Syntheses of C12,N13 heterocyclic bridged fused indenopyrrolocarbazoles

Article abstract of DOI:10.1021/jo0108360

Tandem alkylation/cyclization of indenopyrrolocarbazole 4a, a C12 carbon analogue of indolocarbazole K252c, was carried out by general solid-phase and solution-phase methods. Alkylation of fused pyrroloindenylcarbazole 4a derivatives with appropriate mono

Full text of DOI:10.1021/jo0108360

J . Org. Chem. 2002, 67, 3235-3241
3235
Syn th eses of C12,N13 Heter ocyclic Br id ged F u sed
In d en op yr r oloca r ba zoles
Ted L. Underiner,* J ohn P. Mallamo, and J asbir Singh†
Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway,
West Chester, Pennsylvania 19380
tunderin@cephalon.com
Received August 16, 2001
Tandem alkylation/cyclization of indenopyrrolocarbazole 4a , a C12 carbon analogue of indolocar-
bazole K252c, was carried out by general solid-phase and solution-phase methods. Alkylation of
fused pyrroloindenylcarbazole 4a derivatives with appropriate monoacetals of diketones afforded
the corresponding C12-substituted acetal alcohols. Acid-catalyzed cyclization of these adducts yielded
C12,N13-bridged tetrahydrofuran, pyran, and dioxane compounds 10-13.
In tr od u ction
Over 50 alkaloids of the indolocarbazole family1 have
been characterized including the well-known stauro-
sporin,2 rebeccamycin,3 and K252a.4 Key features of this
As part of our work in preparing ATP competitive
kinase inhibitors, we explored solid-phase and solution-
phase chemistries to synthesize C12,N13 heterocyclic
bridged fused indenopyrrolocarbazoles 5 by a tandem
alkylation/cyclization process beginning with 13H-indeno-
[2,1-a]pyrrolo[3,4-c]carbazole (4a ,8 a C12 analogue of 4c).
family include an indolocarbazole heterocyclic core with
a fused lactam or imide ring and a pendant sugar
(pyranose or furanose). The novel structure of these
natural products and their diverse biological properties,
especially with regard to cell signaling, growth, and
proliferation, have stimulated synthetic interest toward
the preparation of biologically active analogues of this
family of compounds.5 For example, simple tetrahydro-
furan analogues 1-3 of arcyriaflavin A (4b) and stauro-
sporine aglycon K252c (4c) have been reported to be
PKC6 and chk1 kinase7 inhibitors.
* To whom correspondence should be addressed.
† Current address: MediChem, Inc. 2501 Davey Road, Woodridge,
IL 60517
(1) Gribble, G. W.; Berthel, S. J . In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: New York, 1993; Vol. 12,
pp 365-409.
(2) For leading references, see: Schupp, P.; Eder, C.; Proksch, P.;
Wray, V. V.; Schneider, B.; Herderich, M.; Paul, V. V. J . Nat. Prod.
1999, 62, 959-62.
(3) For leading references, see: Moreau, P.; Anizon, F.; Sancelme,
M.; Prudhomme, M.; Severe, D.; Riou, J .-F.; Goossens, J .-F.; Henichart,
J .-P.; Bailly, C.; Labourier, E.; Tazzi, J .; Fabbro, D.; Meyer, T.;
Aubertin, A. M. J . Med. Chem. 1999, 42, 1816-22.
(4) Kase, H.; Iwahashi, K.; Nakanishi, S.; Matsuda, Y.; Yamada,
K.; Takahashi, M.; Murakata, C.; Sato, A.; Kaneko, M. Biochem.
Biophys. Res. Commun. 1987, 142, 436-40.
(5) Pindur, U.; Kim, Y.-S., Mehrabani, F. Curr. Med. Chem. 1999,
6, 26-69 and references therein.
(6) McCombie, S. W.; Bishop, R. W.; Carr, D.; Dobek, E.; Kirkup,
M. P.; Kirschmeier, P.; Lin, S.-I.; Petrin, J .; Rosinski, K.; Shankar, B.
B.; Wilson, O. Biorg. Med. Chem. Lett. 1993, 3, 1537-42.
Resu lts a n d Discu ssion
Solid-phase chemical techniques were well suited for
the rapid preparation of analogues of 4a . Indeed, the
solubility and reactivity characteristics of 4a initially
made traditional solution-phase chemistry quite prob-
lematic. For example, the acidities of the indole, the
lactam, and the C12 hydrogens were comparable, and the
behavior of 4a in the presence of a variety of organic and
inorganic basic reagents appeared variable. Presumably,
oxidation at C12 and C5 occurred readily in the presence
of such bases. To overcome these solubility, selectivity,
and reactivity issues, solid-phase chemical techniques
were initially investigated.
(7) J ackson, J . R.; Gilmartin, A.; Imburgia, C.; Winkler, J . D.;
Marshall, L. A.; Roshak, A. Cancer Res. 2000, 60, 566-72.
(8) Hudkins, R. L.; Knight, E., J r. US Patent 5,705,511.
10.1021/jo0108360 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

3236 J . Org. Chem., Vol. 67, No. 10, 2002
Underiner et al.
Sch em e 2. Alk yla tion of 4a -Rin k w ith 7
Sch em e 1. Alk yla tion of 4a -Rin k w ith Ald eh yd es
In work described more completely elsewhere,9 treat-
ment of 4a -Rin k with excess EtMgBr afforded an anionic
species that could be alkylated selectively at C12 with
aldehydes and ketones (Scheme 1) to ultimately yield a
mixture of diastereomeric alcohols 6. As shown in Scheme
2, it was envisioned that a similar reaction with mono-
protected dialdehydes (e.g., 7) and/or monoprotected
ketoaldehydes would also afford the expected secondary
alcohols, which could then undergo acid-catalyzed cy-
clization to afford compounds such as 5.13
In the first example, alkylation of 4a -Rin k with 4,4-
diethoxybutyraldehyde (7)14 followed by cleavage with 1%
TFA in CH2Cl2 afforded a mixture of adducts (Scheme
2). Analyses of these products by LC/MS suggested that
the mixture consisted of diastereomeric cyclic acetals 8,
hemiacetals 9, and the fully cyclized adduct 10. Although
reversed-phase preparative HPLC could be used to isolate
individual reaction products, pyridinium tosylate-cata-
lyzed equilibration of the complex product mixture af-
forded predominantly a single diastereomeric product
(10) in 30% overall yield after isolation by preparative
HPLC.
