Synthesis of pyrrolidin-2-ones and of staurosporine aglycon (K-252c) by intermolecular Michael reaction

Article abstract of DOI:10.1021/jo9825106

Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially fungi, as structurally rare natural substances. Responsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group of compounds with many interesting biological properties are related to staurosporinone. The most important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and substituted acetate Michael donors. With this method also enantioselective syntheses can be carried out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the biological activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl- , and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. Just like the total synthesis of staurosporinone within three steps, the easiest and shortest approach reported up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses, which open the easy access to a new family of compounds.

Full text of DOI:10.1021/jo9825106

J . Org. Chem. 1999, 64, 4697-4704
4697
Syn th esis of P yr r olid in -2-on es a n d of Sta u r osp or in e Aglycon
(K-252c) by In ter m olecu la r Mich a el Rea ction
Siavosh Mahboobi,* Ernst Eibler, Markus Koller, Sunil Kumar KC, and Alfred Popp
Faculty of Chemistry and Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
Dieter Schollmeyer
Institute of Organic Chemistry, University of Mainz, D-55099 Mainz, Germany
Received December 28, 1998
Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially
fungi, as structurally rare natural substances. Responsible for naming and also the most important
representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its
aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group
of compounds with many interesting biological properties are related to staurosporinone. The most
important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent
can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of
pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and
substituted acetate Michael donors. With this method also enantioselective syntheses can be carried
out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the
lactam partial structure, which is essential for the biological activity, is obtained. Besides indole
substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl-,
and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably
high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. J ust like the
total synthesis of staurosporinone within three steps, the easiest and shortest approach reported
up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses,
which open the easy access to a new family of compounds.
Sch em e 1
In tr od u ction
Among carbazole alkaloids the indolo[2,3-a]pyrrolo[3,4-
c]carbazoles represent a structurally rare type of natural
substance. Compounds showing this heterocyclic skeleton
are most common in low plants, especially fungi. The
first-isolated and most important example is staurospo-
rine (1), an aminohexose-bound alkaloid isolated from
Streptomyces staurosporeus in 1977.1 The lactam-type
heterocyclic moiety of 2, staurosporinone or K-252c (2),
is also found in a Nocardiopsis strain (Scheme 1).2,3
Among the widespread biological activities of the
foregoing compounds, inhibition of protein kinase C
(PKC) is the most important property in some cases.4,5
Compounds such as 3 are precursors in most known
preparative routes to 2.6,7 The major disadvantage of
these syntheses is the inability to produce nonsymmetri-
cally substituted staurosporinones, because the isomeric
mixtures obtained by reduction of the imides of type 3
* To whom correspondence should be addressed. Fax: (+49)-941-
943-4809. E-mail: siavosh.mahboobi@chemie.uni-regensburg.de.
(1) Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J .;
Tsuchiya, H.; Takahashi, Y.; Masuma, R. J . Antibiot. 1977, 30, 275-
282.
(2) Nakanishi, S.; Matsuda, Y.; Iwahashi, K.; Kase, H. J . Antibiot.
1986, 39, 1066-1071.
could not be separated till now.8,9 Another limitation of
this type of syntheses is the inselectivity of the reduction
step, because the reaction could not be stopped at the
lactam stage.10
(3) Yasuzawa, T.; Iida, T.; Yoshida, M.; Hirayama, N.; Takahashi,
M.; Shirahata, K.; Sano, H. J . Antibiot. 1986, 39, 1072-1078.
(4) Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto, M.;
Tomita, F. Biochem. Biophys. Res. Commun. 1986, 38, 397-402.
(5) Bradshaw, D.; Hill, C. H.; Nixon, J . S.; Wilkinson, S. E. Agents
Action 1993, 38, 135-147.
(8) Kleinschroth, J .; Barth, H.; Hartenstein, J .; Scha¨chtele, C.;
Rudolph, C.; Osswald, H. (Goedecke AG), Ger. Offen. DE 3,835,842,
1990; Chem. Abstr. 1990, 113, P152248b.
(9) Kleinschroth, J .; Hartenstein, J .; Scha¨chtele, C.; Rudolph, C.;
Marme, D.; Pa¨tzold, S. (Goedecke AG), Ger. Offen. DE 4,217,963, 1993;
Chem. Abstr. 1994, 120, P 153691x.
(6) Hughes, I.; Raphael, R. A. Tetrahedron Lett. 1983, 24, 1441-
1444.
(7) Xie, G.; Lown, J . W. Tetrahedron Lett. 1994, 35, 5555-5558.
(10) Mahboobi, S. Unpublished results.
10.1021/jo9825106 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/27/1999

4698 J . Org. Chem., Vol. 64, No. 13, 1999
Mahboobi et al.
Sch em e 2a
Other syntheses of 2 including cycloaddition steps, e.g.,
are too long and low in yield.11-20 To avoid these disad-
vantages, a new access to indolo[2,3-a]pyrrolo[3,4-c]-
carbazoles is elaborated. An adequate precursor should
be a bis-indolo-γ-butyrolactam 8e (Scheme 1).
Compounds of the basic structure 8e are known to be
biologically active by themselves, depending on their
stereochemistry at C-3 and C-4, but often the reported
activity is low, probably because mixtures of diastereo-
mers have been synthesized and tested.21,22 Nevertheless,
these mixtures are part of patent claims.23
Syn th esis
For the synthesis of the pyrrolidin-2-ones we used a
Michael addition route using nitroethene derivatives and
substituted acetate Michael donors, which promised a
facile way for the introduction of different substituents
in the 3 and 4 positions of the desired five-ring lactam.
To study different experimental conditions, we first
synthesized a couple of model compounds using different
substitution patterns. We started with commercially
available aryl and heteroaryl aldehydes or heteroaro-
mates, which were converted into the desired nitroeth-
enes by literature methods.24-27 Additionally, we pre-
pared some 2-phenyl-substituted indoles by known
methods and converted them to the corresponding nitro-
ethene derivatives (Scheme 2), which should provide
some steric restraint in the γ-lactams (see Scheme 2 and
Table 1).
a
Method A: step 1 (1) NaH/EtI, (2) DMF/POCl3; step 2 CH3NO2,
NH4OAc. Method B: N,N-dimethyl-2-nitroethenamine, TFA (R1-
R3 see Table 1).
Ta ble 1
cpd
method (step)
R1
R2
phenyl
4-OMe-phenyl
phenyl
4-OMe-phenyl
H
R3
4a
4b
4c
4d
5c
5d
5e
5f
A(1)
A(1)
A(1)
A(1)
B
H
H
OMe
OMe
H
H
B
OMe
H
H
OMe
OMe
H
H
A(2)
A(2)
A(2)
A(2)
phenyl
4-OMe-phenyl
phenyl
Et
Et
Et
Et
5g
5h
4-OMe-phenyl
Sch em e 3a
Syn th esis of 3,4-Disu bstitu ted P yr r olid in -2-on es
by Mich a el Rea ction . The Michael reaction itself was
performed at -78 °C in the presence of freshly prepared
LDA in THF (Scheme 3). Formation of diastereomers was
observed during every reaction. Therefore we first studied
the influence of the temperature on the ratio of diaster-
eomers. For compounds 7b, 7i, and 7j this ratio was
1
examined by H NMR analysis. Interestingly, even the
sterically more demanding 2-phenyl-substituted indoles
(11) Sarstedt, B.; Winterfeld, E. Heterocycles 1983, 20, 469-476.
(12) J oyce, R. P.; Gainor, J . A.; Weinreb, S. M. J . Org. Chem. 1987,
52, 1177-1185.
a
For R1 and R2 see Table 2.
(13) Moody, C. J .; Rahimtoola, K. F.; Porter, B.; Ross, B. C. J . Org.
Chem. 1992, 57, 2105-2114.
show only moderate to low diastereomeric selectivity with
only a small influence of different temperatures (Table
3).
