Synthesis of HKI 0231B

Article abstract of DOI:10.1021/jo051762l

The total synthesis of HKI 0231B (1b) was completed in 12 linear steps and 15.6% overall yield. An unusual anionic cyclization provided access to intermediate 61 and the embedded benz[cd]-indol-3-(1H)-one ring system 3. Directed ortho-lithiation in the presence of a ketone followed by formylation and finally acid-catalyzed methanolysis complete the synthesis. Studies directed toward the construction and reactivity of the lactam acetal functionality present in HKI 0231A (1a) are also reported.

Full text of DOI:10.1021/jo051762l

Synthesis of HKI 0231B
Alex Scopton and T. Ross Kelly*
E. F. Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
ross.kelly@bc.edu
Received August 21, 2005
The total synthesis of HKI 0231B (1b) was completed in 12 linear steps and 15.6% overall yield.
An unusual anionic cyclization provided access to intermediate 61 and the embedded benz[cd]-
indol-3-(1H)-one ring system 3. Directed ortho-lithiation in the presence of a ketone followed by
formylation and finally acid-catalyzed methanolysis complete the synthesis. Studies directed toward
the construction and reactivity of the lactam acetal functionality present in HKI 0231A (1a) are
also reported.
Introduction
In 2001, scientists at the Hans Knoll Institute in Jena,
Germany, reported the isolation, structure, and biological
activity of two novel alkaloids from the fermentation
broth of Streptomyces sp. HKI 0231.1 The structural
assignments were made primarily on the basis of mass
spectrometry and 1D and 2D NMR measurements. The
compounds (Figure 1), designated as 0231A (1a) and
0231B (1b), were shown to inhibit one of the key enzymes
involved in the inflammatory process, 3R-hydroxysteroid
dehydrogenase.2 On the basis of their unique polycyclic
framework and potential as lead structures for the
development of antiinflammatory agents, their synthesis
was undertaken. Our initial focus was on the simpler of
the two compounds, 0231B (1b). Shortly after our efforts
had commenced, Komoda et al.3 proved the structure of
1b through total synthesis. Their key step was a regio-
selective cyclization of the 6-methyl-3-cinnamoylindole
derivative 2, which allowed access to the embedded benz-
[cd]indol-3-(1H)-one ring system 3.4 Herein, we now
FIGURE 1.
report a full account of our synthesis of 1b and efforts
toward the synthesis of 1a.
Results and Discussion
Our initial retrosynthetic analysis (Figure 2) suggested
that the tetrasubstituted double bond in 1b might be
formed at a late stage in the synthesis via an intramo-
lecular aldol-type condensation of 4. Compound 4 should
be accessible via directed lithiation of 5 followed by
quenching with a suitable electrophile. The amide 5
would in turn be prepared from the commercially avail-
able m-anisoyl chloride (6) and the appropriately func-
tionalized aminonaphthol derivative 7.
(1) Kleinwa¨chter, P.; Schlegel, B.; Groth, I.; Ha¨rtl, A.; Gra¨fe, U. J.
Antibiot. 2001, 54, 510.
(2) Penning, T. M. J. Pharm. Sci. 1985, 74, 651.
(3) (a) Komoda, T.; Shinoda, Y.; Nakatsuka, S. Biosci. Biotechnol.
Biochem. 2003, 67, 659. (b) For another attempted synthesis, see: Wu,
T.; Kraus, G. Abstracts of Papers; 226th National Meeting of the
American Chemical Society, New York, Sept 7-11, 2003; American
Chemical Society: Washington, DC, 2003.
(4) For another synthesis of this tricyclic ring system, see: Hegedus,
L. S.; Sestrick, M. R.; Michaelson, E. T.; Harrington, P. J. J. Org. Chem.
1989, 54, 4141.
We initially thought that the most direct route to
access the desired 7 was via an electrophilic substitution
10.1021/jo051762l CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/25/2005
10004
J. Org. Chem. 2005, 70, 10004-10012

Synthesis of HKI 0231B
SCHEME 1. Various Electrophilic Substitutions
of 8
FIGURE 2.
of a suitably functionalized naphthalene unit. A search
of the literature revealed work by Miller and Morello5 in
1948, which was later confirmed by Harnik and Jensen6
in 1965. Both publications reported that substitution of
aminonaphthol derivative 8 by succinic anhydride (9)
occurred exclusively in the 3-position to give the acid 10
(eq 1). We thought that if the regiochemistry of substitu-
SCHEME 2. Synthesis of Aminonaphthol 14
tion proved to be general for other electrophiles, then this
would offer a very quick route to a specific embodiment
of the desired naphthalene fragment 7. Despite the fact
that we were able to reproduce the specific reaction in
eq 1, its scope appeared limited. Numerous attempts to
directly methylate the 3-position under Lewis acid ca-
talysis, with a variety of electrophiles (i.e., MeI, MeBr,
MeCl), were all met with failure. The regioselectivity of
electrophilic substitution on this system (8) appeared to
be extremely sensitive to the conditions employed. For-
mylation with R,R-dichloromethyl methyl ether7 occurred
in the 8-position to give 11, and treatment with 1 equiv
of elemental bromine8 gave substitution in the 4-position
to yield 12 (Scheme 1). Ultimately, it was found that by
slightly modifying the conditions in eq 1, acylation with
acetic anhydride occurred with the desired regioselectiv-
ity and in good yield.9,10 Initially ketone 13 appeared as
a promising substrate for the construction of the desired
naphthalene fragment. Unfortunately it required five
more steps (Scheme 2) to convert 13 to 14; an eight-step
sequence to install a methyl group on an aromatic ring
was unacceptable. Development of a shorter route to 14
was thus undertaken (vide infra).
Meanwhile, we turned our attention toward construct-
ing the pentacyclic core found in 1b. For the initial
studies we chose to use the commercially available 15
as a model system for the naphthalene unit. We were
fairly confident that the chemistry would be transferable
since the real system only differed by a methyl group.
As shown in Scheme 3, acylation of 15 with 6 in the
presence of 1 equiv of pyridine11 gave 21 in near-
quantitative yield. Directed ortho-lithiation of 21 with
n
3.2 equiv of BuLi in THF at 0 °C, followed by addition
of DMF and warming to room temperature, gave hy-
droxylactam 22 in 74% yield.12 Unfortunately, all at-
(10) For discussions of the effects of MeNO2 on AlCl3-catalyzed
aromatic substitution, see: (a) DeHaan, F. P.; Covey, W. D.; Delker,
G. L.; Baker, N. J.; Feigon, J. F.; Ono, D.; Miller, K. D.; Stelter, E. D.
J. Org. Chem. 1984, 49, 3959. (b) DeHaan, F. P.; Delker, G. L.; Covey,
W. D.; Bellomo, A. F.; Brown, J. A.; Ferrara, D. M.; Haubrich, R. H.;
Lander, E. B.; MacArthur, C. J.; Meinhold, R. W.; Neddenriep, D.;
Schubert, D. M.; Stewart, R. G. J. Org. Chem. 1984, 49, 3963. (c) Covey,
W. D.; DeHaan, F. P.; Delker, G. L.; Dawson, S. F.; Kilpatrick, P. K.;
Rattinger, G. B.; Read, W. G. J. Org. Chem. 1984, 49, 3967.