The methodology depicted in Scheme 2 was used to
prepare the C12,N13 heterocyclic bridged compounds
11-13 shown in Scheme 3. The ketones 1415 and 1516
were prepared by literature methods. Ketone 16 was
prepared by alkylating diethoxyethanol17 with methallyl
chloride followed by ozonolysis of the resulting allyl ether.
The THF-bridged compound 11 was isolated as a single
isomer, presumably with the same relative stereochem-
istry as obtained for the preparation of 10; in contrast,
the pyran (12) and dioxane (13) bridged derivatives were
In model reactions with 4,4′-dimethoxybenzhydrol, the
lactam of indenopyrrolocarbazole 4a could be selectively
alkylated to give 4a -DMBH (Scheme 1).9 As reported
eleswhere,9 the relatively nucleophilic lactam nitrogen
provided an appropriate handle to covalently link 4a
onto a resin, and the search for a suitable linker/resin
combination resulted in the selection of Rink acid resin
(0.64 mmol/g, Calbiochem-Novabiochem Corp). Thus,
TsOH-catalyzed dehydrative coupling of 4a with Rink
acid resin proceeded efficiently to give material (4a -Rin k )
whose loading was determined by cleavage with 1% TFA
in CH2Cl2 to be 0.50 mmol/g.9
This mode of attachment provided the additional bene-
fit of protecting the lactam from unwanted functional-
ization. The crystal strucutres of staurosporin bound to
PKA10 and cdk211 as well as molecular modeling studies12
of other indolopyrrolocarbazoles and bisindoylmaleimdes
indicated the lactam/imide group of these molecules
participates in the same key H-bonding interactions as
the natural ligand ATP.5 Thus, in this series of analogues,
an unsubstituted lactam ring was considered an essen-
tial element of the pharmacaphore for ATP site recogni-
tion.
(9) Singh, J .; Hudkins, R. L.; Mallamo, J . P.; Underiner, T. L.;
Tripathy, R. US patent 6,127,401, 2000. Tripathy, R.: Learn, K. S.;
Reddy, D.; Iqbal, M.; Singh, J .; Mallamo, J . M. Tetrahedron Lett. 2002,
43, 217-20.
(10) Prade, L.; Engh, R. A.; Girod, A.; Kinzel, V.; Huber, R.;
Bossemeyer, D. Structure 1997, 5, 1627-37.
(11) Toledo, L. M.; Lydon, N. B. Structure 1997, 5, 1551-56.
(12) Furet, P.; Caravatti, G.; Lydon, N.; Priestle, J . P.; Sowadski, J .
M.; Trinks, U.; Traxler, P. J . Comput.-Aided Mol. Des. 1995, 9, 465-
72. Toledo, L. M.; Lydon, N. B.; Elbaum, D. Curr. Med. Chem. 1999,
6, 775-805.
(13) A similar strategy was implemented in the total syntheses of
indolocarbazole K252a: Wood, J . L.; Stoltz, B. M.; Dietrich, H.-J . J .
Am. Chem. Soc. 1995, 117, 10413-14.
(14) Paquette, L. A.; Backhaus, D.; Braun, R.; Underiner, T. L.;
Fuchs, K. J . Am. Chem. Soc. 1997, 119, 9662-71.
(15) Schmidt, U.; Riedl, B. Synthesis 1993, 809-14.
(16) Brenner, J . E. J . Org. Chem. 1961, 26, 22-7.
(17) Bernard, D.; Doutheau, A.; Gore, J . Synth. Commun. 1987, 17,
1807-14.

Syntheses of Bridged Fused Indenopyrrolocarbazoles
J . Org. Chem., Vol. 67, No. 10, 2002 3237
21.19 On the other hand, reaction of 4a -TBDP S with
aldehyde 21 in the presence of Triton B proceeded
smoothly to afford a 9:1 mixture of isomers 22-tBDP S
and 23-tBDP S as determined by HPLC analysis of the
crude reaction mixture. Analysis by TLC (silica gel)
indicated that the ∆Rf for 22-tBDP S and 23-tBDP S was
>5, and so these isomeric alcohols were easily separated
by column chromatography (Scheme 4). To confirm that
the 9:1 product ratio was a thermodynamic product
distribution, the individual alcohols were treated with
Triton B, and each returned an exclusive 9:1 mixture of
22-tBDP S and 23-tBDP S as determined by HPLC.
Whether this equilibration occurred by simple deproto-
nation of the indenyl methine (C12) followed by prefer-
ential diastereofacial protonation or by regeneration of
the aldehyde followed by alkylation is not certain at this
time. However, the latter seems less likely since alkyla-
tion of 4a -tBDP S with only 1 equiv of aldehyde 21
inevitably led to incomplete conversion to 22-tBDP S and
23-tBDP S due to the apparent instability of the aldehyde
to the basic reaction conditions. If the latter equilibration
mechanism were operational, an equilibrated mixture of
alcohols and 4a -tBDP S would be expected; however, only
22-tBDP S and 23-tBDP S were detected by HPLC.