(14) Beccalli, E. M.; Gelmi, M. L.; Marchesini, A. Tetrahedron 1998,
54, 6909-6918.
(15) Wood, J . L.; Stoltz, B. M.; Dietrich, H.-J .; Pflum, D. A. (Yale
University), PCT Int. Appl. WO 9707081 A2, 1997; Chem. Abstr. 1997,
126, 212287.
(16) Harris, W.; Hill, C. H.; Keech, E.; Malsher, P. Tetrahedron Lett.
1993, 34, 8361-8364.
In contrast to these results the formation of unsubsti-
tuted bisindolylnitrobutanoates (7e) showed high dias-
teroselectivity and, what is even more important, high
sensitivity to just that temperature the reaction mixture
was allowed to warm to. Workup at 195 K instead of 293
K converted the ratio of diastereomers from 99:1 (195 K)
to 10:90 (293 K).
For the reactions affording 7e and 7f, both diastereo-
mers were preparatively separated by column chroma-
tography and, for 7e, further investigated (see below).
We took a two-way approach in order to examine the
influence of chiral substituents on our reaction sequence.
At first we replaced the methyl ester function by a chiral
isopentyl ester moiety, affording the optically pure
compound 10b prepared from 3-indoleacetic acid (10a )
(Scheme 4). This ester was then subjected to a Michael
addition with the 3-indolylnitroethene 5c at -78 °C.
(17) (a) Wood, J . L.; Stoltz, B. M.; Dietrich, H.-J .; Pflum, D. A.;
Petsch, D. J . J . Am. Chem. Soc. 1997, 119, 9641-9651. (b) Wood, J .
L.; Stoltz, B. M.; Goodman, S. N.; Onwueme, K. J . Am. Chem. Soc.
1997, 119, 9652-9661.
(18) Wood, J . L.; Stoltz, B. M.; Dietrich, H.-J . J . Am. Chem. Soc.
1995, 117, 10413-10414.
(19) Moody, C. R.; Rahimtoola, K. F. J . Chem. Soc., Chem. Commun.
1990, 1667-1668.
(20) Stoltz, B. M. Dissertation, Yale University, 1997.
(21) Fabre, S.; Prudhomme, M.; Rapp, M. Bioorg. Med. Chem. Lett.
1993, 1, 193-196.
(22) Sancelme, M.; Fabre, S.; Prudhomme, M. J . Antibiot. 1994, 47,
792-798.
(23) Slater, M. J .; Cockerill, G. S.; Littler, E. (Wellcome Foundation
Ltd.), PCT WO 93/18, 765, 1993; Chem. Abstr 1994, 120, P106760j.
(24) Hu¨nig, S.; Ma¨rkl, G.; Sauer, J . Integriertes Organisches Prak-
tikum; Verlag Chemie: Weinheim, New York, 1979.
(25) Bu¨chi, G.; Mak, C.-P. J . Org. Chem. 1977, 42, 1784.
(26) Mahboobi, S.; Grothus, G.; Angerer, E. v. Arch. Pharm. (Wein-
heim) 1994, 327, 481-492.
The mixture of crude reaction products 9 was analyzed
for diastereomeric ratios by HPLC. The diastereomeric
(27) Mahboobi, S.; Popp, A.; Burgemeister, T.; Schollmeyer, D.
Tetrahedron: Asymmetry 1998, 9, 2369-2376.

Pyrrolidinone and Staurosporine Aglycon
J . Org. Chem., Vol. 64, No. 13, 1999 4699
Ta ble 2. Mich a el Don or s (6a -c) a n d Mich a el Accep tor s (5a -j) a n d P r od u cts of th e Mich a el Rea ction (7a -l) a n d of th e
Su bsequ en t La cta m iza tion (8a -l)
acc
don
R2
R1
5a cf.24
5a
6a
6b
6b
6c
6b
6b
6b
6b
6b
6b
6b
7a
7b
7c
7d
7e
7f
7h
7i
8a 28
8b
8c
8d
8e
8f
8h
8i
8j
phenyl
phenyl
3-pyridyl
3-indolyl
phenyl
3-indolyl
3-indolyl
3-pyridyl
3-indolyl
3-indolyl
3-indolyl
3-indolyl
3-indolyl
3-indolyl
3-indolyl
5bcf.24
5ccf.24
5ccf.25
5d cf.25
5ecf.26
5fcf.26
5 gcf.26
5h cf.26
5j27
3-indolyl
3-(5-methoxyindolyl)
3-(2-phenylindolyl)
3-(1-ethyl-2-(4-methoxyphenyl)indolyl)
3-(1-ethyl-5-methoxy-2-phenyl)-indolyl
3-(1-ethyl-5-methoxy-2-(4-methoxyphenyl))-indolyl
1-butyloxycarbonyl-2-(2S)-pyrrolidinyl
7j
7k
7l
8k
8l
Ta ble 3. Ra tio of Dia ster eom er s d u r in g th e Mich a el
Rea ction
workup temp (K)
ratio of diastereomers
7b
7b
7e
7e
7i
7i
7j
7j
195
293
195
293
293
195
293
195
52:48a
84:16a
99:1b
10:90b
61:39a
59:41a
67:33a
74:26a
a
b
Assigned by 1H NMR analysis. Assigned by quantitative
separation of the diastereomers [erythro:threo].
Sch em e 4
F igu r e 1. ORTEP plot of 7e.
failed because no suitable crystals could be obtained. The
ratio of enantiomers of this reaction was similar to that
stated above.
So we tried to determine the relative configuration of
the nitrobutanoate 7e. We took a suitable crystal from
the racemic mixture of diastereomer A of 7e. This crystal
showed a conformation as shown in Figure 1 (ORTEP
plot29 of 7e diastereomer A with 30% probability for
ellipsoids).30 The two bulky indole substituents adopt an
antiperiplanar conformation, so pointing to opposite
directions. The erythro configuration was assured. This
matches exactly to our results found for the temperature
dependence of the Michael reaction, as the erythro form
is sterically less demanding and should therefore be the
favored product of a kinetically controlled reaction.
The lactam formed from the diastereomer A therefore
adopts an s-cis configuration whereas the diastereomer
B derived lactam should adopt an s-trans configuration.
Each of the two diastereomers of 7e and 7f was
submitted to hydrogenation and lactamization sepa-
rately. Surprisingly, the erythro-diastereomers produced
much more cis-lactams (62% 8e, 56% 8f) than the threo-
diastereomers which only yielded the trans-lactams 8e
and 8f in 8% and 12% yield, respectively.
We tried to shift the chiral information nearer to the
reacting center, similar to our procedure for the 2-fold
excess of this reaction was about 90%. However, the
enantiomeric excess was nearly negligible (about 10% for
each diastereomer). We explain this minimal chiral
induction by the large distance between the localization
of the chiral information (ester function) and the reacting
center. To obtain more starting material for the growth
of a single crystal for X-ray structure analysis, we
transesterified the diastereomer A of methyl butanoate
7e, to assign the stereogenic centers of all diastereomeric
nitrobutanoates by this way. This approach, however,
(28) Langlois, M.; Guillonneau, C.; Vo, V. T.; Maillard, J .; Lannoy,
J .; Nguyen, H. N.; Morin, R.; Manuel, C.; Benharkarte, M. Eur. J . Med.
Chem. Chim. Ther. 1978, 13, 161-164.
(29) 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.
(30) Crystallographic data (excluding structure factors) for the
reported structure have been deposited at the Cambridge Crystal-
lographic Data Center and allocated the deposition number CCDC
117005.

4700 J . Org. Chem., Vol. 64, No. 13, 1999
Mahboobi et al.
Sch em e 5
Sch em e 6
diastereoselective reaction using two chiral educts in a
Michael addition.27 The reaction between our standard
Michael donor 6b and the chiral nitroethene Michael
acceptor 5j27 yielded two diastereomers in equal quanti-
ties (Scheme 5). The reacting temperature, however, had
to be risen to room temperature because otherwise no
reaction could be observed.
prepared as a mixture with the 3-methoxy isomer8,9).
