Synthetic Approaches to Indolo[6,7-α]pyrrolo[3,4-c]carbazoles: Potent Cyclin D1/CDK4 Inhibitors

Article abstract of DOI:10.1021/jo035606v

Synthesis of indolo[6,7-α]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the synthesis of 2 were identified that required new methods f

Full text of DOI:10.1021/jo035606v

Syn th etic Ap p r oa ch es to In d olo[6,7-a ]p yr r olo[3,4-c]ca r ba zoles:
P oten t Cyclin D1/CDK4 In h ibitor s
Margaret M. Faul,*,†,‡ Thomas A. Engler,*,§ Kevin A. Sullivan,‡ J ohn L. Grutsch,‡
Marcella T. Clayton,‡ Michael J . Martinelli,‡ J oseph M. Pawlak,‡ Michael LeTourneau,‡
D. Scott Coffey,‡ Steven W. Pedersen,‡ Stanley P. Kolis,‡ Kelly Furness,§ Sushant Malhotra,§
Rima S. Al-awar,§ and J ames E. Ray§
Global Chemical Process Research and Development, Indianapolis, Indiana 46285, and
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285
mfaul@amgen.com; tae@lilly.com
Received October 31, 2003
Synthesis of indolo[6,7-a]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by
oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the
synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole
acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction
of functionality (-OR, NR2) at C12 and N13 facilitating structure-activity relationship (SAR)
evaluation of this indolocarbazole platform.
In tr od u ction
carbazole alkaloids with [a]annulation,10,13,14 we recently
reported a new class of indolo[6,7-a]pyrrolo[3,4-c]carba-
zoles represented by 1a , 1d , and 1g that were potent
inhibitors of cyclin D1/CDK4 in vitro, in whole cells12 and
in solid tumors upon intravenous administration.15
Our initial efforts in this area focused on the potent
CDK4 inhibitor 1a ; however, its low aqueous solubility
(<1 µg/mL at a variety of pHs) presented a challenge for
clinical development. Further evaluation of the indolo-
[6,7-a]pyrrolo[3,4-c]carbazole platform SAR revealed that
large substituents were tolerated at C12 and N13. For
example, 1b and 1e both had IC50 values e75 nM in
cyclin D1/CDK4 assays; unfortunately, their aqueous
solubilities were only marginally better than 1a . To
improve the aqueous solubility of this platform, we
turned our attention to introducing amino-containing
substituents at the C12 and N13 positions as represented
The eukaryotic cell division cycle is a tightly controlled
process that is regulated by the cyclin/CDK family of
protein kinase complexes. Stringent control of this pro-
cess is essential to ensure that DNA synthesis and
subsequent mitotic division is accurately executed. There
is now strong evidence that CDKs, their regulators, and
substrates are the targets of genetic alteration in many
human cancers.1-4 Their frequent deregulation in human
tumors make them attractive targets for the identifica-
tion of new anti-neoplastic agents.5 A number of small
molecules such as flavopiridol6,7 and UCN-018 have been
identified as inhibitors of the CDKs and are currently
showing promising results in early clinical trials (Chart
1).
Intensive effort has been expended in recent years to
identify novel inhibitors of cyclin D1/CDK4.9-12 Although
most of this effort has focused on the pyrrolo[3,4-c]-
(9) Sanchez-Martinez, C.; Shih, C.; Faul, M. M.; Zhu, G.; Paal, M.;
Somoza, C.; Li, T.; Krumrich, C.; Winneroski, L.; Xun, Z.; Brooks, H.
B.; Patel, P.; Schultz, R. M.; DeHahn, T. D.; Kirmani, K.; Spencer, C.
D.; Watkins, S. A.; Considine, E.; Dempsey, J . A.; Ogg, C. Bioorg. Med.
Chem. Lett. 2003, 13, 3835-3839.
(10) Zhu, G.; Conner, S. E.; Zhou, X.; Shih, C.; Li, T.; Brooks, H. B.;
Considine, E.; Dempsey, J . A.; Faul, M. M.; Ogg, C.; Patel, B.; Schultz,
R. M.; Spencer, C. D.; Teicher, B.; Watkins, S. A. J . Med. Chem. 2003,
46, 2027-2030.
(11) Zhu, G.; Conner, S.; Zhou, X.; Shih, C.; Brooks, H. B.; Considine,
E.; Dempsey, J . A.; Ogg, C.; Patel, B.; Schultz, R. M.; Spencer, C. D.;
Teicher, B.; Watkins, S. A. Bioorg. Med. Chem. Lett. 2003, 13, 1231-
1235.
(12) Engler, T. A.; Furness, K.; Malhotra, S.; Sanchez-Martinez, C.;
Shih, C.; Xie, W.; Zhu, G.; Zhou, X.; Conner, S.; Faul, M. M.; Sullivan,
K. A.; Kolis, S. P.; Brooks, H. B.; Patel, B.; Schultz, R. M.; DeHahn, T.
B.; Kirmani, K.; Spencer, C. D.; Watkins, S. A.; Considine, E. L.;
Dempsey, J . A.; Ogg, C. A.; Stamm, N. B.; Anderson, B. D.; Campbell,
R. M.; Vasudevan, V.; Lytle, M. L. Bioorg. Med. Chem. Lett. 2003, 13,
2261-2267.
† Current address: Chemical Process Research and Development,
Amgen, Inc., One Amgen Center Dr., 29-M-B, Thousand Oaks, CA
91320.
‡ Global Chemical Process Research and Development.
§ Lilly Research Laboratories.
(1) Damiens, E.; Meijer, L. Pathol. Biol. 2000, 48, 340-351.
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10.1021/jo035606v CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004
J . Org. Chem. 2004, 69, 2967-2975
2967

Faul et al.
CHART 1
SCHEME 1
by analogues 1d and 1g. The aqueous solubility of 1d
and 1g, as their mesylate salts was 8.6 and 8.5 mg/mL,
respectively. To support toxicological and pharmacologi-
cal evaluation of these compounds, we required a syn-
thetic route that would afford multigram quantities of
material for pre-clinical evaluation. Although numerous
synthetic approaches to pyrrolo[3,4-c]carbazole alkaloids
have been reported,16-18 no synthetic details have ap-
peared on the synthesis of this new indolo[6,7-a]pyrrolo-
[3,4-c]carbazole class. This manuscript describes the first
full disclosure of our synthetic efforts in this area, with
1a -g as representative examples.
other. In addition, a number of synthetic challenges were
identified with each of these approaches that included
(i) identification of an efficient and scaleable method for
the synthesis of 7-substituted indoles 3 and 619 and (ii)
development of a robust oxidation procedure for conver-
sion of maleimides 2 to carbazoles 1. Furthermore, it was
critical that a general route to the synthesis of 1 was
developed that would enable structure-activity relation-
ship (SAR) evaluation of this platform and allow for the
facile introduction of functionality (-OR, NR2) at C12 and
N13.12 This manuscript describes our efforts in achieving
these goals.
In d ole-Oxoa ceta te Syn th esis. 1-Methyl-R-oxoindole-
3-acetates 4a -c were prepared in good yields by treat-
ment of 6-methoxyindoles 7 or 8 with oxalyl chloride,
followed by in situ quench of the acid chloride with MeOH
or NaOMe at low temperature (r60 °C) (Scheme 2).
The indole required for synthesis of 4c was not com-
mercially available but was prepared from 2-(2-nitro-
phenyl)ethanol 9. Silyl protection of 9 followed by a
Bartoli indole synthesis produced the protected 7-hy-
droxyethylindole 11 in 54% yield (Scheme 3).20 Glyoxy-
lation via the procedure outlined above afforded, after
in situ desilylation, 4c in three steps and 31% overall
yield from 9.
Resu lts a n d Discu ssion
We envisioned that indolo[6,7-a]pyrrolo[3,4-c]carba-
zoles 1a -g could be prepared by oxidative cyclization of
aryl indolylmaleimides 2a -e (Scheme 1). The aryl in-
dolylmaleimides would be prepared either (i) by conden-
sation of N-methylindole-7-acetamide 3 with the substi-
tuted glyoxylates 4 (strategy A) or (ii) by condensation
of the substituted indole-3-acetamides 5 with alkyl (1-
methyl indol-7-yl)oxoacetates 6 (strategy B). At the outset
of this work, it was not clear if one set of coupling
partners would offer a significant advantage over the
(16) Gribble, G. W.; Berthel, S. J . Tetrahedron 1992, 48, 8869-8880.
(17) Gribble, G. W.; Berthel, S. J . Stud. Nat. Prod. Chem. 1993,
(Stereoselective Synthesis (Pt. H)), 365-409.
(19) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett.
2003, 5, 1899-1902.
(20) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129-2132.
(18) Knoelker, H.-J .; Reddy, K. R. Chem. Rev. 2002, 102, 4303-4427.
2968 J . Org. Chem., Vol. 69, No. 9, 2004

Synthetic Approaches to Indolo[6,7-a]pyrrolo[3,4-c]carbazoles
SCHEME 2 a
SCHEME 4 a
a
Key: (a) s-BuLi, TMEDA, MTBE; (b) (EtO2C)2, 59%; (c) TFA;
(d) TFAA, DMSO, 81%; (e) NaH, MeI, DMF, 85%.
a
Key: (a) (i) (COCl)2, THF, (ii) MeOH, 79%; (b) NaH, DMF,
SCHEME 5 a
Br(CH2)3OTBDMS, 100%; (c) (i) (COCl)2, Et2O, (ii) NaOMe, MeOH,
79%.
