A new strategy toward indole alkaloids involving an intramolecular cycloaddition/rearrangement cascade

Article abstract of DOI:10.1021/jo049808i

The intramolecular Diels-Alder reaction between an amidofuran moiety tethered onto an indole component was examined as a strategy for the synthesis of Aspidosperma alkaloids. Furanyl carbamate 23 was acylated using the mixed anhydride 26 to provide amidof

Full text of DOI:10.1021/jo049808i

A New Str a tegy tow a r d In d ole Alk a loid s In volvin g a n
In tr a m olecu la r Cycloa d d ition /Rea r r a n gem en t Ca sca d e
Albert Padwa,* Michael A. Brodney, Stephen M. Lynch, Paitoon Rashatasakhon,
Qiu Wang, and Hongjun Zhang
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received February 2, 2004
The intramolecular Diels-Alder reaction between an amidofuran moiety tethered onto an indole
component was examined as a strategy for the synthesis of Aspidosperma alkaloids. Furanyl
carbamate 23 was acylated using the mixed anhydride 26 to provide amidofuran 22 in 68% yield.
Further N-acylation of this indole furnished 27 in 88% yield. Cyclization precursors were prepared
by removing the carbamate moiety followed by N-alkylation with the appropriate alkyl halides.
Large substituent groups on the amido nitrogen atom causes the reactive s-trans conformation of
the amidofuran to be more highly populated, thereby facilitating the Diels-Alder cycloaddition.
The reaction requires the presence of an electron-withdrawing substituent on the indole nitrogen
in order for the cycloaddition to proceed. Treatment of N-allyl-bromoenamide 48 with n-Bu3SnH/
AIBN preferentially led to the 6-endo trig cyclization product 50, with the best yield (91%) being
obtained under high dilution conditions. The initially generated cyclohexenyl radical derived from
48 produces the pentacyclic heterocycle 50 by either a direct 6-endo trig cyclization or, alternatively,
by a vinyl radical rearrangement pathway.
The indole nucleus is a key structural feature found
in numerous natural products, many of which exhibit
potent pharmacological activity.1 As a result, the chem-
istry of substituted indoles has received an enormous
amount of attention.2 It is well-known that indole be-
haves as an enamine toward electrophiles and undergoes
Michael addition to electron-deficient alkenes.3 Our
interest in the synthesis and reactivity of the indole
moiety is ongoing and centers around its [4 + 2]-cycload-
dition chemistry.4 Wenkert’s previous observations have
already demonstrated the feasibility of Diels-Alder
chemistry with five-membered aromatic heterocycles.5
Compounds such a furans, N-benzenesulfonylpyrroles,
and benzofurans have been used as dienophiles with both
1,3-butadiene and isoprene at elevated temperatures.6,7
Since indole derivatives could prove to be appropriate
starting materials for alkaloid syntheses if suitable
cycloaddition chemistry can be developed, selected at-
tempts have been made to use the 2,3-double bond of
indole in Diels-Alder reactions.5-9 However, the electron-
rich indole ring shows only a low tendency to act as a
dienophile. In bimolecular Diels-Alder reactions that
occur with normal electron demand, indole acts as a
dienophile only if electron-withdrawing groups are present
in the 1- and 3-position.5,8 Long reaction times and high
temperatures are necessary for the reaction to proceed.5-9
Use of the indole ring in [4 + 2]-cycloaddition chemistry
has mainly been limited to Diels-Alder reactions with
inverse electron-demand heterodienes.10-12 Thus, the
Snyder group has nicely demonstrated that indoles can
react as dienophiles in formal [4 + 2]-cycloadditions with
1,2,4,5-tetrazines, 1,2,4-triazines, pyridazines, and tetra-
(1) Szantay, C. Pure Appl. Chem. 1990, 62, 1299. Hibino, S.; Choshi,
T. Nat. Prod. Rep. 2002, 19, 148 and earlier reviews in the series.
(2) For recent reviews, see: Sundberg, R. J . Indoles; Academic
Press: New York, 1996. Gribble, G. J . Chem. Soc., Perkin Trans. 1
2000, 1045. Gribble, G. Contemp. Org. Synth. 1994, 1, 145. Alvarez,
M.; Salas, M.; J oule, J . A. Heterocycles 1991, 32, 1391. Baudin, J . B.;
Comenil, M. G.; J ulia, S. A.; Lorne, R.; Mauclaire, L. Bull. Soc. Chim.
Fr. 1996, 133, 329. Black, D. S. C. Synlett 1993, 246. Hughes, D. L.
Org. Prep. Proc. Int. 1993, 25, 607. Gribble, G. W. Comprehensive
Heterocyclic Chemistry, 2nd ed.; Pergamon Press: New York, 1996;
Vol. 2, pp 207-257.
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4. Pindur, U.; Adam, R. J . Heterocycl. Chem. 1988, 25, 1.
(4) Padwa, A.; Price, A. T. J . Org. Chem. 1995, 60, 6258. Padwa,
A.; Price, A. T. J . Org. Chem. 1998, 63, 556.
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E.; Moeller, P. D. R.; Piettre, S. R. J . Am. Chem. Soc. 1988, 110, 7188.
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Synthesis 1996, 669. Dean, F. M. Adv. Heterocycl. Chem. 1981, 30,
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dron Lett. 1988, 29, 5605. Kraus, G. A.; Bougie, D.; J acobsen, R. A.;
Su, Y. J . Org. Chem. 1989, 54, 2425.
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10.1021/jo049808i CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/27/2004
J . Org. Chem. 2004, 69, 3735-3745
3735

Padwa et al.
SCHEME 1
SCHEME 2
chlorothiophene 1,1-dioxide.12 Indole magnesium salts
were also found to undergo facial [4 + 2]-cycloaddition
reactions with 2-phenylsulfonyl 1,3-dienes.13
In recent years, we have been investigating the in-
tramolecular [4 + 2]-cycloaddition/ rearrangement cas-
cade of 2-amidofurans as a strategy for the synthesis of
hexahydroindolinone alkaloids (Scheme 1).14 Intramo-
lecular cycloaddition reactions often benefit from higher
reactivity and greater control of stereoselectivity relative
to their intermolecular counterparts. Specifically, con-
necting two π-substrates via a “tether” generally facili-
tates the rate of the [4 + 2]-cycloaddition reaction. Our
experience with this domino sequence prompted us to
examine a Diels-Alder approach to various indole alka-
loids, wherein an indole moiety participates as the
dienophilic partner. One of the specific problems posed
by the indole Aspidosperma skeleton found in aspi-
dospermidine (4) and vindoline (5) involves the construc-
tion of the quaternary C(7) center.15 Because this center
is contained within the six-membered C ring, a reaction
that fashions both the C ring and the spirocyclic BE
junction represents a very efficient strategy for the
construction of this polycyclic array that is also present
in many of the strychnos alkaloids.16
In earlier work from our laboratory, we reported the
efficient participation of the indole C(2)-C(3) double bond
as the 2π component in 1,3-dipolar cycloadditions with
push-pull carbonyl ylides (i.e., 6 f 8).4 A later report
by Boger outlined a similar approach to the Vinca
alkaloids using a tandem intramolecular Diels-Alder/
dipolar cycloaddition sequence of 1,3,4-oxadiazoles across
the indole double bond (Scheme 2).20
More recently, our group published a preliminary
account of a concise and efficient synthesis of the ABCE
tetracyclic core of the aspidosperma skeleton, in which
the key step was a normal electron-demand Diels-Alder
reaction of an amidofuran across a tethered indole.21 The
[4 + 2]-cycloaddition/ rearrangement sequence was found
to be remarkably efficient given that two aromatic rings
were compromised in the reaction. Herein, we provide a
full account of the initial methodology, as well as its
general extension to prepare some related pentacyclic
analogues.
Kuehne’s17 use of a tandem ammonium ion rearrange-
ment/intramolecular Diels-Alder cycloaddition and the
more recent amido-diene cycloaddition sequence reported
by Rawal18 are the only approaches that construct the C
ring and the BE junction in one synthetic step.19
(12) Benson, S. C.; Palabrica, C. A.; Snyder, J . K. J . Org. Chem.
1987, 52, 4610. Benson, S. C.; Gross, J . L.; Snyder, J . K. J . Org. Chem.
1990, 55, 3257. Benson, S. C.; Li, J . H.; Snyder, J . K. J . Org. Chem.
1992, 57, 5285. Lee, L.; Snyder, J . K. Adv. Cycloaddit. 1999, 6, 119-
171. Wan, Z. K.; Woo, G. H. C.; Snyder, J . K. Tetrahedron 2001, 57,
5497. Li, J . H.; Snyder, J . K. J . Org. Chem. 1993, 58, 516. Wan, Z.;
Snyder, J . K. Tetrahedron Lett. 1997, 38, 7495. Benson, S. C.; Lee, L.;
Yang, L.; Snyder, J . K. Tetrahedron 2000, 56, 1165.
(13) Backvall, J . E.; Plobeck, N. A. J . Org. Chem. 1990, 55, 4528.