With trans-8f, the same oxidation conditions led to 12%
of 9f. In both cases the isolation of a byproduct (detectable
by thin layer chromatography (TLC)) analogous to 11e
was not possible (Scheme 6).
A more profound investigation of the 7l diastereomers
at the nitrobutanoate level proved to be impracticle due
to complicated NMR spectra, even at elevated tempera-
tures. Therefore, the two 7l diastereomers 7lA and 7lB
were separated and subjected to reduction and lactam-
ization, affording the diastereomers 8lA and 8lB as pure
compounds. We examined the two diasteromers at the
lactam stage (8lA and 8lB). The protons could be as-
signed exactly by high-temperature COSY and NOESY
experiments, but determination of the relative stereo-
chemistry by the Karplus-Conroy equation was impos-
sible (J H3-H4 ) 8.0 Hz for 8lA and J H3-H4 ) 8.3 Hz for
8lB corresponding to a torsion angle of ∼10° or ∼150°).
According to NOESY 8lA shows s-trans configuration for
3-H and 4-H. Nevertheless, the Michael reaction showed
a very good diastereoselectivity as only two of the possible
four optically active diastereomers have been formed. The
assumption that the two diastereomers are epimers could
not be verified up to now, because no suitable crystals
for X-ray analysis could be obtained till now.
Oxid a tive Rin g Closu r e of 3,4-Bisa r ylp yr r olid in -
2-on es. Syn th esis of Sta u r osp or in on e (K-252c). To
examine whether the lactams 8 are suitable substrates
for oxidative ring closure reactions, at first tert-butyl
hypochlorite in the presence of triethylamine, which is a
well-known reactant in carbazole syntheses,13 was tested
using the lactams 8b and 8e (both as mixtures of
diastereomers). No preparatively useful results could be
obtained in any case. For 8b, e.g., oxidation by DDQ in
dry benzene under addition of a catalytic amount of
p-toluenesulfonic acid21 also did not yield cyclized prod-
ucts, while in the case of the diastereomeric mixture of
8e, the cyclization product 2 could be obtained in 60%
yield besides 2% of pyrrolinone 11e isolated only from
large scale oxidations, which might be an intermediate
in a possible sequence with ring closure being the last
step. Separate oxidation trials showed that cis- and trans-
8e were both converted to 2.
This synthetic route is presenting the shortest prepa-
ration of the staurosporine aglycon (three steps from
commercially available or easy obtainable compounds).
Until now, other syntheses of staurosporinone comprise
more steps.6,7,11-14
Con clu sion
The reported method is useful for the synthesis of 3,4-
disubstituted pyrrolidin-2-ones, with a broad variety of
possible substituents. The formation of two new stereo-
genic centers during the Michael addition key step causes
some problems, acquiring stereochemically pure products.
The influence of some experimental parameters on the
ratio of diastereomers was examined, and with the chiral
substituent near the reacting center a good stereoselec-
tivity could be obtained.
Furthermore, the pyrrolidinones were processed to give
staurosporinone derivatives. The overall yield and the
simplicity of the reaction steps favors our reaction
sequence in contrast to the published routes to stauro-
sporinone. With our method, asymmetrically substituted
staurosporinone derivatives are easily accessible and,
what is more important, they can be achieved without
separation of complex mixtures of isomers.
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. Proton nuclear
magnetic resonance spectra, mass spectra, and microanalyses
were performed by Zentrale Analytik, University of Regens-
burg. FT-IR spectroscopy was performed on a FT-IR spectrom-
eter. All chemical shifts are quoted on the δ-scale. Optical
rotations were measured on a polarimeter. Thin-layer chro-
matography (TLC) was carried out on Al sheets coated with
60F245 silica. Compounds were detected using a spray of 3%
w/v vanillin in 96% ethanol followed by 5% w/v H2SO4 in 96%
ethanol. Column chromatography 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.
For lactam 8f, the behavior of the separated diaster-
eomers was studied: cis-8f yielded 15% of the analogous
cyclization product 9f (which until now could only be
X-r a y cr ysta l str u ctu r e a n a lysis of 7e was performed
with an Enraf Nonius Turbo-CAD4 equipped with a rotating

Pyrrolidinone and Staurosporine Aglycon
J . Org. Chem., Vol. 64, No. 13, 1999 4701
anode on a poor quality single crystal with a size of 0.16 ×
0.32 × 0.45 mm: orthorhombic space group Pna21; wavelength
used, Cu KR with graphite monochromator, 1.541 78 Å; T )
298(2) K; unit cell dimensions a ) 16.524(3), b ) 7.823(1), c )
14.0968(8); V ) 1822.1(4) Å3; Z ) 4, d(calc) ) 1.376 g/cm3;
absorption µ ) 0.8 mm-1 (no correction); θ range for data
collection, 1.5-75°; index ranges 0 e h e 20, 0 e k e 9, e l e
17. No. of reflections collected: 4166 (with Friedel pairs). No.
of independent reflections: 3737 [Rσ ) 0.045]. The structure
was solved by direct methods. Structure refinement was by
full-matrix least squares on F2 with anisotropic temperature
factors for all non-hydrogen atoms. Goodness-of-fit on F2:
1.023. Final R indices [I > 2σ(I)]: R1 ) 0.132, wR2 ) 0.391.
The final difference Fourier map showed minimum and
maximum values of -0.58 and 1.41 e Å-3. The absolute
configuration could not be determined. The Flack absolute
structure parameter is 0.2(10).
NMR (90 MHz, CDCl3) δ 1.26 (t, J ) 7 Hz, 3H), 3.94 (s, 3H),
4.09 (q, J ) 7 Hz, 2H), 6.98-7.67 (m, 9H), 7.62, 7.99
(AB-system, J AB ) 15 Hz, 2H). Anal. Calcd for C19H18N2O3
(322.37): C, 70.79; H, 5.63; N, 8.69. Found: C, 70.62; H, 5.63;
N, 8.69.
Gen er a l P r oced u r e for th e Mich a el Ad d ition of Acetic
Acid Der iva tives to Nitr oeth en yl Com p ou n d s. Meth od
A. To a solution of dry diisopropylamide (2.39 mL, 17.0 mmol)
in dry THF (7 mL) in a three-necked flask, equipped with a
deep-temperature thermometer and a septum, was added
n-BuLi (10.4 mL, 17.0 mmol) at -78 °C within 30 min. After
the solution was stirred at 0 °C for 30 min and recooled to
-78 °C, the acetic ester derivative (8.21 mmol), dissolved in
dry THF (50 mL), was added by a syringe within 30 min. The
mixture was stirred at -78 °C for 30 min, and subsequently
the nitroethenyl derivative (9.03 mmol), dissolved in dry THF
(20 mL), was added by syringe. The mixture was vigorously
stirred for 3 h at -78 °C, then saturated NH4Cl solution was
added, and the mixture was allowed to warm to room tem-
perature. The aqueous phase was extracted with ethyl acetate,
the organic extract was washed with water and dried over Na2-
SO4, and the solvent was evaporated in vacuo. The crude
product was purified by column chromatography.
1-E t h yl-2-(4-m et h oxyp h en yl)-1H -3-in d oleca r b a ld e-
h yd e (4b). To a suspension of NaH (60 mmol) (60% suspension
in mineral oil) in 100 mL of dry DMF was added a solution of
2-(4-methoxyphenyl)-1H-indole (40 mmol) in 85 mL of dry
DMF at 0 °C within 15 min, and this mixture was stirred for
30 min at this temperature. Subsequently, ethyl iodide (50
mmol), dissolved in 40 mL of dry DMF, was added dropwise.