SCHEME 3 a
a
Key: (a) CH2dNMe2Cl, CH2Cl2, 100%; (b) NaCN, DMSO,
EtOAc, 80 °C, 82%; (c) KOH, t-BuOH or Rhodococcus rhodochrous,
toluene, 88%.
16 was removed by chromatography and although methyl
ester 6a remained as an impurity, it was expected that
it would also undergo the condensation reaction to
generate 2 and would not pose a problem in the synthesis
of 1.
Aceta m id e Syn th esis. Two approaches for the syn-
thesis of 6-methoxyindole-3-acetamides 5a and 5b were
evaluated. Synthesis via gramine 17 afforded 5a in four
steps and 65% yield (Scheme 5).22-24 On large scale,
hydrolysis of 18 to 5a was problematic due to competitive
formation of the carboxylic acid. Although not widely
published, we found that selective hydrolysis of indole-
3-acetonitrile 18 to 5a could be performed in 88% yield
using whole cells of Rhodococcus rhodochrous J -1 in
toluene as a solvent.25 However, due to the limited
availability of the R. rhodochrous organism this reaction
was not amenable to large scale.
a
Key: (a) TBDMSCl, imidazole, CH2Cl2, 96%; (b) CH2dCHMgBr;
-45 °C, THF, 56%; (c) (COCl)2, Et2O; NaOMe, MeOH, 57%.
Two approaches were evaluated for synthesis of N-
methyl (indol-7-yl)oxoacetates 6. Our first approach
involved halogen-metal exchange of 7-bromo N-meth-
ylindole, and treatment of the lithiated intermediate with
dimethyl oxalate to afford a 57% yield of 6a . Although
this approach was expedient, the high cost of 7-bromo-
indole (>$50/g) discouraged application of this chemistry
on large scale.
Our second approach to 6 was based upon a directed
metalation of the readily available N-Boc indoline 12.21
Reaction of 12 with s-BuLi/TMEDA followed by addition
of diethyl oxalate afforded a 59% yield of 13, which
crystallized directly from the reaction mixture (Scheme
4). The major byproduct of this reaction was indoline 15
formed by reaction of the aryllithium with 12. Although
levels of 15 could be controlled by rigorously maintaining
the reaction temperature at -78 °C, further improvement
in the yield was not realized. Removal of the N-Boc
protecting group and trifluoroacetic anhydride mediated
oxidation of the resultant indoline afforded ethyl (indol-
7-yl)-oxo acetate 15 in 81% yield. Methylation of 14 with
NaH/MeI in DMF afforded an 85% yield of 6b that was
contaminated with methyl ester 6a and ketal 16. Ketal
Our second approach to 5a was based upon develop-
ment of work previously reported for reduction of indole
oxo-acetates to their corresponding indole-3-acetates.26,27
(22) Brewster, J . H.; Eliel, E. L. Org. React. 1953, VII, 99-197.
(23) Kozikowski, A. P.; Ishida, H. Heterocycles 1980, 14, 55-58.
(24) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J . Org. Chem.
1999, 64, 2465-2470.
(25) Mauger, J .; Nagasawa, T.; Yamada, H. Tetrahedron 1989, 45,
1347-1354.
(26) Demopoulos, V. J . Synth. Commun. 1989, 19, 2585-2594.
(27) Stiller, E. T.; Diassi, P. A.; Gerschutz, D.; Meikle, D.; Moetz,
J .; Principe, P. A.; Levine, S. D. J . Med. Chem. 1972, 15, 1029-1032.
(21) Iwao, M.; Kuraishi, T. Heterocycles 1992, 34, 1031-1038.
J . Org. Chem, Vol. 69, No. 9, 2004 2969

Faul et al.
SCHEME 6 a
TABLE 1. Syn th esis of th e In ver sed Ar ylin d olyl
Ma leim id es (eq 1)
entry indole 4
R1
R2
6-OMe
-(CH2)3OH 6-OMe
7-(CH2) 2OH
yield, % product 2
a
1
2
3
a
b
c
H
65
62
72
a
b
d
Key: (a) (i) (COCl)2, THF, (ii) NH4OH, 90%; (b) NaH2PO2‚xH2O,
dioxane/H2O, 81%.
H
SCHEME 7 a
though this approach was successful it was not attractive
for scale-up, as previously described.33 Therefore, a
related sequence via the cyanocarbonate 22 was devel-
oped. Hydrogenation of 22 afforded 23, that upon hy-
drolysis using KOH/t-BuOH at reflux afforded an effi-
cient, robust and practical synthesis of 3 in 3 steps and
78% overall yield from readily available reagents.33
Ar ylin d olyl Ma leim id e Syn th esis. A number of
methods have been reported to prepare 3,3′-bisindolyl-
maleimides by condensation of R-oxo-indole-3-acetates
with indole-3-acetamides.36,37 This technology was di-
rectly applicable to the synthesis of novel 3, 7′-bisindolyl-
maleimides 2a , 2b, and 2d affording the desired products
in 62-72% yield (eq 1, Table 1).
As a comparison, 2a was obtained in only 52% yield
when the reacting partners were reversed (eq 2), dem-
onstrating that the synthesis of 2a via strategy B was
less efficient than strategy A (Scheme 1). The reason for
the lower yield was due to competitive hydrolysis of 6b
to its corresponding (indolyl-7-yl)-R-oxoacetic acid, which
does not participate in the condensation reaction, but is
instead further decarbonylated to N-methyl-7-indolecar-
boxylic acid. A number of conditions (alternative bases,
methods of elimination and solvents) were examined to
improve the yield of this reaction but were unsuccessful.
a
Key: (a) (EtO)2P(O)CN, LiCN; (b) EtOCOCl, NaCN, n-Bu4NCl,
THF, 92%; (c) THF, SmI2, 85% from 21; (d) H2 (50 psi), 10% Pd/C,
EtOAc, 99%; (e) KOH, t-BuOH, reflux, 85% from 23.
Although not previously reported, we were interested in
determining if a similar strategy could be applied to the
corresponding indole-3-glyoxylamides. Thus, indole-3-
glyoxylamide 19 was prepared in 90% yield by treatment
of 7 with oxalyl chloride, followed by in situ quench with
NH4OH at low temperature (-60 °C). Upon reduction of
19 with sodium hypophosphite in dioxane/water at reflux
an 81% yield of 5a was obtained. This approach was very
efficient on large scale and provided access to a variety
of indole-3-acetamide derivatives (Scheme 6).
For the synthesis of N-methylindole-7-acetamide 3, we
envisioned starting from readily available 7-formylindole
2028 and proceeding via acetonitrile 23 (Scheme 7).
However, this approach presented a significant challenge
since few reagents are known to directly homologate aryl
aldehydes to aryl acetonitriles in good yield.29-31 Thus,
two new synthetic routes were developed.32,33 Our initial
approach, based upon the work of Kurihara, involved
conversion of 20 to 23 via cyanophosphonate 21. Al-
Ca r ba zole F or m a tion : The final step of the process
involved the oxidative cyclization of 2 to 1. A number of
methods to prepare indolocarbazoles by oxidation of the
(28) Dobson, D. R.; Gilmore, J .; Long, D. A. Synlett 1992, 79-80.
(29) Van Leusen, A. M.; Oomkes, P. G. Synth. Commun. 1980, 10,
399-403.
(30) Schoellkopf, U.; Schroeder, R. Angew. Chem. 1973, 85, 402-
403.
(34) Yoneda, R.; Harusawa, S.; Kurihara, T. J . Org. Chem. 1991,
56, 1827-1832.
(31) Santiago, B.; Meyers, A. I. Tetrahedron. Lett. 1993, 34, 5839-
5842.
(32) Engler, T. A.; Furness, K.; Malhotra, S.; Diefenbacher, C.;
Clayton, J . R. Tetrahedron Lett. 2003, 44, 2903-2905.
(33) Kolis, S. P.; Clayton, M. T.; Grutsch, J . L.; Faul, M. M.
Tetrahedron Lett. 2003, 44, 5707-5710.
(35) Au, A. T. Synth. Commun. 1984, 743-748.
(36) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J . Org. Chem.
1998, 63, 6053-6058.
(37) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. Tetrahedron
Lett. 1999, 40, 1109-1112.
2970 J . Org. Chem., Vol. 69, No. 9, 2004

Synthetic Approaches to Indolo[6,7-a]pyrrolo[3,4-c]carbazoles
TABLE 2. P h otoch em ica l Con d ition s Eva lu a ted for
Syn th esis of 1 fr om 2a
TABLE 3. Syn th esis of th e In ver sed BIMs (eq 3)
entry
oxidant
volumea (mL/g)
yield, %
92
89
91
incomplete
47
dec
1
2
3
4
5
6
DDQ
DDQ
DDQ
DDQ
none
1000
500
250
100
1000
1000
DDQ, cat. p-TsOH
a
All reactions performed in EtOAc.
entry BIM 2
R1
R2
yield, % product 1
2,2′-bisindole bond have been reported,38,39 and although
no reports on the oxidation of the 3,7′-bisindolylmaleim-
ide system have been published, a close analogy was
reported by our group for the synthesis of aryl- and
heteroaryl[a]pyrrolo[3,4-c]carbazoles via both photochem-
istry and Heck cyclization strategies.40 Due to the dif-
ficulty in accessing the Heck reaction partners for
synthesis of 1, we focused our efforts on the photocycliza-
tion reaction (Table 2). Our initial conditions involved
treatment of 2a with DDQ (1.1 equiv) in EtOAc (1000
mL/g) and afforded a 92% yield of 1a after 1 h. However,
the photochemical reaction presented numerous chal-
lenges: (i) it was difficult to perform on large scale; (ii)
it required high dilution, minimizing throughput; (iii)
removal of the DDQ byproducts by extractive workup was
problematic due to the competing insolubility of the
indolocarbazole product; and (iv) DDQ in the final
product, had to be removed to ppm levels due to its
known toxic effects. Thus, a variety of conditions were
examined to improve this chemistry.
