999, 64, 2465.
(14) (a) References 4b , 5a,b, and 6c. (b) Kleinschroth, J .; Harten-
stein, J .; Rudolph, C.; Scha¨chtele, C. Bioorg. Med. Chem. Lett. 1995,
5, 55. (c) Ohkubo, M.; Kojiri, K.; Kondo, H.; Tanaka, S.; Kawamoto,
H.; Nishimura, T.; Nishimura, I.; Yoshinari, T.; Arakawa, H.; Suda,
H.; Morishima, H.; Nishimura, S. Bioorg. Med. Chem. Lett. 1999, 9,
1219.
Initially, each hydrogen atom of these molecules was
assigned by two-dimensional NMR correlations and 1D
(20) (a) J ardine, I. Podophyllotoxins. In Anticancer Agents Based
on Natural Products Models; Academic Press: Orlando, 1980. (b) Issell,
B. F., Muggia, F. M., Carter, S. K., Eds. Etoposide (VP-16), current
status and new developments; Academic Press: Orlando, 1984. (c)
Sta¨helin, H.; Wartburg, A.-v. From Podophyllotoxin glucoside to
Etoposide. Progress Drug Res. 1989, 33, 169.
(21) (a) Cushman, M.; Nagarathnam, D.; Gopal, D.; He, H.-M.; Lin,
C. M.; Hamel, E. J . Med. Chem. 1992, 35, 2293. (b) Hodgson, S. T.;
J enkins, D. C.; Knick, V.; Rapson, E.; Watts, S. D. Bioorg. Med. Chem.
Lett. 1992, 2, 1257.
(15) Moody, C. J .; Rahimtoola, K. F.; Porter, B.; Ross, B. C. J . Org.
Chem. 1992, 57, 2105.
(16) Nomak, R.; Snyder, J . K. 216th ACS National Meeting (Boston,
MA), Abstracts-Division of Org. Chem. 1998, Communication 543.
(17) Broka, C. A. (Hoffman-La Roche A.-G.) Eur. Patent 695755,
1996; Chem. Abstr. 1996, 124, 289516.
(18) Ikuina, Y.; Kanai, F.; Shiotsu, Y.; Iida, T.; Yamashita, K.;
Saitoh, Y.; Akinaga, S.; Tamaoki, T.; Murakata, C. 217th ACS National
Meeting (Anaheim, CA), Abstracts-Division of Med. Chem. 1999,
Communication 089.
(22) (a) Elslager, E. F.; J ohnson, J . L.; Werbel, L. M. J . Med. Chem.
1983, 26, 1753. (b) Maronn, J . Semin. Oncol. 1988, 15 (Suppl. 2), 17.
(c) Roth, B.; Baccanari, D. P.; Sigel, C. W.; Hubbell, J . P.; Eady, J .;
Kao, J . C.; Grace, M. E.; Rauckman, B. S. J . Med. Chem. 1988, 31,
122.
(23) Adeva, M.; Caballero, E.; Garc´ıa, F.; Medarde, M.; Sahagu´n,
H.; Tome´, F. Tetrahedron Lett. 1997, 38, 6893.
(24) Raimondi, L.; Brown, F. K.; Gonza´lez, J .; Houk, K. N. J . Am.
Chem. Soc. 1992, 114, 4796.
(19) Steglich, W. Pure Appl. Chem. 1989, 61, 281.

Open Analogues of Arcyriaflavin A
J . Org. Chem., Vol. 65, No. 11, 2000 3389
Sch em e 2a
F igu r e 1. Most stable conformations of ketones 5 as deduced
from NMR and MM.
F igu r e 2. Hydrazones 10 and hydroxy derivatives 11 obtained
from ketones 5. Most stable conformation of compounds
11a ,d ,g.
boat conformation (B) as compared to the chair confor-
mation (A), for this series of compounds. The stabilization
due to the interaction between the aromatic moieties in
compounds 5a and 5g is counterbalanced by the higher
steric hindrance of the methoxy group in position 2′ of
compound 5d (R1 ) OCH3), accounting for the shift in
the stability from the chair conformation, A, to the boat
conformation, B. The absence of stabilization due to the
presence of the phenyl group on the imide nitrogen is in
agreement with the lower stability of the chair conforma-
tion A in compounds 5b,c,e,f,h ,i.
a
Key: (i) acetone, NaOH, rt; (ii) TBDMSTf, Et3N, CH2Cl2, rt;
(iii) C6H6, rt; (iv) H+, CH2Cl2; (v) p-MeO-C6H4-NH-NH2‚HCl,
HOAc/EtOH 1:1, reflux; (vi) DDQ, C6H6, rt.
NOE experiments, which unequivocally indicated their
stereochemistries. The NOE experiments for the ketone
5a , carrying a phenyl substituent on the imide nitrogen,
revealed a noticeable effect between H4R/H2′, which
requires a chair conformation A (Figure 1). The chair was
also found to be the most stable conformation of 5a , the
difference being 3.5 kJ /mol, in the molecular mechanics
calculations. Compound 5g also showed NOEs between
Despite all the NMR and modeling evidence, definitive
confirmation of the endo geometry was still needed for
the ketones obtained by hydrolysis of the Diels-Alder
products. Hydrazones 10 were prepared in order to obtain
crystalline products, but it was not possible to isolate
crystals of sufficient quality for X-ray diffraction studies,
and their NMR spectra were also inconclusive. Fortu-
nately, alcohols 11 obtained by NaBH4/MeOH treatment
of 5 showed fully resolved multiplets in the 1H NMR
spectra, with larger vicinal coupling constants charac-
teristic of a chair conformation (11a ,d ,g: J 3a,4R ) 12.8
Hz; J 3a,4â ) 4.4 Hz; J 3a,7a ) 4.4 Hz; J 4R,4â ) 12.4 Hz; J 4R,5
) 12.4 Hz; J 4â,5 ) 4.4 Hz; J 5,6R ) 12.0 Hz; J 5,6â ) 2.1 Hz;
H
4R/H2′ although an additional NOE between H7â/H4â,
which requires a boat conformation as depicted in B
(Figure 1) to bring these hydrogens together, was also
observed. These NOEs can be explained in terms of an
equilibrium between the chair (A) and boat (B) conforma-
tions, in agreement with the similar stability calculated
for both conformations of 5g.