Sch em e 3. Ta n d em Alk yla tion /Cycliza tion
4a -Rin k w ith Keton es 14-16
These observations (i.e., thermodynamic stability and
apparent ∆Rf) have implications for assigning the relative
stereochemistry of the isomeric alcohols 22-tBDP S and
23-tBDP S and, ultimately, compound 10. Newman pro-
jections (viewed down the carbinol (C1′)-indene (C12)
carbon bonds) for conformations of 22-tBDP S and 23-
tBDP S that would facilitate an intramolecular hydrogen
bond between the indole NH and the oxygen of the
hydroxyl group are depicted in Figure 1. The stabilization
afforded by such an intramolecular interaction is bal-
anced by the restricted rotation around the C1′-C2′-
C3′-C4′ bonds of the pendant alkyl chain imposed by the
aromatic core and/or the indene hydrogen. If the balance
favors formation of an intramolecular H-bond, the overall
basicity of the molecule would be expected to be relatively
low (i.e., the relative Rf,silica would be high). On the other
hand, if the energetic cost of achieving a conformation
that would facilitate the formation of an intramolecular
H-bond is too high, the overall basicity of this alcohol
would be expected to be relatively high (i.e., the relative
Rf,silica would be low). The degrees of freedom along the
C1′-C4′ bonds in the conformation of 23-tBDP S depicted
in Figure 1 are more severely restricted than those for
22-tBDP S. That is to say, for 23-tBDP S, conformational
restrictions inhibit the formation of an intramolecular
H-bond, and this may account for the alcohol’s low Rf
(Rf,silica ) 0.1). For 22-tBDP S, a conformation conducive
for intramolecular H-bonding can more readily be ac-
commodated, and this may account for its observed high
Rf (Rf,silica ) 0.5). These arguments (and those that follow)
suggest that 22-tBDP S (Rf,silica ) 0.5) is the preferred
product from alkylating 4a -tBDP S with aldehyde 21.
prepared as a mixture of diastereomers that were sepa-
rated by preparative reversed-phase HPLC. Attempts to
assign relative stereochemistry to the adducts 10-13 by
crystallographic techniques are curently in progress. The
stereochemical assignment of 10 will be addressed in the
following section.
Preparing multigram quantities of the bridged inde-
nopyrrolocarbazoles 5 via the solid-phase method de-
scribed above proved impractical and uneconomical with
respect to the resin, reagents, and solvents. As alluded
to earlier, attempts to alkylate 4a under strongly basic
conditions proved problematic, and typically only highly
insoluble material was recovered from these reactions.
It had been reported that Triton B-catalyzed alkylation
of flourene (17) with aldehydes and ketones gave product
mixtures consisting of addition (18), addition-elimina-
tion (19), and other products (e.g., 20).18 The product
distribution depended on the particular reaction condi-
tions and the aldehydes utilized.
Treatment of each isomeric alcohol 22-tBDP S and 23-
tBDP S with BF3 etherate afforded diastereomers 10a -
tBDP S and 10b-tBDP S, respectively. Under these re-
action conditions, various degrees of desilylation of the
lactam occurred. If the unprotected material was desired,
it was more efficient to treat this crude product mixture
This method proved unsuccessful when applied to the
reaction of 4a with 1,3-dioxane-protected succinaldehyde
(19) Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.; Miyashiro,
J . M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie, J . L.; Seibert, K.;
Isakson, P. C. J . Med. Chem. 1997, 40, 1619-33.
(18) Ghera, E.; Sprinzak, Y. J . Am. Chem. Soc. 1960, 82, 4945-52.

3238 J . Org. Chem., Vol. 67, No. 10, 2002
Underiner et al.
Sch em e 4. Solu tion -P h a se Ta n d em Alk yla tion /Cycliza tion of 4a -tBDP S w ith Ald eh yd e 21
F igu r e 1. Newman projections of alcohols 22-t BDP S and
23-tBDP S depicting the orientation for intramolecular H-
bonding.
with aqueous HF buffered with KF to afford 10.20
Otherwise, chromatography was necessary to separate
10-tBDP S from 10.
1
It was observed by HNMR and HPLC that diastere-
omer 10b completely isomerized to 10a in DMSO (Scheme
4). Presumably, epimerization of the C12 methine of 10b
occurred to yield the apparently more stable diastereomer
10a . To rationalize these observations, compuational
chemistry studies were carried out. Depictions of the
SYBYL21-minimized structures (with AM1 geometry
optimization) for each isomer of 10 are shown in Figure
2. A structure in which the N13 and C12 atoms are
F igu r e 2. SYBYL21-minimized structures of 10a and 10b.
bridged by a trans-substituted THF ring is undoubtedly
too strained to be isolated or observed. The most promi-
nent structural feature that distinguishes the two iso-
mers depicted in Figure 2 is the orientation of the plane
defined by the THF ring relative to the planar aromatic
portion of the molecule. For 10a , the angle between these
planes is slightly less than 90°; in the case of 10b, this
angle is nearly 220° (Figure 2). As a consequence, the
endo-hydrogens (shown as dark gray in the second right-
(20) Kendall, P. M.; J ohnson, J . V.; Cook, C. E. J . Org. Chem. 1979,
44, 1421-24.
(21) SYBYL Molecular Modeling System (version 6.6), Tripos As-
sociates, St. Louis, MO. Please see the Experimental Section for details
concerning generation of these minimized structures.

Syntheses of Bridged Fused Indenopyrrolocarbazoles
J . Org. Chem., Vol. 67, No. 10, 2002 3239
hand structure of Figure 2) on the THF ring of 10a
appear to reside in the aromatic ring current. Thus, the
signals in the 1HNMR sprectrum for the endo-protons
would be expected to appear significantly upfield of those
of the exo-protons.6,22, Since the exo- and endo-hydrogens
for 10b are situated in more similar environments, a less
dramatic difference in chemical shifts for these protons
in the H NMR spectrum would be expected. Signals in
1H NMR (CDCl3) for these methylene protons of 10a -
tBDP S appeared at δ 0.93, 1.14, 2.05, and 2.27, while
those for 10b-tBDP S appeared at δ 2.60, 2.69, 2.91, 3.05.