We initially focused on use of EtOAc as the solvent and
determined that the reaction could be performed in 250
mL/g with minimal impact on the yield (Table 2, entries
1-3). For this reaction to be successful, both DDQ and
2a had to be dissolved in the reaction solvent prior to
the start of the reaction. If the concentration of the
reaction is increased to 100 mL/g incomplete reaction was
observed (entry 4). Attempts to reduce the amount of
DDQ were unsuccessful, and in the absence of DDQ, 1a
was isolated in only 47% yield (entry 5). Use of DDQ with
cat. p-TsOH resulted in decomposition (entry 6). At-
tempts to perform the reaction in alternative solvents
where the solubility of 2a , DDQ and 1a could be
increased (acetone, dioxane, DMF, xylenes, diphenyl
ether, THF) were unsuccessful resulting in either incom-
plete reaction or decomposition. Alternative oxidants
(SeO2, MnO2, benzoquinone cat. p-TsOH, phenyliodine-
(III) bis(trifluoroacetate) (PIFA) with or without BF3-
OEt2,41 cat. FeCl2/O2, CuCl2, Pd(OTf)2,42 PdCl2, Pd-
(OAc)2,43,44 I2 cat. AIBN) also gave incomplete reaction
or decomposition. Although a wide variety of alternative
conditions were examined we have been unable to
identify a successful alternative to DDQ/hν for the
synthesis of this class of compounds.
1
2
3
4
5
a
b
e
c
f
6-OMe
6-OMe
7-(CH2)2OH
6-OMe
7-(CH2)2Br
H
87
55
95
87
92
a
b
e
c
f
-(CH2)3OH
H
-(CH2)3Br
H
Fortunately, the optimum conditions for synthesis of
1a from 2a could be successfully applied to substrates
2b-e (eq 3, Table 3), as well as a variety of other
analogues.12 For the synthesis of 1d and 1g, although
oxidation could be performed on 2b and 2d prior to
bromide formation in good yields, the preferred strategy
was to perform the photooxidation reaction on the
bromides 2c and 2e due to the higher solubility of the
resulting carbazoles 1c and 1f in organic solvents, which
facilitated isolation and chromatographic purification.
Bromides 2c and 2e were readily prepared from 2b and
2d in 69-71% yield via standard conditions (CBr4/PPh3,
DMF or CH2Cl2/THF).
The final steps for the synthesis of 1d and 1g involved
displacement of the bromide by the desired amine. This
was performed via standard SN2 chemistry, using 2-ami-
noethanol or piperidine in DMF at 60 °C, to afford 1d
and 1g in 42 and 95% yield, respectively. The advantage
of this approach is that a variety of amines can be
incorporated from the key late stage bromide intermedi-
ates 1c and 1f. By using this chemistry the SAR of 1 was
expanded to examine a diverse collection of aminoalkyl-
substituted indolocarbazoles as described in our publica-
tion detailing the biological activity of this class of
compounds.12
Con clu sion s
A new class of indolo[6,7-a]pyrrolo[3,4-c]carbazoles,
exemplified by 1a , 1d , and 1g, have been identified as
potent inhibitors of cyclin D1/CDK4. The hitherto optimal
synthetic route to these compounds employed N-methyl-
7-formylindole 20 as the starting material for the syn-
thesis of N-methylindole-7-acetamide 3. Coupling of 3
with (indol-3-yl)oxoacetates 4 afforded the 3,7′-bisindolyl-
maleimides 2, which upon DDQ photooxidation in EtOAc
yield 1. The syntheses proceed in six to eight steps and
16-36% overall yield.
Exp er im en ta l Section
(38) Gallant, M.; Link, J . T.; Danishefsky, S. J . J . Org. Chem. 1993,
58, 343-349.
Unless otherwise noted, reagents and solvents were used
as received from commercial suppliers. TLC was performed
on Kiesegel 60 F254 plates (Merck) using reagent grade
(39) Link, J . T.; Gallant, M.; Danishefsky, S. J .; Huber, S. J . Am.
Chem. Soc. 1993, 115, 3782-3783.
(40) Sanchez-Martinez, C.; Faul, M. M.; Shih, C.; Sullivan, K. A.;
Grutsch, J . L.; Cooper, J . T.; Kolis, S. P. J . Org. Chem. 2003, 68, 8008-
8014.
(41) Faul, M. M.; Sullivan, K. A. Tetrahedron. Lett. 2001, 42, 3271-
3273.
(42) Ohkubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M.; Morishima,
H. Tetrahedron 1997, 53, 585-592.
(43) Harris, W.; Hill, C. H.; Keech, E.; Malsher, P. Tetrahedron Lett.
1993, 34, 8361-8364.
(44) Wang, J .; Rosingana, M.; Watson, D. J .; Dowdy, E. D.; Discordia,
R. P.; Soundarajan, N.; Li, W.-S. Tetrahedron. Lett. 2001, 42, 8935-
8937.
J . Org. Chem, Vol. 69, No. 9, 2004 2971

Faul et al.
solvents. Flash chromatography was performed using Merck
acetamide 19 (97.35 g) and 10% Pd-C (19.5 g) were taken up
in 50:50 H2O/dioxane (350 mL) and diluted with dioxane (875
mL). The reaction mixture was treated dropwise over 1.5 h
with a solution of NaH2PO2‚xH2O in water (325 mL). During
the addition, the reaction mixture was heated to reflux and
stirred for 9 h. The reaction mixture was cooled to rt, treated
with Hyflo (50 g), stirred for 15 min, then filtered through a
pad of Hyflo (130 g prepared from 25% dioxane/H2O). The filter
cake was washed with 9:1 dioxane/H2O (4 × 200 mL) and the
filtrate concentrated in vacuo. The wet residue was diluted
with water (800 mL) and concentrated in vacuo until 2350 mL
of distillate was collected. Water (350 mL) was added to the
reaction mixture, which was cooled in an ice-water bath for
20 min. The tan solid that precipitated out of solution was
filtered, washed with water, and dried (78.67 g). The isolated
material was treated with EtOAc (200 mL), heated to reflux,
and then cooled and stirred at 0-5 °C for 30 min. The solution
was filtered to afford 73.9 g (81%) 5a as a light tan solid: 1H
NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.42 (d, 1H, J )
8.8 Hz), 7.24 (s, 1H), 7.04 (d, 1H, J ) 2.2 Hz), 6.85 (d,1H, J )
2.2 Hz). 6.81 (s, 1H), 6.40 (app dd, 1H, J ) 8.59 Hz, 4.8 Hz),
3.74 (s, 3H), 3.43 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.9,
155.4, 136.7, 122.2, 121.6, 119.2 108.9, 108.4, 94.3, 55.1 32.6;
IR (KBr) ν 3378, 3189, 1652, 1627, 1580, 1559, 1502, 1456,
1396, 1287, 1266, 1205, 1165, 1128, 1026, 815 cm-1; HRMS
1
silica gel 60 (230-400 mesh). H NMR was performed at 300
MHz and 13C NMR at 75 MHz in CDCl3 unless otherwise
specified. Chemical shifts are in ppm downfield from internal
tetramethylsilane. Mass spectral, combustion, and infrared
analysis were performed by the Eli Lilly and Co. Physical
Chemistry Department.
6-Met h oxy-1-m et h yl-R-oxo-1H -in d ole-3-a cet ic
Acid
Meth yl Ester (4a ). A solution of 7 (25.0 g, 185 mmol) in THF
(500 mL) at 0 °C was treated dropwise with oxalyl chloride
(25.8 g, 17.8 mL, 203.4 mmol) at such a rate that the reaction
temperature did not exceed 1 °C (2-4 min). The reaction was
stirred at 0 °C for 2 h and then quenched with MeOH (29.6 g,
37.5 mL, 924.5 mmol). The solid that precipitated was collected
and dried to afford 34.1 g (79%) of 4a : 1H NMR (300 MHz,
DMSO-d6) δ12.26 (s, 1H), 8.35 (d, 1H, J ) 3.29 Hz), 8.05 (d,
1H, J ) 8.42 Hz), 7.07 (d, 1H, J ) 2.19 Hz), 6.94 (d, 0.5H, J )
2.56 Hz), 6.92 (d, 0.5H, J ) 2.19 Hz) 3.90 (s, 2H), 3.82 (s, 3H);
13C NMR (75 MHz, DMSO-d6) δ 178.4, 163.9, 157.0, 137.7,
137.6, 121.7, 119.2, 112.3, 112.5, 95.8, 55.2, 52.4; IR (KBr) ν
3437, 3188, 2954,1729, 1619, 1586, 1521, 1495, 1448, 1415,
1380, 1254, 1230, 1161, 1140, 1115, 1092, 750 cm-1; MS (FD+)
m/z calcd for C12H11NO4 233.2, found 233.1. Anal. Calcd for
C
12H11NO4: C, 61.8; H, 4.75; N, 6.01. Found: C, 61.4; H, 4.71;
N, 5.97.