For imides without an N-phenyl substituent (5b,e,h ,
R ) Me; 5c,f,i, R ) H) and for the 2,5-dimethoxyphenyl
derivative (5d , R ) Ph, Ar2), the aforementioned NOE
between the H4R and H2′ was not observed in agreement
with the greater stability (g7 kJ /mol) calculated for the
J 6R,6â ) 12.0 Hz; J 6R,7 ) 12.5 Hz; J 6â,7 ) 4.4 Hz; J 7,7a )
4.2 Hz). The NOE studies also supported the structure
and conformation depicted in Figure 2 for alcohols 11
({H3a}: H7a, H4â; {H4â}: H3a, H5â; {H5â}: H7, H3a, H4â, H6â;
{H6R}: H2′, H4R; {H6â}: H2′, H5â, H7, H6R; {H7}: H2′, H3a
,

3390 J . Org. Chem., Vol. 65, No. 11, 2000
Ta ble 1. Resu lts of th e Diels-Ald er Rea ction u n d er Differ en t Con d ition s
Adeva et al.
entry
solvent
CH2Cl2
Ta
reagentsa R ) Ph (time)
products (yield,b %)
reagentsa R ) Me (time)
products (yield,b %)
1
2
3
4
5
6
7
8
9
-10 °C
Ar1 (20 d)
Ar3 (20 d)
Ar1 (3 d)
Ar2 (3 d)
Ar3 (3 d)
Ar1 (2 d)
Ar3 (2 d)
Ar3 (3 d)
Ar1 (2 d)
Ar3 (2 d)
Ar1 (5 h)
Ar1 (2 h)
4a (>90)
4g (>90)
4a (>95)
4d (>95)
4g (>95)
4a (>95)
4g (>95)
4g (>95)
4a (>95)
4g (>95)
4a (>85)
4a f 12a (>85)
Ar1 (40 d)
Ar3 (20 d)
Ar1 (4 d)
Ar2 (3 d)
Ar3 (3 d)
Ar1 (2 d)
4b (>70)
4g (>90)
4b (>95)
4e (>95)
4h (>95)
4b (>95)
benzene
xylene
rt
rt
CH2Cl2
DMF
rt
rt
Ar1 (2 d)
4b (>95)
10
11
12
benzene
xylene
reflux
reflux
Ar1 (5 h)
Ar1 (2 h)
4b (>85)
4b (>85)
13
Ar3 (2 h)
Ar1 (5 h)
4g f 12g (>65)
14
15
CH2Cl2
DMF
reflux
reflux
4a + 12a
Ar1 (5 h)
4b (>90)
(30+70)
Ar3 (5 h)
Ar1 (2 h)
4 g (>90)
Ar3 (5 h)
Ar1 (2 h)
4h (>90)
4b f 12b (>65)
16
4a f 12a (>85)
17
Ar3 (2 h)
12g (>65)
a
b
Maleimide (R ) Ph or Me) and diene 3 (Ar). Yields are deduced from 1H NMR of crude reaction products.
H
5â, H6â; {H7a}: H2′, H3a; {H2′}: 3′-OCH3, H6R, H7, H7a),
and the calculated minimal energy conformations are also
in good agreement with the NMR data.
The imide ring opening, leading to compounds 11,
might result from the attack of the methanol used as
solvent. The cis-fused imide ring of compounds 5a ,d ,g
was no longer present, which explains the observed
change in the conformational preferences between the
starting 5a ,d ,g (a chair with an axial Ar group, boat-
chair equilibrium, or boat) and 11a ,d ,g (a chair with an
equatorial Ar group).
To further confirm these studies, the Diels-Alder
reactions were carried out between maleimides (R ) Ph,
Me) and dienes 3, in different solvents, at -10 °C, room
temperature, and under reflux (Table 1). These reactions
were checked by NMR of the crude reaction products or
the hydrolyzed material. In all cases, the initial reaction
product was the endo product 4, although a low percent-
age of a compound presumed to be the exo isomer can be
observed in some cases (Ar ) Ar1, R ) Me). To investigate
whether this minor product is formed under thermody-
namic control, the reactions were carried out at increas-
ing temperature in solvents of different boiling point or
polarity, namely CH2Cl2, benzene, xylene, and DMF. As
can be observed in Table 1, entries 12-17, conversion of
the initially produced 4 into a new product 12 was
observed when refluxing in CH2Cl2, xylene, or DMF.
Surprisingly, these new products are different from the
minor products assigned as exo cycloadducts 4′, and their
structures 12 were established as a result of their
hydrolysis to the same ketones 5 as those obtained from
cycloadducts 4 (Figure 3). An exhaustive NMR study of
12a confirmed the proposed structure, with an endo
stereochemistry and a boat conformation. Indeed, a
similar isomerization has been described in structurally
related cycloadducts.25
F igu r e 3. Products of the reaction between maleimides and
dienes 3. (for Ar and R, see Table 1).
previous compound 6a , our first group of synthetic
targets was a series of methoxy-substituted analogues).
The two possible regioisomers 6 and 7 were detected in
the crude product mixture of the reaction in all cases,
and in some cases could be isolated. The most charac-
1
teristic differences in the H NMR of both regioisomers
lie in the signals shown in Figure 4 for compounds 6 and
7, specifically in the narrow aromatic doublet of the
proton ortho to the methoxy group (6b: H-10: 7.47 ppm,
deshielded by the CdO group, and 7b: H-9: 6.79 ppm,
shielded by the aromatic ring, Ar). The outcome of these
reactions, yielding compounds 6 and 7 is shown in Table
2. The regioisomeric ratios are in agreement with the
regioselectivity observed in the Fischer reaction with
cyclohexanones,10 thus, in all cases pyrrolo[3,4-c]carba-
zoles are the major products and pyrrolo[2,3-c]carbazoles
the minor ones.
Following the synthetic strategy depicted in Scheme
1, the perhydroindole-2,3,5-triones were subjected to
Fischer indolization with p-methoxyphenylhydrazine, to
afford tetrahydrocarbazoles in good to moderate yields
(Scheme 2) (owing to the cytotoxic properties of our
(25) Crilley, M. M. L.; Larsen, D. S.; Stoodley, R. J .; Tome´, F.
Tetrahedron Lett. 1993, 34, 3305.

Open Analogues of Arcyriaflavin A
J . Org. Chem., Vol. 65, No. 11, 2000 3391
rationale to support the regio- and stereochemical out-
come of those reactions. Further transformations of these
analogues are currently under way, and the biological
activities of the present and forthcoming compounds,
similar and more elaborated, will be communicated in
due course.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Unless
otherwise stated, 1H and 13C NMR spectra were recorded at
200.13 and at 50.3 MHz, respectively, in deuteriochloroform
solutions and with tetramethylsilane as internal standard. IR
spectra were recorded using FTIR apparatus. Mass spectra
were obtained by EI or FAB methods. Normal and flash
chromatographies were performed on Merck 60 silica gel
(0.063-0.2 mm or 0.040-0.063 mm). TLC was developed on
precoated silica gel polyester plates with the UV 254 fluores-
cent indicator. Microanalyses were carried out in a CHN
elemental analyzer at the Inorganic Chemistry Laboratory of
the Faculty of Pharmacy (Salamanca). Solvents of analytical
grade were used as purchased and, when necessary, dried
using standard procedures.
F igu r e 4. Indolization intermediates to regioisomeric prod-
ucts 6 and 7.