(14) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org. Chem.
1997, 62, 4088. Padwa, A.; Brodney, M. A.; Dimitroff, M. J . Org. Chem.
1998, 63, 5304. Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S.
J . Org. Chem. 1999, 64, 4617.
(15) The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic Press:
San Diego, 1990; Vol. 37, pp 145-204.
Resu lts a n d Discu ssion
(16) Aimi, N.; Sakai, S.-I. In The Alkaloids; Brossi, A., Ed.; Academic
Press: San Diego, 1989; Vol. 36, pp 1-68.
We started our studies by carrying out the N-alkylation
of furan 13 with 3-(2-bromoethyl)indole (14), which
(17) Kuehne, M. E.; Roland, D. M.; Hafter, R. J . Org. Chem. 1978,
43, 3705. Kuehne, M. E.; Bornmann, W. G.; Earley, W. G.; Marko, I.
J . Org. Chem. 1986, 51, 2913.
(18) Rawal, V. H.; Michoud, C.; Monestel, R. F. J . Am. Chem. Soc.
1993, 115, 3030. Rawal, V. H.; Iwasa, S. J . Org. Chem. 1994, 59, 2685.
(19) For a very recent paper using a related approach, see: Bodwell,
G. J .; Li, J . Angew. Chem., Int. Ed. 2002, 41, 3261.
(20) Wilke, G. D.; Elliott, G. I.; Blagg, B. S. J .; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J . Am. Chem.
Soc. 2002, 124, 11292.
(21) Lynch, S. M.; Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643.
3736 J . Org. Chem., Vol. 69, No. 11, 2004

New Strategy toward Indole Alkaloids
SCHEME 3 a
SCHEME 4 a
a
Reagents: (a) Cs2CO3, DMF/THF (4:1), 80 °C, 80%; (b)
Bu4NHSO4, NaOH, AcCl, CH2Cl2, rt, 90%; (c) Bu4NHSO4, NaOH,
ClSO2(C6H4)p-NO2, CH2Cl2, rt, 31%; (d) benzene (sealed tube), 240
°C, 18 h.
provided indole 15 in 80% yield (Scheme 3). Not unex-
pectedly, thermolysis of 15, which lacks an electron-
withdrawing group on the indole, failed to induce cy-
clization even at temperatures above 200 °C. N-Acylation
of 15 under phase-transfer conditions provided 16 in 90%
yield.
a
Reagents: (a) 24, i-BuO2CCl, N-methylmorpholine, filter, then
25, 0 °C, 68%; (b) Bu4NHSO4, NaOH, AcCl, CH2Cl2 rt, 88%; (c)
O(CO2Me)2, DMAP THF, rt, 70%; (d) benzene, sealed tube, 200
°C; (e) MgClO4, CH3CN, 50 °C, 77%.
Cyclization to 18 did occur, but only in 30% isolated
yield (62% based on recovered starting material), after
heating at 240 °C for 18 h. We also examined the
thermolysis of the related indole 17, which contains the
strong electron-withdrawing nitrobenzenesulfonyl (nosyl)
group on the nitrogen atom. Heating a sample of 17 in
toluene at 200 °C for 18 h furnished the rearranged
cycloadduct 19 but again in only 36% yield.
Somewhat encouraged by the above results, we searched
for a way to increase the efficiency of the cycloaddition
reaction. In previous studies, structural features that
facilitated the intramolecular Diels-Alder reaction of
amidofurans were discovered.22,23 We reasoned that the
incorporation of a carbonyl group in the tether adjacent
to the indole ring should facilitate the reaction by
providing a favorable FMO electronic effect. We found,
however, that the independently synthesized furanyl
indoles 20 and 21 resisted cycloaddition even at temper-
atures up to 300 °C. Dramatic effects on the rate of the
Diels-Alder reaction were previously noted to occur
when an amido group was used to anchor the diene and
dienophile.24 In one example involving an intramolecular
dipolar cycloaddition, a severe steric interaction was
found in the transition state, while no such interaction
was identifiable in either the starting material or product
ground states.25
Introduction of a carbonyl group on the tethered
dipolarophile relieved the source of the strain. Similarly,
the effects of amide and ester-linked tethers on the
diastereoselectivity of intramolecular Diels-Alder reac-
tions have been attributed to relative transition state
stabilities.26 J ung and Gervay, however, reported data
for intramolecular Diels-Alder reactions of furans that
suggest that substitution on the tether results in an
increase in the population of reactive rotomers.27 Thus,
the rate enhancement encountered could also originate
from a restricted rotation that enforces a more reactive
conformer in the lowest energy ground state.
With this possibility in mind, we decided to synthesize
an indolyl-tethered amidofuran such as 22 in order to
evaluate its cycloaddition behavior. Initially, we had
envisioned 22 arising from simple acylation of 23 with
the acid chloride derived from indole acetic acid (24).
However, under a variety of conditions (DMAP, 4 Å
molecular sieves, etc.), furanyl carbamate 23 proved to
be remarkably resistant toward acylation. After some
experimentation, we found that the addition of 25, formed
by the action of n-BuLi on 23, to a solution of the mixed
anhydride 26 provided 22 in 68% yield (Scheme 4).
Subsequent N-acylation under phase-transfer conditions
smoothly produced 27 in 88% yield. Similarly, treatment
of 22 with dimethyl pyrocarbonate in the presence of
DMAP afforded the closely related N-carbomethoxy-
(24) Oppolzer, W.; Fro¨stl, W. Helv. Chim. Acta 1975, 58, 590.
Oppolzer, W.; Fro¨stl, W.; Weber, H. P. Helv. Chim. Acta 1975, 58, 593.
(25) Weingarten, M. D.; Prein, M.; Price, A. T.; Snyder, J . P.; Padwa,
A. J . Org. Chem. 1997, 62, 2001.
(26) White, J . D.; Demnitz, F. W. J .; Oda, H.; Hassler, C.; Snyder,
J . P. Org. Lett. 2000, 2, 3313. Turner, C. I.; Williamson, R. M.; Padon-
Row, M. N. J . Org. Chem. 2001, 66, 3963. Tantillo, D. J .; Houk, K. N.;
J ung, M. E. J . Org. Chem. 2001, 66, 1938.
(27) J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224.
Sternbach, D. D.; Rossana, D. M.; Onan, D. D. Tetrahedron Lett. 1985,
26, 591. Giessner-Prettre, C.; Hu¨kel, S.; Maddaluno, J .; J ung, M. E.
J . Org. Chem. 1997, 62, 1439.
(22) Padwa, A.; Gin, J . D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J .
Org. Chem. 2002, 64, 3412.
(23) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
J . Org. Chem, Vol. 69, No. 11, 2004 3737

Padwa et al.
SCHEME 5
protected indole 28 in 60% yield. Unfortunately, all of
our attempts to effect the [4 + 2]-cycloaddition of 27 (or
28) resulted only in the removal of the thermally labile
tert-butyloxy carbonyl group to give 29 (or 30). While 29
should still be a viable cyclization precursor, the use of
temperatures exceeding 300 °C failed to promote the
desired cycloaddition; only starting indole was recovered.
Upon further consideration, this result is not so
surprising: conformational preferences about an amide
bond have been implicated in the efficiency of other
cyclization reactions.28 The strong preference of secondary
amides to adopt an s-cis conformation is well estab-
lished.29 More than likely, 29 resides predominantly in
the s-cis conformation where the furan ring is far
removed from the indole π-bond (eq 1). We reasoned that
replacing the hydrogen with a larger group would cause
the reactive s-trans conformation to be more highly
populated, and therefore the cycloaddition will be more
prone to occur.
These cycloadditions do require the presence of an
electron-withdrawing substituent on the indole nitrogen
in order for the reaction to proceed. For example, indole
38, which contains a methyl substituent on the indole
nitrogen, failed to undergo the cycloaddition even at 300
°C. The failure of 38 to undergo the Diels-Alder reaction
is consistent with FMO theory.31 Placement of an alkyl
substituent on the nitrogen atom raises the LUMO
energy of the indole C2-C3 π-bond, thereby diminishing
the rate of the normal electron-demand Diels-Alder
reaction.
At this stage of our investigations we decided to study
the effect of substitution on the furan ring and how it
would influence the Diels-Alder reaction. In particular,
we were interested in knowing whether the incorporation
of functionality at the 3-position of the furan would effect
its reactivity toward cycloaddition. Our hope was to use
the furan ring to install the requisite ethyl group that is
common to many members of the aspidosperma alkaloid
family (i.e., 5). With this in mind, we prepared the desired
3-ethyl-substituted furan 45. We were quite disappointed
to find that 45 did not undergo cycloaddition analogous
to that observed with the unsubstituted furan 33. In
seeking a possible explanation for its lack of reactivity,
we carried out some molecular mechanics calculations.
Low-energy conformers of indole 45 were obtained using
Monte Carlo conformation searching (MCMM) as impli-
cated by MacroModel 7.032 with either MM2* or MMFF
parameters.