Also evident in Figure 2 is the closer proximity of the
indene C12 methine to the pair of endo THF methylene
protons for isomer 10b compared to that for the major
isomer 10a . To confirm the relative proximity of these
protons, NOE experiments were carried out, and the
minor isomer 10b-tBDP S revealed signal enhancements
between the indene C12 methine and endo THF meth-
ylene protons; such an effect was not observed for the
major isomer 10a . These spectral data support the
assignment of the major stereoisomer to structure 10a
and are consistent with the proposed structure assigned
to its alcoholic precursor 22-tBDP S.
These computational chemistry calculations also offer
an explanation for the observed isomerization of 10b to
10a . As shown in Figure 2, two eclipsing interactions are
apparent for 10b: the C12 methine hydrogen with the
carbon-carbon bond of the bridging THF ring and the
indene carbon-carbon bond with the carbon-oxygen
bond of the THF ring (shown as dark gray bonds in the
third right-hand structure of Figure 2). On the other
hand, 10a enjoys a more stable gauche conformation for
these same groups. Computational chemistry (AM1)
calculations21 indicate that 10a is thermodynamically
more stable than 10b by 2.14 kcal/mol. Thus, the
observed epimerization of 10b to 10a is consistent with
theoretical calculations and supports the stereochemical
assignment that was made on the basis of the spectral
evidence.
t BDP S, and the predicted thermodynamic stability of
10a over 10b. The biological activity of these new
compounds is currently under investigation and will be
reported in due course.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents and solvents were obtained
from commercial sources and used without further purification.
HMPA was dried over CaH and decanted prior to use. NMR
spectra were recorded at either 300 or 400 MHz (proton) and
100 MHz (carbon) in the solvent indicated with TMS as an
internal reference. Coupling constants (J ) are given in hertz.
Flash chromatography was carried out in the solvents indi-
cated with Biotage Flash silica gel cartridges. Preparative
HPLC was carried out with a Zorbax RX-8, 4 × 25 cm column
eluted with a mixture of MeCN and water containing 0.1%
trifluoroacetic acid. Elemental analyses were carried out by
Micro-Analysis, Inc. (Wilmington, DE). Low-resolution mass
spectra were obtained by ion spray ionization. High-resolution
mass spectrometry (FAB) were carried out by M-Scan (West
Chester, PA).
P r ep a r a tion of Rin k -Resin -Bou n d 4a (4a -Rin k ). A
three-neck round-bottom flask fitted with an overhead me-
chanical stirrer and a Dean-Stark trap was sequentially
charged with Rink acid resin (10.00 g, 0.64 mmol/g), 1-methyl-
2-pyrolidinone (80 mL), benzene (350 mL), 4a 8 (3.00 g), and
p-toluenesulfonic acid (1.00 g). The reaction mixture was
warmed to reflux for 20 h, and then filtered. The resin was
washed with THF (5 × 175 mL) and the filtrate set aside. The
resin was then sequentially washed with DMSO (4 × 100 mL),
2% aqueous NaHCO3 (4 × 100 mL), water (4 × 100 mL),
DMSO (2 × 200 mL), THF (4 × 100 mL), and ethyl acetate (4
× 100 mL). The resin was dried under vacuum (24 h) to afford
11.70 g (0.47 mmol/g) of 4a -Rin k .
The original THF washings were evaporated, the residue
was diluted with water (750 mL), and the resulting precipitate
was filtered and sequentially washed with water, 2% aqueous
NaHCO3 (4 × 100 mL), and water (4 × 100 mL). After the
precipitate was dried under vacuum, 4a (1.28 g) was recovered.
Gen er a l P r oced u r e for th e Solid -P h a se Syn th esis of
Br id ged In d en op yr r oloca r ba zoles (10a ). To a suspension
of 4a -Rin k (1.25 g) in THF (24 mL) was added a 1.0 M solution
of EtMgBr in THF (6.25 mL), and the reaction was stirred for
1 h prior to the addition of HMPA (5.0 mL). After the reaction
was stirred for 10 min, diethoxybutyraldehyde14 (3.0 g) was
added, and the reaction was stirred for 20 h. The reaction was
quenched with 10% aqueous NH4Cl (5 mL) and filtered. The
resin was successively washed with 10% aqueous NH4Cl (3 ×
10 mL), water (3 × 10 mL), THF (3 × 10 mL), DMF (3 × 10
mL), water (3 × 10 mL), THF (3 × 10 mL), and ether (3 × 10
mL). The resin was dried under vacuum, taken up in meth-
ylene chloride (15 mL), and treated with trifluoroacetic acid
(0.15 mL). After being stirred for 1 h, the reaction was filtered,
and the filtrate was evaporated. The resulting residue was
taken up in methylene chloride (20 mL) and treated with
pyridinium tosylate (50 mg). After being stirred for 4 h, the
reaction mixture was washed with saturated aqueous NaHCO3
and brine and dried over MgSO4. After filtration and solvent
evaporation, the residue was purified by preparative HPLC
(60% MeCN/water). The appropriate fractions were neutralized
by addition of solid NaHCO3 and extracted into methylene
chloride (3 × 50 mL). The organic layer was dried over MgSO4,
filtered, and evaporated to afford 70.2 mg (39%) of 10a as a
white powder which had the following characteristics: 13C
NMR (DMSO-d6) δ 171.7, 143.1, 142.2, 141.3, 140.0, 139.9,
136.5, 129.1, 127.8, 127.3, 127.0, 126.7, 124.0 (2C), 122.5,
121.5, 121.4, 118.2, 112.0, 88.0, 79.1, 56.5, 45.5, 33.3, 24.7; 1H
NMR (DMSO-d6) δ 9.26 (d, J ) 7.5, 1H), 8.63 (s, 1H), 8.05 (d,
J ) 7.7, 1H), 7.90 (d, J ) 8.3, 1H), 7.75 (d, J ) 7.0, 1H), 7.53
(dd, J ) 8.2, 7.2, 1H), 7.45 (dd, J ) 7.5, 7.4, 1H), 7.38 (dd, J )
8.6, 7.4, 1H), 7.34 (dd, J ) 7.7, 7.2, 1H), 6.88 (d, J ) 6.2, 1H),
5.64 (app dt, J ) 8.6, 3.7, 1H), 4.95 (s, 2H), 4.57 (d, J ) 3.7,
1H), 2.23 (m, 1H), 1.97 (m, 1H), 0.96 (m, 1H), 0.63 (m, 1H),
Finally, chiral HPLC (Chiralcel OD) was utilized for
the preparative separation of the constitutive enanti-
omers of 10a -tBDP S. This method provided baseline
resolution of the two enantiomers. The individual isomers
were deprotected as described before to afford each
enantiomer of 10a . The optical purity of each enantiomer
so isolated was assessed by analytical chiral HPLC and
was found to be 97% ee and 90% ee, respectively.