Ta ble 2. Regioisom er ic Ra tios 6:7 of th e In d oliza tion
Rea ction of 5a -e,h by 1H NMR (Isola ted Yield s of 6 a n d
7)
R
Gen er a l P r oced u r e for th e P r ep a r a tion of (E)-4-(n -
Meth oxyp h en yl)-3-bu ten -2-on es (1a-c). To the correspond-
ing benzaldehyde (10.2 mmol) dissolved in aqueous ethanol
(136 mL, 50% v/v) were slowly added from a dropping funnel
acetone (3.6 mL, 51.0 mmol) and then a 10% solution of NaOH
(12.0 mL, 30.0 mmol). After 45, 30, or 75 min, respectively, a
precipitate was filtered from the solution, corresponding to the
double-condensation products 2a ,b. The filtrate was neutral-
ized with 2 N HCl and extracted with CH2Cl2. The organic
layer was washed with brine, dried (Na2SO4), and evaporated
under vacuum. Crystallization gave compounds 1a -c as
yellow crystals.
1 (Ar ) Ar1) (crystallization from CH2Cl2/hexane 1:1, 78%):
mp 84 °C; IR (KBr): 1670, 1625, 1580, 1500 cm-1; 1H NMR δ
2.36 (s, 3H), 3.88 (s, 9H), 6.62 (d, J ) 16.2 Hz, 1H), 6.78 (s,
2H),7.63 (d, J ) 16.2 Hz, 1H); 13C NMR δ 27.2 (q), 56.0 (q,
2C), 60.7 (q), 105.7 (d, 2C), 126.4 (d), 129.8 (s), 140.5 (s), 143.1
(d), 153.8 (s, 2C), 197.7 (s); MS (FAB) m/z 236 (M+, 100). Anal.
Calcd for C13H16O4: C, 66.09; H, 6.83. Found: C, 66.29; H,
6.95.
Ar
Ph (6:7, %)
Me (6:7, %)
H (6:7, %)
Ar1
Ar2
Ar3
a , 5:1 (81, -)
d , 3:1 (33, -)
b, 2:1 (35, 15)
e, 7:3 (32, 19)
h , 7:2 (27, 4)
c, 3:1 (42, 5)
The regiochemistry of the Fischer indolization reaction
under less than extremely acidic conditions can be
explained by the relative stabilities of the intermediate
enehydrazines 13 and 14 (Figure 4), which lead to the
indolization products.26 In an attempt to confirm this
hypothesis, we carried out molecular modeling studies
on the enehydrazines (13 or 14), and the results were
compared with the experimental outcome of the indoliza-
tion reaction. Overall, the major product formed was that
coming from the most stable intermediate enehydrazine
13 (>5 kJ /mol more stable than isomer 14), thus sup-
porting former studies on this kind of reaction.27
The aromatization of 6 and 7 with DDQ afforded the
carbazole derivatives 8 and 9 (Scheme 2), with a planar
aromatic system. The NMR data agree with the reported
structures and the high deshielding of H-10 upon trans-
formation of 6 (7.46-7.50 ppm) into 8 (8.51-9.16 ppm),
and the shielding of H-9 when 7 (6.79-7.26 ppm) was
converted into 9 (6.54-6.57 ppm). The conformational
change induced by the aromatization can also be followed
by the 1H NMR deshielding of the N(2)-Me in planar
compounds 8b,h (6: 2.74, 2.79, 8: 3.22, 3.18 ppm) and
9b (7: 2.45, 9: 3.12 ppm).
1 (Ar ) Ar2) (crystallization from CH2Cl2/hexane 1:1, 88%):
yellow crystals; mp 64 °C; MS (EI) m/z 206 (M+, 19), 175 (100).
Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.75;
H, 6.75.
1 (Ar ) Ar3) (crystallization from diethyl ether/hexane 1:1,
96%): yellow crystals; mp 85 °C; MS (FAB) m/z 206 (M+, 64),
191 (100). Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found:
C, 69.68; H, 6.80.
(1E,4E)-1,5-Bis(3,4,5-tr im eth oxyp h en yl)-1,4-p en ta d ien -
3-on e (2, Ar ) Ar1) (crystallization from ethanol, 8%): yellow
crystals; mp 128 °C; IR (KBr) 1650, 1620, 1580, 1500 cm-1
;
1H NMR δ 3.90 (s, 6H), 3.91 (s, 12H), 6.85 (s, 4H), 6.99 (d, J
) 15.8 Hz, 2H), 7.67 (d, J ) 15.8 Hz, 2H); 13C NMR δ 56.2 (q,
4C), 60.9 (q, 2C), 105.9 (d, 4C), 124.8 (d, 2C), 130.3 (s, 2C),
140.5 (s, 2C), 143.2 (d, 2C) 153.5 (s, 4C), 188.4(s); MS (FAB)
m/z 461 (M++ 2Na, 10), 185 (100).
In summary, we have extended the synthetic utility,
already reported by us,9,23,28 of different 1-aryl-3-tert-
butyldimethylsiloxy-1,3-butadienes by preparing a range
of open analogues of arcyriaflavin A lacking the E ring.
NMR and molecular modeling studies for both the Diels-
Alder and Fischer indolization processes on arylsiloxy-
dienes and isoindole-1,3,5-triones, respectively, offer a
Gen er a l P r oced u r e for th e P r ep a r a tion of (E)-3-ter t-
Bu t yld im et h ylsiloxy-1-(n -m et h oxyp h en yl)-1,3-Bu t a d i-
en es (3 Ar 1-3). To a solution of the given compound (1 Ar 1-3
)
(0.85 mmol) in CH2Cl2 (20 mL) under Ar were added dropwise
triethylamine (0.66 mL, 4.61 mmol) and tert-butyldimethyl-
silyltriflate (0.49 mL, 2.12 mmol). The reaction mixture was
allowed to react for 1 h and then Et3N (0.19 mL) added, diluted
in CH2Cl2, washed diluted with aqueous saturated NaHCO3
and brine, and dried (Na2SO4). Evaporation of the solvent in
vacuo gave the corresponding dienes.
3 (Ar ) Ar1) (100%): yellow oil; 1H NMR δ 0.15 (s, 6H), 0.94
(s, 9H), 3.77 (s, 3H), 3.81 (s, 6H), 4.33 (s, 1H), 4.37 (s, 1H),
6.41 (d, J ) 15.5 Hz, 1H), 6.54 (s, 2H), 6.68 (d, J ) 15.5 Hz,
1H).
(26) (a) Hughes, D. L.; Zhao, D. J . Org. Chem. 1993, 58, 228. (b)
Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 609.
(27) (a) Robinson, B. Chem. Rev. 1969, 69, 227. (b) Robinson, B. In
The Fischer Indole Synthesis; Wiley & Sons: New York, 1982. (c)
Sundberg, R. J . Indoles; Academic Press: London, 1996; and references
therein.