The resulting solution was allowed to come to room temper-
ature within 1 h. After it recooled to 0 °C, POCl3 (5.50 mL)
was added dropwise and the solution was stirred for 30 min
at room temperature. Finally the solution was poured into a
mixture of 100 mL of 5 N NaOH and 100 mL of ice water, a
pH value of approximately 9 was adjusted with 5 N NaOH
and 200 mL of ethyl acetate was added. After this mixture
stirring was for 30 min, the organic phase was separated, and
the aqueous phase was extracted with ethyl acetate (2 × 100
mL). The organic phase was dried over Na2SO4. The solution
was allowed to evaporate in the open air overnight, and then
the precipitate was filtered off. After the solvent was carefully
removed in vacuo, a second fraction crystallized. Purification
of the precipitate by column chromatography (CH2Cl2) yielded
the aldehyde as colorless crystals (8.94 g, 32.0 mmol, 80%):
Meth od B. This method is similar to method A, but after
the addition of the nitroethenyl compound the reaction mixture
was stirred for 3 h at -78 °C and then it was allowed to warm
to room temperature overnight.
Meth yl 4-Nitr o-2,3-d ip h en ylbu ta n oa te (7a ). Meth od B.
Column chromatography (CH2Cl2) yielded the product as
colorless crystals (56%): melting range 100-136 °C (mixture
1
of diastereomers); IR (KBr) 3000, 2954, 1740, 1553 cm-1; H
NMR (250 MHz, CDCl3) δ 3.25-3.31 (m, 1.5H), 3.61-3.67 (m,
1.5H), 3.95-4.33 (m, 2.5H), 4.73-4.86 (m, 0.5H), 4.95-5.02
(m, 1H), 7.02-7.58 (m, 10H); MS m/z (%) 299 (6) [M+•], 252
(10), 193 (18), 121 (100), 77 (32). Anal. Calcd for C17H17NO4
(299.33): C, 68.21; H, 5.72; N, 4.68. Found: C, 68.04; H, 5.66;
N, 4.86.
Meth yl 2-(3-1H-In dolyl)-4-n itr o-3-ph en ylbu tan oate (7b).
Meth od A. Column chromatography (CH2Cl2) yielded the
product as colorless crystals (58%): melting range 162-168
mp 147-148 °C; IR (KBr) 2981, 2838, 1642 cm-1 1H NMR
;
(90 MHz, CDCl3) δ 1.33 (t, J ) 7 Hz, 3H), 3.93 (s, 3H), 4.12 (q,
J ) 7 Hz, 2H), 6.92-7.14 (m, 3H), 7.33-7.50 (m, 5H), 9.76 (s,
1H). Anal. Calcd for C18H17NO2 (279.34): C, 77.40; H, 6.13;
N, 5.01. Found: C, 77.09; H, 6.23; N, 5.01.
°C (mixture of diastereomers); IR (KBr) 3415, 1730, 1555 cm-1
;
1H NMR (90 MHz, CDCl3) δ 3.40 (s, 1.5 H), 3.67 (s, 1.5 H),
4.28-4.53 (m, 4H), 7.16-7.38 (m, 10H), 8.15 (br s, 0.5 H) 8.40
(br s, 0.5 H).
1-E t h yl-5-m et h oxy -2-p h en yl-1H -3-in d oleca r b a ld e-
h yd e (4c). The synthesis of compound 4c was effected as
described for the indole derivative 4b. Purification of the
precipitate by column chromatography (CH2Cl2) yielded the
aldehyde as colorless crystals (9.07 g, 33.0 mmol, 83%): mp
Meth od B. Column chromatography (CH2Cl2) yielded the
product as colorless crystals (55%): melting range 155-157
°C (mixture of diastereomers); IR (KBr) 3413, 1733, 1553 cm-1
;
1H NMR (90 MHz, CDCl3) δ 3.40 (s, 2.5 H), 3.67 (s, 0.5 H),
4.28-4.53 (m, 4H), 7.16-7.38 (m, 10H), 8.15 (br s, 0.85 H) 8.40
(br s, 0.15 H); MS m/z (%) 338 (9) [M+•], 188 (100), 160 (23).
Anal. Calcd for C19H18N2O4 (338.36): C, 67.45; H, 5.36; N, 8.27.
Found: C, 66.76; H, 5.20; N, 8.22.
128-129 °C; IR (KBr) 2979, 2961, 1645 cm-1 1H NMR (90
;
MHz, CDCl3) δ 1.30 (t, J ) 7 Hz, 3H), 3.92 (s, 3H), 4.09 (q, J
) 7 Hz, 2H), 6.89-7.07 (m, 1H), 7.26-7.36 (m, 1H), 7.53 (m,
5H), 7.96 (d, J ) 4 Hz), 9.70 (s, 1H). Anal. Calcd for C18H17
-
Meth yl 2-(3-1H-In d olyl)-4-n itr o-3-(3-p yr id yl)bu ta n oa te
(7c). Meth od B. Column chromatography (CH2Cl2/ethyl ac-
etate 1:1) yielded the product as colorless crystals (21%); mp
NO2 (279.34): C, 77.40; H, 6.13; N, 5.01. Found: C, 77.25; H,
6.21; N, 4.90.
1-Eth yl-2-(4-m eth oxyph en yl)-3-(2-n itr o-(E)-1-eth en yl)-
1H-in d ole (5f). A solution of compound 4b (25.1 mmol) and
ammonium acetate (2.00 g) in freshly distilled nitromethane
(28.0 mL) was heated to reflux for 4 h. The solution was
allowed to cool to room temperature overnight, the precipitate
was filtered off and was washed with 30 mL of diethyl ether.
The mother liquor was concentrated and the residue was puri-
fied by column chromatography (CH2Cl2), yielding the product
as yellow crystals (7.90 g, 25.0 mmol, 98%): mp 183-184 °C
1
203-205 °C; IR (KBr) 3413, 1721, 1551 cm-1; H NMR (250
MHz, DMSO-d6) δ 3.15 (s, 3H), 4.03-4.92 (m, 4H), 6.90-7.38
(m, 5H), 7.64-7.93 (m, 2H), 8.31-8.55 (m, 2H), 11.13 (s, 1H);
MS m/z (%) 339 (12) [M+•], 293 (3), 188 (100). Anal. Calcd for
C
18H17N3O4 (339.35): C, 63.71; H, 5.05; N, 12.38. Found: C,
63.85; H, 5.09; N, 12.43.
Eth yl 3-(3-1H-In d olyl)-4-n itr o-2-(3-p yr id yl)bu ta n oa te
(7d ). Met h od B. Column chromatography (CH2Cl2/ethyl
acetate/hexane 5:2:1) yielded the product as yellowish crystals
1
(ethyl acetate); IR (KBr) 3129, 2840, 1611 cm-1; H NMR (90
1
(19%): mp 161-163 °C; IR (KBr) 3413, 1715, 1546 cm-1; H
MHz, CDCl3) δ 1.31 (t, J ) 7 Hz, 3H), 3.93 (s, 3H), 4.13 (q, J
NMR (250 MHz, CDCl3) δ 1.16 (t, J ) 6 Hz, 3H), 4.15 (q, J )
6 Hz, 2H), 4.39-4.73 (m, 2H), 5.01-5.13 (m, 2H), 6.93-7.48
(m, 6H), 7.59-8.79 (m, 2H), 8.19-8.49 (m, 2H); MS m/z (%)
353 (15) [M+•], 307 (1), 165 (70), 143 (100). Anal. Calcd for
) 7 Hz, 2H), 7.00-7.82 (m, 8H), 7.76, 8.03 (AB-system, J AB
)
12.6 Hz, 2H). Anal. Calcd for C19H18N2O3 (322.37): C, 70.79;
H, 5.63; N, 8.69. Found: C, 70.70; H, 5.63; N, 8.67.
1-Eth yl-5-m eth oxy-3-(2-n itr o-(E)-1-eth en yl)-2-p h en yl-
1H-in d ole (5g). The synthesis of compound 5g was effected
as described for the indole derivative 5f. Purification of the
precipitate by column chromatography (CH2Cl2) yielded the
product as yellow crystals (7.97 g, 25.0 mmol, 98%): mp 162-
C
19H19N3O4 (353.38): C, 64.58; H, 5.42; N, 11.89. Found: C,
64.27; H, 5.42; N, 11.92.