Preparative chiral HPLC separation of the enantiomers
of 10a was impractical for solubility reasons.
Con clu sion
General solid-phase and solution-phase routes to pre-
pare heterocyclic bridged derivatives of fused indenopyr-
rolocarbazoles were developed and involved a tandem
alkylation/cyclization reaction sequence. This represents
a method for the concise preparation of C12,N13-bridged
indenopyrrolocarbazole analogues 5 starting from the
C12 carbon analogue 4a of the natural product 4c. The
structures of 10a and 10b were assigned on the basis of
their NMR spectral data, the chromatographic charac-
teristics of their precursor alcohols 22-tBDP S and 23-
(22) Emsley, J . W.; Feeney, J .; Sutcliffe, L. H. High Resolution
Nuclear Magnetic Resonance Spectroscopy; Pergamon: New York,
1975; Vol. 1.

3240 J . Org. Chem., Vol. 67, No. 10, 2002
Underiner et al.
also CH2Cl2 peak at 5.75 (s, 0.2 H); MS (m/z) for M + H
(C25H19N2O2), calcd 379, obsd 379. Anal. Calcd for C25H18N2O2
with 0.1(CH2Cl2): C, 77.92; H, 4.74; N, 7.24. Found: C, 77.91;
H, 4.74; N, 7.22.
(C26H21N2O3), calcd 409.1552, obsd 409.1556. Adduct 13b had
the following properties: 1H NMR (CDCl3) δ 9.58-9.22 (m,
1H), 7.82 (d, J ) 7.4, 1H), 7.60-7.40 (m, 3H), 7.37-7.27 (m,
3H), 7.21 (d, J ) 8.1, 1H), 5.81 (s, 1H), 5.21 (s, 1H), 5.10-4.80
(m, 2H), 4.59 (d, J ) 13.5, 1H), 4.38 (dd, J ) 13.5, 5.3, 1H),
4.21 (d, J ) 13.1, 1H), 3.82 (d, J ) 13.2, 1H), 1.13 (s, 3H);
HRMS (m/z) for M + H+ (C26H21N2O3), calcd 409.1552, obsd
409.1550.
P r ep a r a tion of 11. Following the general procedure, 4a -
Rin k (150.2 mg) was alkylated with ethyl 5,5-diethoxy-2-
oxopentanoate15 (14, 1.5 mL). After workup and cleavage from
the resin, the crude reaction product mixture was taken up in
methylene chloride (20 mL) and treated with BF3 etherate (20
uL). After being stirred for 2.5 h, the solution was washed with
saturated aqueous NaHCO3 and brine prior to being dried over
MgSO4. After filtration and solvent removal, the resulting
residue was purified by preparative HPLC (55% f 75% MeCN/
water gradient) to afford 11 (6.4 mg, 20%), which had the
following properties: 1H NMR (DMSO-d6) δ 9.36 (d, J ) 7.7,
1H), 8.68 (s, 1H), 8.00 (d, J ) 7.7, 1H), 7.83 (d, J ) 8.3, 1H),
7.58-7.15 (m, 5H), 6.97 (d, J ) 5.9, 1H), 4.93 (s, 2H), 4.82 (s,
1H), 4.48 (q, J ) 7.1, 2H), 2.42-2.10 (m, 2H), 1.37 (t, 3H, J )
7.1), 1.25-0.63 (m, 2H); HRMS (m/z) for M + H+ (C28H23N2O4),
calcd 451.1642, obsd 451.1658.
P r ep a r a tion of 6-ter t-Bu tyld ip h en ylsilyl-6,7,12,13-tet-
r ah ydr o-5H-in den o[2,1-a ]pyr r olo[3,4-c]car bazol-5-on e (4a-
tBDP S). To a solution of 4a 8 (6.2 g) in DMF (150 mL) were
added TEA (9.7 mL), tert-butylchlorodiphenylsilane ((tBDPS)-
Cl, 10.5 mL), and a catalytic amount of dimethylaminopyri-
dine. The mixture was heated at 50 °C for 15 h. Additional
triethylamine (5.0 mL) and (tBDPS)Cl (5.0 mL) was then
added, and the reaction was kept at 50 °C for another 20 h.
The reaction was quenched with aqueous NaHCO3 and ex-
tracted into EtOAc. The organic layer was washed with water
(2 × 100 mL) and brine before being dried over MgSO4. After
filtration and solvent evaporation, the resulting residue was
triturated with 1:1 ether/hexane to afford the product (9.1 g,
83%). An analytical sample was isolated by flash chromatog-
raphy (20% EtOAc/hexane) and had the following spectral
properties: 1H NMR (DMSO-d6) δ 11.95 (s, 1H), 9.21 (d, J )
1.8, 1H), 7.80-7.20 (m, 16H), 7.13 (dd, J ) 8.1, 2.7, 1H), 4.83
(s, 2H), 4.13 (s, 2H), 1.25 (s, 9H). Anal. Calcd for C37H32N2-
OSi: C, 80.98; H, 5.88; N, 5.11. Found: C, 81.11; H, 5.75.