(28) (a) Acosta, J . C.; Caballero, E.; Gra´valos, D. G.; Medarde, M.;
Sahagu´n, H.; Stoodley, R. J .; Tome´, F. Bioorg. Med. Chem. Lett. 1997,
7, 2955. (b) Caballero, E.; Medarde, M.; Pelaez-Lamamie de Clairac,
R.; Sahagu´n, H.; Tome´, F. Tetrahedron 1998, 54, 6111.

3392 J . Org. Chem., Vol. 65, No. 11, 2000
Adeva et al.
3 (Ar ) Ar2) (100%): yellow oil. 3 (Ar ) Ar3) (100%): yellow
(()-(3a R,7S,7a S)-2-P h en yl-7-(2,5-d im et h oxyp h en yl)-
p er h yd r oisoin d ole-1,3,5-tr ion e (5d ) (precipitation in diethyl
ether, 66%): white solid; mp 79 °C; HRMS (FAB) calcd for
C22H21NO5 380.1497, found m/z 380.1450.
oil.
Gen er al P r ocedu r e for th e P r epar ation of (()-(3aR,7S,-
7a S)-2-Su bstitu ted -7-(n -m eth oxyp h en yl)p er h yd r oisoin -
d ole-1,3,5-tr ion es (5). Diels-Ald er Rea ction . The corre-
sponding diene and maleimide (7.8 mmol each) were dissolved
in 25 mL of dry benzene. They were allowed to react at room
temperature in the dark. The reaction was monitored by 1H
NMR and TLC (reaction time: 2-4 days). For the preparation
of cycloadduct 4h , the reaction was carried out under reflux
for 2-4 h. Benzene was evaporated to give cycloadducts 4 (95-
100% yield) as deduced by NMR.
(()-(3a S,4S,7a R)-2-P h en yl-6-ter t-bu tyld im eth ylsiloxy-
4-(3,4,5-tr im eth oxyph en yl)-3a,4,7,7a-tetr ah ydr oisoin dole-
1,3-d ion e (4a ) (crystallization from ethyl acetate/hexane,
84%): yellow crystals; mp 125 °C; IR (KBr) 2954, 1715, 1590,
1502 cm-1; 1H NMR δ 0.21 (s, 6H), 0.97 (s, 9H), 2.54 (dd, J )
18.3, 10.24 Hz, 1H), 3.04 (dt, J ) 18.3, 2.2 Hz, 1H), 3.40 (m,
2H), 3.74 (s, 6H), 3.80 (s, 3H), 4.02 (bt, J ) 6.6 Hz, H), 5.20
(dd, J ) 6.6, 2.2 Hz), 6.36 (s, 2H), 6.55 (m, 2H), 7.32 (m, 3H);
13C NMR δ -4.2 (q), -4.5 (q), 17.8 (s), 23.8 (t), 25.0 (q), 38.7
(d), 41.4 (d), 44.0 (d), 55.9 (q, 2C), 60.5 (q), 104.4 (d), 106.1 (d,
2C), 125.9 (d, 2C), 128.2 (d), 128.7 (d, 2C), 131.4 (s), 134.8 (s),
137.2 (s), 150.4 (s), 152.9 (s, 2C), 176.2 (s), 178.2 (s). Anal. Calcd
for C29H37NO6Si: C, 66.51; H, 7.12; N, 2.67. Found: C, 66.39;
H, 7.02; N, 2.60.
(()-(3a R,7S,7a S)-2-Met h yl-7-(2,5-d im et h oxyp h en yl)-
p er h yd r oisoin d ole-1,3,5-tr ion e (5e) (precipitation in diethyl
ether, 41%): brown solid; mp 163 °C.
(()-(3a R,7S,7a S)-7-(2,5-Dim et h oxyp h en yl)p er h yd r o-
isoin d ole-1,3,5-tr ion e (5f) (precipitation in diethyl ether,
21%): white solid; mp 98 °C; MS (EI) m/z 303 (M+ 100).
(()-(3a R,7S,7a S)-2-P h en yl-7-(3,4-d im et h oxyp h en yl)-
p er h yd r oisoin d ole-1,3,5-tr ion e (5g) (hexane/AcOEt 1:9,
41%): white solid; mp 218 °C; IR (KBr) 1713, 1594, 1501 cm-1
;
1H NMR (400 MHz) δ 2.69 (dd, J ) 18.2, 10.6 Hz, 1H), 2.78
(dd, J ) 18.2, 4.6 Hz, 1H), 2.90 (dd, J ) 17.5, 9.0 Hz, 1H),
3.17 (dd, J ) 17.5, 2.5 Hz, 1H), 3.57 (td, J ) 9.0, 2.5 Hz, 1H),
3.64 (dd, J ) 9.0, 5.8 Hz, 1H), 3.79 (s, 3H), 3.78 (m, 1H), 3.84
(s, 3H), 6.67 (dd, J ) 8.0, 2.0 Hz, 1H), 6.71 (d, J ) 2.0 Hz,
1H), 6.81 (d, J ) 8.0 Hz, 1H), 7.03 (dd, J ) 8.0, 1.2 Hz, 2H),
7.36 (m, 3H); 13C NMR (100 MHz) δ 36.6 (t), 38.2 (d), 39.0 (d),
41.8 (t), 44.5 (d), 55.8 (q, 2C), 111.0 (d), 111.3 (d), 119.7 (d),
126.1 (d, 2C), 128.7 (d), 129.0 (d, 2C), 130.4 (s), 131.3 (s), 148.3
(s), 148.8 (s), 174.9 (s), 176.9 (s), 207.0 (s); MS (FAB) m/z 379
(M+, 100). Anal. Calcd for C22H21NO5: C, 69.64; H, 5.57; N,
3.69. Found: C, 69.43; H, 5.45; N, 3.52.
(()-(3a R,7S,7a S)-2-Met h yl-7-(3,4-d im et h oxyp h en yl)-
p er h yd r oisoin d ole-1,3,5-tr ion e (5h ) (precipitation in di-
ethyl ether, 70%): violet solid; mp 83 °C; MS (EI) m/z 317 (M+,
100). Anal. Calcd for C17H19NO5: C, 64.34; H, 6.03; N, 4.41.
Found: C, 64.19; H, 5.93; N, 4.33.
Hyd r olysis of Silyl En ol Eth er s. The cycloadduct (6.8
mmol) in 75 mL of CH2Cl2 was treated with 5 mL of
concentrated HCl and then stirred for 2 h. After workup
(dilution with CH2Cl2, aqueous NaHCO3, brine, and Na2SO4
and evaporation) by precipitation in diethyl ether or by column
chromatography and crystallization (in CH2Cl2/diethyl ether)
triones 5 were obtained. Yields after precipitation obtained for
the two steps cycloaddition-hydrolysis process.