(5) Miller, L. E.; Morello, E. F. J. Am. Chem. Soc. 1948, 70, 1900.
(6) Harnik, M.; Jensen, E. V. Isr. J. Chem. 1965, 3, 13.
(7) Fieser, M.; Fieser, L. Reagents for Organic Synthesis; Wiley &
Sons: New York, 1969; Vol. 2, p 120.
(8) In the presence of excess Br2, further substitution occurred in
the 8-position.
(9) Although reaction of Ac2O did occur with the desired regiose-
lectivity in PhNO2, the yield was not nearly as high (∼50%) and
removal of the PhNO2 proved difficult and time-consuming on a large
scale.
(11) Acylation without the presence of a proton scavenger gave
incomplete reaction, and stronger bases such as Et3N or Hunig’s base
led to acylation at the phenol. Schotten-Baumann conditions also
proved ineffective in completing this transformation.
J. Org. Chem, Vol. 70, No. 24, 2005 10005

Scopton and Kelly
SCHEME 3. Aldol-type Condensation Model
Studies
FIGURE 3.
FIGURE 4.
solved our problem, but not in the way we had initially
anticipated.
tempts to effect the intramolecular aldol-type condensa-
tion to form 23, under a variety of conditions, resulted
in either recovery of 22 or complete decomposition of the
material. We initially thought that the acidic OH proton
in the hemiaminal functionality present in 22 might be
impeding the ring closure. To eliminate this variable, a
slightly modified sequence to that described for the
construction of 22 was employed. The phenol in 15 was
first TBS-protected13 and the crude TBS ether 24 was
acylated as before to give 25 in 88% yield over two steps.
Lithiation of 25 with 2.2 equiv of nBuLi followed by
quenching with DMF gave 26 in 55% yield.12 Many
attempts to methylate the hemiaminal in 26 under acidic
and basic conditions led either to decomposition or to a
complex mixture of products. However, it was eventually
found that reacting 26 with a large excess of MeI (>20
equiv) in the presence of 5 equiv of Ag2O led smoothly to
the desired methylated product,14 which was treated
directly with TBAF to remove the TBS ether and give
isoindolone 27 in 99% yield from 26. Unfortunately, all
attempts to advance 27 to the desired 28 resulted in
either recovered starting material or complete decompo-
sition (as with 22).
To work out the conditions to generate a lithiated
species such as 29, we again called upon the desmethyl
15 for use as a model system. Initial studies did not show
much promise. All attempts at directed peri-lithiation16
on compounds such as 32 (Figure 4) resulted in only
recovered starting material; 2-3 equiv of the standard
n
s
t
alkyllithiums (i.e., BuLi, BuLi, and BuLi) at a range
of temperatures failed to show lithiation at any position
t
on the ring system. In the presence of excess BuLi (>5
equiv) at room temperature for extended periods of time
(g4 h) lithiation did occur, albeit at the undesired
6-position (33).17 In an attempt to force peri-lithiation,
the 6-position was blocked with a TMS group18 (treat-
ment of 33 with TMSCl) to give 34. However, further
functionalization of this ring system via directed lithia-
tion failed. The demethylated 35 also proved to be of no
use.
Since we were unable to directly lithiate the necessary
ring system, our attention was turned toward generating
the desired anion by metal-halogen exchange (Scheme
4). Thus, aminonaphthol 15 was N-acylated, brominated
at the 8-position (contrast 8 f 12) and TIPS-protected19,20
in a very efficient three-step sequence to give, after one
At this point we decided to rework our strategy for the
ring construction. Specifically, it was thought that the
troublesome carbon-carbon bond should be formed at an
earlier stage in the synthesis. We felt that the most direct
way to accomplish this was through the generation of a
lithiated species such as 29, followed by quenching with
a suitably functionalized electrophile (30; known com-
pound15) to give 31 (Figure 3). Ultimately this strategy
(15) (a) Weeks, D. P.; Crane, J. P. J. Org. Chem. 1973, 38, 3375. (b)
Jung, M. E.; Blum, R. B. J. Chem. Soc., Chem. Commun. 1981, 962.
(16) (a) Clayden, J. Regioselective Synthesis of Organolithiums by
Deprotonation. In Organolithiums: Selectivity for Synthesis; Tetra-
hedron Organic Chemistry Series; Elsevier Science: London, 2002; Vol.
23, Chapt. 2, pp 30-31. (b) Betz, J.; Bauer, W. J. Am. Chem. Soc. 2002,
124, 8699. (c) Kraus, G. A.; Kim, J. J. Org. Chem. 2002, 67, 2358.
(17) Determined on the basis of D2O quench, which gave two new
singlets in the 1H NMR spectrum.
(18) Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54,
4372.
(19) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley & Sons: New York, 1999.
(12) For related reactions, see: (a) Broadhurst, M. J.; Hassall, C.
H. J. Chem. Soc., Perkin Trans. 1 1982, 2227. (b) Mali, R. S.; Yeola, S.
N. Synthesis 1986, 755. (c) Epsztajn, J.; Jo´z´wiak, A.; Kołuda, P.; Sado-
kierska, I.; Wilkowska, I. D. Tetrahedron 2000, 56, 4837.
(13) Swenton, J. S.; Bonke, B. R.; Chen, C. P.; Chou, C. T. J. Org.
Chem. 1989, 54, 51.
(20) Only silyl-based protecting groups could be successfully intro-
duced on the phenol after the bromination reaction. Various benzyl
groups were attempted, but all led to either recovered starting material
or low yields.
(14) Mizutani, T.; Honzawa, S.; Tosaki, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2002, 41, 4680.
10006 J. Org. Chem., Vol. 70, No. 24, 2005

Synthesis of HKI 0231B
SCHEME 4. Carbon-Carbon Bond Formation via
Metal-Halogen Exchange
FIGURE 5.