To test this hypothesis, several tertiary amides derived
from 29 were prepared. This necessitated a more experi-
mentally benign protocol for removing the carbamate
moiety from 27, and we found that MgClO4 in CH3CN
efficiently provided 29.30 Alkylating the sodium salt of
29 with methyl iodide, benzyl bromide, or allyl iodide
provided the desired indoles 31-33 in high yield (Scheme
5). Indole 31, which contains the relatively small methyl
group on the amido nitrogen, resisted cycloaddition even
at temperatures up to 300 °C. In stark contrast, ther-
molysis of related indoles that contain a larger substitu-
ent group on the amide nitrogen did result in products
derived from a Diels-Alder reaction. Thus, heating a
sample of the N-benzyl indole 32 gave the novel azatri-
cycle 39 in 56% yield. Similarly, the thermolysis of the
N-allyl-substituted indole 33 cleanly afforded 40 in 77%
yield after only 2 h.
We also examined the cyclization of indoles 34 and 35,
which bear an iodo functionality on the side chain that
may allow for eventual functionalization of the D-ring of
the aspidosperma skeleton. We were pleased to note that
heating both indoles 34 and 35 at 200 °C for 2 h furnished
the rearranged cycloadducts 41 and 42 in 74 and 84%
yields, respectively. Furans 36 and 37, which contain the
N-methoxycarbonyl group on the indole nitrogen, also
produced the rearranged cycloadducts 43 and 44 on
heating at 200 °C in 91 and 50% yields, respectively.
The calculations show that a restricted rotation exists
about the amide bond as a consequence of a steric
interaction between the furanyl ethyl group and the
N-allyl substituent. This interaction prevents the furan
ring from adopting the proper conformation necessary for
(28) For recent examples, see: J ones, K.; Wilkinson, J .; Ewin, R.
Tetrahedron Lett. 1994, 35, 7673. Tamura, O.; Matsukida, H.; Toyao,
A.; Takeda, Y.; Ishibashi, H. J . Org. Chem. 2002, 67, 5537.
(29) Stewart, W. E.; Siddall, T. H. Chem. Rev. 1970, 70, 517. See
also: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
J ohn Wiley & Sons: New York, 1994; p 620.
(31) Fleming, I.; Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(32) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.
(30) Stafford, J . A.; Brackeen, M. F.; Karanewsky, D. S.; Valvano,
N. L. Tetrahedron Lett. 1993, 34, 7873.
3738 J . Org. Chem., Vol. 69, No. 11, 2004

New Strategy toward Indole Alkaloids
SCHEME 6
SCHEME 7
Beckwith36 revealed that the formation of the six-
membered ring is not solely due to a 6-endo trig cycliza-
tion but is the result of a rapid rearrangement of the
methylene cyclopentyl radical, via a reversible 3-exo trig
cyclization.38 More than likely, this pathway is also
involved in the formation of 50, especially since the
reaction was carried out at low concentrations of n-Bu3-
SnH (0.01 M), which facilitates the radical rearrange-
ment and minimizes the formation of the 5-exo trig
product. Interestingly, our attempts to cyclize the N-(3-
iodopropyl)-substituted azatetracycle 41 failed and in-
stead afforded the reduction product 51 in 78% yield
(Scheme 7). The failure of 41 to cyclize to 52 is presum-
ably reflective of the slower rate of addition of the alkyl
radical to the enamido π-bond.39
The strychnos alkaloids constitute an important class
of naturally occurring compounds that has attracted the
attention of synthetic chemists due to the interesting
biological properties of some of its members.40 These
alkaloids share as part of their structure the pentacyclic
strychnan framework in which rings C and E are joined
by a bridged juncture and ring E bears an exocyclic olefin.
Our general interest in using the [4 + 2]-cycloaddition/
rearrangement of indolyl-substituted amidofurans as a
synthetic method led us to consider an approach to (()-
dehydrotubifoline (56)41 that makes use of the readily
available cycloadduct 54. To apply this strategy to
dehydrotubifoline (56), we hoped to form the C15-C20
bond by making use of Rawal’s elegant intramolecular
Heck protocol.42 Our retrosynthetic analysis of 56 is
shown in Scheme 8. Dehydrotubifoline would be obtained
from 55, which, in turn, would be prepared from tetra-
the cycloaddition to proceed. We thought that by using a
furanyl substrate that possessed a smaller substituent
in the 3-position we would be able to overcome the
conformation issue. There is some evidence in the litera-
ture indicating that a bromo group in the 3-position of
furans accelerates the Diels-Alder reaction.33 If the
cycloaddition were to proceed, the resulting vinyl bromide
present in the rearranged cycloadduct could then be used
as a handle to install the desired ethyl group by a variety
of methods. To evaluate this possibility, bromofuran 46
(R ) Br) was prepared. Unfortunately, this furan was
rather unstable and afforded intractable material when
subjected to thermolysis.
To use the cycloaddition/ rearrangement strategy for
assembly of the aspidosperma skeleton, we needed to
address the problem of assembling the final D-ring of the
pentacyclic skeleton. With this in mind, we subjected
cycloadduct 40 to sodium borohydride reduction. The
resulting alcohol was obtained as a single diastereomer
in 90% yield and subsequently protected as the corre-
sponding tert-butyldimethylsilyl derivative 47. Treatment
of 47 with NBS in CH2Cl2 gave the corresponding
bromoenamide 48. Exposure of 48 to several radical
cyclization conditions preferentially led to the 6-endo trig
cyclization product 50, with the best yields (91%) being
obtained using n-Bu3SnH/AIBN in refluxing benzene
under slow addition conditions (Scheme 6). By analogy
with related results obtained in our laboratory,34 we
assume that the initially generated cyclohexenyl radical
49 derived from 48 would produce the pentacyclic het-
erocycle 50 either by a direct 6-endo trig cyclization or
alternatively by a vinyl radical rearrangement pathway.35
Early studies by Beckwith36 and Stork37 have shown that
vinyl radical cyclization generally leads to a mixture of
both 5-exo and 6-endo products. The kinetic work of
(36) Beckwith, A. L. J .; O’Shea, D. M. Tetrahedron Lett. 1986, 27,
4525.
(37) Stork, G.; Mook, R., J r. Tetrahedron Lett. 1986, 27, 4529.
(38) Crich, D.; Hwang, J . T.; Liu, H. Tetrahedron Lett. 1996, 37,
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(39) Vazquez, A. N.; Garcia, A.; Dominguez, D. J . Org. Chem. 2002,
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(40) Bosch, J .; Bonjoch, J . Pentacyclic Strychnos Alkaloids. In
Studies in Natural Products Chemistry; Rahman, A., Ed.; Elsevier:
Amsterdam, 1988; Vol. 1, p 31. Husson, H. P. In Indoles: Monoterpenes
Indole Alkaloids; Saxton, J . E., Ed.; Wiley: New York, 1988; Chapters
1 and 7.
(41) Fevig, J . M.; Marquis, R. W., J r.; Overman, L. E. J . Am. Chem.
Soc. 1991, 113, 5085. Harley-Mason, J .; Crawley, G. C. J . Chem. Soc.,
Chem. Commun. 1971, 93, 685. Takano, S.; Hirama, M.; Ogasawara,
K. Tetrahedron Lett. 1982, 23, 881. Rawal, V. H.; Michoud, C.;
Monestel, R. F. J . Am. Chem. Soc. 1993, 115, 3030.
(33) Klein, L. L. J . Org. Chem. 1985, 50, 1770. Crawford, K. R.; Bur,
S. K.; Straub, C. S.; Padwa, A. Org. Lett. 2003, 5, 3337.
(34) Rashatasakhon, P.; Ozdemir, A. D.; Willis, J .; Padwa, A. Org.
Lett. 2004, 6, 917.
(35) Stork, G.; Baine, N. H. J . Am. Chem. Soc. 1982, 104, 2321.
J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237.
Motherwell, W. B.; Crich, D. Free Radical Reactions in Organic
Synthesis; Academic Press: London, 1992.
J . Org. Chem, Vol. 69, No. 11, 2004 3739

Padwa et al.
SCHEME 8
takes place implies that refunctionalization at the keto
carbonyl center is more likely to be accomplished prior
to the installation of the (Z)-2-iodobut-2-enyl group.
Further work to achieve this goal is in progress and will
be reported at a later date.
The work reported herein describes a novel approach
to the core structure of the aspidosperma alkaloids. As
typified in the synthesis of the model compound 40, the
Diels-Alder approach delivers a material in which the
ABCE tetracyclic core of aspermidine is rapidly as-
sembled. Our studies show that these intramolecular [4
+ 2]-cycloaddition reactions are remarkably efficient
given that two aromatic systems are compromised in the
reaction. This synthetic strategy should prove to be useful
for the construction of different members of the Aspi-
dosperma family because the piece-wise construction of
the cascade precursor allows for incorporation of varied
functionality. Furthermore, the discovery of a facile
radical method of closing the D ring may allow for the
implementation of synthetic routes to a variety of aspi-
dosperma alkaloids.