(()-(3a R,7S,7a S)-7-(3,4-Dim et h oxyp h en yl)p er h yd r o-
isoin d ole-1,3,5-tr ion e (5i) (precipitation in diethyl ether,
22%): white solid; mp 94 °C; MS (EI) m/z 303 (M+, 100).
(()-(3a R,7S,7a S)-2-P h en yl-7-(3,4,5-tr im eth oxyp h en yl)-
p er h yd r oisoin d ole-1,3,5-tr ion e (5a ) (precipitation in diethyl
ether, 62%): white solid; mp 118 °C; IR (KBr) 1700, 1595, 1515
F isch er In d oliza tion Rea ction s. Hyd r op yr r olo[3,4-c]-
ca r ba zoles (6) a n d Hyd r op yr r olo[3,4-b]ca r ba zoles (7). A
0.86 mmol portion of trione was dissolved in 100 mL of AcOH/
EtOH (1:1 vol/vol). After addition of 1.72 mmol of p-methox-
yphenylhydrazine, the reaction mixture was refluxed for 1.5-4
h and then basified with caution (solid NaHCO3), extracted
with AcOEt, washed with brine, and dried (Na2SO4). Evapora-
tion of the solvent, followed by precipitation in diethyl ether,
crystallization (diethyl ether/CH2Cl2), or column chromatog-
raphy (SiO2 or Al2O3) gave the corresponding pyrrolocarba-
zoles. Depending on the case, a single regioisomer or both
regioisomers were isolated.
1
cm-1; H NMR (400 MHz) δ 2.69 (dd, J ) 17.9, 9.3 Hz, 1H),
2.78 (dd, J ) 17.9, 5.2 Hz, 1H), 2.89 (dd, J ) 17.9, 9.3 Hz,
1H), 3.18 (dd, J ) 17.9, 2.0 Hz, 1H), 3.58 (td, J ) 9.3, 2.0 Hz,
1H), 3.65 (dd, J ) 9.3, 5.6 Hz, 1H), 3.77 (s, 6H), 3.81 (s, 3H),
3.83 (m, 1H), 6.36 (s, 2H), 6.97 (dd, J ) 6.9, 1.4 Hz, 2H), 7.2
(m, 3H); 13C NMR (100 MHz) δ 36.4 (t), 38.3 (d), 39.9 (d), 42.1
(t), 44.7 (d), 56.0 (q, 2C), 60.8 (q), 105.1 (d, 2C), 126.1 (d, 2C),
128.8 (d), 129.1 (d, 2C), 131.3 (s), 133.6 (s), 137.4 (s), 153.2 (s,
2C), 174.8 (s), 176.8 (s), 206.7 (s); MS (FAB) m/z 409 (M+, 8),
185 (100). Anal. Calcd for C23H23NO6: C, 67.47; H, 5.66; N,
3.42. Found: C, 67.21; H, 5.52; N, 3.15.
(()-(3a S ,4S ,10cS )-2-P h e n yl-9-m e t h oxy-4-(3,4,5-t r i-
m eth oxyp h en yl)-3a ,4,5,10c-tetr a h yd r o-6H-p yr r olo[3,4-c]-
ca r ba zole-1,3-d ion e (6a ) (diethyl ether precipitation, 81%):
(()-(3a R,7S,7a S)-2-Meth yl-7-(3,4,5-tr im eth oxyp h en yl)-
p er h yd r oisoin d ole-1,3,5-tr ion e (5b) (precipitation in diethyl
ether, 65%): white solid; mp 188 °C; IR (KBr) 1698, 1591, 1511
1
white solid; mp 188 °C; IR (KBr) 3340, 1715, 1600 cm-1; H
NMR (DMSO) δ 3.07 (dd, J ) 16.2, 7.2 Hz, 1H), 3.22 (dd, J )
16.2, 4.5 Hz, 1H), 3.39 (s, 6H), 3.62 (s, 3H), 3.65 (m, 1H), 3.75
(s, 3H), 4.03 (dd, J ) 7.6, 4.8 Hz, 1H), 4.57 (d, J ) 8.0 Hz,
1H), 6.58 (s, 2H), 6.72 (dd, J ) 8.0, 2.4 Hz, 1H), 6.78 (m, 2H),
7.23 (d, J ) 8.7 Hz, 1H), 7.30 (d, J ) 2.4 Hz, 1H), 7.35 (m,
3H), 11.00 (bs, 1H); 13C NMR (DMSO) δ 26.2 (t), 39.2 (d), 40.4
(d), 45.4 (d), 55.4 (q), 55.8 (q, 2C), 59.9 (q),102.2 (d), 102.6 (s),
106.4 (d, 2C), 110.4 (d), 111.4 (d), 126.6 (d, 2C), 127.0 (s), 128.0
(d), 128.6 (d, 2C), 131.2 (s), 132.3 (s), 135.7 (s), 136.6 (s), 136.8
(s), 152.3 (s, 2C), 153.3 (s), 175.7 (s), 176.1 (s); MS (EI) m/z
512 (M+, 15), 105 (100). Anal. Calcd for C30H28N2O6: C, 70.30;
H, 5.51; N, 5.47. Found: C, 70.15; H, 5.40; N, 3.40.
1
cm-1; H NMR (400 MHz) δ 2.55 (dd, J ) 18.3, 12.1 Hz, 1H),
2.78 (dd, J ) 18.3, 4.5 Hz, 1H), 2.84 (dd, J ) 17.7, 9.5 Hz,
1H), 2.95 (s, 3H), 3.11 (dd, J ) 17.7, 3.8 Hz, 1H), 3.48 (td, J )
9.5, 3.8 Hz, 1H), 3.57 (dd, J ) 9.5, 4.9 Hz, 1H), 3.73 (ddd, J )
12.1, 4.9, 4.5 Hz, 1H), 3.88 (s, 9H), 6.42 (s, 2H); 13C NMR δ
25.0 (q), 37.0 (t), 38.2 (d), 39.2 (d), 41.5 (t), 44.3 (d), 56.1 (q,
2C), 60.8 (q), 105.1 (d, 2C), 133.8 (s), 137.3 (s), 153.1 (s, 2C),
175.7 (s), 177.7 (s), 206.8 (s); MS (EI) m/z 347 (M+, 100). Anal.
Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C,
62.1; H, 6.01; N, 3.98.