SCHEME 5. Ring Construction Model Study
recrystallization, 36 in 80% overall yield. In this par-
ticular case, it was found that metal-halogen exchange
occurred at a faster rate than deprotonation of the acidic
amide proton, so that once the initial carbanion was
formed it was rapidly quenched via either an intra- or
intermolecular protonation.21 To prevent this complica-
tion, 36 was treated first with 1 equiv of MeLi (for NH
t
deprotonation)22 and then with 2 equiv of BuLi at low
temperature. Warming to 0 °C readily generated what
was thought to be anion 37.23 But when the reaction
mixture was quenched with a proton source, the expected
38 was not formed; instead the cyclized product 39 was
obtained, which contained the three rings of the right-
hand side of the desired ring system (vide supra). We felt
that this reaction, thought to be driven by migration of
the TIPS24 and then elimination of TIPSO- (40 f 41),
could be utilized if the key intermediate 42 could be
synthesized.
To work out conditions to not only synthesize but also
cyclize 42, amide 21 was employed as a model system.
To our dismay, reaction of 21 under the bromination
conditions (1 equiv of Br2 in HOAc) shown in Scheme 4
yielded only undesired regioisomer 43 (Figure 5). Chang-
ing to a less polar solvent (benzene, CH2Cl2 or CCl4) gave
mixtures of 44 and 45 along with recovered 21. Despite
many attempts, the desired 44 could not be separated
from crude reaction mixtures. All other brominating
agents tried (NBS, pyridinium tribromide, and cyanogen
bromide) gave exclusively 43, under a wide range of
conditions.
In a last-ditch effort to utilize the novel cyclization
methodology of Scheme 4, we decided to drive the
bromination to dibromide 45. At least in theory, having
two bromines on the molecule should not matter. Since
the reaction would ultimately be quenched with a proton
source, the second bromine present could simply be
(21) This was ultimately determined when the reaction was quenched
with D2O and deuterium failed to incorporate into the ring system.
(22) For other examples of where this has been necessary, see: (a)
Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072. (b) Kelly,
T. R.; Silva, R. A.; De Silva, H.; Jasmin, S.; Zhao, Y. J. Am. Chem.
Soc. 2000, 122, 6935.
(23) For a discussion on the kinetics of halogen-lithium exchange,
see: Clayden, J. Regioselective Synthesis of Organolithiums by X-Li
Exchange. In Organolithiums: Selectivity for Synthesis; Tetrahedron
Organic Chemistry Series; Elsevier Science: London, 2002; Chapt. 3,
pp 116-117.
(24) For discussions of silicon group migrations, see: (a) Colvin, E.
Rearrangement reactions with migration of silicon. In Silicon in
Organic Synthesis; Butterworth Monographs in Chemistry and Chemi-
cal Engineering; Butterworth: London, 1981; pp 30-39. (b) Brook, M.
A. Rearrangements. In Silicon in Organic, Organometallic, and
Polymer Chemistry; Wiley & Sons: New York, 2000; pp 511-551. (c)
Clayden, J. Organolithium Rearrangements. In Organolithiums: Se-
lectivity for Synthesis; Tetrahedron Organic Chemistry Series; Elsevier
Science: London, 2002; Chapt. 8, pp 340-346.
t
exchanged off by use of excess BuLi. This idea was
ultimately borne out as shown in Scheme 5. Amide 21
was forcibly dibrominated (3 days) with excess bromine
(5 equiv) and then TIPS-protected to yield 46 in 77% yield
over two steps. By slightly modifying the conditions used
t
on 36 (4 equiv of BuLi instead of 2), 46 was smoothly
transformed into 47 in very good overall yield.
At this stage, all that was needed to complete the
desired ring system was an aldehyde unit. After a
considerable amount of experimentation, it was found
that ortho-lithiation of 47 could be effected in the
presence of excess lithium tetramethylpiperidide (5 equiv)
J. Org. Chem, Vol. 70, No. 24, 2005 10007

Scopton and Kelly
SCHEME 6. Synthesis of HKI 0231B (1b)
at -10 °C.25,26 Despite the fact that dianion 48 could be
formed, attempts to react this species with electrophiles
other than D2O initially led to either rapid decomposition
of the starting material or unproductive consumption of
the carbanion.27 By screening various conditions it was
eventually realized that when the temperature was
lowered to -78 °C, 48 would react in the appropriate
manner with TMSCl-activated ethyl formate (49) to give
the desired cyclic hemiaminal 23 in a hard-fought 75%
yield.
Now that we possessed the necessary tools to construct
the ring system in 1b, we decided to revisit our synthesis
of the essential aminonaphthol 14. As already noted,
despite the fact that our synthesis of 14 was workable,
its length seemed less than ideal when compared with
the rapid manner in which we were able to construct the
pentacyclic core. For the final solution to this problem
we opted to construct the appropriately functionalized
naphthalene unit from the readily available p-methoxy-
benzyl chloride (50; Scheme 6). Thus, reaction of the
derived Grignard reagent 51 with CuI at -78 °C gener-
ated benzylic copper(I) species 52.28 Simultaneous addi-
tion of ethyl crotonate (53) and TMSCl,29 followed by
warming to -30 °C provided ester 54 in near-quantitative
yield.28 Dehydrative cyclization of 54 in hot PPA30 gave
tetralone 55, which due to its volatility was not purified
but treated directly with hydroxylamine hydrochloride
and pyridine in refluxing aqueous ethanol to yield oxime
56 in 71% yield over two steps. Oxime 56 could be
tosylated in good yield in dimethoxyethane to furnish
57.31 With tosyl oxime 57 in hand we were only an
aromatization and a deprotection away from the desired
aminonaphthol 14. After unsuccessfully exhausting vir-
tually all common literature methods for the Semmler-
Wolff reaction,32-34 the aromatization was finally achieved
in reasonable yield by the action of KOH in refluxing
methanol.35 The methyl ether in 58 was cleaved with
BBr3, to give 14. Despite the fact that this route to 14
(c) Horiguchi, Y.; Matsuzawa, S.; Nadamura, E.; Kuwajima, I. Tetra-
hedron Lett. 1986, 27, 4025. (d) Johnson, C. R.; Marren, T. J.
Tetrahedron Lett. 1987, 28, 27. (e) van Heerden, P. S.; Bezuidenhoudt,
B. C. B.; Steenkamp, J. A.; Ferreira, D. Tetrahedron Lett. 1992, 33,
2383.
(30) (a) Gilmore, R. C. J. Am. Chem. Soc. 1951, 73, 5879. (b) He,
W.; Huang, F. C.; Gavai, A.; Chan, W. K.; Amato, G.; Yu, K. T.;
Zilberstein, A. Bioog. Med. Chem. Lett. 1998, 8, 3659.
(31) Running this reaction in DMF, DMSO, or THF resulted in only
recovered starting material.
(32) Acidic conditions: (a) Bauer, L.; Hewitson, R. E. J. Org. Chem.
1962, 27, 3982. (b) Newman, M. S.; Hung, W. M. J. Org. Chem. 1973,
38, 4073. (c) El-Sheikh, M. I.; Cook, J. M. J. Org. Chem. 1980, 45, 2585.