{1-[3-(ter t-Bu tyldim eth ylsilan yloxy)pr opyl]-6-m eth oxy-
(ES+) exact mass calcd for
C11H12N2O2 204.0899, found
204.0899.
1H-in d ol-3-yl}oxoa cetic Acid Meth yl Ester (4b). To a
solution of 8 (2.45 g, 7.66 mmol) in Et2O (40 mL) at 0 °C was
added oxalyl chloride (1.07 g, 8.42 mmol). The reaction was
stirred for 30 min while warming to rt. The reaction was cooled
to -78 °C, and NaOMe (5.25 mL, 22.98 mmol) as a 25 wt %
solution in MeOH introduced. The reaction was stirred over-
night and allowed to warm to rt. The mixture was poured into
EtOAc, washed with H2O, saturated NaHCO3 (aq), and brine,
and dried (MgSO4). The resultant solution was concentrated
in vacuo and the crude product purified by silica gel chroma-
tography (75:25 hexane/EtOAc to 65:35 hexane/EtOAc gradi-
ent) to give 2.46 g (79%) of 4b as an oil: 1H NMR (300 MHz,
DMSO-d6) δ 8.30 (s, 1H), 8.02 (d, J ) 8.4 Hz, 1H), 7.14 (d, J
) 2 Hz, 1H), 6.93 (dd, J ) 2.0, 8.4 Hz, 1H), 4.32 (t, J ) 6.8 Hz,
2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.55 (t, J ) 6.0 Hz, 2H), 1.98
(app quintet, J ) 6.4 Hz, 2H), 0.86 (s, 9H), 0.01 (s, 6H); 13C
NMR (75.5 MHz, DMSO-d6) δ 177.8, 163.8, 157.2, 139.9, 137.7,
122.1, 119.8, 112.5, 111.6, 94.8, 59.2, 55.4, 52.4, 43.3, 31.9, 25.7,
17.8, -5.56. IR (CHCl3) ν 3022, 1730, 1640 cm-1; MS (electro-
spray) m/z 406 (M+ + 1). Anal. Calcd for C21H31NO5Si: C,
62.19; H, 7.70; N, 3.45. Found: C, 61.97; H, 7.57; N, 3.60.
(1-Meth yl-1H-in d ol-7-yl)oxoa cetic Acid Eth yl Ester
(6b). A solution of 14 (3.00 g, 13.8 mmol) dissolved in DMF
(12 mL) was added dropwise to a slurry of NaH (60%
dispersion in mineral oil, 0.66 g, 16.6 mmol) in DMF (7 mL)
under N2 at 0 °C keeping the temperature of the reaction
mixture below 6 °C. The resulting mixture was stirred at 0 °C
for 30 min. A solution of CH3I (9.8 mL, 69.1 mmol) dissolved
in DMF (7 mL) was added dropwise by syringe keeping the
temperature of the reaction mixture below 14 °C. The resulting
mixture was stirred at rt for 18 h, quenched by addition of a
0.1 N HCl solution, and extracted with EtOAc. The organic
layer was washed with brine and dried (MgSO4). The solution
was concentrated in vacuo and the crude product purified by
silica gel chromatography (9:1 hexanes/EtOAc) to give 2.71 g
(85%) 6a /6b as an 8:1 mixture. 6b: 1H NMR (300 MHz,
DMSO-d6) δ 7.98 (app dd, 1H, J ) 7.9 Hz, 0.92 Hz), 7.58 (dd,
1H, J ) 7.7 Hz, 1.1 Hz), 7.48 (d, 1H, J ) 3.3 Hz), 7.21 (t, 1H,
J ) 7.7 Hz), 6.67 (d, 1H, J ) 2.9 Hz) 4.44 (q, 2H, J ) 7.3 Hz),
3.81 (s, 3H), 1.35 (t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz,
DMSO-d6) δ 186.1, 164.0, 133.6, 133.0, 131.3, 128.0, 126.9,
118.7, 118.3, 102.2, 62.3, 37.5, 13.8; IR (CDCl3) ν 3688, 3019,
1733, 1677, 1521 cm-1. Anal. Calcd for C13H13NO3: C, 67.5;
H, 5.67; N, 6.06. Found: C, 67.1; H, 5.49; N, 6.03.
1-[3-(ter t-Bu tyld im eth ylsila n yloxy)p r op yl]-6-m eth oxy-
1H-in d ole (8). To a solution of 7 (10.0 g, 67.9 mmol) and (3-
bromopropoxy)-tert-butyldimethylsilane (18.0 g, 71.3 mmol) in
DMF (300 mL) was added NaH (60% mineral oil dispersion,
0.353 g, 8.82 mmol). The reaction was stirred for 2 h, quenched
with saturated NaHCO3 (aq), diluted with EtOAc (400 mL),
washed with saturated NaHCO3 (aq) and brine, and dried
(MgSO4). The solution was concentrated in vacuo and the crude
oil purified by filtration through a plug of silica gel (85:15
hexane/EtOAc) to give 22.1 g (100%) of 8 that was used without
further purification: 1H NMR (300 MHz, DMSO-d6) δ 7.38 (d,
J ) 8.4 Hz, 1H), 7.15 (d, J ) 3.2 Hz, 1H), 6.92 (d, J ) 2.0 Hz,
1H), 6.65 (dd, J ) 2.4, 8.4 Hz, 1H), 6.32 (d, J ) 3.2 Hz, 1H)
4.16 (t, J ) 6.4 Hz, 2H), 3.77 (s, 3H), 3.53 (t, J ) 6 Hz, 2H),
1.90 (app quintet, J ) 6.8 Hz, 2H), 0.87 (s, 9H), 0.01 (s, 6H);
13C NMR (75.5 MHz, DMSO-d6) δ 155.5, 136.3, 127.1, 122.2,
120.9, 108.9, 100.4, 93.0, 59.5, 55.2, 41.9, 32.6, 25.7, 17.8,
-5.50; MS (electrospray) m/z 320 (M+ + 1).
[7-(2-Hydr oxyeth yl)-1H-in dol-3-yl]oxoacetic Acid Meth -
yl Ester (4c). A solution of 11 (47.0 g, 170 mmol) in Et2O (600
mL) was cooled to 4 °C (ice bath), and a 2 M solution of oxalyl
chloride in THF (92.0 mL, 184 mmol) was added dropwise.
The ice bath was removed and the reaction allowed to warm
to rt (1.5 h). The reaction was cooled to -78 °C, and a solution
of NaOMe in MeOH (85.1 mL, 25wt %, 357 mmol) was
introduced over 5 min. The cold bath was removed, and the
reaction was allowed to warm to rt (1 h). The reaction was
quenched with H2O (500 mL) and poured into EtOAc (400 mL).
The water layer was separated and extracted with EtOAc (2
× 200 mL). The organic layers were combined, washed with
saturated NH4Cl (aq) (400 mL) and brine (500 mL), and dried
(MgSO4). The solution was concentrated in vacuo and the
product purified by silica gel chromatography (70:30 hexanes/
EtOAc) to give 23.9 g (57%) 4c as a yellow solid: 1H NMR
(400 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.36 (s, 1H), 8.03 (dd, J
) 7.7, 1.5 Hz, 1H), 7.20 (dd, J ) 7.7, 7.7 Hz, 1H), 7.14 (dd, J
) 7.7, 1.5 Hz, 1H), 4.72 (br s, 1H), 3.88 (s, 3H), 3.70 (t, J ) 6.6
Hz, 2H), 3.04 (t, J ) 6.6 Hz, 2H); 13C NMR (75.5 MHz, DMSO-
d6) δ 178.6, 164.0, 137.9, 136.0, 125.4, 124.3, 122.9, 118.9,
112.6, 61.1, 52.4, 34.1 (one signal is not apparent); IR (CHCl3)
ter t-Bu tyldim eth yl[2-(2-n itr oph en yl)eth oxy]silan e (10).
A solution of 2-(2-nitrophenyl)ethanol (100 g, 590 mmol) in
CH2Cl2 (800 mL) was treated with imidazole (117 g, 777 mmol)
followed by tert-butyldimethylsilyl chloride (562 g, 826 mmol).
ν 3622, 3276, 3016, 1731, 1644 cm-1. Anal. Calcd for C13H13
-
NO4: C, 63.15;H, 5.30;N, 5.66. Found: C, 62.87;H, 5.20;N, 5.72.
6-Meth oxyin d ole-3-a ceta m id e (5a ). 6-Methoxyindole-3-
2972 J . Org. Chem., Vol. 69, No. 9, 2004

Synthetic Approaches to Indolo[6,7-a]pyrrolo[3,4-c]carbazoles
A white precipitate formed upon the addition, and the reaction
was stirred 2.5 h. The mixture was filtered, diluted with CH2-
Cl2 (300 mL), washed with 0.1 N HCl (300 mL), H2O (400 mL),
saturated NaHCO3 (aq) (400 mL), brine (400 mL), and dried
(MgSO4). The solution was concentrated in vacuo to give 160
g (96%) of 10 as a transparent oil that was used without
further purification: 1H NMR (400 MHz, DMSO-d6) δ 7.99 (dd,
J ) 1, 8 Hz, 1H), 7.73 (ddd, J ) 1, 6.5, 7 Hz, 1H), 7.5-7.65
(m, 2H), 3.90 (t, J ) 6.6 Hz, 2H), 3.14 (t, J ) 6.6 Hz, 2H), 0.87
(s, 9H), 0.1 (s, 6H); 13C NMR (75.5 MHz, DMSO-d6) δ 149.8,
133.1, 132.8, 132.7, 127.6, 124.0, 62.7, 34.9, 25.6, 17.8, -5.7;
HRMS (M+ + 1) calcd for C14H24NO3Si 282.1525, found
282.1519.