(()-(3a R,7S,7a S)-7-(3,4,5-Tr im eth oxyp h en yl)p er h yd r o-
isoin d ole-1,3,5-tr ion e (5c) (precipitation in diethyl ether,
(()-(3a S ,4S ,10c S )-2-Me t h y l-9-m e t h ox y-4-(3,4,5-t r i-
m eth oxyp h en yl)-3a ,4,5,10c-tetr a h yd r o-6H-p yr r olo[3,4-c]-
ca r ba zole-1,3-d ion e (6b) (hexane/AcOEt 3:7 and diethy ether
precipitation, 35%): white solid; mp 240 °C; MS (EI) m/z 450
(M+ 100). Anal. Calcd for C25H26N2O6: C, 66.65; H, 6.21; N,
5.82. Found: C, 66.40; H, 6.11; N, 5.76.
68%): white solid; mp 94 °C; IR (KBr) 3219, 1715, 1509 cm-1
;
1H NMR (400 MHz) δ 2.61 (dd, J ) 18.4, 12.4 Hz, 1H), 2.74
(dd, J ) 18.4, 3.8 Hz, 1H), 2.81 (dd, J ) 17.4, 8.0 Hz, 1H),
3.01 (dd, J ) 17.4, 1.6 Hz, 1H), 3.45 (m, 1H), 3.52 (dd, J )
9.4, 5.3 Hz, 1H), 3.64 (ddd, J ) 12.4, 5.3 Hz, J ) 3.8 Hz, 1H),
3.80 (s, 9H), 6.38 (s, 2H), 8.50 (bs, 1H); 13C NMR (100 MHz) δ
36.9 (t), 39.1 (d), 39.4 (d), 41.6 (t), 45.4 (d), 56.2 (q, 2C), 60.9
(q), 105.2 (d, 2C), 133.6 (s), 153.2 (s, 2C), 153.6 (s), 175.7 (s),
177.8 (s), 206.8 (s); MS (EI) m/z 333 (M+, 100). Anal. Calcd for
(()-(3aS,4S,10cS)-9-Meth oxy-4-(3,4,5-tr im eth oxyph en yl)-
3a ,4,5,10c-tetr a h yd r o-6H-p yr r olo[3,4-c]ca r ba zole-1,3-d i-
on e (6c) (hexane/AcOEt 3:7 and precipitation in diethyl ether,
42%): white solid; mp 245 °C; HRMS (FAB) calcd for
C
17H19NO6: C, 61.25; H, 5.74; N, 4.20. Found: C, 61.15; H,
5.67; N, 3.11.
C
24H24N2O6 437.1712, found m/z 437.1726.

Open Analogues of Arcyriaflavin A
J . Org. Chem., Vol. 65, No. 11, 2000 3393
(()-(3aS,4S,10cS)-2-P h en yl-9-m eth oxy-4-(2,5-dim eth oxy-
ph en yl)-3a,4,5,10c-tetr ah ydr o-6H-pyr r olo[3,4-c]car bazole-
1,3-d ion e (6d ) (hexane/AcOEt 1:1 and precipitation in diethyl
ether, 33%): white solid; mp 279 °C.
9-Meth oxy-4-(3,4,5-tr im eth oxyp h en yl)-6H-p yr r olo[3,4-
c]ca r ba zole-1,3-d ion e (8c) (66%); red crystalline solid; mp
>300 °C; HRMS (FAB) calcd for C24H20N2O6 433.1399, found
m/z 433.1380.
2-P h en yl-9-m eth oxy-4-(2,5-d im eth oxyp h en yl)-6H-p yr -
r olo[3,4-c]ca r ba zole-1,3-d ion e (8d ) (38%): orange crystaline
solid; mp 132 °C.
2-Meth yl-9-m eth oxy-4-(2,5-d im eth oxyp h en yl)-6H-p yr -
r olo[3,4-c]ca r ba zole-1,3-d ion e (8e) (54%): yellow crystaline
solid; mp 266 °C; HRMS (FAB) calcd for C24H20N2O5 417.1450,
found m/z 417.1452.
2-Meth yl-9-m eth oxy-4-(3,4-d im eth oxyp h en yl)-6H-p yr -
r olo[3,4-c]ca r ba zole-1,3-d ion e (8h ) (82%): brown crystalline
solid; mp 238 °C; HRMS (FAB) calcd for C24H20N2O5 417.1450,
found m/z 417.1404.
(()-(3a S,4S,10cS)-2-Met h yl-9-m et h oxy-4-(2,5-d im et h -
oxyp h en yl)-3a ,4,5,10c-t et r a h yd r o-6H -p yr r olo[3,4-c]ca r -
ba zole-1,3-d ion e (6e) (hexane/AcOEt 1:1 and precipitation
in diethyl ether, 32%): red solid; mp 286 °C; MS (EI) m/z 420
(M+, 100).
(()-(3a S,4S,10cS)-2-Met h yl-9-m et h oxy-4-(3,4-d im et h -
oxyp h en yl)-3a ,4,5,10c-t et r a h yd r o-6H -p yr r olo[3,4-c]ca r -
ba zole-1,3-d ion e (6h ) (hexane/AcOEt 3:7 and precipitation
in diethyl ether, 27%): white solid; mp 150 °C; HRMS (FAB)
calcd for C24H24N2O5 421.1763, found m/z 421.1712.
(()-(3a R,10S,10a S)-2-Met h yl-8-m et h oxy-10-(3,4,5-t r i-
m eth oxyp h en yl)-3a ,4,10,10a -tetr a h yd r o-5H-p yr r olo[3,4-
b]ca r ba zole-1,3-d ion e (7b) (hexane/AcOEt 2:8 and diethyl
ether precipitation, 15%): brown solid; mp 255 °C; IR (KBr)
2-Met h yl-8-m et h oxy-10-(3,4,5-t r im et h oxyp h en yl)-5H -
p yr r olo[3,4-b]ca r ba zole-1,3-d ion e (9b) (66%): brown crys-
talline solid; mp 252 °C; IR (KBr) 3284, 1695, 1589, 1503 cm-1
;
1H NMR δ 3.12 (s, 3H), 3.55 (s, 3H), 3.85 (s, 6H), 3.96 (s, 3H),
6.57 (d, J ) 2.4 Hz, 1H), 6.77 (s, 2H), 7.07 (dd, J ) 8.8, 2.4
Hz, 1H), 7.39 (d, J ) 8.8 Hz, 1H), 7.88 (s, 1H), 9.01 (bs, 1H);
13C NMR δ 23.9 (q), 55.4 (q), 56.3 (q, 2C), 61.1 (q), 104.4 (d),
106.1 (d), 106.3 (d, 2C), 112.2 (d), 117.8 (d), 118.8 (s), 123.2
(s), 125.5 (s), 130.1 (s), 131.0 (s), 135.6 (s), 136.3 (s), 138.1 (s),
142.3 (s), 153.5 (s, 2C), 154.4 (s), 168.4 (s), 168.9 (s); HRMS
(FAB) calcd for C25H22N2O6 447.1556, found m/z 447.1541.
2-Meth yl-8-m eth oxy-10-(2,5-d im eth oxyp h en yl)-5H-p yr -
r olo[3,4-b]ca r ba zole-1,3-d ion e (9e) (23%): green crystalline
solid; mp 248 °C; HRMS (FAB) calcd for C24H20N2O5 417.1450,
found m/z 417.1439.