SCHEME 9
Exp er im en ta l Section
F u r a n -2-ylca r ba m ic Acid Eth yl Ester (13). To a solution
of 3.0 g (23 mmol) of 2-furoyl chloride in 25 mL of Et2O at 0
°C was added a solution of 1.8 g (28 mmol) of sodium azide in
15 mL of H2O, and the biphasic mixture was vigorously stirred
at room temperature for 4 h. The organic layer was separated,
dried over MgSO4, and concentrated under reduced pressure.
The resulting crude white solid was dissolved in 20 mL of
EtOH and heated at reflux for 15 h behind a protective shield.
The solvent was removed under reduced pressure, and the
resulting residue was purified by flash silica gel chromatog-
raphy using a 5% ethyl acetate-hexane mixture to provide
3.0 g (84%) of 13 as a pale yellow solid: mp 27-28 °C; IR (neat)
1716, 1618, 1552, and 1260 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.29 (t, 3H, J ) 6.8 Hz), 4.22 (q, 2H, J ) 6.8 Hz), 6.07 (brs,
1H), 6.34 (dd, 1H, J ) 3.2 and 1.6 Hz), 6.96 (brs, 1H), and
7.07 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.6, 62.1, 95.8,
111.5, 136.6, 145.2, and 153.2. Anal. Calcd for C7H9NO3: C,
54.17; H, 5.85; N, 9.03. Found: C, 54.02; H, 6.13; N, 9.12.
[2-(1-Acet yl-1H -in d ol-3-yl)-et h yl]fu r a n -2-ylca r b a m ic
Acid Eth yl Ester (16). To a solution containing 1.2 g (7.6
mmol) of furan-2-yl carbamic acid ethyl ester (13) and 150 mL
of a 4:1 DMF/THF mixture at room temperature was added
7.4 g (23 mmol) of cesium carbonate. The reaction mixture was
stirred at room temperature for 30 min, and 2.2 g (10 mmol)
of 3-(2-bromo-ethyl)-indole was added in one portion. The
mixture was heated at 90 °C for 12 h and then cooled to room
temperature, quenched with H2O, and extracted with ether.
The organic layer was washed with H2O, dried over MgSO4,
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography using a 5% ethyl
acetate-hexane mixture to provide 1.8 g (80%) of furan-2-yl-
[2-(1H-indol-3-yl)-ethyl]carbamic acid ethyl ester (15) as a pale
cyclic ketone 54. Indeed, we found that the thermolysis
of the easily synthesized indolyl-tethered amidofuran 53
proceeded smoothly at 200 °C and furnished the expected
cycloadduct 54 in 87% yield.
Conversion of the keto carbonyl group of 54 into an
olefinic π-bond was our initial goal. Reduction of 54 with
sodium borohydride afforded the cyclic carbamate 57 as
the major product. Our attempts to introduce the re-
quired double bond needed for the Heck reaction only
resulted in the elimination of hydrogen iodide giving the
propargylic-substituted amide 58 in good yield. In a
typical example, the reaction of 57 with DBU gave 58 in
78% yield. Further reaction of 58 with additional base
for longer periods of time furnished diene 59 (Scheme
9). Because of this discouraging result, we abandoned
further work toward dehydrotubifoline using carbamate
57. The facility with which hydrogen iodide elimination
yellow oil: IR (neat) 3416, 1702, 1616, 1460, and 1296 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.25 (t, 3H, J ) 7.2 Hz), 3.12 (t,
2H, J ) 8.0 Hz), 3.95 (t, 2H, J ) 8.0 Hz), 4.21 (q, 2H, J ) 7.2
Hz), 6.07 (brs, 1H), 6.41 (dd, 1H, J ) 3.2 and 2.4 Hz), 6.99 (d,
1H, J ) 2.4 Hz), 7.13-7.24 (m, 2H), 7.28 (dd, 1H, J ) 2.0 and
1.2 Hz), 7.35 (d, 1H, J ) 8.0 Hz), 7.67 (d, 1H, J ) 8.0 Hz), and
8.19 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 24.8, 49.8,
62.4, 101.9, 111.2, 111.3, 112.6, 118.9, 119.4, 122.1, 122.2,
127.6, 136.4, 138.7, 148.3, and 155.3. Anal. Calcd for
(42) Rawal, V. H.; Michoud, C.; Monestel, R. F. J . Am. Chem. Soc.
1993, 115, 3030. Rawal, V. H.; Iwasa, S. J . Org. Chem. 1994, 59, 2685.
Birman, V. B.; Rawal, V. H. Tetrahedron Lett. 1998, 39, 7219. Birman,
V. H.; Rawal, V. H. J . Org. Chem. 1998, 63, 9146.
(43) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron
1994, 50, 371.
C
17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.48; H,
6.04; N, 9.32.
To a solution containing 1.0 g (3.4 mmol) of indole 15 in 40
(44) Piers, E. Synthesis 1998, 590.
mL of CH2Cl2 at room temperature was added 0.13 g (0.4
3740 J . Org. Chem., Vol. 69, No. 11, 2004

New Strategy toward Indole Alkaloids
mmol) of tetrabutylammonium hydrogen sulfate followed by
0.67 g (17 mmol) of freshly powdered NaOH. The reaction
mixture was stirred at room temperature for 5 min, and then
0.6 g (8 mmol) of acetyl chloride was added dropwise. The
reaction mixture was stirred at room temperature for 1 h,
quenched with H2O, and extracted with CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was subjected to
flash silica gel chromatography using a 5% ethyl acetate-
hexane mixture to afford 1.0 g (90%) of 16 as a colorless oil:
and 5.2 Hz), 3.56-3.63 (m, 1H), 3.79-3.85 (m, 1H), 4.27 (q,
2H, J ) 6.8 Hz), 4.64 (s, 1H), 5.70-6.18 (brs, 1H), 6.99 (d, 1H,
J ) 7.6 Hz), 7.08 (dt, 1H, J ) 7.6 and 0.8 Hz), 7.27-7.31 (m,
1H), 7.45 (d, 1H, J ) 8.0 Hz), 8.16 (d, 2H, J ) 8.8 Hz), and
8.36 (d, 2H, J ) 8.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.8,
29.9, 36.6, 37.4, 45.6, 62.3, 73.1, 100.5, 116.3, 123.2, 124.6,
125.9, 128.9, 129.7, 135.7, 136.7, 139.2, 145.2, 150.6, and 202.5.
Anal. Calcd for C23H21N3O7S: C, 57.13; H, 4.38; N, 8.70.
Found: C, 57.02; H, 4.22; N, 8.83.
F u r a n -2-yl-(2-1H-in d ol-3-yl-a cetyl)ca r ba m ic Acid ter t-
Bu tyl Ester (22). To a solution of 0.18 g (1.0 mmol) of furan-
2-yl carbamic acid tert-butyl ester (23) in 4 mL of THF at 0 °C
was added dropwise 0.9 mL (1.1 mmol) of n-BuLi (1.3 M in
hexane). The reaction mixture was stirred at 0 °C for 20 min.
In a separate flask, 0.18 g (1.0 mmol) of indole-3-acetic acid
was dissolved in 5 mL of THF at 0 °C, and 0.11 mL (1.0 mmol)
of 4-methylmorpholine and 0.13 mL (1.0 mmol) of isobutyl
chloroformate were added dropwise. After 5 min, the white
precipitate that formed was removed via filtration and washed
with 2 mL of THF. The filtrate was cooled to 0 °C, and the
preformed lithiate was added dropwise via syringe. After
stirring at 0 °C for an additional 20 min, the reaction was
quenched with H2O and extracted with EtOAc. The organic
layer was washed with saturated aqueous NaHCO3, dried over
MgSO4, and concentrated under reduced pressure. The residue
was subjected to flash silica gel chromatography using a 5%
ethyl acetate-hexane mixture to afford 0.23 g (68%) of 22 as
a white solid: mp 100-102 °C; IR (neat) 3380, 1772, 1746,
1705, 1603, and 1142 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.46
(s, 9H), 4.28 (s, 2H), 6.15 (dd, 1H, J ) 3.2 and 0.8 Hz), 6.42
(dd, 1H, J ) 3.2 and 2.0 Hz), 7.03 (d, 1H, J ) 2.4 Hz), 7.11-
7.20 (m, 2H), 7.27 (d, 1H, J ) 7.6 Hz), 7.35 (dd, 1H, J ) 2.0
and 1.2 Hz), 7.61 (d, 1H, J ) 7.6 Hz), and 8.30 (brs, 1H); 13C
NMR (CDCl3, 100 MHz) δ 27.9, 34.1, 84.1, 106.2, 107.8, 111.4,
118.9, 119.5, 122.0, 123.9, 127.5, 136.1, 140.7, 144.1, 151.6,
and 173.7. Anal. Calcd for C19H20N2O4: C, 67.05; H, 5.92; N,
8.23. Found: C, 67.23; H, 6.04; N, 8.15.
1
IR (neat) 1721, 1612, 1506, and 1457 cm-1; H NMR (CDCl3,
400 MHz) δ 1.19 (t, 3H, J ) 6.8 Hz), 2.56 (s, 3H), 2.99 (t, 2H,
J ) 7.2 Hz), 3.91 (t, 2H, J ) 7.2 Hz), 4.14 (q, 2H, J ) 6.8 Hz),
6.05 (brs, 1H), 6.35 (t, 1H, J ) 2.0 Hz), 7.21-7.24 (m, 2H),
7.24-7.28 (m, 1H), 7.31-7.35 (m, 1H), 7.53 (d, 1H, J ) 7.4
Hz), and 8.40 (d, 1H, J ) 6.8 Hz); 13C NMR (CDCl3, 100 MHz)
δ 14.6, 24.2, 24.6, 48.8, 62.5, 102.3, 111.3, 116.8, 118.9, 119.4,
122.8, 123.7, 125.5, 130.6, 136.0, 138.8, 147.9, 155.1, and 168.6;
HRMS calcd for C19H20N2O4 340.1423, found 340.1408.