Met h yl 2,3-Bis(3-1H -in d olyl)-4-n it r ob u t a n oa t e (7e).
Meth od A. Column chromatography (CH2Cl2-CH2Cl2/ethyl
acetate 19:1) yielded the two diastereomers of 7e.
164 °C (ethyl acetate); IR (KBr) 3141, 2834, 1605 cm-1 1H
;

4702 J . Org. Chem., Vol. 64, No. 13, 1999
Mahboobi et al.
Dia ster eom er A: colorless crystals (10%); mp 192-194 °C
(MeOH); IR (KBr) 3450, 1742, 1560 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 3.25 (s, 3H), 4.45 (dd, 1H, J ) 11.7, 4.0 Hz), 4.48
(d, 1H, J ) 11.5 Hz), 4.60 (m, 1H), 4.77 (dd, 1H, J ) 11.7, 9.6
Hz), 6.99-7.87 (m, 10H), 11.03 (s, 1H), 11.23 (s, 1H); EI-MS
m/z (%) 377 (10) [M+•], 188 (100).
Dia ster eom er B: pale brown crystals (0.1%); mp 132 °C
(MeOH); IR (KBr) 3411, 1732, 1549 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 3.20 (s, 3H), 4.20-4.88 (m, 4H), 6.79-7.90 (m,
10H), 11.00 (s, 1H), 11.30 (s, 1H); EI-MS m/z (%) 377 (6) [M+•],
188 (100).
Meth od B. Dister eom er A: yield 1%.
Dister eom er B: yield 10%.
Meth yl 2-(3-1H-In d olyl)-3-(5-m eth oxy-1H-in d ol-3-yl)-4-
n itr obu ta n oa te (7f). Meth od B. Column chromatography
(CH2Cl2/ethyl acetate 19:1) yielded the two diastereomers of
7f.
7.91-8.20 (m, 1H); MS m/z (%) 541 (4) [M+•], 526 (2), 480 (1),
353 (24), 307 (100), 188 (42). Anal. Calcd for C31H31N3O6
(541.60): C, 68.75; H, 5.77; N, 7.76. Found: C, 68.98; H, 5.99;
N, 7.49.
Meth yl 2-(1H-3-In d olyl)-4-n itr o-3-((2S)-N-ter t-bu tylox-
yca r bon ylp yr r olid in -2-yl)bu ta n oa te (7l). Meth od B. Col-
umn chromatography (CH2Cl2/ethyl acetate 9.5:0.5) yielded the
product as two diastereomers:
Dia ster eom er A: colorless foam (27%); mp 79-82 °C;
[R]2D0 ) -55.4° (c ) 1.02, MeOH); IR (KBr) 3401, 2977, 1734,
1686, 1553 cm-1; 1H NMR (250 MHz, CDCl3) δ 1.35-1.63 (m,
9H), 1.66-2.19 (m, 4H), 2.89-3.58 (m, 3H), 3.65, 3.74 (2s, 3H),
3.92-4.17 (m, 1H), 4.18-4.84 (m, 2H), 4.90-5.14 (m, 1H),
7.05-7.43 (m, 4H), 7.49-7.67 (m, 1H), 8.19, 8.58 (2 br s, 1H);
MS m/z 432 [M + H]+•, 863 [2M + H]+•. Anal. Calcd for
C
22H29N3O6 (431.49): C, 61.24; H, 6.77; N, 9.74. Found: C,
60.85; H, 6.88; N, 9.55.
Dia ster eom er A: brownish oil (12%); IR (neat) 3440, 1710,
1550 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 3.29 (s, 3H), 3.80
(s, 3H), 4.46-4.61 (m, 3H), 4.71-4.80 (m, 1H), 6.75 (dd, J )
8.8, 2.4 Hz, 1H), 7.05-7.19 (m, 3H), 7.23 (d, J ) 8.8 Hz, 1H),
7.38-7.43 (m, 2H), 7.48 (d, J ) 2.5 Hz, 1H), 7.84 (d, J ) 7.1
Hz, 1H), 10.87 (d, J ) 2.1 Hz, 1H), 11.22 (d, J ) 1.8 Hz, 1H);
EI-MS m/z (%) 407 (9) [M+•], 376 (1), 361 (3), 219 (23), 218
(23), 188 (100), 173 (83), 160 (20), 130 (29).
Dia ster eom er B: pale brown oil (24%); IR (neat) 3450,
1715, 1545 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 3.50 (s, 3H),
3.80 (s, 3H), 4.28-4.70 (m, 4H), 6.58-7.85 (m, 9H), 10.85 (d,
J ) 2.2 Hz, 1H), 11.10 (d, J ) 2.5 Hz, 1H); EI-MS m/z (%) 407
(5) [M+•], 361 (3), 219 (1), 218 (4), 188 (100), 173 (94), 160 (35),
130 (56).
Dia ster eom er B: off white foam (26%); mp 121-123 °C;
IR (KBr) 3411, 2977, 1735, 1679, 1553 cm-1 1H NMR (250
;
MHz, CDCl3) δ 1.34-1.61 (m, 9H), 1.79-2.11 (m, 4H), 2.92-
3.59 (m, 3H), 3.63-3.74 (m, 3H), 3.92-5.12 (m, 4H), 7.12-
7.25 (m, 2H), 7.27-7.30 (m, 1H), 7.35-7.41 (m, 1H), 7.61-
7.70 (m, 1H), 8.28 (br s, 1H); MS m/z 432 [M + H]+•, 863 [2M
+ H]+•. Anal. Calcd for C22H29N3O6 (431.49): C, 61.24; H, 6.77;
N, 9.74. Found: C, 60.81; H, 6.79; N, 9.53.
Gen er a l P r oced u r e for th e Red u ction of Nitr obu ta -
n oa tes a n d Su bsequ en t La cta m iza tion . A solution of the
nitrobutanoates 7a -k (0.23 mmol) in dry diethyl ether (1 mL)
and dry ethanol (1 mL) was hydrogenated over Raney-Ni (0.5
g) with 12 bar of H2. After 48 h the autoclave was flushed with
nitrogen, the reaction mixture was filtered through Celite, and
the Celite pad was washed with warm ethanol. The solvent
was evaporated under reduced pressure, the residue was
dissolved in toluene (5 mL), NaH (10 mg, 80% suspension in
mineral oil) was added, and the mixture was refluxed for 2
days. Toluene was removed in vacuo and the residue purified
by column chromatography.
Meth yl 2-(2-1H-In d olyl)-4-n itr o-3-(2-p h en ylin d ol-3-yl)-
bu ta n oa te (7h ). Meth od B. Recrystallization from ethanol
yielded the product as colorless crystals (59%): mp 221-223
°C; IR (KBr) 3406, 1721, 1553 cm-1 1H NMR (400 MHz,
;
DMSO-d6) δ 3.08 (s, 3H), 11.73 (s, 1H), 4.11-4.14 (m, 1H),
4.73 (m, 2H), 5.07 (br s, 1H), 6.61 (m, 1H), 6.88-7.71 (m, 12H),
7.92 (m, 1H), 11.35 (s, 1H); MS m/z (%) 453 (11) [M+•], 265
(22), 219 (100). Anal. Calcd for C27H23N3O4 (453.50): C, 71.51;
H, 5.11; N, 9.27. Found: C, 71.52; H, 5.22; N, 9.77.
Meth yl 3-(1-Eth yl-2-(4-m eth oxyp h en yl)-1H-3-in d olyl)-
2-(1H-3-in d olyl)-4-n itr obu ta n oa te (7i). Meth od A. Column
chromatography (CH2Cl2) yielded the product as colorless
crystals (44%).