(d) Tamura, Y.; Yoshimoto, Y.; Sakai, K.; Kita, Y. Synthesis 1980, 483.
(e) Mallory, F. B.; Luzik, E. D.; Mallory, C. W.; Carroll, P. J. J. Org.
Chem. 1992, 57, 366.
(33) Basic conditions: (a) Garst, M. E.; Cox, D. D.; Harper, R. W.;
Kemp, D. S. J. Org. Chem. 1975, 40, 1169. (b) Kelly, T. R.; Chandra-
kumar, N. S.; Saha, J. K. J. Org. Chem. 1989, 54, 980.
(34) Neutral conditions: (a) Weidner, J. J.; Weintraub, P. M.;
Schnettler, R. A.; Peet, N. P. Tetrahedron 1997, 53, 6303. (b) Smith,
A. B., III; Kanoh, N.; Ishiyama, H.; Minakawa, N.; Rainier, J. D.; Hartz,
R. A.; Cho, Y. S.; Cui, H.; Moser, W. H. J. Am. Chem. Soc. 2003, 125,
8228.
(25) Flippin, L. A.; Muchowski, J. M. J. Org. Chem. 1993, 58, 2631.
(26) This temperature is extremely important for the success of the
transformation. Running the reaction at slightly higher (0 °C) or lower
(-20 °C) temperatures resulted in incomplete lithiation.
(27) Presumably due to the base-induced decomposition of ethyl
formate, DMF (when used as the aldehyde source), or THF.
(28) van Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D.
Tetrahedron 1996, 52, 12313.
(29) For discussions and examples where TMSCl has been used to
accelerate the conjugate addition of organocopper and organocuprate
reagents, see: (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985,
26, 6015. (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019.
(35) Inferior yields were obtained with LiOH, NaOH, or CsOH. The
use of other alcohols (i.e., EtOH, iPrOH, nBuOH) as solvent also
resulted in a reduction in yield.
10008 J. Org. Chem., Vol. 70, No. 24, 2005

Synthesis of HKI 0231B
SCHEME 7. Attempted Synthesis of Amide Acetal
FIGURE 6.
At least qualitatively, failure to form the acetal appears
to be due to the lack of donation from the lone pairs of
the nitrogen into the carbonyl of lactam 64. Instead, the
nitrogen appears to be participating in the extended
π-system of the ketone, as is evidenced by formation of
67. Further evidence for this participation is shown in
eq 2. Thus, treatment of 64 with NaBH4 yields compound
69, where only the lactam has been reduced and the
“ketone” remains untouched.
utilizes more bond-forming reactions as opposed to
functional group transformations, it is in actuality not
much shorter than the synthesis of 14 described in
Scheme 2. The crude amine (14) was then acylated with
6 as before to give amide 5936 in 88% yield for the two
steps. This time dibromination was effected much more
rapidly than with 21, presumably due to the increased
electron density caused by the methyl group. Bromination
was then followed by TIPS protection to furnish key
intermediate 60 in very good yield. Treatment of 60
under conditions identical to those used to convert 46 to
47 provided 61 in almost quantitative yield. Generation
of dianion 62 and then formylation produced a 70% yield
of 63, with all unreacted 61 being recoverable. Acid-
catalyzed methylation then completed the 12-step se-
quence and finally allowed us access to HKI 0231B (1b).
Spectra for synthetic 1b are in excellent agreement with
those reported for naturally occurring HKI 0231B.1
With the ability to construct and isolate hemiaminal
63, it was thought that if the correct oxidation state could
be achieved, we might be able to advance that intermedi-
ate to HKI 0231A (1a). Due to lack of material, the
desmethyl 23 was used as a model system. As shown in
Scheme 7, obtaining the correct oxidation state proved
easy enough. Thus, treatment of hemiaminal 23 with
PDC in DMF gave lactam 64 in excellent yield.37 Based
on the known literature methods,38,39 our strategy was
to generate immonium intermediate 65 in situ by treat-
ing 64 with a strong methylating agent (Meerwein’s salt
or methyl triflate), followed by adding a solution of
methoxide in MeOH.40 Ultimately, formation of lactam
acetal 66 was never realized, despite screening of a range
of solvents (CH2Cl2, CHCl3, and MeCN) and methoxide
sources [NaOMe, Mg(OMe)2, and LiOMe]. Depending
upon the conditions employed, the only product that ever
appeared to be present (as judged by 1H NMR spectra of
crude reaction mixtures) was 67, which presumably arose
from initial formation of the delocalized cationic adduct
68 from 64 (Figure 6).
It is not surprising that the majority of amide/lactam
acetals known in the literature are inherently unstable
in the presence of water.41 The simplest of amide acetals
rapidly decompose in water, with a half-life of <1 s at
all values of pH.41a It is interesting to note that, during
isolation, the lactam acetal functionality in 1a survives
not only column chromatography on SiO2 but also further
purification by reverse-phase HPLC in the presence of
an aqueous mobile phase.1 The inherent stability of this
classically sensitive functionality would appear to be due
to the electron sink created by the embedded R,â-
unsaturated ketone, which draws electron density from
the nitrogen lone pair and thereby prevents decomposi-
tion of the acetal via expulsion of methanol. Therefore,
the very R,â-unsaturated ketone functionality that sta-
bilizes the lactam acetal may also be preventing its
formation from 64.
In conclusion, we report the synthesis of HKI 0231B
(1b) in 12 steps and 15.6% overall yield, as summarized
in Scheme 6. Our experiments regarding construction
and reactivity of the lactam acetal functionality present
in 1a have also been summarized.
Experimental Section42
Preparation of Grignard Reagent 51.28 To a three-
necked, 100 mL round-bottomed flask equipped with an
addition funnel, reflux condenser and argon inlet adapter, were
added magnesium turnings (9.55 g, 393 mmol), THF (36 mL),
and a catalytic amount of iodine (one crystal; ca. 10-20 mg).
To the rapidly stirred mixture was added p-methoxybenzyl
chloride (PMBCl, 50, 13 mL, 95 mmol) as a solution in THF
(24 mL) via the addition funnel. After the reaction had
initiated (as evidenced by the reaction becoming cloudy), the
solution was added at such a rate as to maintain a gentle
reflux. Once the addition was complete (ca. 1 h), the now
(36) All attempts at applying the chemistry that afforded 11 to
desmethyl derivatives of 59 were met with failure.
(37) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1,
1183.
(38) For reviews of amide/lactam acetal formation, see: (a) Meer-
wein, v. H.; Florian, W.; Scho¨n, N.; Stopp, G. Justus Liebigs Ann. Chem.
1961, 641, 1. (b) Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979,
35, 1675. (c) Anand, N.; Singh, J. Tetrahedron 1988, 44, 5975.