7-Acetyl-6-oxo-1,2,5,6,6a ,7-h exah ydr opyr r olo[2,3-d]car -
ba zole-3-ca r boxylic Acid Eth yl Ester (18). A solution of
0.5 g (1.3 mmol) of furan 16 in 5 mL of benzene was heated in
a sealed tube at 240 °C for 18 h. The solution was concentrated
under reduced pressure, and the residue was subjected to flash
silica gel chromatography using a 5% ethyl acetate-hexane
mixture to provide 0.15 g (30%) of 18 as a yellow solid: mp
174-175 °C; IR (KBr) 1716, 1673, 1595, 1481, and 1403 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.37 (t, 3H, J ) 7.2 Hz), 2.03
(dd, 1H, J ) 12.0 and 5.6 Hz), 2.16-2.25 (m, 1H), 2.28 (s, 3H),
2.95 (dd, 1H, J ) 21.8 and 3.0 Hz), 3.09 (dd, 1H, J ) 21.8 and
5.0 Hz), 3.70-3.77 (m, 1H), 3.92 (dd, 1H, J ) 10.8 and 8.4
Hz), 4.26-4.34 (m, 2H), 4.45 (s, 1H), 5.81-6.22 (brs, 1H), 6.98-
7.04 (m, 2H), 7.19-7.27 (m, 1H), and 8.20 (d, 1H, J ) 8.0 Hz);
13C NMR (CDCl3, 100 MHz) δ 14.8, 24.0, 36.8, 36.9, 45.9, 62.1,
72.8, 100.2, 115.7, 118.2, 122.0, 123.3, 124.6, 129.4, 134.3,
141.0, 170.0, and 204.6. Anal. Calcd for C19H20N2O4: C, 67.05;
H, 5.92; N, 8.23. Found: C, 67.10; H, 6.05; N, 8.38.
Eth yl-N-[3-[1-(4-n itr oben zen esu lfon yl)-1H-in dol]-2-eth -
yl]-N-(2-fu r yl)-ca r ba m a te (17). To a solution containing 0.25
g (0.84 mmol) of indole 15 and 15 mL of CH2Cl2 at room
temperature were added 0.03 g (0.09 mmol) of tetrabutylam-
monium hydrogen sulfate and 0.2 g (4.2 mmol) of powdered
NaOH. The reaction mixture was stirred at room temperature
for 5 min, and then 0.4 g (1.8 mmol) of 4-nitrobenzenesulfonyl
chloride in 5 mL of CH2Cl2 was added dropwise to the solution.
The mixture was stirred at room temperature for 2 h,
quenched with 10 mL of H2O, and extracted with CH2Cl2. The
combined organic layers were dried over MgSO4 and concen-
trated under reduced pressure. The residue was subjected to
flash silica gel chromatography using a 5% ethyl acetate-
hexane mixture to give 0.13 g (31%) of 17 as a yellow oil: IR
(neat) 1716, 1609, 1531, 1445, and 1374 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.12-1.16 (m, 3H), 2.96 (t, 3H, J ) 6.8 Hz), 3.85
(t, 2H, J ) 7.6 Hz), 4.02-4.12 (m, 2H), 5.93 (brs, 1H), 6.31
(dd, 1H, J ) 3.2 and 2.0 Hz), 7.15 (d, 1H, J ) 1.2 Hz), 7.24 (t,
1H, J ) 7.2 Hz), 7.29-7.32 (m, 1H), 7.33 (s, 1H), 7.51 (d, 1H,
J ) 7.6 Hz), 7.93 (d, 1H, J ) 7.6 Hz), 7.98 (d, 2H, J ) 9.2 Hz),
and 8.21 (d, 2H, J ) 8.8 Hz); 13C NMR (CDCl3, 100 MHz) δ
14.5, 24.5, 48.6, 62.5, 102.3, 111.3, 113.7, 120.1, 121.4, 123.3,
124.1, 124.7, 125.6, 128.2, 131.3, 135.2, 138.8, 143.4, 147.9,
150.7, 155.0; HRMS calcd for C23H21N3O7S 483.1100, found
483.1111.
Eth yl-7-(4-n itr oben zen esu lfon yl)-6-oxo-1,2,5,6,6a ,7-h exa-
h yd r o-p yr r olo[2,3-d ]-ca r ba zole-3-ca r boxyla te (19). A so-
lution of 0.05 g (0.10 mmol) of indole 17 in 13 mL of toluene
was heated at 200 °C for 18 h in a sealed tube. The solution
was concentrated under reduced pressure, and the residue was
subjected to flash silica gel chromatography using a 5% ethyl
acetate-hexane mixture to give 0.02 g (36%) of 19 as a pale
yellow oil: IR (KBr) 2985, 1713, 1522, and 1385 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.34 (t, 3H, J ) 7.2 Hz), 1.97-2.03 (m,
1H), 2.89 (dd, 1H, J ) 21.0 and 3.0 Hz), 3.04 (dd, 1H, J ) 21.0
F u r a n -2-yl-[2-(1-Acet yl-1H -in d ol-3-yl)a cet yl]ca r b a m -
ic Acid ter t-Bu tyl Ester (27). To a solution of 2.0 g (5.9
mmol) of indole 22 in 40 mL of CH2Cl2 at 0 °C was added 0.2
g (0.6 mmol) of tetrabutylammonium hydrogen sulfate followed
by 1.2 g (29 mmol) of freshly powdered NaOH. After the
mixture was stirred for 5 min, 1.1 mL (15 mmol) of acetyl
chloride was slowly added and the reaction mixture was stirred
at 0 °C for 15 min and then at room temperature for 15 min.
The reaction was quenched with H2O, and aqueous layer was
extracted with CH2Cl2. The combined organic layer was dried
over MgSO4, and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography using
a 5% ethyl acetate-hexane mixture to afford 1.97 g (88%) of
27 as a white solid: mp 102-103 °C; IR (neat) 1777, 1751,
1705, 1608, 1454, and 1147 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.43 (s, 9H), 2.60 (s, 3H), 4.27 (s, 2H), 6.15 (dd, 1H, J ) 3.2
and 0.8 Hz), 6.42 (dd, 1H, J ) 3.2 and 2.0 Hz), 7.26-7.30 (m,
1H), 7.34-7.38 (m, 2H), 7.51-7.53 (m, 2H), and 8.43 (d, 1H, J
) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 24.2, 27.9, 33.8, 84.4,
106.3, 111.5, 115.0, 116.8, 119.1, 123.8, 124.5, 125.6, 130.5,
135.7, 140.9, 143.7, 151.6, 168.8, and 172.4. Anal. Calcd for
C
21H22N2O5: C, 65.96; H, 5.80; N, 7.33. Found: C, 66.17; H,
5.75; N, 7.37.
2-(1-Acetyl-1H-in d ol-3-yl)-N-fu r a n -2-yla ceta m id e (29).
To a solution of 1.2 g (3.1 mmol) of indole 27 in 30 mL of CH3-
CN was added 0.07 g (0.3 mmol) of magnesium perchlorate.
The solution was heated to 45 °C for 1.5 h and then cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was triturated with EtOAc, and
the resultant white solid was collected via filtration to afford
0.25 g of 29. The filtrate was concentrated and subjected to
flash silica gel chromatography using a 5% ethyl acetate-
hexane mixture to collect an additional 0.44 g (77% total) of
29 as a white solid: mp 164-165 °C; IR (neat) 3257, 1669,
1536, 1449, and 1388 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.64
J . Org. Chem, Vol. 69, No. 11, 2004 3741

Padwa et al.