3,4-Diph en yl-2-pyr r olidin on e (8a). Recrystallization from
diethyl ether yielded the product as colorless crystals (80%):
mp 170-172 °C; IR (KBr) 3212, 2909, 1694 cm-1 1H NMR
;
(250 MHz, CDCl3) δ 3.85-3.40 (m, 4H), 7.68-7.05 (m, 11H);
MS m/z 237 (87) [M+•], 194 (11), 180 (100). Anal. Calcd for
C16H15NO (237.30): C, 80.98; H, 6.37; N, 5.95. Found: C, 79.30;
H, 6.35; N, 5.88.
Meth od B. Column chromatography (CH2Cl2) yielded the
product as colorless crystals (41%): melting range 98-106 °C;
3-(3-1H-In d olyl)-4-p h en yl-2-p yr r olid in on e (8b). Recrys-
tallization from CH2Cl2/hexane yielded the product as colorless
crystals (18%): mp 199-212 °C; IR (KBr) 3255, 2884-3060,
1667 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 3.32-4.04 (m, 4H),
6.61-7.46 (m, 10H), 7.78-7.97 (m, 2H); MS m/z 276 (100)
[M+•], 232 (6), 218 (20), 157 (55), 130 (46). Anal. Calcd for
IR (KBr) 3411, 2952, 1737, 1553 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 0.99-1.18 (m, 3H), 3.31-3.60 (m, 3H), 3.70-3.98 (m,
5H), 4.21-5.40 (m, 4H), 6.70-6.89 (m, 1H), 7.11-7.37 (m, 4H),
7.16-7.25 (m, 3H), 7.26-7.34 (m, 2H), 7.39-7.60 (m, 2H),
7.66-7.84 (m, 1H), 7.88-8.19 (m, 1H); MS m/z (%) 511 (5)
[M+•], 596 (1), 450 (1), 323 (28), 277 (100), 188 (7). Anal. Calcd
for C30H29N3O5 (511.58): C, 70.44; H, 5.71; N, 8.21. Found:
C, 70.23; H, 5.81; N, 8.07.
Met h yl 3-(1-E t h yl-5-m et h oxy-2-p h en yl-1H -3-in d olyl)-
2-(1H-3-in d olyl)-4-n itr obu ta n oa te (7j). Meth od A. Column
chromatography (CH2Cl2) yielded the product as off white
crystals (44%).
C
18H16N2O (276.34): C, 78.24; H, 5.84; N, 10.14. Found: C,
77.98; H, 5.79; N, 10.23.
3-(3-1H-In d olyl)-4-(3-p yr id yl)-2-p yr r olid in on e (8c). Col-
umn chromatography (ethyl acetate/MeOH 5:2) yielded the
product as colorless crystals (34%): melting range 138-164
°C (mixture of diastereomers); IR (KBr) 3247, 2877-3058, 1690
cm-1 1H NMR (250 MHz, DMSO-d6) δ 3.03-3.78 (m, 4H),
;
6.60-7.21 (m, 6H), 7.52-7.77 (m, 2H), 8.12-8.28 (m, 2H),
10.63 (br s, 1H); MS m/z 277 (100) [M+•], 233 (11), 219 (27),
157 (62), 130 (69). Anal. Calcd for C17H15N3O (277.33): C,
73.63; H, 5.45; N, 15.15. Found: C, 73.29; H, 5.32; N, 14.84.
4-(3-1H-In d olyl)-3-(3-p yr id yl)-2-p yr r olid in on e (8d ). Re-
crystallization from acetone yielded the product as colorless
crystals (77%): mp 200-205 °C; IR (KBr) 3330, 3238-2898,
1692 cm-1; 1H NMR (250 MHz, CD3OD) δ 3.56-4.02 (m, 4H),
7.83-7.42 (m, 6H), 7.63-7.76 (m, 1H), 8.32-8.47 (m, 2H); MS
m/z 277 (100) [M+•], 233 (24). Anal. Calcd for C17H15N3O
(277.33): C, 73.63; H, 5.45; N, 15.15. Found: C, 73.97; H, 5.47;
N, 14.91.
3,4-Bis-(3-1H-in d olyl)-2-p yr r olid in on e (8e). Dia ster e-
om er A. According to the general procedure for the reduction
of nitrobutanoates and subsequent lactamization, the crude
product was obtained from 7e (diastereomer A). Column
chromatography (CH2Cl2/ethyl acetate 1:1) yielded the product
Meth od B. Column chromatography (CH2Cl2) yielded the
product as off white crystals (46%): melting range 99-103 °C;
IR (KBr) 3413, 2952, 1734, 1553 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 0.99-1.17 (m, 3H), 3.35-3.80 (m, 4H), 3.82-3.97 (m,
4H), 4.18-5.39 (m, 4H), 6.68-6.95 (m, 2H), 7.03-7.25 (m, 5H),
7.27-7.65 (m, 6H), 7.91-8.19 (m, 1H); MS m/z (%) 511 (7)
[M+•], 596 (1), 450 (2), 323 (42), 277 (100), 188 (41). Anal. Calcd
for C30H29N3O5 (511.58): C, 70.44; H, 5.71; N, 8.21. Found:
C, 70.59; H, 5.85; N, 7.95.
Meth yl 3-(1-Eth yl-5-m eth oxy-2-(4-m eth oxyp h en yl)-1H-
3-in dolyl)-2-(1H-3-in d olyl)-4-n itr obu ta n oa te (7k ). Meth od
B. Column chromatography (CH2Cl2) yielded the product as
off white crystals (60%): melting range 100-104 °C; IR (KBr)
3409, 2952, 1737, 1551 cm-1 1H NMR (250 MHz, CDCl3) δ
;
0.99-1.16 (m, 3H), 3.34-3.76 (m, 3H), 3.87-3.95 (s, 8H), 4.21-
5.39 (m, 4H), 6.75-6.88 (m, 1H), 6.91 (m, 1H), 7.11-7.37 (m,
4H), 7.14-7.17 (m, 1H), 7.17-7.25 (m, 2H), 7.30-7.55 (m, 3H),

Pyrrolidinone and Staurosporine Aglycon
J . Org. Chem., Vol. 64, No. 13, 1999 4703
as colorless crystals (87%): mp 233-237 °C (dec); IR (KBr)
3270, 1685, 1460 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 3.30-
3.40 (m, 1H), 3.66-3.72 (m, 0.5H), 3.77-3.85 (m, 0.5H), 4.00-
4.09 (m, 1H), 4.15-4.28 (m, 1H), 6.70-7.58 (m, 10H), 7.91 (s,
0.5H), 8.00 (s, 0.5H), 10.52 (s, 0.5H), 10.64 (s, 0.5H), 10.83 (s,
0.5H), 10.86 (s, 0.5H); MS m/z 315 (62) [M+•], 258 (11), 158
(100), 157 (65).
(m, 3H), 3.59-3.84 (m, 6H), 3.86-3.98 (m, 4H), 4.03-4.11 (m,
1H), 4.15-4.33 (m, 1H), 6.67-6.63 (m, 1H), 6.75-7.08 (m, 6H),
7.08-7.32 (m, 4H), 7.37-7.84 (m, 1H), 10.76-10.91 (m, 1H),
lactam-NH not observed; MS m/z 479 (100) [M+•], 449 (4), 322
(81), 294 (35), 157 (5). Anal. Calcd for C30H29N3O3 (479.58):
C, 75.13; H, 6.09; N, 8.76. Found: C, 74.86; H, 5.94; N,
8.85.
Dia ster eom er B. According to the general procedure for
the reduction of nitrobutanoates and subsequent lactamization
the crude product was obtained from 7e (diastereomer B).