(39) For related transformations that result in amide cleavage,
see: (a) Charette, A. B.; Chua, P. Synlett 1998, 163. (b) Keck, G. E.;
McLaws, M. D.; Wager, T. T. Tetrahedron 2000, 56, 9875.
(40) Attempts to isolate the immonium intermediate in dry form
and then treat it with methoxide in MeOH also failed.
(41) (a) McClelland, R. A. J. Am. Chem. Soc. 1978, 100, 1844. (b)
McClelland, R. A. J. Am. Chem. Soc. 1984, 106, 7579.
(42) See Supporting Information for general experimental proce-
dures.
J. Org. Chem, Vol. 70, No. 24, 2005 10009

Scopton and Kelly
darkgreen reaction mixture was allowed to stir for an ad-
ditional hour and then standardized.43 The solution of 52 was
used immediately in the next step without further manipula-
tion.
Hz, 1H), 7.04 (d, J ) 8.4 Hz, 1H), 6.86 (dd, J ) 8.4 and 2.8
Hz, 1H), 3.80 (s, 3H), 3.19 (ddd, J ) 17.6, 4.4, and 1.8 Hz,
1H), 2.73 (ddd, J ) 15.4, 3.7, and 1.8 Hz, 1H), 2.38 (dd, J )
17.6 and 11.0 Hz, 1H), 2.13 (dd, J ) 15.4 and 11.7 Hz, 1H),
1.96 (m, 1H), 1.10 (d, J ) 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 157.7, 155.5, 131.7, 130.8, 129.6, 116.8, 107.1, 55.4,
37.4, 31.7, 28.4, 21.5; IR (KBr) ν 3397, 3050, 2999, 2957, 2838,
1630 cm-1; m/z (ESI-MS) 206.16 (MH+). Anal. Calcd for C12H15-
NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.44; H, 7.45; N,
6.89.
Ethyl 4-(Methoxyphenyl)-3-methylbutanoate (54).28 A
1 L round-bottomed flask was charged with freshly pulverized
CuI (9.55 g, 50.1 mmol), THF (250 mL), and TMEDA (8.3 mL,
55 mmol). Once all the CuI had dissolved (ca. 5-10 min), the
colorless solution was cooled to -78 °C and 51 (41.5 mL of a
1.21 M solution in THF, 50.2 mmol) was added dropwise via
syringe over 20 min. The resulting dark brown reaction
mixture was stirred for 30 min and then a solution of ethyl
crotonate (53, 3.1 mL, 25 mmol), TMSCl (16.0 mL, 125 mmol),
and THF (125 mL; made by adding 53 to THF followed by the
TMSCl) was added via cannula over 20 min. The reaction
mixture was then allowed to warm to -30 °C and stir at that
temperature for 18 h. The still cold reaction was poured into
a mixture of saturated NH4Cl (600 mL) and concentrated NH4-
OH (400 mL). The resulting blue mixture was extracted with
Et2O (2 × 500 mL). The organic extracts were pooled, washed
with H2O (2 × 500 mL) and saturated NaCl solution (1 × 500
mL), dried with MgSO4, and filtered. Removal of solvents in
vacuo gave a mixture of solid and oil. The crude product was
triturated with hexanes (200 mL) and filtered under vacuum.
The white solid (Wurtz-like coupling product from excess
organocopper reagent 52) was washed with hexanes (2 × 25
mL) and discarded. Concentration of the filtrate and washes
in vacuo gave 9.45 g of a slightly cloudy oil. Purification by
flash column chromatography (4.5 × 15 cm silica), initially
with 19:1 hexanes/Et2O and then 9:1 hexanes/Et2O, yielded
5.84 g (99%) of the title compound as a clear, colorless oil. This
3,4-Dihydro-7-methoxy-3-methyl-1(2H)-naphthale-
none, O-[(4-Methylphenyl)sulfonyl]oxime (57). To a two-
necked 250 mL round-bottomed flask equipped with a septum
and an argon inlet adapter was added NaH (1.21 g, 60%
dispersion in mineral oil, 50 mmol), which was then washed
with hexanes (3 × 30 mL). After the NaH was dried to a fine
powder under a stream of argon, TsCl (5.73 g, 30.1 mmol) and
1,2-dimethoxyethane (DME; 20 mL) were added. The oxime
(56, 2.05 g, 10.0 mmol), as a solution in DME (50 mL), was
transferred into the vigorously stirred slurry via cannula over
5 min [CAUTION: H2 gas released]. The flask and cannula
were then washed thoroughly with DME (10 mL) and the
resulting heterogeneous reaction mixture was stirred at 70 °C
for 24 h. After being cooled to room temperature, the mixture
was poured into H2O (150 mL) [CAUTION: possible re-
maining NaH] and extracted with EtOAc (3 × 100 mL). The
organic extracts were pooled, washed with H2O (1 × 150 mL)
and saturated NaCl solution (1 × 150 mL), dried with MgSO4,
and filtered. Removal of solvents in vacuo gave 4.10 g of a pale
orange solid. Recrystallization from Et2O (ca. 600 mL) yielded
3.17 g (88%) of the title compound as colorless prisms, mp 150-
151 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J ) 8.2 Hz, 2H),
7.34 (app dd, J ) 8.2 and 2.8 Hz, 3H), 7.04 (d, J ) 8.4 Hz,
1H), 6.90 (dd, J ) 8.4 and 2.8 Hz, 1H), 3.79 (s, 3H), 3.14 (ddd,
J ) 17.9, 4.4, and 1.8 Hz, 1H), 2.71 (ddd, J ) 15.5, 4.1, and
1.8 Hz, 1H), 2.44 (s, 3H), 2.34 (dd, J ) 15.5 and 11.0 Hz, 1H),
2.14 (dd, J ) 17.9 and 11.6 Hz, 1H), 1.92 (m, 1H), 1.07 (d, J )
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.0, 157.6, 144.8,
132.9, 132.5, 129.7, 129.3, 128.8, 128.2, 118.3, 108.3, 55.3, 36.8,
1
material was homogeneous by H and 13C NMR; an analyti-
cally pure sample was obtained by vacuum distillation: bp
134-135 °C/9 Torr; 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J )
8.6 Hz, 2H), 6.82 (d, J ) 8.6 Hz, 2H), 4.10 (q, J ) 7.3 Hz, 2H),
3.77 (s, 3H), 2.56 (dd, J ) 13.6 and 6.6 Hz, 1H), 2.43 (dd, J )
13.6 and 7.3 Hz, 1H), 2.30 (dd, J ) 14.5 and 5.9 Hz, 1H), 2.26-
2.18 (m, 1H), 2.10 (dd, J ) 14.5 and 7.7 Hz, 1H), 1.24 (t, J )
7.3 Hz, 3H), 0.93 (d, J ) 5.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.7, 157.6, 132.1, 129.9, 113.5, 60.1, 55.2, 42.1, 41.1,
32.5, 19.6, 14.3; IR (neat) ν 2963, 2930, 2910, 2871, 2832, 1735,
1614 cm-1; m/z (ESI-MS) 259.13 (MNa+). Anal. Calcd for
C14H20O3: C, 71.16; H, 8.53. Found: C, 71.13; H, 8.61.