(s, 3H), 3.83 (s, 2H), 6.33-6.36 (m, 2H), 7.00 (dd, 1H, J ) 2.0
and 1.2 Hz), 7.31-7.35 (m, 1H), 7.39-7.43 (m, 1H), 7.48 (s,
1H), 7.54 (d, 1H, J ) 8.0 Hz), 7.75 (brs, 1H), and 8.43 (d, 1H,
J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 24.2, 33.4, 96.1,
111.7, 114.9, 117.1, 118.9, 124.3, 124.7, 126.2, 129.8, 135.8,
136.1, 145.0, 166.5, and 168.7. Anal. Calcd for C16H14N2O3: C,
68.07; H, 5.00; N, 9.92. Found: C, 67.82; H, 5.01; N, 9.81.
a 5% ethyl acetate-hexane mixture to afford 0.1 g (77%) of
40 as a pale orange solid: mp 202-203 °C; IR (neat) 1726,
1685, 1475, 1393, and 758 cm-1; 1H NMR (CDCl3, 400 MHz) δ
2.33 (s, 3H), 2.62 (d, 1H, J ) 16.6 Hz), 2.88 (dd, 1H, J ) 20.4
and 2.4 Hz), 2.97 (d, 1H, J ) 16.6 Hz), 3.01 (dd, 1H, J ) 20.4
and 6.0 Hz), 4.13 (dd, 1H, J ) 15.6 and 6.0 Hz), 4.38 (dd, 1H,
J ) 15.6 and 5.6 Hz), 4.53 (s, 1H), 5.10 (dd, 1H, J ) 5.6 and
2.4 Hz), 5.28-5.34 (m, 2H), 5.78-5.87 (m, 1H), 7.00-7.05 (m,
2H), 7.23-7.27 (m, 1H), and 8.14 (d, 1H, J ) 8.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 24.1, 36.7, 43.0, 45.9, 50.1, 71.4, 94.4,
118.1, 119.2, 121.0, 125.4, 129.7, 131.1, 134.5, 140.7, 141.1,
169.8, 171.5, and 203.0. Anal. Calcd for C19H18N2O3: C, 70.79;
H, 5.63; N, 8.69. Found: C, 70.54; H, 5.70; N, 8.55.
2-(1-Acetyl-1H-in d ol-3-yl)-N-(3-ch lor op r op yl)-N-fu r a n -
2-yl-a ceta m id e. To a solution of 0.6 g (2.2 mmol) of indole 29
in 10 mL of DMF was added 1.0 g (2.4 mmol) of NaH (60%
dispersion in mineral oil). The reaction mixture was stirred
at room temperature for 30 min, and 0.35 mL (3.3 mmol) of
1-chloro-3-iodopropane was added dropwise. After an ad-
ditional 30 min of stirring at room temperature, the reaction
was quenched with H2O and extracted with EtOAc. The
organic layer was washed with H2O, dried over MgSO4, and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography using a 5% ethyl
acetate-hexane mixture to provide 0.42 g (54%) of the titled
compound as a pale yellow oil: IR (neat) 1710, 1685, 1608,
1449, and 1383 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.01-2.08
(m, 2H), 2.57 (s, 3H), 3.54 (t, 2H, J ) 6.8 Hz), 3.58 (s, 2H),
3.79 (t, 2H, J ) 6.8 Hz), 6.13 (dd, 1H, J ) 3.2 and 0.8 Hz),
6.44 (dd, 1H, J ) 3.2 and 2.0 Hz), 7.22-7.27 (m, 2H), 7.31-
7.35 (m, 2H), 7.37 (d, 1H, J ) 8.0 Hz), and 8.40 (d, 1H, J )
8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 24.1, 30.8, 31.2, 42.3,
46.7, 105.2, 111.6, 115.6, 116.8, 118.9, 123.7, 123.8, 125.5,
130.2, 135.7, 140.5, 148.4, 168.6, and 171.4; HRMS calcd for
2-(1-Acetyl-1H-in d ol-3-yl)-N-ben zyl-N-fu r a n -2-yla ceta -
m id e (32). To a solution of 0.16 g (0.6 mmol) of 29 in 8 mL of
4:1 DMF/THF were added 0.36 g (1.1 mmol) of Cs2CO3 and
0.15 mL (1.2 mmol) of benzyl bromide. The reaction mixture
was heated at 80 °C for 1.5 h and then cooled to room
temperature, quenched with H2O, and extracted with EtOAc.
The combined organic layer was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure. The residue
was subjected to flash silica gel chromatography using a 5%
ethyl acetate-hexane mixture to provide 0.17 g (80%) of 32
as a pale yellow oil: IR (neat) 1704, 1607, 1501, 1451, and
1384 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.56 (s, 3H), 3.64 (s,
2H), 4.84 (s, 2H), 5.90 (d, 1H, J ) 3.2 Hz), 6.35 (dd, 1H, J )
3.2 and 2.0 Hz), 7.24-7.30 (m, 8H), 7.33-7.37 (m, 1H), 7.39
(d, 1H, J ) 8.0 Hz), and 8.43 (d, 1H, J ) 8.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 24.1, 30.8, 52.3, 105.5, 111.5, 115.8, 116.8,
118.9, 123.7, 123.8, 125.5, 127.8, 128.6, 128.7, 130.3, 135.8,
137.0, 140.4, 148.2, 168.6, and 171.2; HRMS calcd for
C
23H20N2O3 372.1474, found 372.1491.
7-Acetyl-3-ben zyl-3,5,6a ,7-tetr a h yd r op yr r olo[2,3-d ]ca r -
ba zole-2,6-d ion e (39). A solution of 0.11 g (0.3 mmol) of furan
32 in 2 mL of toluene was heated at 200 °C in a sealed pressure
tube for 12 h. The solution was cooled to room temperature;
the solvent was removed under reduced pressure, and the
residue was subjected to flash silica gel chromatography using
a 5% ethyl acetate-hexane mixture to afford 0.06 g (56%) of
39 as a pale yellow oil: IR (neat) 1724, 1684, 1474, and 1395
1
cm-1; H NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.62 (d, 1H,
C
19H19N2O3Cl 358.1084, found 358.1076.
J ) 16.6 Hz), 2.88 (dd, 1H, J ) 20.4 and 2.4 Hz), 2.97 (d, 1H,
J ) 16.6 Hz), 3.01 (dd, 1H, J ) 20.4 and 6.0 Hz), 4.13 (dd, 1H,
J ) 15.6 and 6.0 Hz), 4.38 (dd, 1H, J ) 15.6 and 5.6 Hz), 4.53
(s, 1H), 5.10 (dd, 1H, J ) 5.6 and 2.4 Hz), 5.28-5.34 (m, 2H),
5.78-5.87 (m, 1H), 7.00-7.05 (m, 2H), 7.23-7.27 (m, 1H), and
8.14 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 24.2,
36.9, 44.5, 46.0, 50.2, 71.4, 94.7, 118.2, 121.1, 125.4, 128.2,
128.3, 129.2, 129.8, 134.5, 135.7, 140.9, 141.2, 169.9, 172.1,
2-(1-Acetyl-1H-in d ol-3-yl)-N-(3-iod op r op yl)-N-fu r a n -2-
yl-a ceta m id e (34). A mixture containing of 0.32 g (0.9 mmol)
of the above indole, 1.35 g (9.0 mmol) of NaI, and 8 mL of
acetone was heated at reflux for 12 h. The reaction mixture
was cooled to room temperature, quenched with H2O, and
extracted with EtOAc. The organic layer was dried over
MgSO4, and the solvent was removed under reduced pressure.
The residue was subjected to flash silica gel chromatography
using a 5% ethyl acetate-hexane mixture to provide 0.38 g
(95%) of 34 as a pale yellow oil: IR (neat) 1705, 1685, 1608,
1454, and 1383 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.07-2.14
(m, 2H), 2.59 (s, 3H), 3.14 (t, 2H, J ) 7.2 Hz), 3.58 (s, 2H),
3.72 (t, 2H, J ) 7.2 Hz), 6.13 (dd, 1H, J ) 3.2 and 0.8 Hz),
6.44 (dd, 1H, J ) 3.2 and 2.0 Hz), 7.23-7.27 (m, 2H), 7.31-
7.34 (m, 2H), 7.36 (d, 1H, J ) 7.6 Hz), and 8.40 (d, 1H, J )
7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 2.2, 24.2, 30.8, 32.3,
49.7, 105.3, 111.7, 115.6, 116.8, 118.9, 123.7, 123.8, 125.5,
130.3, 135.8, 140.6, 148.4, 168.6, and 171.5; HRMS calcd for
and 203.0; HRMS calcd for
372.1473.
C23H20N2O3 372.1474, found
2-(1-Acet yl-1H -in d ol-3-yl)-N-a llyl-N-fu r a n -2-yla cet a -
m id e (33). To a solution of 0.18 g (0.6 mmol) of 29 in 3 mL of
DMF was added 0.03 g (0.7 mmol) of NaH (60% dispersion in
mineral oil). The reaction mixture was stirred at room tem-
perature for 30 min, and 0.07 mL (0.8 mmol) of allyl iodide
was added dropwise. After an additional 30 min of stirring at
room temperature, the reaction was quenched with H2O and
extracted with EtOAc. The organic layer was washed with
H2O, dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography using a 5% ethyl acetate-hexane mixture to
provide 0.1 g (50%) of 33 as a pale yellow oil: IR (neat) 1705,
1680, 1608, 1449, and 1383 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 2.57 (s, 3H), 3.60 (s, 2H), 4.24 (d, 2H, J ) 6.0 Hz), 5.12-
5.17 (m, 2H), 5.78-5.88 (m, 1H), 6.10 (dd, 1H, J ) 3.2 and 0.8
Hz), 6.41 (dd, 1H, J ) 3.2 and 2.0 Hz), 7.22-7.34 (m, 4H),
7.38 (d, 1H, J ) 8.0 Hz), and 8.40 (d, 1H, J ) 8.0 Hz); 13C
NMR (CDCl3, 100 MHz) δ 24.1, 30.7, 51.4, 105.3, 111.5, 115.7,
116.7, 118.3, 118.9, 123.7, 123.8, 125.4, 130.3, 132.6, 135.7,
140.4, 148.3, 168.6, and 171.0; HRMS calcd for C19H18N2O3
322.1317, found 322.1330.