P r ep a r a tion of Ra cem ic (13R,1R)- a n d (13R,1S)-r el-13-
[3-(5,5-Dim eth yl-1,3-d ioxa n -2-yl)-1-h yd r oxyp r op yl]-6,7,-
12,13-tetr a h yd r o-5H-in den o[2,1-a ]pyr r olo[3,4-c]ca r ba zol-
5-on e (22 a n d 23). A solution of 4a -tBDP S (1.00 g) in pyridine
(20.0 mL) was flushed with argon and treated with 2.5 mL of
Triton B (0.45 M in pyridine)17 and 2119 (5 mL). After being
stirred for 2 h, the reaction was extracted into EtOAc and
washed with 10% aqueous CuSO4 (3 × 50 mL) and brine, and
the organic layer was dried over MgSO4. After filtration and
solvent evaporation, the residue was purified by flash chro-
matography (20% f 60% EtOAc/hexane) to first give 22-
tBDP S (990 mg, 76%) and then 23-tBDP S (167 mg, 13%).
These alcohols were analyzed by MS: m/z for M + H+
(C46H49N2O4Si), calcd 721, obsd 721. Further characterization
was carried out after removal of the tBDPS group by the
following method.20 A solution of 22-tBDP S (75 mg) in THF
(16 mL) was added to an aqueous solution (5.8 mL) of HF
(0.175 mL of a 0.1 M aqueous solution) buffered with KF (35.1
mg). The solution was stirred for 24 h, taken up in CH2Cl2,
and washed with aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2 (3 × 100 mL), and the combined organic
layers were immediately passed through a plug of MgSO4.
Evaporation of the filtrate left a residue that was triturated
with ether (3 × 1 mL) to afford 22 (45 mg, 90%): 1H NMR
(DMSO-d6) δ 10.97 (s, 1H) 9.40 (d, J ) 7.3, 1H), 8.53 (s, 1H),
8.01 (d, J ) 7.7, 1H), 7.78 (d, J ) 8.1, 1H), 7.63 (d, J ) 7.1,
1H), 7.48 (t, J ) 7.4, 1H), 7.42 (t, J ) 7.4, 1H), 7.35 (t, J )
7.2, 1H), 7.29 (t, J ) 7.2, 1H), 6.35 (d, J ) 4.1, 1H), 4.95 (s,
2H), 4.63 (m, 1H), 4.50 (d, J ) 3.2, 1H), 4.08 (t, J ) 5.1, 1H),
3.30-3.25 (m, 2H), 3.15 (m, 2H), 1.62 (m, 1H), 1.31 (m, 1H),
0.90 (s, 3H), 0.88-0.70 (m, 2H), 0.53 (s, 3H). Anal. Calcd for
P r ep a r a tion of 12. Following the general procedure, 4a -
Rin k (74.3 mg) was alkylated with 1,1-diethoxy-5-hexanone16
(15; 0.75 mL), cyclized, and purified by preparative HPLC (65%
MeCN/water) to afford 12a (2.10 mg, 15%) and 12b (1.06 mg,
8%), which had the following salient spectral properties: (12a )
1H NMR (DMSO-d6) δ 9.30 (d, J ) 8.3, 1H), 8.55 (s, 1H), 7.97
(d, J ) 7.2, 1H), 7.65 (d, J ) 8.5, 1H), 7.59 (d, J ) 7.5, 1H),
7.48 (m, 1H) 7.39-7.15 (m, 3H), 6.31 (m, 1H), 5.02 (s, 1H),
4.88 (s, 2H), 0.88 (s, 3H); HRMS (m/z) for M + H+ (C27H23N2O2),
calcd 407.1759, obsd 407.1740. (12b) 1H NMR (DMSO-d6) δ
9.43 (d, J ) 8.1, 1H), 8.59 (s, 1H), 7.99 (d, J ) 7.3, 1H), 7.75-
7.65 (m, 2H), 7.49 (m, 1H), 7.43 (m, 1H), 7.36-7.25 (m, 2H),
6.75 (s, 1H), 4.91 (s, 2H), 4.50 (s, 1H), 1.95 (s, 3H); HRMS (m/
z) for M + H+ (C27H23N2O2), calcd 407.1759, obsd 407.1769.
P r ep a r a tion of (1,1-Dieth oxyeth oxy)a ceton e (16). To
a cold (0 °C) suspension of NaH (2.68 g, 60% dispersion in
mineral oil) in THF (150 mL) was added a solution of
1,1-diethoxyethanol17 (9.00 g) in THF (20 mL). The reaction
mixture was stirred at room temperature for 1 h before
methallyl chloride (8.0 mL) was added. The reaction mixture
was heated to reflux overnight, cooled, and filtered through a
plug of Celite. Solvent was removed by rotary evaporation, and
the residue was purified by flash chromatography (20% ether/
hexane) to give 1,1-diethoxyethyl 2-methyl-1-propenyl ether
(11.5 g, 90%), which had the following properties: 1H NMR
(CDCl3) δ 4.95 (s, 1H), 4.89 (s, 1H), 4.63 (t, J ) 7.3, 1H), 3.67
(s, 2H), 3.80-3.65 (m, 2H), 3.65-3.50 (m, 2H), 3.45 (d, J )
5.2, 1H), 1.73 (s, 3H), 1.19 (t, J ) 7.2, 6H). Ozonolysis of a
chilled (-30 °C) solution of this ether (6.00 g) in EtOAc (80
mL) was carried out until no starting material was detectable
by TLC (1 h). At this time, the reaction was purged with
oxygen, treated with Pd(OH)2 (150 mg), and stirred under an
atmosphere of hydrogen overnight. The catalyst was filtered
away, and the filtrate was concentrated by rotary evaporation.