33.0, 28.4, 21.7, 21.1; IR (KBr) ν 2965, 2922, 2860, 1595 cm-1
;
m/z (ESI-MS) 360.17 (MH+), 382.16 (MNa+). Anal. Calcd for
C19H21NO4S: C, 63.49; H, 5.89; N, 3.90. Found: C, 63.44; H,
5.88; N, 3.86.
3,4-Dihydro-7-methoxy-3-methyl-1(2H)-naphthale-
none, Oxime (56). A 100 mL round-bottomed flask (undried)
was charged with PPA (63 g) and 54 (4.95 g, 21.0 mmol). The
mixture was heated at 110 °C with magnetic stirring for 1 h.
The resulting brown mixture was poured (while hot) into H2O
(300 mL) and extracted with Et2O (3 × 150 mL). The organics
were pooled, washed with saturated NaHCO3 solution (3 ×
200 mL), H2O (1 × 200 mL), and saturated NaCl solution
(1 × 200 mL), dried with MgSO4, and filtered. Removal of
solvents in vacuo gave 3.40 g of orange oil. The crude tetralone
[55; 1H NMR (400 MHz, CDCl3) 7.50 (d, J ) 2.8 Hz, 1H), 7.15
(d, J ) 8.0 Hz, 1H), 7.05 (dd, J ) 8.0 and 2.8 Hz, 1H), 3.83 (s,
3H), 2.93-2.89 (m, 1H), 2.76-2.58 (m, 2H), 2.32-2.24 (m, 2H),
1.13 (d, J ) 6.4 Hz, 3H); m/z (ESI-MS) 191.13 (MH+), 213.11
(MNa+)] was dissolved in a mixture of EtOH (140 mL) and
H2O (35 mL). Hydroxylamine hydrochloride (2.92 g, 42.0 mmol)
and pyridine (5.1 mL, 63 mmol) were then added, and the
resulting orange solution was heated at reflux overnight. After
12 h the reaction was poured into H2O (150 mL), and the
cloudy mixture was extracted with Et2O (3 × 150 mL). The
organic extracts were pooled, washed with 1 N HCl (1 × 150
mL), H2O (1 × 150 mL), and saturated NaCl solution (1 × 150
mL), dried with MgSO4, and filtered. Removal of solvents in
vacuo gave 3.30 g of an orange solid. Recrystallization from
hexanes (ca. 250 mL) yielded 3.05 g (71% over two steps) of
the title compound as pale orange prisms, mp 122-123 °C;
1H NMR (400 MHz, CDCl3) δ 9.31 (br s, 1H), 7.42 (d, J ) 2.8
7-Methoxy-3-methyl-1-naphthalenamine (58). A 250 mL
round-bottomed flask (undried) was charged with 57 (2.44 g,
6.79 mmol), KOH (27 mL, 1.0 M solution in MeOH, 27 mmol),
and MeOH (65 mL). The deep red reaction mixture was heated
at reflux with stirring for 6 h. The resulting brown solution
was allowed to cool to room temperature, poured into H2O (200
mL), and extracted with EtOAc (3 × 200 mL). The organic
extracts were pooled, washed with saturated NaHCO3 solution
(1 × 200 mL), H2O (1 × 200 mL), and saturated NaCl solution
(1 × 200 mL), dried with MgSO4, and filtered. Removal of
solvents in vacuo gave 1.32 g of a brown wax. Purification by
flash column chromatography (4.5 × 15 cm silica), initially
with 4:1 EtOAc/hexanes and then with 7:3 EtOAc/hexanes,
yielded 633 mg (50%) of the title compound as a beige solid.
This material was homogeneous by 1H and 13C NMR; an
analytically pure sample was obtained by recrystallization
from hexanes as white needles, mp 113-113.5 °C; 1H NMR
(400 MHz, DMSO-d6) δ 7.54 (d, J ) 8.8 Hz, 1H), 7.35 (d, J )
2.2 Hz, 1H), 7.02 (dd, J ) 8.8 and 2.2 Hz, 1H), 6.81 (s, 1H),
6.50 (s, 1H), 5.50 (s, 2H), 3.85 (s, 3H), 2.28 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 155.1, 143.1, 132.6, 129.4, 128.4, 121.7,
117.4, 114.7, 109.7, 101.3, 55.1, 21.3; IR (KBr) ν 3369, 3307,
3210, 3004, 2926, 1634, 1603 cm-1; m/z (ESI-MS) 188.11
(MH+). Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48.
Found: C, 76.77; H, 6.98; N, 7.48.
N-(7-Hydroxy-3-methyl-1-naphthalenyl)-3-methoxy-
benzamide (59). To a 50 mL round-bottomed flask were
added 58 (348 mg, 1.86 mmol) and CH2Cl2 (15 mL). The clear
solution was cooled to 0 °C and BBr3 (5.6 mL, 1.0 M solution
(43) Lin, H. S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.
10010 J. Org. Chem., Vol. 70, No. 24, 2005

Synthesis of HKI 0231B
in hexanes, 5.6 mmol) was added dropwise via syringe over 1
min. The now cloudy white reaction mixture was stirred at 0
°C for 15 min and then allowed to warm to room temperature
and stir for an additional 14 h. The reaction was then
quenched by the dropwise (over 2 min) addition of 1 N NaOH
(ca. 5 mL), and the resulting mixture was partitioned between
EtOAc (75 mL) and 1 N NaOH (50 mL). The layers were
separated and the organics were extracted with 1 N NaOH (2
× 25 mL). The aqueous extracts were pooled, the pH was
adjusted to ca. 7 (pH paper) with concentrated HCl, and then
the mixture was extracted with EtOAc (3 × 75 mL). The
organic extracts were pooled, washed with saturated NaCl
solution (1 × 100 mL), dried with MgSO4, and filtered.
Removal of solvents in vacuo gave 341 mg of a brown solid.