7-[2-(ter t-Bu tyldim eth ylsilan yloxy)eth yl]-1H-in dole (11).
A solution of 10 (85.6 g, 304 mmol) in THF (1 L) was cooled to
-65 °C, and a 1.0 M solution of vinylmagnesium bromide in
THF (913 mL, 913 mmol) was introduced while maintaining
a temperature below -60 °C. The reaction was stirred for 15
min at -45 °C, additional vinylmagnesium bromide (152 mL,
152 mmol) was added, and the reaction was stirred at -45 °C
for 30 min. The cold reaction was poured into saturated NH4-
Cl (aq) (800 mL) and diluted with EtOAc (500 mL). The two
layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 200 mL). The organic layers were combined,
washed with brine (400 mL), and dried (MgSO4). The solution
was concentrated in vacuo and the product purified by silica
gel chromatography (95:5 hexane/EtOAc) to give 47.1 g (56%)
11 as a transparent brown oil that was used without further
purification: 1H NMR (400 MHz, DMSO-d6) δ 11.02 (br s, 1H),
7.36 (dd, J ) 4.8, 4.8 Hz, 1H), 7.28 (dd, J ) 3, 3 Hz, 1H), 6.86-
6.92 (m, 2H), 6.39 (dd, J ) 1.2, 3.2 Hz, 1H), 3.85 (t, J ) 6.8
Hz, 2H), 3.03 (t, J ) 6.8 Hz, 2H), 0.80 (s, 9H), -0.11 (s, 6H);
MS (electrospray) m/z 276 (M+ + 1).
Eth yl 1-Boc-in d olin eglyoxyla te (13). sec-Butyllithium
(1.3 M in cyclohexanes, 42.1 mL, 54.7 mmol) was added
dropwise to a solution of 1-tert-butyloxycarbonyl-2,3-dihydro-
1H-indole 12 (10.0 g, 45.6 mmol) and TMEDA (8.26 mL, 54.7
mmol) in dry MTBE (100 mL) at -78 °C under N2, keeping
the temperature of the reaction mixture below -65 °C. After
the addition was complete, the reaction mixture was stirred
at -78 °C for 3 h. Diethyl oxalate (13.3 g, 91.2 mmol) dissolved
in MTBE (25 mL) was then added dropwise keeping the
temperature below -65 °C. The reaction mixture was stirred
-78 °C for 1 h before being allowed to warm to rt. The reaction
was then quenched with saturated NH4Cl (150 mL) and
extracted with EtOAc (3 × 100 mL). The EtOAc portions were
combined, washed with brine, and dried (MgSO4). The solution
was concentrated in vacuo and the crude product purified by
silica gel chromatography (9:1 hexanes/EtOAc) to give 8.53 g
(59% yield) of 13: 1H NMR (DMSO-d6) δ 7.44 (d, 0.5H, J )
1.46 Hz), 7.42 (d, 0.5H, J ) 1.09 Hz), 7.22 (dd, 1H, J ) 1.09,
7.69 Hz), 7.09 (m, 1H, J ) 6.59 Hz), 4.14 (app q, 2H, J ) 6.95
Hz), 4.00 (app t, 2H, J ) 8.42 Hz), 3.15 (t, 2H, J ) 8.42 Hz),
1.42 (s, 9H), 1.23 (app t, 3H, J ) 7.14 Hz); 13C NMR (DMSO-
d6) δ 182.5, 159.8, 153.3, 139.9, 132.9, 128.3, 128.1, 123.2,
122.9, 81.5, 61.3, 47.8, 27.8, 27.6, 27.4, 13.7; IR (CHCl3) ν 3019,
2983, 1733, 1703, 1592, 1453, 1439, 1340, 1395, 1344, 1163,
1148, 1042, 840 cm-1; HRMS (ES) exact mass calcd for
2H, J ) 7.0 Hz), 3.72 (app t, 2H, J ) 8.2 Hz), 3.00 (app t, 2H,
J ) 8.6 Hz), 1.31 (t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz,
DMSO-d6) δ 185.8, 164.8, 154.9 132.4 129.8 128.0, 115.1, 109.4,
61.6, 46.7, 26.6, 13.8; IR (CDCl3) ν 3692, 3425, 3027, 1732,
1637, 1578 cm-1; HRMS (ES) exact mass calcd for C12H13NO3
M+ 219.0895, found 219.0895.
Trifluoroacetic anhydride (0.464 mL, 3.28 mmol) was added
dropwise to a solution of DMSO (0.466 mL, 6.57 mmol) in CH2-
Cl2 (9 mL) at -78 °C under N2 keeping the temperature of
the reaction mixture below -65 °C. The reaction mixture was
stirred at -78 °C for 90 min, and then ethyl 7-indolinegly-
oxylate (0.48 g, 2.19 mmol) in CH2Cl2 (5 mL) was added
dropwise. The reaction mixture was stirred under N2 for 1 h
while warming to -30 °C. The reaction mixture was recooled
to -78 °C and Et3N (1.37 mL, 9.85 mmol) added. The reaction
mixture was allowed to warm to rt, washed sequentially with
water, 1 N HCl, saturated NaHCO3 (aq), and brine, and dried
(MgSO4). The solution was concentrated in vacuo to give 0.47
g (99%) of 14: 1H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H),
8.07 (d, 1H, J ) 7.7 Hz), 7.72 (app dd, 1H, J ) 7.3 Hz, 0.7
Hz), 7.50 (t, 1H, J ) 2.9 Hz), 7.25 (t, 1H, J ) 7.7 Hz), 6.67
(dd, 1H, J ) 2.9 Hz, 1.8 Hz), 4.48 (q, 2H, J ) 7.0 Hz), 1.38
(app t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ 187.3,
164.2 133.2, 129.8, 129.2, 128.1, 127.0, 118.7, 115.3, 102.2,
62.1, 13.9; IR (CDCl3) ν 3454, 3026, 1734, 1652, 1589 cm-1
.
Anal. Calcd for C12H11NO3 C, 66.4; H, 5.10; N, 6.45. Found:
C, 66.2; H, 5.07; N, 6.48.
6-Meth oxyin d ole-3-glyoxa m id e (19). A solution of 7 (40
g, 0.272 mmol) in THF (600 mL) was cooled to -5 °C and
treated dropwise with oxalyl chloride (26.1 mL, 1.1 equiv) at
such a rate that the reaction temperature did not exceed 1 °C
(2-4 min). The reaction was stirred at -4 °C for 1.5 h and
then transferred by cannula to 29% NH4OH (200 mL) at such
a rate that the reaction temperature remained below 10 °C
(10 min). The resultant yellow slurry was stirred at -5 °C for
15 min and then filtered (slow). The filter cake was washed
with water (3 × 100 mL) and dried to afford 40.2 g of a yellow
powder. The filtrate was concentrated in vacuo to a volume of
400 mL, and the brown solid that precipitated was filtered,
washed with water (3 × 100 mL), and dried to afford an
additional 20.14 g of solid. The isolated solids were combined
in acetone (250 mL) and the mixture heated briefly to reflux,
then cooled to 0-5 °C and stirred for 10-15 min. The yellow
solid obtained was filtered, washed with the minimal amount
of acetone, and dried to afford 53.58 g (90%) of 19: 1H NMR
(300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.60 (s, 1H), 8.09 (d, 1H,
J ) 8.7 Hz), 8.05 (s, 1H), 7.68 (s, 1H), 7.05 (d, 1H, J ) 2.2
Hz), 6.91 (app dd, 1H, J ) 8.6 Hz, 2.4 Hz), 3.81 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 182.7, 166.0, 156.7 137.4, 137.2,
121.8, 119.9, 112.2 111.9, 95.7 55.2; IR (KBr) ν 3403, 3210,
2832, 1698, 1624, 1587, 1519, 1448, 1396, 1348, 1295, 1260,
1147, 1093, 1023 cm-1; HRMS (ES+) exact mass calcd for
C
11H10N2O3 218.0691, found 218.0694.
3-(6-Meth oxy-1H-in d ol-3-yl)-4-(1-m eth yl-1H-in d ol-7-yl)-
p yr r ole-2,5-d ion e (2a ). Str a tegy A. A slurry of 3 (2.0 g, 10.6
mmol) and 4a (2.73 g, 11.7 mmol) in THF (100 mL) was cooled
to 0 °C in an ice-water bath. t-BuOK (1.0 M in THF, 43.0
mL, 43 mmol) was added dropwise through an addition funnel
while the reaction temperature was maintained <1 °C. The
solution was stirred at 0 °C for 30 min and then warmed to
50 °C. Reaction progress was monitored by HPLC, and after
∼2 h no starting material remained. The reaction mixture was
cooled to rt and 1.0 M HCl added dropwise over a period of 1
h; during this time, the temperature increased to 31 °C and
the color of the reaction mixture changed from purple to
orange. The orange solution was transferred to a separatory
funnel and diluted with water (200 mL). The aqueous layer
was extracted with EtOAc (2 × 200 mL), and the combined
organic layers were washed with saturated NaHCO3 (aq) (200
mL) and brine (100 mL) and dried (MgSO4). The solution was
concentrated in vacuo to afford a brown solid that was purified
by silica gel chromatography (1:2 hexane/EtOAc) to afford 2.56
C
17H21N5O 319.1420, found 319.1410. Anal. Calcd for C17H21-
N5O: C, 63.9; H, 6.63; N, 4.39. Found: C, 64.2; H, 6.44; N, 4.69.