Column chromatography (CH2Cl2/ethyl acetate/methanol 4:4:
1) yielded the product as colorless crystals (8%): mp 169-173
°C; IR (KBr) 3419, 2876, 1707, 1460 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 3.40-4.10 (m, 4H), 6.85-7.50 (m, 10H), 10.78 (s,
1H), 10.82 (s, 1H). EI-MS m/z (%) 315 (83) [M+•], 257 (16), 158
(100), 157 (59), 130 (49). Anal. Calcd for C20H17N3O (315.37):
C, 76.17; H, 5.43; N, 13.32. Found: C, 75.95; H, 5.54; N, 13.06.
3-(2-1H -In d olyl)-3-(5-m et h oxy-1H -in d ol-3-yl)-2-p yr r o-
lid in on e (8f).
3-(1H-3-In d olyl)-4-((2S)-N-ter t.-bu tyloxyca r bon ylp yr -
r olid in -2-yl)-2-p yr r olid in on e (8l). Dia ster eom er A. Col-
umn chromatography (CH2Cl2/methanol 9.5:0.5) yielded the
product as colorless crystals (41%): mp 121-123 °C; [R]D20
)
-5.8° (c ) 0.99, MeOH); IR (KBr) 3284, 2975, 1692 cm-1; H
NMR (400 MHz, CD2Cl2, 253 K) δ 1.31 (s, 3H), 1.41 (s, 6H),
1.64-1.98 (m, 4H), 3.12-3.33 (m, 3H), 3.39 (m, 2H), 3.79 (d,
J ) 8.3 Hz, 1H), 3.87 (dd, J ) 10.1, 10.1 Hz, 1H), 6.65 (m,
1H), 6.85-6.95 (m, 1H), 7.04-7.18 (m, 2H), 7.32-7.39 (m, 1H),
7.55-7.59 (m, 1H), 9.31, 9.46 (2s, 1H); FAB-MS m/z 370 [M +
H]+. Anal. Calcd for C21H27N3O3 (369.47): C, 68.27; H, 7.37;
N, 11.37. Found: C, 67.95; H, 7.29; N, 11.47.
1
Dia ster eom er A (Der ived fr om 7f, Dia ster eom er A).
Column chromatography (CH2Cl2/ethyl acetate/methanol 4:4:
1) yielded the product as pale brown crystals (56%): mp 226-
Dia ster eom er B. Column chromatography (CH2Cl2/metha-
nol 9.5:0.5) yielded the product as colorless crystals (44%): mp
149-151 °C; IR (KBr) 3290, 2975, 1690 cm-1; [R]D20 ) -105.1°
(c ) 0.77, MeOH); 1H NMR (400 MHz, C2D2Cl4, 323 K) δ 1.36
(s, 9H), 1.65-1.90 (m, 4H), 2.99 (dddd, J ) 6.9, 7.2, 8.0, 8.1
Hz, 1H), 3.11-3.19 (m, 1H), 3.40 (dd, J ) 6.9, 10.0 Hz, 1H),
3.43-3.47 (m, 1H), 3.50 (dd, J ) 8.1, 10.0 Hz, 1H), 3.64 (d, J
) 8.0 Hz, 1H), 4.10 (dd, J ) 2.7, 7.2 Hz, 1H), 5.55 (br s, 1H),
7.05 (s, 1H), 7.07 (ddd, J ) 1.0, 7.0, 8.0 Hz, 1H), 7.15 (ddd, J
) 1.2, 7.0, 8.2 Hz, 1H), 7.31 (dd, J ) 0.9, 8.1 Hz, 1H), 7.55
(dd, J ) 1.0, 7.9 Hz, 1H), 8.00 (br s, 1H); FAB-MS m/z 370 [M
+ H]+. Anal. Calcd for C21H27N3O3 (369.47): C, 68.27; H, 7.37;
N, 11.37. Found: C, 68.11; H, 7.38; N, 11.55.
(-)-S-2-Meth yl-1-bu tyl 2,3-Bis(3-1H-in d olyl)-4-n itr obu -
ta n oa te (9). Meth od A. The mixture of diastereomer A of 7e
(0.1 g, 0.26 mmol) and titanium tetrakis((-)-S-2-methyl-1-
butoxide) (0.2 mL, 0.59 mmol) in (-)-S-2-methyl-1-butanol (2
mL) was refluxed for 20 h (TLC control). The mixture was
cooled, and excess alcohol was removed under reduced pres-
sure. The residue was dissolved in diethyl ether, and 2 drops
of 1 N HCl was added. The etheral phase was washed with
water, dried over Na2SO4, and evaporated. The crude product
was purified by column chromatography ((1) hexane/ethyl
acetate 1:10, (2) hexane/ethyl acetate 1:3), affording the
product as colorless crystals (62 mg, 0.14 mmol, 55%): mp 79
°C (diisopropyl ether); IR (KBr) 3420, 3120-2930, 1719, 1551
cm-1; [R]D20 ) -15.8° (c ) 0.01, CHCl3); 1H NMR (250 MHz,
CDCl3) δ 0.52 (t, 3H, J ) 7.3 Hz), 0.63 (d, 3H, J ) 6.6 Hz),
1.00 (m, 2H), 1.32 (m, 1H), 3.56 (m, 2H), 4.56-4.82 (m, 4H),
7.10-7.90 (m, 10H), 8.10 (s, 1H), 8.26 (s, 1H); MS m/z 433 (9)
[M+•], 244 (100), 189 (2), 174 (13), 143 (74). Anal. Calcd for
229 °C (methanol/hexane); IR (KBr) 3265, 1680, 1460 cm-1
;
1H NMR (250 MHz, DMSO-d6) δ 3.37-4.07 (m, 4H), 3.48 (s,
3H), 6.80-7.34 (m, 9H), 7.92 (s, 1H), 10.69 (d, J ) 2.0 Hz,
1H), 10.82 (d, J ) 1.5 Hz, 1H); MS m/z 345 (98) [M+•], 188
(100), 157 (27). Anal. Calcd for C21H19N3O2 (345.40): C, 73.03;
H, 5.54; N, 12.17. Found: C, 73.39; H, 5.21; N, 11.90.
Dia ster eom er B (Der ived fr om 7f, Dia ster eom er B).
Column chromatography (CH2Cl2/ethyl acetate/methanol 4:4:
1) yielded the product as colorless crystals (12%): mp 163-
165 °C (methanol/hexane); IR (KBr), 3270, 1685, 1465 cm-1
;
1H NMR (250 MHz, DMSO-d6) δ 3.63 (s, 3H), 3.66-4.22 (m,
4H), 6.53-7.54 (m, 9H), 7.99 (s, 1H), 10.36 (d, J ) 1.6 Hz,
1H), 10.82 (d, J ) 1.3 Hz, 1H); MS m/z 345 (86) [M+•], 188
(100), 157 (30). Anal. Calcd for C21H19N3O2 (345.40): C, 73.03;
H, 5.54; N, 12.17. Found: C, 73.25; H, 5.33; N, 12.01.
3-(2-1H-In d olyl)-4-(2-p h en yl-1H-in d ol-3-yl)-2-p yr r olid i-
n on e (8h ). Recrystallization from methanol yielded the prod-
uct as colorless crystals (93%): mp 200-203 °C (dec); IR (KBr)
3251-3394, 2875-3054, 1690 cm-1 1H NMR (400 MHz,
;
DMSO-d6) δ 3.53 (m, 1H), 3.81 (m, 1H), 4.29-4.37 (m, 2H),
6.97-7.36 (m, 12H), 7.72 (m, 1H), 7.72 (s, 1H), 11.00 (s, 1H),
11.45 (s, 1H); MS m/z 391 (42) [M+•], 333 (8), 234 (92), 193
(100). Anal. Calcd for C26H21N3O (391.47): C, 79.77; H, 5.41;
N, 10.73. Found: C, 79.74; H, 5.81; N, 10.72.