C
19H19N2O3I 450.0440, found 450.0445.
7-Acetyl-3-(3-iod op r op yl)-3,5,6a ,7-tetr a h yd r op yr r olo-
[2,3-d ]ca r ba zole-2,6-d ion e (41). A solution of 0.36 g (0.8
mmol) of furan 34 in 3 mL of toluene was heated at 200 °C in
a sealed pressure tube for 1.5 h. The solution was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was subjected to flash silica gel
chromatography using a 5% ethyl acetate-hexane mixture to
afford 0.27 g (74%) of 41 as a pale orange solid: IR (neat) 1721,
1680, 1475, 1393, and 1224 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 2.17-2.26 (m, 2H), 2.33 (s, 3H), 2.61 (d, 1H, J ) 16.4 Hz),
2.90 (dd, 1H, J ) 20.4 and 2.8 Hz), 2.95 (d, 1H, J ) 16.4 Hz),
3.03 (dd, 1H, J ) 20.4 and 6.0 Hz), 3.19-3.29 (m, 2H), 3.54-
3.61 (m, 1H), 3.82-3.89 (m, 1H), 4.53 (s, 1H), 5.19 (dd, 1H, J
) 5.6 and 2.0 Hz), 6.93-7.05 (m, 2H), 7.24-7.28 (m, 1H), and
8.14 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 2.0,
24.1, 30.8, 36.7, 41.0, 45.8, 50.2, 71.3, 93.7, 118.2, 120.7, 125.4,
129.8, 134.4, 140.9, 141.1, 169.8, 171.9, and 202.8; HRMS calcd
for C19H19N2O3I 450.0440, found 450.0438.
7-Acet yl-3-a llyl-3,5,6a ,7-t et r a h yd r op yr r olo[2,3-d ]ca r -
ba zole-2,6-d ion e (40). A solution of 0.13 g (0.4 mmol) of furan
33 in 2 mL of toluene was heated at 200 °C in a sealed pressure
tube for 2 h. The solution was cooled to room temperature;
the solvent was removed under reduced pressure, and the
residue was subjected to flash silica gel chromatography using
3742 J . Org. Chem., Vol. 69, No. 11, 2004

New Strategy toward Indole Alkaloids
2-(1-Acetyl-1H-in d ol-3-yl)-N-fu r a n -2-yl-N-[(Z)-3-iod oa l-
lyl]-a ceta m id e (35). To a solution of 0.57 g (2.0 mmol) of
indole 29 in 8 mL of DMF was added 0.09 g (2.2 mmol) of NaH
(60% dispersion in mineral oil). The reaction mixture was
stirred at room temperature for 30 min, and 0.9 g (2.6 mmol)
of (Z)-1-iodo-3-methane sulfonyloxy-1-propene42,43 in 2.0 mL
of DMF was added dropwise. After an additional 30 min of
stirring at room temperature, the reaction was quenched with
H2O and extracted with EtOAc. The organic layer was washed
with H2O, dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography using a 5% ethyl acetate-hexane mixture to
provide 0.37 g (41%) of 35 as a pale yellow oil: IR (neat) 1695,
1608, 1454, 1378, and 1219 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 2.58 (s, 3H), 3.61 (s, 2H), 4.35 (dd, 2H, J ) 6.0 and 1.2 Hz),
6.13 (d, 1H, J ) 2.0 Hz), 6.32 (dt, 1H, J ) 7.6 and 6.0 Hz),
6.41 (dt, 1H, J ) 7.6 and 1.2 Hz), 6.43 (dd, 1H, J ) 3.2 and
2.0 Hz), 7.23-7.27 (m, 2H), 7.31-7.37 (m, 2H), 7.38 (d, 1H, J
) 8.0 Hz), and 8.40 (d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 100
MHz) δ 24.2, 30.6, 52.8, 85.5, 105.7, 111.7, 115.5, 116.8, 118.9,
123.7, 123.9, 125.5, 130.3, 135.7, 136.0, 140.7, 147.9, 168.6,
and 171.3; HRMS calcd for C19H17N2O3I 448.0284, found
448.0285.
7-Acetyl-3-[(Z)-3-iod oa llyl]-3,5,6a ,7-tetr a h yd r op yr r olo-
[2,3-d ]ca r ba zole-2,6-d ion e (42). A solution of 0.37 g (0.8
mmol) of furan 35 in 3.0 mL of toluene was heated at 200 °C
in a sealed pressure tube for 2.0 h. The solution was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was subjected to flash silica gel
chromatography using a 5% ethyl acetate-hexane mixture to
afford 0.31 g (84%) of 42 as a pale yellow oil: IR (neat) 1726,
1690, 1475, and 1398 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.33
(s, 3H), 2.65 (d, 1H, J ) 16.8 Hz), 2.90 (dd, 1H, J ) 20.4 and
2.4 Hz), 2.98 (d, 1H, J ) 16.8 Hz), 3.03 (dd, 1H, J ) 20.4 and
5.2 Hz), 4.22 (ddd, 1H, J ) 16.0, 6.4, and 1.6 Hz), 4.48-4.54
(m, 1H), 4.53 (s, 1H), 5.12 (dd, 1H, J ) 5.6 and 2.4 Hz), 6.29
(dt, 1H, J ) 7.6 and 6.0 Hz), 6.60 (dt, 1H, J ) 7.6 and 2.0 Hz),
6.98-7.06 (m, 2H), 7.24-7.28 (m, 1H), and 8.15 (d, 1H, J )
8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 24.1, 36.8, 45.0, 46.0,
50.1, 71.3, 86.4, 94.9, 118.2, 120.9, 125.4, 129.8, 134.4, 134.8,
140.5, 141.1, 169.8, 171.6, and 202.9. Anal. Calcd for
Hz), 7.24-7.28 (m, 1H), 7.34-7.38 (m, 1H), 7.52 (d, 1H, J )
7.6 Hz), 7.59 (s, 1H), 8.16 (d, 1H, J ) 7.6 Hz), and 8.35 (brs,
1H); 13C NMR (CDCl3, 100 MHz) δ 33.2, 54.0, 95.8, 111.6,
114.1, 115.5, 119.1, 123.5, 124.8, 125.4, 129.8, 135.6, 135.7,
145.2, 151.3, and 167.0. Anal. Calcd for C16H14N2O4: C, 64.42;
H, 4.73; N, 9.39. Found: C, 64.24; H, 4.77; N, 9.27.
3-[(Allyl-fu r a n -2-ylca r ba m oyl)m eth yl]in d ole-1-ca r box-
ylic Acid Meth yl Ester (36). To a solution of 0.24 g (0.8
mmol) of indole 30 in 8 mL of 4:1 DMF/THF were added 0.5 g
(1.6 mmol) of Cs2CO3 and 0.15 mL (1.8 mmol) of allyl bromide.
The reaction mixture was heated at 80 °C for 1 h and then
cooled to room temperature, quenched with H2O, and extracted
with EtOAc. The combined organic layer was washed with
H2O, dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography using a 5% ethyl acetate-hexane mixture to
provide 0.22 g (80%) of 36 as a colorless oil: IR (neat) 1736,
1685, 1608, 1378, and 1260 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 3.59 (s, 2H), 4.00 (s, 3H), 4.24 (d, 2H, J ) 6.4 Hz), 5.12-
5.17 (m, 2H), 5.79-5.89 (m, 1H), 6.10 (d, 1H, J ) 3.2 Hz), 6.40
(dd, 1H, J ) 3.2 and 2.0 Hz), 7.21-7.25 (m, 1H), 7.30-7.34
(m, 2H), 7.43-7.45 (m, 2H), and 8.14-8.16 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 30.8, 51.3, 53.9, 105.3, 111.4, 114.9, 115.3,
118.2, 119.3, 123.0, 124.0, 124.8, 130.3, 132.7, 135.5, 140.4,
148.4, 151.5, and 171.1; HRMS calcd for C19H18N2O4 338.1267,
found 338.1278.