(1H-In d ol-7-yl)-R-oxoa cetic Acid Eth yl Ester (14). Tri-
fluoroacetic acid (15.4 mL, 200 mmol) was added to a solution
of 13 (15.98 g, 50.0 mmol) in CH2Cl2 (182 mL) at rt under N2.
The reaction mixture was stirred at rt for 18 h and then
quenched by slow addition of saturated aq NaHCO3 (300 mL).
The resulting mixture was extracted with CH2Cl2 (3 × 50 mL),
washed with brine, and dried (MgSO4). The solution was
concentrated in vacuo and the crude product purified by silica
gel chromatography (85:15 hexanes/EtOAc) to give 8.83 g (81%)
of ethyl 7-indolineglyoxylate: 1H NMR (300 MHz, DMSO-d6)
δ 7.59 (s, 1H), 7.22 (app d, 1H, J ) 7.0 Hz), 7.16 (app dd, 1H,
J ) 8.2 Hz, 0.9 Hz), 6.48 (app dd, 1H, J ) 6.8 Hz), 4.37 (q,
J . Org. Chem, Vol. 69, No. 9, 2004 2973

Faul et al.
g (65%) 2a as an orange solid: 1H NMR (300 MHz, DMSO-d6)
δ 11.65 (s, 1H), 11.11 (s, 1H), 7.85 (s, 1H), 7.63 (dd, 1H, J )
7.7 Hz, 1.09 Hz), 7.24 (d, 1H, J ) 2.9 Hz), 7.00 (app t., 1H, J
) 15 Hz), 6.92 (dd, 1H, J ) 7.3 Hz, 1.1 Hz), 6.85 (d, 1H, J )
2.2 Hz), 6.49 (d, 1H, J ) 2.9 Hz), 6.24 (d, 1H, J ) 8.8 Hz),
6.15 (app dd, 1H, J ) 9.0 Hz, 4.8 Hz), 3.68 (s, 3H), 3.66 (s,
3H); 13C NMR (75 MHz, DMSO-d6) δ 173.4 172.4 155.8 137.3,
135.2, 134.2, 131.5 130.4, 129.5, 128.2, 124.0, 121.6 121.4,
118.7 118.6 115.2 109.7 105.3, 100.7 94.9, 55.0, 34.6; IR (KBr)
ν 3307, 1751, 1691, 1633, 1616, 1512, 1343, 1298, 1164, 1156
cm-1. Anal. Calcd for C22H17N3O3: C, 71.14; H, 4.61; N, 11.31.
Found: C, 71.34; H, 4.83; N, 11.13.
3-(6-Meth oxy-1H-in d ol-3-yl)-4-(1-m eth yl-1H-in d ol-7-yl)-
p yr r ole-2,5-d ion e (2a ). Str a tegy B. Compounds 6b (7.78 g,
26.91 mol, 80% pure) and 5a (5 g, 24.48 mol) were charged to
a reaction vessel with THF (350 mL). The slurry was cooled
to -3 °C (ice/acetone bath) and t-KOBu (1.0 M in THF, 110
mL) added dropwise at such a rate as to maintain the
temperature below 0 °C. Upon completion of the addition, the
reaction temperature was allowed to rise to ambient temper-
ature (over 30 min) and then heated at reflux for 345 min.
Upon completion, the reaction mixture was allowed to cool to
ambient temperature and partitioned with water (700 mL) and
EtOAc (700 mL). The organic layer was washed with brine
and dried (MgSO4). The solvent was removed in vacuo to yield
8 g of an orange foam of 80% purity. The crude product was
chromatographed by passing it through silica and eluting with
5:1 CH2Cl2/EtOAc to afford 5.32 g (52%) of 2a .
3-[1-(3-Hyd r oxyp r op yl)-6-m eth oxy-1H-in d ol-3-yl]-4-(1-
m eth yl-1H-in d ol-7-yl)-1H-p yr r ole-2,5-d ion e (2b). To a so-
lution of 4b (5.47 g, 13.5 mmol) and 3 (2.55 g, 13.5 mmol) in
DMF (250 mL) was added t-BuOK (1.0 M solution in THF,
40.5 mL, 40.5 mmol). The reaction was stirred at rt for 24 h,
quenched with 1 N HCl, and stirred for 1 h. The reaction
mixture was poured into EtOAc (1.5 L), washed with 1 N HCl,
saturated NaHCO3 (aq), and brine, and dried (MgSO4). The
solution was concentrated in vacuo and the crude red solid
triturated and recrystallized with Et2O/hexane to give 3.6 g
(62%) of 2b as a red solid: 1H NMR (400 MHz, DMSO-d6) δ
11.10 (s, 1H), 7.94 (s, 1H), 7.60 (d, J ) 7.8 Hz, 1H), 7.23 (d, J
) 3 Hz, 1H), 6.98 (m, 2H), 6.85 (d, J ) 7 Hz, 1H), 6.47 (dd, J
) 3 Hz, 1H), 6.07 (d, J ) 9 Hz, 2H), 6.00 (d, J ) 9 Hz, 1H),
4.62 (t, J ) 5.2 Hz, 1H), 4.21 (t, J ) 7.2 Hz, 2H), 3.67 (s, 3H),
3.65 (s, 3H), 3.34 (app quartet, J ) 5.6 Hz, 2H), 1.83 (app
quintet, J ) 6.8 Hz, 2H); 13C NMR (100.6 MHz, DMSO-d6) δ
173.5, 172.4, 155.9, 137.3, 134.6, 134.3, 133.6, 131.6, 129.6,
127.8, 124.2, 121.8, 121.6, 119.1, 118.6, 115.3, 109.7, 104.5,
100.7, 93.9, 57.5, 55.2, 42.8, 34.7, 32.4; IR (KBr) ν 3516, 3176,
1688 cm-1; HRMS (M+ + 1) calcd for C25H24N3O4 430.1767,
found 430.1748. Anal. Calcd for C25H23N3O4: C, 69.92; H, 5.40;
N, 9.78. Found: C, 69.55; H, 5.45; N, 9.59.
3-[1-(3-Br om op r op yl)-6-m et h oxy-1H -in d ol-3-yl]-4-(1-
m eth yl-1H-in d ol-7-yl)-1H-p yr r ole-2,5-d ion e (2c). To a so-
lution of 2b (3.0 g, 7.0 mmol) in DMF (300 mL) were added
PPh3 (2.6 g, 10.5 mmol) and CBr4 (3.3 g, 10.5 mmol). The
reaction mixture was stirred at rt under N2 for 1 h. After 2 h,
the reaction mixture was diluted with EtOAc (300 mL) and
water (800 mL). The aqueous phase was extracted with EtOAc
(3 × 300 mL), and the combined organic phases were washed
with saturated NaHCO3 (aq) and brine and dried (MgSO4).
The solution was concentrated in vacuo and the crude product
purified by silica gel chromatography (3:7 EtOAc/hexanes)
gave 2.4 g (71%) 2c as a red solid: 1H NMR (400 MHz, DMSO-
d6) δ 11.04 (s, 1H), 7.88 (s, 1H), 7.62 (d, J ) 6.1 Hz, 1H), 7.19
(d, J ) 2.6 Hz, 1H), 7.00-6.91 (m, 2H), 6.84 (d, J ) 6.0 Hz,
1H), 6.48 (d, J ) 2.5 Hz, 1H), 6.10 (m, 2H), 4.27 (t, J ) 5.8
Hz, 2H), 3.71 (s, 3H), 3.62 (s, 3H), 3.32 (t, J ) 5.8 Hz, 2H),
2.11 (m, 2H); 13C NMR (100.6 MHz, DMSO-d6) δ 173.4, 172.4,
156.1, 137.1, 134.5, 134.2, 133.2, 131.6, 129.6, 128.5, 124.1,
122.0, 121.6, 119.7, 118.6, 115.1, 109.9, 104.8, 100.8, 93.8, 55.3,
44.2, 34.7, 32.4, 31.4; IR (KBr) ν 3186, 1690 cm-1; HRMS (M+
+ 1) calcd for C25H23BrN3O3 492.0923, found 492.0920.