The crude product (14) was dissolved in THF (15 mL) and
transferred to a two-necked 50 mL round-bottomed flask
equipped with a pressure-equalized addition funnel and argon
inlet adapter. Pyridine (0.140 mL, 1.72 mmol) was then added
and the solution was cooled to 0 °C. A solution of 6 (0.240 mL,
1.72 mmol) in THF (10 mL) was added dropwise via the
addition funnel over 1 h. The reaction was stirred overnight
and allowed to warm to room temperature as the cooling bath
melted. After 12 h the reaction mixture was poured into 1 N
HCl (50 mL) and extracted with EtOAc (3 × 50 mL). The
organic extracts were pooled, washed with 1 N HCl (3 × 50
mL), saturated NaHCO3 solution (1 × 50 mL), H2O (1 × 50
mL), and saturated NaCl solution (1 × 50 mL), dried with
MgSO4, and filtered. Removal of solvents in vacuo gave 531
mg of a purple solid. Purification by flash column chromatog-
raphy (4.5 × 5 cm silica) with 7:3 hexanes/EtOAc yielded 504
mg (88%) of the title compound as a gray solid. This material
(d,J ) 8.1 Hz, 1H), 7.61 (app s, 1H), 7.51 (s, 1H), 7.46 (app t,
J ) 8.1 Hz, 1H), 7.39 (d, J ) 9.6 Hz, 1H), 7.16 (dd, J ) 8.1
and 2.6 Hz, 1H), 3.84 (s, 3H), 2.56 (s, 3H), 1.38 (septet, J )
7.4 Hz, 3H), 1.09 (d, J ) 7.4 Hz, 18H); 13C NMR (100 MHz,
DMSO-d6) δ 164.9, 158.8, 151.2, 135.6, 134.1, 131.9, 131.7,
129.2, 128.9, 128.4, 128.3, 122.0, 120.9, 119.8, 116.9, 112.8,
106.8, 55.2, 23.1, 17.8, 12.5; IR (KBr) ν 3315, 2941, 2868, 1649
cm-1; m/z (ESI-MS) 622.08 (MH+), 644.06 (MNa+). Anal. Calcd
for C28H35Br2NO3Si: C, 54.11; H, 5.68; N, 2.25. Found: C,
54.20; H, 5.67; N, 2.32.
2-(3-Methoxyphenyl)-7-methylbenz[cd]indol-3(1H)-
one (61). A 25 mL round-bottomed-flask was charged with
60 (250 mg, 0.402 mmol) and THF (4 mL). The clear, colorless
solution was cooled to -78 °C, and MeLi (0.250 mL, 1.67 M
solution in Et2O, 0.418 mmol) was added dropwise over 1 min.
The resulting homogeneous yellow/green reaction was stirred
for 30 min and then tBuLi (1.00 mL, 1.64 M solution in
pentane, 1.64 mmol) was added dropwise over 3 min. The now
orange/yellow colored reaction was stirred for 1 h and then
allowed to warm to 0 °C and stirred for an additional 1 h. The
reaction was quenched with saturated NH4Cl solution (15 mL),
diluted with H2O (25 mL), and extracted with EtOAc (3 × 50
mL). The organic extracts were pooled, washed with H2O
(1 × 50 mL) and saturated NaCl solution (1 × 50 mL), dried
with MgSO4, and filtered. Removal of solvents in vacuo gave
181 mg of an orange/yellow solid. Purification by flash column
chromatography (3.5 × 15 cm silica) with 7:3 petroleum ether/
EtOAc yielded 112 mg (97%) of the title compound as a bright
1
yellow solid, mp 248-249 °C; H NMR (400 MHz, DMSO-d6)
δ 12.88 (br s, 1H), 8.55 (s, 1H), 8.15 (d, J ) 8.1 Hz, 1H), 7.75
(d, J ) 9.4 Hz, 1H), 7.51 (app t, J ) 8.1 Hz, 1H; overlaps with
singlet at 7.49), 7.49 (s, 1H), 7.42 (s, 1H), 7.12 (dd, J ) 8.1
and 2.6 Hz, 1H), 6.59 (d, J ) 9.4 Hz, 1H), 3.90 (s, 3H), 2.54 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 188.9, 168.6, 155.1,
145.7, 142.8, 142.6, 142.5, 140.5, 139.0, 134.4, 132.6, 132.3,
129.4, 126.0, 123.7, 122.9, 120.8, 64.8, 31.1; IR (KBr) ν 3444,
3918, 1622 cm-1; m/z (ESI-MS) 290.12 (MH+), 312.11 (MNa+);
HRMS (ESI) calcd for C19H16NO2 (MH+) 290.1181, found
290.1180.
1
was homogeneous by H and 13C NMR; an analytically pure
sample was obtained by recrystallization from 3:1 hexanes/
EtOAc as purple needles, mp 205-206 °C; 1H NMR (400 MHz,
DMSO-d6) δ 10.24 (s, 1H), 9.65 (s, 1H), 7.72 (d, J ) 8.8 Hz,
1H), 7.67 (d, J ) 8.0 Hz, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.48
(app t, J ) 8.0 Hz, 1H), 7.31 (s, 1H), 7.19 (dd, J ) 8.0 and 2.4
Hz, 1H), 7.16 (d, J ) 2.2 Hz, 1H), 7.06 (dd, J ) 8.8 and 2.2
Hz, 1H), 3.86 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 165.2, 158.9, 154.4, 135.6, 131.7, 130.7, 129.3, 129.1,
128.7, 128.3, 126.3, 125.0, 119.7, 118.4, 117.2, 112.6, 104.4,
55.2, 20.9; IR (KBr) ν 3237, 1645, 1629 cm-1; m/z (ESI-MS)
308.13 (MH+), 330.12 (MNa+). Anal. Calcd for C19H17NO3: C,
74.25; H, 5.58; N, 4.56. Found: C, 73.98; H, 5.55; N, 4.59.
N-{4,8-Dibromo-3-methyl-7-[[tris(1-methylethyl)silyl]-
oxy]-1-naphthalenyl}-3-methoxybenzamide (60). A 50 mL
round-bottomed flask (undried) was charged with 59 (322 mg,
1.05 mmol) and benzene (15 mL). A pressure-equalized addi-
tion funnel was attached, sealed with a septum, and filled with
a solution of Br2 (0.215 mL, 4.18 mmol) and benzene (5 mL).
The Br2/benzene solution was added dropwise over 30 min,
and the resulting heterogeneous reaction mixture was stirred
for 23 h. The reaction was diluted with EtOAc (100 mL),
washed with saturated NaHSO3 solution (3 × 50 mL), satu-
rated NaHCO3 solution (3 × 50 mL), H2O (1 × 50 mL) and
saturated NaCl solution (1 × 50 mL), dried with MgSO4, and
filtered. Removal of solvents in vacuo gave 472 mg of a gray
solid. This material was dissolved in DMF (10 mL) and
transferred into a 25 mL round-bottomed flask via syringe.