The resulting residue was purified by flash chromatography
(20% EtOAc/hexane) to afford 16 (4.53 g, 82%), which had the
following properties: 1H NMR (CDCl3) δ 4.6 (t, J ) 7.2, 1H),
4.13 (s, 2H), 3.80-3.65 (m, 2H), 3.63-3.50 (m, 4H), 2.04 (s,
3H), 1.19, (t, J ) 7.0, 6H). Anal. Calcd for C9H18O4: C, 56.82;
H, 9.52. Found: C, 57.13; H, 9.39.
C
30H30N2O4: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.88; H,
6.31; N, 5.66. In a similar manner, 23-tBDP S was converted
to 23, which had the following properties: 1H NMR (DMSO-
d6) δ 11.71 (s, 1H) 9.40 (d, J ) 7.6, 1H), 8.52 (s, 1H), 7.99 (d,
J ) 7.9, 1H), 7.89 (d, J ) 7.3, 1H), 7.66 (d, J ) 8.1, 1H), 7.48
(t, J ) 7.2, 1H), 7.40 (t, J ) 7.2, 1H), 7.31 (t, J ) 7.5, 1H),
7.28 (t, J ) 7.5, 1H), 5.24 (d, J ) 3.8, 1H), 4.93 (s, 2H), 4.83
(m, 1H), 4.59 (d, J ) 4.5, 1H), 3.98 (t, J ) 5.1, 1H), 3.23 (dd,
J ) 10.9, 2.6, 1H), 3.12 (dd, J ) 10.9, 2.6, 1H), 3.03 (d, J )
10.9, 1H), 2.93 (d, J ) 10.9), 1.49 (m, 1H), 1.17 (m, 1H), 0.80
(s, 3H), 0.76 (m, 1H), 0.50 (m, 1H) 0.44 (s, 3H). Anal. Calcd
for C30H30N2O4: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.99;
H, 6.29, N, 5.44.
P r ep a r a tion of 13. Following the general procedure, 4a -
Rin k (230.2 mg) was alkylated with 16 (1.2 mL). After workup
and cleavage from the resin, a portion of the crude reaction
product mixture (10.5 mg from 23.7 mg, 44%) was taken up
in methylene chloride (20 mL) and treated with BF3 etherate
(20 uL). After being stirred for 2.5 h, the solution was washed
with saturated aqueous NaHCO3 and brine prior to being dried
over MgSO4. After filtration and solvent removal, the resulting
residue was purified by preparative HPLC (65% MeCN/water)
to afford 13a (2.34 mg, 27%) and 13b (1.34 mg, 16%). Adduct
13a had the following properties: 1H NMR (CDCl3) δ 9.35-
9.20 (m, 1H), 7.87 (d, J ) 7.6, 1H), 7.62 (d, J ) 7.0, 1H), 7.60-
7.30 (m, 6H), 6.22 (s, 1H), 5.20-4.85 (m, 2H), 4.47 (s, 1H), 3.67
(d, J ) 12.7, 1H) 3.52 (d, J ) 11.8, 1H), 3.40 (d, J ) 12.7, 1H),
3.38 (d, J ) 11.8, 1H), 1.91 (s, 3H); HRMS (m/z) for M+
P r ep a r a t ion of R a cem ic (9R,12S,12a S)-r el-3,9,10,11,-
12,12a -Hexa h yd r o-2-ter t-bu tyld ip h en ylsilyl-9,12-ep oxy-
in den o[1,2,3-fg]in dolo[3,2,1-kl]pyr r olo[3,4-i][1]ben zazocin -
1-on e (10a -t BDP S). A solution of 22-t BDP S (185 mg) in

Syntheses of Bridged Fused Indenopyrrolocarbazoles
J . Org. Chem., Vol. 67, No. 10, 2002 3241
CH2Cl2 (20 mL) was treated with BF3 etherate (10 uL). After
being stirred for 0.25 h, the solution was washed with
saturated aqueous NaHCO3 and brine prior to being dried over
MgSO4. Removal of solvent by rotary evaporation gave a
residue that was purified by flash chromatography (25%
EtOAc/hexane) to afford 10a -tBDP S (129 mg, 82%), which had
the following properties: 1H NMR (DMSO-d6) δ 9.08 (d, J )
7.2, 1H), 7.86 (d, J ) 8.2, 1H), 7.73 (d, J ) 6.9, 1H), 7.70-7.24
(m, 15H), 6.88 (d, J ) 5.9, 1H), 5.72 (m, 1H), 4.86 (s, 2H), 4.55
(d, J ) 3.3, 1H), 2.30-2.20 (m, 1H), 2.10-1.90 (m, 1H), 1.29
(s, 9H), 1.10-0.90 (m, 1H), 0.73-0.66 (m, 1H); MS (m/z) for
M + Na (C41H36N2O2SiNa), calcd 639, obsd 639. Anal. Calcd
for C41H36N2O2Si: C, 79.84; H, 5.88; N, 4.54. Found: C, 80.06;
H, 5.79, N, 4.40.
(t, J ) 7.3, 1H), 7.45-7.25 (m, 3H), 6.57 (m, 1H), 5.10 (m, 1H),
4.88 (s, 2H), 4.67 (m, 1H), 3.10 (m, 1H), 2.85 (m, 1H), 2.73 (m,
1H), 2.63 (m, 1H); MS (m/z) for M + Na (C25H18N2O2Na), calcd
401, obsd 401.
Separ ation of th e En an tiom er s of 10a-tBDP S by Ch ir al
HP LC a n d P r ep a r a tion of both En a n tiom er s of 10a . 10a -
tBDP S was dissolved in a minimum amount of CHCl3/EtOH
(1:4), and aliquots (500 uL) were eluted off a chiralcel OD
HPLC column (1 × 25 cm) with 100% EtOH at a flow rate of
1.5 mL/min. Fractions were collected and evaporated sepa-
rately (Rt for enantiomer A was 24-27 min, Rt for enantiomer
B was 36-39 min). Desilylation of each fraction was carried
out as described above, and the individual products were
purified by preparative HPLC as described for the preparation
of 10a via the solid-phase chemistry route. The HPLC reten-
tion times and MS spectral data of each enantiomer cor-
responded to authentic 10a . Enantiomer A was obtained in
97% ee and enantiomer B was obtained in 90% ee as deter-
mined by analytical chiral HPLC using a chiralcel OD column
(0.46 × 5 cm) eluted with 1:1 MeOH/EtOH at a flow rate of
0.25 mL/min (Rt for enantiomer A was 14 min, Rt for enanti-
omer B was 20.5 min).