3-[7-(2-H yd r oxyet h yl)-1H -in d ol-3-yl]-4-(1-m et h yl-1H -
in d ol-7-yl)-1H-p yr r ole-2,5-d ion e (2d ). t-BuOK (1.0 M in
THF, 6.2 mL, 6.2 mmol) was added dropwise to solution of 3
(1.20 g, 6.35 mmol) in DMF (50 mL) followed after 5 min by a
solution of 4c (1.57 g, 6.35 mmol) in DMF (25 mL) dropwise
over 10 min giving a yellow-brown solution. After 90 min,
additional t-BuOK (6.6 mL, 6.6 mmol) was introduced, and
the reaction was stirred for 24 h. The maroon-purple reaction
mixture was quenched with 1 N HCl and concentrated to 20-
30 mL and the red slurry diluted with EtOAc. The two layers
were separated, and the organic layer was washed with H2O,
saturated NaHCO3 (aq), and brine and dried (MgSO4). The
resultant solution was concentrated onto SiO2 in vacuo and
the product purified by silica gel chromatography (7:3 EtOAc/
hexanes) to give 1.24 g (50%) of 2d as a red solid. Also a
product of chromatography was a mixture of the product and
the starting acetamide (10:1, 0.365 g). The yield of the product
based on recovered starting material was 72%: 1H NMR (400
MHz, DMSO-d6) δ 11.81 (s, 1H), 11.14 (s, 1H), 7.86 (d, J ) 3
Hz, 1H), 7.60 (d, J ) 8 Hz, 1H), 7.27 (d, J ) 3 Hz, 1H), 6.96
(dd, J ) 7, 7 Hz, 1H), 6.87 (d, J ) 7 Hz, 1H), 6.81 (d, J ) 7 Hz,
1H), 6.49 (d, J ) 3 Hz, 1H), 6.43 (dd, J ) 8, 8 Hz, 1H), 6.25 (d,
J ) 8 Hz, 1H), 4.67 (t, J ) 5 Hz, 1H), 3.70 (s, 3H), 3.64 (m,
2H), 2.90 (t, J ) 6.7 Hz, 2H); HRMS (M+ + 1) calcd for
C
C
23H20N3O3 386.1505, found 386.1495. Anal. Calcd for
23H19N3O3: C, 71.68; H, 4.97; N, 10.90. Found: C, 71.33; H,
5.13; N, 10.83.
3-[7-(2-Br om oeth yl)-1H-in d ol-3-yl]-4-(1-m eth yl-1H-in -
d ol-7-yl)-1H-p yr r ole-2,5-d ion e (2e). Meth od A. CBr4 (3.05
g, 9.20 mmol) was added in one portion to a solution of 2d
(2.88 g, 7.47 mmol) and PPh3 (2.32 g, 8.84 mmol) in DMF (50
mL), and the mixture stirred at rt for 4 h. The solution was
concentrated to about 10 mL, poured into EtOAc, washed with
water, saturated NaHCO3 (aq), and brine, and dried (MgSO4).
The solution was concentrated onto SiO2 in vacuo and the
product purified by silica gel chromatography (30 to 50%
EtOAc/hexanes) to afford 2.31 g (69%) of 2e as an orange
solid: 1H NMR (400 MHz, acetone-d6) δ 11.13 (s, 1H), 9.90 (s,
1H), 8.30 (d, J ) 3 Hz, 1H), 7.62 (m, 1H), 7.17 (d, J ) 3 Hz,
1H), 6.92-6.98 (m, 3H), 6.44-6.55 (m, 3H), 3.82 (s, 3H), 3.68
(t, J ) 8 Hz, 2H), 3.39 (t, J ) 8 Hz, 2H); 13C NMR (62.9 MHz,
DMSO-d6) δ 173.5, 172.4, 135.2, 134.2, 131.6, 131.0, 129.5,
129.2, 125.0, 124.0, 122.6, 122.4, 121.5, 120.1, 119.5, 118.6,
115.1, 105.5, 100.7, 34.7, 33.9, 33.1 (one aromatic signal is
buried); IR (KBr) ν 3430, 1756, 1699 cm-1; HRMS (M++1) calcd
for C23H19BrN3O2 448.0661, found 448.0665. Anal. Calcd for
C
23H18BrN3O2: C, 61.62; H, 4.05; N, 9.37. Found: C, 61.60;
H, 4.20; N, 9.08.
Meth od B. To a solution of 2d (0.5 g, 1.3 mmol) in CH2-
Cl2/THF (40/30 mL) were added PPh3 (0.3 g, 1.3 mmol) and
CBr4 (0.4 g, 1.3 mmol). The reaction mixture was stirred at rt
and under N2 for 1 h. Another 1 equiv of PPh3 (0.3 g, 1.3 mmol)
was added followed by 1 equiv of CBr4 (0.4 g, 1.3 mmol). This
operation was repeated one more time after 1 h. The reaction
was monitored by TLC and was completed after 1 h. The
reaction mixture was diluted with EtOAc (100 mL), washed
with saturated NaHCO3 (aq) and brine, and dried (MgSO4).
The solution was concentrated in vacuo and the product
purified by silica gel chromatogprahy (1:1 EtOAc/hexanes) to
give 0.5 g (87%) 2e as a red solid.
9-Meth oxy-3-m eth yl-3H-in d olo[6,7-a ]p yr r olo[3,4-c]ca r -
ba zole-4,6(5H,11H)-d ion e (1a ). A solution of 2a (3.00 g, 8.08
mmol) and DDQ (1.83 g, 8.08 mmol) in EtOAc (1 L) was
irradiated in a 1 L photolysis reactor using a Hanovia medium-
pressure Hg lamp through a Pyrex filter at 25-45 °C for ∼3
h. The reaction solution was washed with aqueous 0.1 N NaOH
(4 × 150 mL) and brine (150 mL) and dried (MgSO4). The
solution was concentrated in vacuo and the solid triturated
with CH2Cl2 (150 mL), filtered, and dried to afford 2.59 g (87%)
1a as an orange-red solid: 1H NMR (300 MHz, DMSO-d6) δ
12.60 (s, 1H), 11.07 (s, 1H), 8.86 (d, 1H, J ) 8.8 Hz), 8.25 (d,
1H, J ) 8.8 Hz), 8.04 (d, 1H, J ) 8.4 Hz), 7.57 (d, 1H, J ) 2.9
2974 J . Org. Chem., Vol. 69, No. 9, 2004

Synthetic Approaches to Indolo[6,7-a]pyrrolo[3,4-c]carbazoles
Hz), 7.20 (d, 1H, J ) 2.2 Hz), 7.02 (dd, 1H, J ) 8.8, 2.2 Hz),
6.85 (d, 1H, J ) 2.9 Hz). 3.95 (s, 3H), 3.93 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ 170.6, 159.1, 142.0, 141.6, 132.4, 131.8,
127.4, 126.3, 125.1, 123.1, 120.4, 117.4, 115.2, 114.0, 113.2,
112.0, 109.6, 103.5, 94.8, 55.3, 38.4; IR (CHCl3) ν 3363, 3194,
3042, 2978, 2931, 2828, 1746, 1707, 1630, 1615 cm -1; HRMS
(ES+) calcd for C22H15N3O3 369.1110, found 369.1108.
lamp through a Pyrex filter for 0.5 h. The dark red mixture
was washed with 0.1 N NaOH (500 mL) and brine (500 mL)
and dried (MgSO4). The resultant solution was concentrated
in vacuo and purified by silica gel chormatopgraphy (30:70
EtOAc/hexanes) to afford 0.70 g (95%) of 1e as a red solid: 1H
(400 MHz, DMSO-d6) δ 12.15 (s, 1H), 11.07 (s, 1H), 8.85 (d, J
) 8 Hz, 1H), 8.57 (d, J ) 8 Hz, 1H), 8.05 (d, J ) 8 Hz, 1H),
7.58 (d, J ) 3 Hz, 1H), 7.38 (d, J ) 8 Hz, 1H), 7.29 (dd, J ) 8
Hz, 1H), 6.84 (d, J ) 3 Hz, 1H), 4.81 (t, J ) 5 Hz, 1H), 3.88 (s,
3H), 3.84 (m, 2H), 3.30 (t, J ) 7 Hz, 2H); 13C NMR (75.5 MHz,
DMSO-d6) δ 170.6, 170.5, 141.6, 139.5, 132.6, 131.8, 127.7,
127.1, 127.0, 123.1, 122.9, 122.0, 121.5, 120.7, 120.5, 117.8,
114.8, 113.6, 112.1, 103.4, 61.2, 38.4, 34.3; IR (KBr) v 3455,
3187, 1734, 1696 cm-1; HRMS (M+ + 1) calcd for C23H18N3O3
384.1348, found 384.1347.
11-(3-Hyd r oxyp r op yl)-9-m eth oxy-3-m eth yl-3H-in d olo-
[6,7-a ]p yr r olo[3,4-c]ca r ba zole-4,6(5H,11H)-d ion e (1b). A
solution of 2b (2.0 g, 4.65 mmol) and DDQ (1.06 g, 4.65 mmol)
in EtOAc (1 L) was photolyzed with 450 W Hanovia lamp
through a Pyrex filter for 2.25 h. The mixture was purified by
plug filtration through silica gel eluting with EtOAc and
recrystallized from toluene/MeOH/hexane to give 1.1 g (55%)
of 1b as a red solid: 1H NMR (300 MHz, DMSO-d6) δ 11.07 (s,
1H), 8.98 (d, J ) 8.4 Hz, 1H), 8.36 (d, J ) 8.8 Hz, 1H), 7.97 (d,
J ) 8.8 Hz, 1H), 7.56 (d, J ) 3.2 Hz, 1H), 7.40 (d, J ) 1.6 Hz,
1H), 7.04 (dd, J ) 2.4, 8.6 Hz, 1H), 6.81 (d, J ) 3.2 Hz, 1H),
4.90 (t, J ) 7.2 Hz, 2H), 4.86 (br s, 1H), 3.94 (s, 3H), 3.83 (s,
3H), 3.57 (t, J ) 5.2 Hz, 2H), 2.14 (app quintet, J ) 6 Hz, 2H);
13C NMR (75.5 MHz, DMSO-d6) δ 170.4, 170.2, 159.3, 143.7,
140.1, 132.4, 131.7, 126.4, 125.3, 125.2, 122.6, 120.7, 117.9,
114.5, 114.2, 114.1, 113.4, 109.8, 102.9, 93.9, 57.8, 55.4, 43.1,
38.2, 32.3; IR (KBr) ν 3560, 3178, 1744, 1696 cm-1. Anal. Calcd
for C25H21N3O4: C, 70.25; H, 4.95; N, 9.83. Found: C, 70.58;
H, 5.06; N, 9.58.