To the solution was added imidazole (184 mg, 2.70 mmol) and
triisopropylsilyl chloride (TIPSCl, 0.300 mL, 1.40 mmol). The
resulting homogeneous red/brown reaction mixture was stirred
at room temperature for 2 h, then poured into H2O (100 mL),
and extracted with EtOAc (3 × 50 mL). The organic extracts
were pooled, washed with 1 N HCl (1 × 50 mL), H2O (3 × 50
mL) and saturated NaCl solution (1 × 50 mL), dried with
MgSO4, and filtered. Removal of solvents in vacuo gave 1.13 g
of red oil, which was passed through a plug of silica (2.5 × 5
cm) with 19:1 hexanes/EtOAc and then recrystallized from
hexanes (606 mg in ca. 15 mL) to yield 590 mg (91%) of the
title compound as white hairs: mp 120-121 °C; 1H NMR (400
MHz, DMSO-d6) δ 10.38 (s, 1H), 8.33 (d, J ) 9.6 Hz, 1H), 7.65
8-Hydroxy-9-methoxy-5-methylbenz[cd]isoindolo[2,1-
a]indol-1(8H)-one (63). A 10 mL Schlenk flask was charged
with 61 (60.6 mg, 0.210 mmol) and THF (3 mL). The hetero-
geneous yellow reaction mixture was cooled to -10 °C (acetone/
ice bath), and lithium tetramethylpiperidide (Li-TMP; 1.31 mL,
0.800 M solution in THF/hexanes, 1.05 mmol) was added via
cannula over 1 min. The resulting red/brown homogeneous
reaction was stirred for 1 h and then cooled to -78 °C. A
solution of ethyl formate (49; 0.170 mL, 0.210 mmol), TMSCl
(0.270 mL, 2.11 mmol), and THF (1 mL; prepared by adding
49 to THF followed by the TMSCl) was then added via cannula
over 2 min. The now orange reaction mixture was allowed to
warm to room temperature overnight as the cooling bath
evaporated. After 12 h, the reaction was quenched with 1 N
HCl (3 mL), diluted with H2O (50 mL), and extracted with 4:1
CHCl3/EtOH (3 × 50 mL). The organics were pooled, dried with
MgSO4, and filtered. Removal of solvents in vacuo gave 73.7
mg of an orange/yellow solid. Purification by flash column
chromatography (2.5 × 15 cm Brockmann I basic alumina)
with 199:1 CHCl3/MeOH (200 mL), 99:1 CHCl3/ MeOH (200
mL), and then 98:2 CHCl3/MeOH (500 mL) yielded 18.4 mg
(30%) of recovered 61 and 46.3 mg (70%) of the title compound
1
as a bright orange solid: mp 223-224 °C (decomp); H NMR
(400 MHz, DMSO-d6) δ 7.97 (d, J ) 8.0 Hz, 1H), 7.75 (d, J )
9.6 Hz, 1H), 7.60 (app t, J ) 8.0 Hz, 1H), 7.55 (s, 1H), 7.45 (d,
J ) 9.6 Hz, 1H), 7.40 (s, 1H), 7.23 (d, J ) 8.0 Hz, 1H), 6.80 (d,
J ) 9.6 Hz, 1H), 6.55 (d, J ) 9.6 Hz, 1H), 3.93 (s, 3H), 2.52 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 188.8, 165.0, 156.6,
146.7, 143.0, 141.8, 141.4, 141.3, 140.4, 139.8, 137.4, 132.9,
132.7, 125.5, 123.5, 123.1, 117.1, 90.8, 65.2, 31.2; IR (KBr) ν
2922, 2844, 1735 cm-1; m/ z (ESI-MS) 318.11 (MH+); HRMS
(ESI) calcd for C20H16NO3 (MH+) 318.1130, found 318.1124.
J. Org. Chem, Vol. 70, No. 24, 2005 10011

Scopton and Kelly
8,9-Dimethoxy-5-methylbenz[cd]isoindolo[2,1-a]indol-
1(8H)-one [HKI 0231B (1b)]. A 10 mL round-bottomed flask
equipped with a reflux condenser was charged with 63 (15.7
mg, 0.0495 mmol, dried by azeotropic removal of water with
anhydrous toluene), camphorsulfonic acid (CSA; 11.5 mg,
0.0495 mmol), and MeOH (2 mL). The heterogeneous orange
reaction mixture was heated at a gentle reflux (oil bath
temperature 70 °C) for 36 h. The resulting homogeneous yellow
solution was allowed to cool to room temperature, poured into
saturated NaHCO3 solution (25 mL), and extracted with CH2-
Cl2 (3 × 25 mL). The organics were pooled, washed with
saturated NaHCO3 solution (2 × 25 mL) and saturated NaCl
solution (1 × 25 mL), dried with MgSO4, and filtered. Removal
of solvents in vacuo gave 20.0 mg of a yellow solid. Purification
by preparative TLC with 98:2 CH2Cl2/MeOH (plate eluted
three times) yielded 15.2 mg (93%) of 1b as a yellow solid: mp
IR (KBr) ν 3420, 2926, 1723, 1629, 1618, 1587, 1557, 1488,
1435, 1398, 1339, 1328, 1270, 1199, 1139, 1087, 1030, 951, 895,
868, 851, 789, 736 cm-1; m/z (ESI-MS) 332.06 (MH+); HRMS
(ESI) calcd for C21H18NO3 (MH+) 332.1287, found 332.1273;
UV-vis (MeOH) λmax (log ꢀ) 463 (4.91), 437 (5.02), 419 (4.92),
383 (4.97), 366 (4.97), 288 (5.11), 238 (5.38) nm. These data
are in excellent agreement with the spectra of the natural
product.
Acknowledgment. We thank Mr. Jack Beierle for
initial preparations of 8. We also thank Dr. Iva´n
Cornella, Dr. Simon Bushell, and Professor Costa Met-
allinos for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 8, 11, 12-
1
135-136 °C (lit.1 mp 135 °C); H NMR (500 MHz, CDCl3) δ
1
14, 16, 19, 20-22, 23, 25-27, 36, 39, 46, 47, 64, and 69; H
8.23 (d, J ) 7.3 Hz, 1H), 7.64 (d, J ) 9.6 Hz, 1H), 7.58 (app t,
J ) 7.8 Hz, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 7.04 (d, J ) 8.5 Hz,
1H), 6.78 (s, 1H), 6.71 (d, J ) 9.6 Hz, 1H), 4.00 (s, 3H), 2.98
(s, 3H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 181.3, 156.1,
148.7, 137.5, 134.7, 133.0, 132.9, 132.6, 131.3, 128.9, 127.7,
124.5, 123.8, 118.0, 113.3, 113.1, 109.1, 86.7, 55.8, 51.0, 22.1;
NMR spectra for compounds 13, 23, 39, 47, 61, 63, 64, and
1
69; and H and 13C NMR spectra for compounds 22, 26, 27,
and 1b. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051762L
10012 J. Org. Chem., Vol. 70, No. 24, 2005