4-(1-Eth yl-2-(4-m eth oxyp h en yl)-1H-3-in d olyl)-3-(1H-3-
in d olyl)-2-p yr r olid in on e (8i). Column chromatography (eth-
yl acetate) yielded the product as a colorless powder (23%):
melting range 220-225 °C (ethyl acetate, mixture of diaster-
eomers); IR (KBr) 3404, 3276, 2973, 1692 cm-1; 1H NMR (250
MHz, DMSO-d6) δ 0.92-1.08 (m, 3H), 3.54-3.60 (m, 1H),
3.65-4.17 (m, 7H), 4.19-4.33 (m, 1H), 6.70-7.34 (m, 10H),
7.40-7.55 (m, 1H), 7.71-7.94 (m, 2H), 10.67-10.87 (m, 1H),
lactam-NH not observed; MS m/z 449 (100) [M+•], 419 (1), 292
(72), 264 (35), 157 (20). Anal. Calcd for C29H27N3O2 × 1 ethyl
acetate (493.61): C, 75.43; H, 6.33; N, 8.51. Found: C, 75.21;
H, 6.04; N, 8.97.
4-(1-E t h yl-5-m et h oxy-2-p h en yl-1H -3-in d olyl)-3-(1H -3-
in d olyl)-2-p yr r olid in on e (8j). Column chromatography (eth-
yl acetate) yielded the product as a colorless powder (32%):
mp 273-275 °C (ethyl acetate); IR (KBr) 3413, 3226, 2975,
1677 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 0.92-1.05 (m, 3H),
3.52-3.58 (m, 1H), 3.60-3.95 (m, 7H), 4.16-4.35 (m, 1H),
6.70-6.99 (m, 4H), 7.01-7.07 (m, 1H), 7.10-7.15 (m, 1H),
7.20-7.28 (m, 1H), 7.29-7.52 (m, 5H), 7.76-7.85 (m, 1H),
10.73-10.87 (m, 1H), lactam-NH not observed; MS m/z 449
(100) [M+•], 419 (1), 292 (54), 264 (23), 157 (4). Anal. Calcd for
C
25H27N3O4 (433.51): C, 69.27; H, 6.28; N, 9.69. Found: C,
69.19; H, 6.23; N, 9.65.
Meth od B. According to the general procedure for the
Michael addition of acetic acid derivatives with nitroethenyl
compounds, 10b and 5c were reacted to yield compound 9 as
colorless crystals (61%).
(-)-S-2-Meth yl-1-bu tyl 3-1H-In d olyl Aceta te (10b). A
mixture of (-)-S-2-methyl-1-butanol (5.00 mL, 80.0 mmol), (3-
1H-indolyl)acetic acid (10a ) (14.0 g, 80.0 mmol), and concen-
trated H2SO4 (5 drops) in toluene (150 mL) was refluxed for
1.5 h, cooled, poured into ice water, and extracted with diethyl
ether. The etheral layer was washed with saturated NaHCO3
solution and water, dried over MgSO4, and evaporated under
reduced pressure. The crude product was purified by column
chromatography (CH2Cl2), affording the product as a colorless
oil (16 g, 81%): IR (neat) 3415, 3123-2934, 1740, 1458 cm-1
;
[R]2D0 ) +12.2° (c ) 0.01, CHCl3); 1H NMR (250 MHz, DMSO-
d6) δ 0.81-0.84 (m, 6H), 1.30 (m, 2H), 1.62 (m, 1H), 3.74 (s,
2H), 3.83 (m, 2H), 6.94-7.50 (m, 5H), 10.92 (s, 1H). Anal. Calcd
for C15H19NO2 (245.32): C, 73.34; H, 7.81; N, 5.71. Found: C,
73.11; H, 7.71; N, 5.59.
C
29H27N3O2 × 1 ethyl acetate (537.66): C, 73.72; H, 6.56; N,
7.81. Found: C, 73.82; H, 6.81; N, 7.80.
4-(1-Eth yl-5-m eth oxy-2-(4-m eth oxyp h en yl)-1H-3-in d o-
lyl)-3-(1H-3-in d olyl)-2-p yr r olid in on e (8k ). Column chro-
matography (ethyl acetate) yielded the product as a colorless
powder (38%): mp 261 °C (dec) (ethyl acetate); IR (KBr) 3218,
6,7,12,13-Tetr ah ydr o-5H-in dolo[2,3-a ]pyr r olo[3,4-c]car -
ba zol-5(6H)-on e (2). (Sta u r osp or in Aglycon (K-252c)). 8e
(mixture of diastereomers A and B) (0.20 g, 0.63 mmol) was
1
2935, 1694 cm-1; H NMR (250 MHz, DMSO-d6) δ 0.93-1.06

4704 J . Org. Chem., Vol. 64, No. 13, 1999
Mahboobi et al.
ether, dec); IR (KBr) 3420, 1655, 1540 cm-1 1H NMR (250
MHz, DMSO-d6) δ 4.54 (s, 2H), 6.71-7.47 (m, 10H), 8.19 (s,
1H), 11.24 (d, J ) 1.5 Hz, 1H), 11.36 (d, J ) 1.3 Hz, 1H); MS
m/z 313 (100) [M+•], 130 (44).
6,7,12,13-Tet r a h yd r o-9-m et h oxy-5H-in d olo[2,3-a ]p yr -
r olo[3,4-c]ca r ba zol-5(6H)-on e (9f). Prepared analogous to
2 as colorless crystals from the following substrates: 8f
(diastereomer A) 32 mg, 0.09 mmol, 15%; 8f (diastereomer B)
26 mg, 0.08 mmol, 12%. Data: mp >350 °C (methanol); IR
(KBr) 3435, 3320, 1645, 1555 cm-1; 1H NMR (250 MHz, DMSO-
d6) δ 3.91 (s, 3H), 4.98 (s, 2H), 7.09-9.29 (m, 7H), 8.48 (s, 1H),
11.28 (s, 1H), 11.40 (s, 1H); MS m/z 341 (100) [M+•]. Anal. Calcd
for C21H15N3O2 (341.37): C, 73.89; H, 4.43; N, 12.31. Found:
C, 74.24; H, 4.68; N, 11.95.
suspended in dry benzene (105 mL) and DDQ (0.30 g, 1.33
mmol), and p-toluenesulfonic acid monohydrate (15.0 mg, 0.08
mmol)) was added. The mixture was stirred for 24 h at ambient
temperature and then the solvent was evaporated below 25
°C. The residue was dissolved in ethyl acetate (150 mL),
washed with saturated NaHSO3 solution (2 × 50 mL) and
brine (2 × 50 mL), and dried over Na2SO4. The solvent was
removed under reduced pressure, and the crude product was
purified by column chromatography (CH2Cl2/ethyl acetate/
methanol 20:3:0.5) affording the product as pale yellow crystals
(0.12 g, 0.38 mmol, 60%): mp 310 °C (ethanol/diethyl ether,
;
dec; cf.11 313 °C); IR (KBr) 3440, 3315, 1645, 1560, 1455 cm-1
;
1H NMR (400 MHz, DMSO-d6) δ 4.97 (s, 2H), 7.21-7.25 (m,
1H), 7.29-7.33 (m, 1H), 7.41-7.45 (m, 1H), 7.46-0.50 (m, 1H),
7.73 (d, J ) 8.1 Hz, 1H), 7.80 (d, J ) 8.1 Hz, 1H), 8.05 (d, J )
7.8 Hz, 1H), 8.50 (s, 1H), 9.26 (d, J ) 7.9 Hz, 1H), 11.33 (s,
1H), 11.50 (s, 1H); MS m/z 311 (83) [M+•], 282 (100), 255 (58),
227 (22), 201 (13).
Su p p or tin g In for m a tion Ava ila ble: X-ray structural
data for compound 7e, including tables of atomic coordinates,
bond lengths, and bond angles. This material is available free
of charge via the Internet at http://pubs.acs.org.
3,4-Bis(3-1H-in d olyl)-2,5-d ih yd r o-1H-2-p yr r olon e (11e).
Isolated as a byproduct from the column chromatography of 2
as colorless crystals (8 mg, 0.03 mmol, 2%): mp 101 °C (diethyl
J O9825106