3333, 1700, 1591, 1510 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
2.45 (s, 3H), 3.20 (dd, J ) 17.0, 10.8 Hz, 1H), 3.40 (ddd, J )
10.8, 8.2 Hz, J ) 2.3 Hz, 1H), 3.49 (dd, J ) 8.2, 6.8 Hz, 1H),
3.63 (dd, J ) 17.0, 2.3 Hz, 1H), 3.73 (s, 9H), 3.78 (s, 3H), 4.73
(d, J ) 6.8 Hz, 1H), 6.19 (s, 2H), 6.78 (dd, J ) 9.4, 2.4 Hz,
1H), 6.79 (d, J ) 2.4 Hz, 1H), 7.20 (d, J ) 9.4 Hz, 1H), 8.24
(bs, 1H); 13C NMR δ 18.7 (t), 24.0 (q), 38.4 (d), 39.1 (d), 46.9
(d), 56.0 (q, 3C), 60.7 (q), 100.6 (d), 105.7 (d, 2C), 110.5 (s),
111.5 (d, 2C), 126.6 (s), 131.5 (s), 132.6 (s), 135.2 (s), 136.9 (s),
152.7 (s, 2C), 154.2 (s), 177.5 (s), 179.3 (s); MS (EI) m/z 450
(M+, 100). Anal. Calcd for C25H26N2O6: C, 66.65; H, 6.21; N,
5.82. Found: C, 66.36; H, 6.05; N, 5.72.
Gen er al P r ocedu r e for th e P r epar ation of (()-(3aR,7S,-
7a S)-2-P h en yl-7-(n -m eth oxyp h en yl)-5-(n -n itr op h en ylh y-
d r a zon o)p er h yd r oisoin d ol-1,3,5-tr ion e (10). A 60 mg (0.16
mmol) portion of 5c was dissolved in 6 mL of MeOH with 4
drops of AcOH, and 2,4-dinitrohydrazine (38.0 mg, 0.16 mmol)
was added. The reaction was stirred at reflux for 75 min and
precipitation in cold ethanol and crystallization gave the
product 10.
(()-(3aR,10S,10aS)-8-Meth oxy-10-(3,4,5-tr im eth oxyph en -
yl)-3a ,4,10,10a -t et r a h yd r o-5H -p yr r olo[3,4-b]ca r b a zole-
1,3-d ion e (7c) (hexane/AcOEt 2:8 and precipitation in diethyl
ether, 5%): brown solid; mp 185 °C. Anal. Calcd for C24H24
-
N2O6: C, 66.04; H, 5.54; N, 6.42. Found: C, 65.88; H, 5.29; N,
6.21.
(()-(3a R ,10S ,10a S )-2-M e t h y l-8-m e t h o x y -10-(2,5-
d im et h oxyp h en yl)-3a ,4,10,10a -t et r a h yd r o-5H -p yr r olo-
[3,4-b]ca r ba zole-1,3-d ion e (7e) (hexane/AcOEt 2:8 and di-
ethyl ether precipitation, 19%): brown solid; mp 185 °C; MS
(EI) m/z 420 (M+, 100).
(()-(3a R,7S,7a S)-2-P h en yl-7-(3,4-d im eth oxyp h en yl)-5-
(2,4-d in itr op h en ylh yd r a zon o)p er h yd r oisoin d ol-1,3,5-tr i-
on e (10, Ar ) Ar3) (crystallization in CH2Cl2/diethyl ether 10:
1, 55%): orange solid; mp 214 °C; IR (KBr) 3317, 1713, 1594,
1
1517 cm-1; H NMR δ 2.86 (dd, J ) 17.4, 11.0 Hz, 1H), 2.97
(()-(3a R ,10S ,10a S )-2-Me t h yl-8-m e t h oxy-10-(3,4-t r i-
m eth oxyp h en yl)-3a ,4,10,10a -tetr a h yd r o-5H-p yr r olo[3,4-
b]ca r ba zole-1,3-d ion e (7h ) (hexane/AcOEt 3:7 and precipi-
tation in diethyl ether, 5%): brown solid; mp 112 °C; MS (EI)
m/z 420 (M+, 88), 278 (100). Anal. Calcd for C24H24N2O5: C,
68.55; H, 6.66; N, 5.75. Found: C, 68.30; H, 6.49; N, 5.66.
(dd, J ) 17.4, 2.5 Hz, 1H), 3.16 (dd, J ) 15.3, 6.2 Hz, 1H),
3.31 (dd, J ) 15.3, 2.6 Hz, 1H), 3.63 (m, 1H), 3.83 (m, 2H),
3.90 (s, 6H), 6.92 (m, 3H), 7.09 (m, 2H), 7.35 (m, 3H), 8.04 (d,
J ) 9.5 Hz, 1H), 8.37 (dd, J ) 9.5, 2.5 Hz, 1H), 9.14 (d, J )
2.5 Hz, 1H), 11.14 (bs, 1H); 13C NMR δ 28.9(t), 31.5 (t), 37.7
(d), 39.9 (d), 44.9 (d), 56.0 (q, 2C), 111.2 (d), 111.4 (d), 116.6
(d), 119.8 (d), 123.5 (d), 126.2 (d, 2C), 129.0 (d), 129.3 (d, 2C),
129.7 (s), 130.4 (d), 131.5 (s), 138.7 (s), 144.8 (s), 148.7 (s), 149.1
(s), 153.1 (s, 2C), 175.1 (s), 177.1 (s). Anal. Calcd for
Gen er a l P r oced u r e for th e Ar om a tiza tion of Hyd r o-
p yr r oloca r ba zoles. A 0.12 mmol portion of the corresponding
hydropyrrolocarbazole dissolved in 5 mL of benzene was
reacted with 0.30 mmol of 2,3-chloro-5,6-dicyano-p-benzo-
quinone (DDQ) for 3 h at rt. The crude reaction mixture was
diluted in AcOEt, washed with NaHCO3 and brine, dried (Na2-
SO4), and evaporated. Precipitation in diethyl ether or chro-
matography (SiO2) gave the corresponding aromatized prod-
ucts.
C
28H25N5O8: C, 60.11; H, 4.50; N, 12.52. Found: C, 59.96; H,
4.41; N, 12.37.
Gen er a l P r oced u r e for th e Red u ction of 5 to (()-
(1R,2S,3R,5R)-Met h yl-2-p h en ylca r b a m oyl-5-h yd r oxy-3-
(n -m eth oxyp h en yl)cycloh exa n eca r boxyla te (11). To a
solution of the compounds 5a ,d ,g (100.0 mg, 0.24 mmol) in
anhydrous MeOH (1.3 mL) at 0 °C was added NaBH4 (18.1
mg, 0,08 mmol) dissolved in anhydrous MeOH (2.13 mL). Once
the addition was finished, the ice bath was removed, and the
reaction was stirred at room temperature for 15-20 min. The
reaction mixture was extracted with AcOEt, washed with
brine, and dried (Na2SO4). Column chromatography and
precipitation in diethyl ether gave the pure compounds 11.