11-(3-Br om op r op yl)-9-m et h oxy-3-m et h yl-3H -in d olo-
[6,7-a ]p yr r olo[3,4-c]ca r ba zole-4,6(5H,11H)-d ion e (1c). A
solution of 2c (0.7 g, 1.4 mmol) and DDQ (0.3 g, 1.4 mmol) in
EtOAc/dioxane (600/400 mL) was irradiated with a 450 W
Hanovia medium-pressure lamp through a Pyrex filter. After
1 h, the reaction mixture was washed with 0.1 N NaOH (500
mL) and brine (500 mL) and dried (MgSO4). The solution was
concentrated in vacuo and the product purified by silica gel
chromatography (EtOAc) to afford 0.6 g (87%) of 1c as a red
solid: 1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.99 (d,
J ) 8.7 Hz, 1H), 8.30 (d, J ) 8.9 Hz, 1H), 7.99 (d, J ) 8.9 Hz,
1H), 7.58 (d, J ) 3.0 Hz, 1H), 7.41 (d, J ) 1.8 Hz, 1H), 7.06
(dd, J ) 8.7, 2.1 Hz, 1H), 6.83 (d, J ) 3.0 Hz, 1H), 4.96 (t, J )
7.2 Hz, 2H), 3.96 (s, 3H), 3.84 (s, 3H), 3.70 (t, J ) 6.1 Hz, 2H),
2.51 (m, 2H); HRMS (M+ + 1) calcd for C25H21N3O3 490.0766,
found 490.0764.
3,5-Dih yd r o-11-[3-[(2-h yd r oxyet h yl)a m in o]p r op yl]-9-
m eth oxy-3-m eth yl-3H-in d olo[6,7-a ]p yr r olo[3,4-c]ca r ba -
zole-4,6(5H,11H)-d ion e (1d ). A mixture of1c (150 mg, 0.30
mmol), 2-aminoethanol (0.25 mL, 3.81 mmol), and DMF (10
mL) was heated at 65 °C overnight. The reaction was allowed
to cool and concentrated to a red oil. The oil was taken up in
EtOAc, washed with H2O, saturated NaHCO3 (aq), and brine,
and dried (MgSO4). The solution was concentrated in vacuo,
and a 0.154 mM solution of methansulfonic acid in CH3CN
(1.95 mL) was added to the crude product. The resultant
organic layer was extracted with H2O (10 and 5 mL), and the
combined aqueous solutions were freeze-dried. The salt was
obtained dissolved in H2O (2 mL) and 0.1 N NaOH (3 mL)
added. The product that precipitated was collected by filtra-
tion, rinsed with H2O, and freeze-dried to give 73 mg (42%) of
1d : 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J ) 8 Hz, 1H),
8.37 (d, J ) 9 Hz, 1H), 7.98 (d, J ) 9 Hz, 1H), 7.57 (d, J ) 3
Hz, 1H), 7.42 (d, J ) 2 Hz, 1H), 7.03 (dd, J ) 8, 2 Hz, 1H),
6.81 (d, J ) 3 Hz, 1H), 4.91 (t, J ) 7 Hz, 2H), 4.48 (br s, 1H),
3.95 (s, 3H), 3.83 (s, 3H), 3.48 (t, J ) 6 Hz, 2H), 2.64 (t, J ) 6
Hz, 2H), 2.58 (t, J ) 6 Hz, 2H), 2.07 (m, 2H); 13C NMR (100.6
MHz, DMSO-d6) δ 170.4, 170.2, 159.3, 143.7, 140.1, 132.5,
131.7, 126.4, 125.3, 125.2, 122.7, 120.8, 118.0, 114.5, 114.12,
114.10, 113.4, 110.0, 102.9, 94.0, 60.3, 55.5, 51.7, 45.9, 44.0,
38.2, 29.3; IR (KBr) ν 3371, 1742, 1694 cm-1; HRMS (M+ + 1)
calcd for C27H27N4O4 471.2032, found 471.2035.
10-(2-Br om oet h yl)-3-m et h yl-3H -in d olo[6,7-a ]p yr r olo-
[3,4-c]ca r b a zole-4,6(5H,11H)-d ion e (1f). A solution of 2e
(2.23 g, 4.98 mmol) and DDQ (1.13 g, 4.98 mmol) in dioxane
(800 mL) was irradiated with a 450W Hanovia mercury arc
lamp through a Pyrex filter for 2.5 h. The dark solution was
concentrated to about 40 mL and poured into EtOAc. The
EtOAc solution was washed with 0.1 N NaOH, saturated
NaHCO3 (aq), and brine, dried (MgSO4), and concentrated to
about 50 mL. Hexanes (2-3 mL) were added and the solution
allowed to stand 4 h. Filtration afforded 1.41 g (64%) of 1f as
a red solid that was dried under vacuum at 75 °C. The mother
liquor was concentrated onto silica gel and purified (30:70
EtOAc/hexanes) to afford an additional 0.62 g (28%) of 1f: 1H
NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.10 (s, 1H), 8.91
(d, J ) 8 Hz, 1H), 8.55 (d, J ) 8 Hz, 1H), 8.07 (d, J ) 8 Hz,
1H), 7.60 (d, J ) 3 Hz, 1H), 7.47 (d, J ) 8 Hz, 1H), 7.33 (dd,
J ) 8, 8 Hz, 1H), 6.85 (d, J ) 3 Hz, 1H), 3.92 (t, J ) 7.5 Hz,
2H), 3.88 (s, 3H), 3.70 (t, J ) 7.5 Hz, 2H). Anal. Calcd for
C
23H16BrN3O2: C, 61.90; H, 3.61; N, 9.42. Found: C, 61.61;
H, 3.55; N, 9.48.
3-Meth yl-10-[2-(1-p ip er id in yl)eth yl]-3H-in d olo[6,7-a ]-
p yr r olo[3,4-c]ca r ba zole-4,6(5H,11H)-d ion e (1g). A solution
of 1f (100 mg, 0.22 mmol) and piperidine (0.21 mL, 2.2 mmol)
in DMF (5 mL) was heated at 60 °C overnight. The mixture
was cooled and the product separated by directly injecting the
mixture in two 2.5 mL portions onto a 7 µm C18 reversed-
phase HPLC column (19 × 300 mm) with gradient elution with
95:5 H2O (0.1% HCl)/CH3CN to 5:95 H2O (0.1% HCl):CH3CN.
Fractions containing product where passed through an SCX
column, washing first with MeOH and EtOAc, and then a 1:1
mixture of 2 M NH3 in MeOH and EtOAc. Concentration of
the latter afforded 95 mg (95%) of 1g as an orange solid: 1H
NMR (400 MHz, DMSO-d6) δ 12.32 (br s, 1H), 11.07 (s, 1H),
8.83 (d, J ) 7 Hz, 1H), 8.55 (d, J ) 8 Hz, 1H), 8.03 (d, J ) 8
Hz, 1H), 7.57 (d, J ) 3 Hz, 1H), 7.35 (d, J ) 7 Hz, 1H), 7.28
(dd, J ) 7, 7 Hz, 1H), 6.83 (d, J ) 3 Hz, 1H), 3.87 (s, 3H), 3.32
(br t, J ) 7.6 Hz, 4H), 2.74 (m, 2H), 2.59 (m, 2H), 1.60 (m,
4H), 1.45 (m, 2H); 13C NMR (100.6 MHz, DMSO-d6) δ 170.5,
170.5, 141.6, 139.3, 132.6, 131.8, 127.7, 127.0, 126.3, 124.2,
122.9, 121.9, 121.5, 120.63, 120.57, 117.8, 114.8, 113.5, 112.2,
103.4, 59.2, 54.2, 38.4, 28.2, 25.5, 24.1; IR (KBr) ν 3214, 1744,
1695 cm-1; HRMS (M+ + 1) calcd for C28H27N4O2 451.2134,
found 451.2158.
Ack n ow led gm en t. We thank Professors Marvin
Miller, Bill Roush, Peter Wipf, Ted Taylor, Paul Wender,
and Leo Paquette for helpful discussions during the
course of this work. Mr. Paul Dodson and Mr. Michael
Henshaw are acknowledged for their analytical support
for this project. Dr. Sam Wendel is acknowledged for
his help in developing the enzymatic hydrolysis of 18.
We thank Drs. Walter Xie, C. Richard King, Bruno
Geithlen, J ulia L. Barkin, Michael K. Hilinski, and Gene
Kogut for help with scale-up and synthesis of inter-
mediates.
10-(2-Hydr oxyeth yl)-3-m eth yl-3H-in d olo[6,7-a ]pyr r olo-
[3,4-c]ca r ba zole-4,6(5H,11H)-d ion e (1e). A solution of 2d
(0.80 g, 2.0 mmol) and DDQ (0.50 g, 2.0 mmol) in EtOAc (1000
mL) was irradiated with a 450 W Hanovia medium-pressure
J O035606V
J . Org. Chem, Vol. 69, No. 9, 2004 2975