Com p u t a t ion a l Ch em ist r y Met h od s. Computational
chemistry was performed using the SYBYL21 software package
running on a Silicon Graphic R4400 workstation. Molecular
models of 10a and 10b were constructed by modifying the
structure of staurosporin that was extracted from the Brook-
haven Protein Databank (pdb code 1stc). Atoms corresponding
to the glycoside portion of staurosporin were deleted, and the
indole nitrogen (N12) of the resulting 4c was modified to an
sp3 carbon to generate 4a . Molecular models of 10a and 10b
were constructed using standard bond lengths and bond angles
of the SYBYL fragment library, and atoms types of the
appropriate atoms were reassigned to the relevant types using
the “type-only” option. Energy minimizations were realized
with the SYBYL/MAXIMIN2 option by applying the conjugate
gradient algorithm and setting a root-mean-square gradient
of the forces acting on each atom to 0.05 kcal/mol as the
convergence criterion. These SYBYL-minimized structures
were subsequently subjected to full geometry optimizations in
AM1 using double precision with the “precise” option and using
the “mmok” command for the amide bond of the lactam.
P r ep a r a t ion of R a cem ic (9S,12R,12a S)-r el-3,9,10,11,-
12,12a -Hexa h yd r o-2-ter t-bu tyld ip h en ylsilyl-9,12-ep oxy-
in den o[1,2,3-fg]in dolo[3,2,1-kl]pyr r olo[3,4-i][1]ben zazocin -
1-on e (10b-tBDP S). A solution of 23-tBDP S (25 mg) in
CH2Cl2 (10 mL) was treated with BF3 etherate (3 uL). After
being stirred for 0.5 h, the solution was washed with saturated
aqueous NaHCO3 and brine prior to being dried over MgSO4.
Removal of solvent by rotary evaporation gave a residue that
was purified by flash chromatography (silica gel, 25% EtOAc/
hexane) to afford 10b-tBDP S (15 mg, 70%), which had the
following spectral properties: 13C NMR (CDCl3) δ 176.7, 146.1,
141.9, 141.8, 141.1, 139.1, 135.8, 135.7, 135.7, 135.2, 134.8,
133.5, 133.3, 129.9, 129.8, 129.7, 129.5, 128.0, 128.0, 127.9,
127.9, 127.7, 127.0, 126.0, 123.1, 122.1, 121.8, 121.2, 120.5,
1
116.5, 109.1, 87.1, 81.6, 54.7, 51.9, 38.0, 33.4, 29.0, 19.9; H
NMR (CDCl3) δ 9.38 (d, J ) 7.1, 1H), 7.72-7.68 (m, 5H), 7.57-
7.33 (m, 11H), 7.18 (t, J ) 7.5, 1H) 6.41 (dd, J ) 7.4, 5.0, 1H),
5.20 (t, J ) 4.8, 1H), 4.63 (s, 2H), 4.42 (d, J ) 4.0, 1H), 3.05
(m, 1H), 2.92 (m, 1H), 2.70 (m, 1H), 2.55 (m, 1H), 1.40 (s, 9H);
HRMS (m/z) for M + H+ (C41H37N2O2Si), calcd 617.2617, obsd
617.2624.
P r ep a r a t ion of R a cem ic (9R,12S,12a S)-r el-3,9,10,11,-
12,12a-Hexah ydr o-9,12-epoxyin den o[1,2,3-fg]in dolo[3,2,1-
kl]p yr r olo[3,4-i][1]ben za zocin -1-on e (10a ). A solution of
10a -tBDP S (98 mg) in THF (16 mL) was added to an aqueous
solution (5.9 mL) of HF (0.175 mL of a 0.1 M aqueous solution)
buffered with KF (35.3 mg). The solution was stirred for 24 h,
taken up in DCM, and washed with aqueous NaHCO3. The
aqueous layer was extracted with DCM (3 × 100 mL), and the
combined organic layers were immediately passed through a
plug of MgSO4 and evaporated to leave a residue that was
triturated with 1:1 ether/hexane to afford 10a (53 mg, 88%).
The HPLC retention time and spectral data (NMR and MS)
were identical to those obtained for the preparation of 10a by
the solid-phase method described above.
Ack n ow led gm en t. We thank Ms. Alyssa Reiboldt
for her chiral HPLC expertise and Dr. Mohamed Iqbal
for acquiring and interpreting the NMR spectroscopic
data.
P r ep a r a t ion of R a cem ic (9S,12R,12a S)-r el-3,9,10,11,-
12,12a-Hexah ydr o-9,12-epoxyin den o[1,2,3-fg]in dolo[3,2,1-
kl]p yr r olo[3,4-i][1]ben za zocin -1-on e (10b). Following the
procedure for the preparation of 10a , 10b-tBDP S was desi-
lyated as described above. Prior to acquiring the spectral data,
partial isomerization to 10a had occurred. Data for 10b: 1H
NMR (DMSO-d6) δ 9.20 (d, J ) 7.5, 1H), 8.6 (s, 1H), 7.97 (d,
J ) 7.7, 1H), 7.69 (d, J ) 8.2, 1H), 7.57 (d, J ) 7.3, 1H), 7.48
Su p p or tin g In for m a tion Ava ila ble: Description of the
HPLC method, 1H NMR and reversed-phase HPLC chromato-
grams for compounds 10b-TBDP S and 11-13, and chiral
HPLC chromatograms for individual enantiomers of 10a . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0108360