(()-(1R ,2S ,3S ,5R )-Me t h yl-2-p h e n ylca r b a m oyl-5-h y-
d r oxy-3-(3,4,5-tr im eth oxyp h en yl)cycloh exa n eca r boxyl-
a te (11a ) (32%): light brown solid; mp 65 °C; IR (KBr) 3359,
1596, 1505 cm-1; 1H NMR (400 MHz) δ 2.07 (dt, J ) 12.0, 4.0
Hz, 1H), 2.19 (c, J ) 12.0 Hz, 1H), 2.42 (dt, J ) 12.4, 4.4 Hz,
1H), 2.52 (c, J ) 12.4 Hz, 1H), 2.79 (dt, J ) 12.4, 4.4 Hz, 1H),
3.02 (dt, J ) 12.0, 4.2 Hz, 1H), 3.10 (dd, J ) 4.4, 4.2 Hz, 1H),
3.69 (s, 9H), 3.83 (s, 3H), 3.85 (m, 1H),6.35 (bs, H), 6.46 (s,
2H), 7.02 (m, 1H), 7.22 (m, 2H), 7.43 (bd, 2.8, 2H); 13C NMR
(100 MHz) δ 32.8 (t), 34.9 (t), 44.1 (d), 44.2 (d), 49.1 (d), 52.1
2-P h en yl-9-m et h oxy-4-(3,4,5-t r im et h oxyp h en yl)-6H -
p yr r olo[3,4-c]ca r ba zole-1,3-d ion e (8a ) (76%): brown solid;
mp 282 °C; IR (KBr) 3309, 1695, 1618, 1514 cm-1; 1H NMR
(py-d5) δ 3.83 (s, 6H), 3.95 (s, 3H), 3.99 (s, 3H), 5.13 (bs, 1H),
7.26 (s, 2H), 7.34 (m, 1H), 7.46 (dd, J ) 8.9, 2.5 Hz, 1H), 7.54
(m, 2H), 7.67 (d, J ) 8.9 Hz, 1H), 7.83 (m, 2H), 8.00 (s, 1H),
9.16 (d, J ) 2.5 Hz, 1H); 13C NMR (py-d5) δ 55.8 (q), 56.4 (q,
2C), 60.7 (q), 108.0 (d), 108.5 (d, 2C), 112.8 (d), 117.5 (d), 118.9
(d), 119.6 (s), 122.1 (s), 122.2 (s), 127.8 (d, 2C), 127.9 (d), 129.2
(d, 2C), 133.5 (s), 134.1 (s), 136.0 (s), 138.2 (s, 2C), 139.1 (s),
145.8 (s), 153.5 (s, 2C), 155.2 (s), 168.0 (s), 168.5 (s); HRMS
(FAB) calcd for C30H24N2O6 509.1712, found m/z 509.1712.
2-Met h yl-9-m et h oxy-4-(3,4,5-t r im et h oxyp h en yl)-6H -
p yr r olo[3,4-c]ca r ba zole-1,3-d ion e (8b) (59%): yellow crys-
taline solid; mp 286 °C; HRMS (FAB) calcd for C25H22N2O6
447.1556, found m/z 447.1533.

3394 J . Org. Chem., Vol. 65, No. 11, 2000
Adeva et al.
(q), 56.2 (q, 2C), 60.7 (s), 70.2 (d), 104.5 (d, 2C), 119.8 (d, 2C),
124,2 (d), 128.7 (d, 2C), 137.1 (s), 137.2 (s), 137.8 (s), 153.5 (s,
2C), 169.7 (s), 173.2 (s); MS (EI) m/z 444 (M+, 100). Anal. Calcd
for C24H29NO7: C, 65.00; H, 6.59; N, 3.16. Found: C, 64.83;
H, 6.51; N, 3.09.
6.65 (s, 2H), 6.77 (m, 2H), 7.33 (m, 3H); 13C NMR δ -4.3 (q),
18.1 (s), 25.6 (q), 33.5 (t), 39.7 (d), 42.0 (d), 44.3 (d), 56.1 (q),
60.9 (q), 97.1 (d), 105.8 (d), 126.4 (d), 128.6 (d), 129.1 (d), 131.6
(s), 136.1 (s), 137.2 (s), 153.1 (s), 153.7 (s), 176.2 (s), 176.5 (s).
(()-(1R ,2S ,3S ,5R )-Me t h yl-2-p h e n ylca r b a m oyl-5-h y-
d r oxy-3-(2,5-d im e t h oxyp h e n yl)cycloh e xa n e ca r b oxyl-
a te (11d ) (25%): light brown solid; mp 90 °C; HRMS (FAB)
calcd for C23H27NO6 414.1916, found m/z 414.1889.
(()-(1R ,2S ,3S ,5R )-Me t h yl-2-p h e n ylca r b a m oyl-5-h y-
d r oxy-3-(3,4-d im e t h oxyp h e n yl)cycloh e xa n e ca r b oxyl-
a te (11g) (45%): light brown solid; MS (FAB) m/z 414 (M+,
100).
Gen er a l P r oced u r e for th e Isom er iza tion of Diels-
Ald er Ad d u cts to (() (3a S,4S,7a R)-2-P h en yl-6-ter t-bu tyl-
d im et h ylsiloxy-4-(n -m et h oxyp h en yl)-3a ,4,5,7a -t et r a h y-
d r oisoin d ole-1,3-d ion e (12). The compounds 4a ,b,g in DMF
or xylene were stirred at reflux for 4 h. Evaporation of the
solvent gave the compounds 12 (100%).
Ack n ow led gm en t. Financial support came from
DGICYT (SAF98-0103) and J unta de Castilla y Leo´n
(SA24/99, Consejer´ıa de Educacio´n y Cultura and
European Social Fund). M.A. and H.S. thank the
University of Salamanca for their predoctoral grants,
and R.P.L.C. acknowledges the Spanish MEC for his
“contrato de reincorporacio´n”. The authors acknowledge
the kind suggestions and results discussion of one of
the reviewers.
Su p p or tin g In for m a tion Ava ila ble: Tables of 1H and 13C
1
data of all the synthesized compounds and copies of H and
13C NMR spectra of one representative compound of each class
(4a , 5a ,b, 6b, 7b, 8b, 9b, 10, 11a , and 12a ). This material is
available free of charge via the Internet at http://pubs.acs.org.
(()-(3a S,4S,7a R)-2-P h en yl-6-ter t-bu tyld im eth ylsiloxy-
4-(3,4,5-tr im eth oxyph en yl)-3a,4,5,7a-tetr ah ydr oisoin dole-
1
1,3-d ion e (12a ): H NMR δ 2.52 (m, 2H), 3.50 (m, 2H), 3.77
(s, 6H), 3.80 (m, 1H), 3.82 (s, 3H), 5.24 (d, J ) 4.00 Hz, 1H)
J O991815X