3-Allyl-2,6-d ioxo-1,2,3,5,6,6a -h exa h yd r op yr r olo[2,3-d ]-
ca r ba zole-7-ca r boxylic Acid Meth yl Ester (43). A solution
of 0.05 g (0.16 mmol) of furan 36 in 1.5 mL of toluene was
heated at 200 °C in a sealed pressure tube for 2 h. The solution
was cooled to room temperature; the solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography using a 5% ethyl acetate-hexane
mixture to afford 0.05 g (91%) of 43 as a colorless oil: IR (neat)
1726, 1690, 1480, 1388, and 1065 cm-1; 1H NMR (CDCl3, 400
MHz) δ 2.57 (d, 1H, J ) 16.4 Hz), 2.94 (dd, 1H, J ) 20.4 and
2.8 Hz), 2.96 (d, 1H, J ) 16.4 Hz), 3.04 (dd, 1H, J ) 20.4 and
4.8 Hz), 3.84 (brs, 3H), 4.12 (dd, 1H, J ) 15.6 and 6.4 Hz),
4.41 (dd, 1H, J ) 15.6 and 5.6 Hz), 4.73 (brs, 1H), 5.11 (dd,
1H, J ) 4.8 and 3.2 Hz), 5.28-5.34 (m, 2H), 5.79-5.89 (m,
1H), 6.94-7.01 (m, 2H), 7.23-7.27 (m, 1H), and 7.91 (brs, 1H);
13C NMR (CDCl3, 100 MHz) δ 36.6, 43.0, 46.3, 50.6, 53.2, 70.7,
95.7, 116.1, 119.1, 121.0, 124.3, 129.7, 131.2, 134.3, 140.0,
140.7, 154.0, 171.7, and 202.3; HRMS calcd for C19H18N2O4
338.1267, found 338.1263.
3-{[(2-Br om o-allyl)-fu r an -2-ylcar bam oyl]m eth yl}-in dole-
1-ca r boxylic Acid Meth yl Ester (37). To a solution of 0.18
g (0.6 mmol) of indole 30 in 8 mL of 4:1 DMF/THF were added
0.38 g (1.2 mmol) of Cs2CO3 and 0.17 mL (1.3 mmol) of 2,3-
dibromopropene. The reaction mixture was heated at 80 °C
for 1 h and then cooled to room temperature, quenched with
H2O, and extracted with EtOAc. The combined organic layer
was washed with H2O, dried over MgSO4, and concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography using a 5% ethyl acetate-hexane
mixture to provide 0.18 g (74%) of 37 as a pale yellow oil: IR
(neat) 1741, 1690, 1613, 1372, and 1255 cm-1; 1H NMR (CDCl3,
400 MHz) δ 3.63 (s, 2H), 4.01 (s, 3H), 4.51 (s, 2H), 5.54 (d, 1H,
J ) 2.0 Hz), 5.72 (d, 1H, J ) 2.0 Hz), 6.21 (d, 1H, J ) 3.2 Hz),
6.41 (dd, 1H, J ) 3.2 and 2.0 Hz), 7.21-7.25 (m, 1H), 7.30-
7.34 (m, 2H), 7.42-7.45 (m, 2H), and 8.14 (d, 1H, J ) 6.4 Hz);
13C NMR (CDCl3, 100 MHz) δ 30.8, 53.9, 55.6, 105.9, 111.5,
114.5, 115.3, 119.3, 119.4, 123.1, 124.1, 124.9, 127.8, 130.2,
135.5, 140.6, 147.5, 151.5, and 171.2; HRMS calcd for
C
19H17N2O3I: C, 50.91; H, 3.82; N, 6.25. Found: C, 50.96; H,
4.08; N, 5.97.
3-[2-(ter t-Bu toxyca r bon ylfu r a n -2-yl-a m in o)-2-oxoeth -
yl]in d ole-1-ca r boxylic Acid Meth yl Ester (28). To a solu-
tion of 2.3 g (6.8 mmol) of indole 22 in 40 mL of THF was added
1.1 g (8.2 mmol) of dimethyl pyrocarbonate followed by 0.08 g
(0.7 mmol) of 4-(dimethyl-amino)pyridine. The reaction mix-
ture was stirred at room temperature for 3 h and concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography using a 5% ethyl acetate-hexane
mixture to afford 1.9 g (70%) of 28 as a white solid: mp 90-
91 °C; IR (neat) 1787, 1746, 1613, 1260, and 1152 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.44 (s, 9H), 4.01 (s, 3H), 4.25 (s,
2H), 6.14 (d, 1H, J ) 3.2 Hz), 6.41 (t, 1H, J ) 2.0 Hz), 7.26 (t,
1H, J ) 7.2 Hz), 7.32-7.36 (m, 2H), 7.54 (d, 1H, J ) 7.2 Hz),
7.64 (s, 1H), and 8.18 (d, 1H, J ) 7.2 Hz); 13C NMR (CDCl3,
100 MHz) δ 27.9, 33.8, 53.9, 84.3, 106.2, 111.4, 114.1, 115.2,
119.4, 123.1, 124.6, 124.9, 130.4, 135.4, 140.7, 143.7, 151.5,
151.6, and 172.3. Anal. Calcd for C21H22N2O6: C, 63.31; H,
5.57; N, 7.03. Found: C, 63.39; H, 5.65; N, 7.00.
3-[2-(N-F u r a n -2-yl-a m in o)-2-oxoeth yl]in d ole-1-ca r box-
ylic Acid Meth yl Ester (30). To a solution of 0.3 g (0.75
mmol) of indole 28 in 5 mL of CH3CN was added 0.02 g (0.09
mmol) of magnesium perchlorate. The solution was heated to
45 °C for 1.5 h and then cooled to room temperature, and the
solvent was evaporated under reduced pressure. The residue
was subjected to flash silica gel chromatography using a 5%
ethyl acetate-hexane mixture to afford 0.18 g (81%) of 30 as
a white solid: mp 138-139 °C; IR (neat) 3242, 1736, 1654,
1557, 1454, and 1383 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.75
(s, 2H), 3.97 (s, 3H), 6.31-6.32 (m, 2H), 6.97 (t, 1H, J ) 1.4
C
19H17N2O4Br 416.0372, found 416.0361.
3-(2-Br om oa llyl)-2,6-d ioxo-1,2,3,5,6,6a -h exa h yd r op yr -
r olo[2,3-d ]ca r ba zole-7-ca r boxylic Acid Meth yl Ester (44).
A solution of 0.16 g (0.4 mmol) of furan 37 in 1.5 mL of toluene
was heated at 200 °C in a sealed pressure tube for 2 h. The
solution was cooled to room temperature; the solvent was
removed under reduced pressure, and the residue was sub-
jected to flash silica gel chromatography using a 5% ethyl
J . Org. Chem, Vol. 69, No. 11, 2004 3743

Padwa et al.
acetate-hexane mixture to afford 0.08 g (50%) of 44 as a pale
yellow oil: IR (neat) 1731, 1690, 1485, 1383, and 1311 cm-1
preheated oil bath at 90 °C, and the mixture was heated at
reflux for 12 h. The solvent was removed under reduced
pressure, and the resulting residue was subjected to flash silica
gel chromatography to afford 0.16 g (91%) of 50 as a white
solid: mp 152-154 °C; IR (neat) 1697, 1659, 1479, 1397, and
;
1H NMR (CDCl3, 400 MHz) δ 2.62 (d, 1H, J ) 16.6 Hz), 2.95
(dd, 1H, J ) 20.8 and 3.2 Hz), 3.00 (d, 1H, J ) 16.6 Hz), 3.05
(dd, 1H, J ) 20.8 and 4.8 Hz), 3.84 (brs, 3H), 4.40 (d, 1H, J )
16.0 Hz), 4.63 (d, 1H, J ) 16.0 Hz), 4.74 (brs, 1H), 5.17 (dd,
1H, J ) 5.2 and 3.2 Hz), 5.72 (d, 1H, J ) 2.0 Hz), 5.90 (d, 1H,
J ) 2.0 Hz), 6.98 (t, 1H, J ) 7.2 Hz), 7.20-7.28 (m, 2H), and
7.91 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 36.6, 46.1, 48.3,
50.5, 53.2, 70.8, 96.1, 116.1, 120.6, 121.6, 124.4, 126.3, 129.8,
134.0, 139.6, 140.7, 153.9, 171.9, and 202.1. Anal. Calcd for
C19H17N2O4Br: 416.0372. Found: 416.0363.
1
750 cm-1; H NMR (CD3CN, 400 MHz) δ -0.03 (s, 3H), 0.05
(s, 3H), 0.73 (s, 9H), 1.80 (m, 1H), 1.88 (m, 2H), 2.03 (m, 2H),
2.14 (dd, 1H, 15.6 and 4.0 Hz), 2.27 (s, 3H), 2.34 (d, 1H, 16.4
Hz), 2.81 (d, 1H, 16.4 Hz), 3.47 (ddd, 1H, 13.0, 8.0, and 3.6
Hz), 3.70 (ddd, 1H, 13.0, 6.4, and 6.4 Hz), 4.23 (ddd, 1H, 7.2,
6.4, and 4.0 Hz), 4.61 (d, 1H, 4.4 Hz), 6.96 (ddd, 1H, 7.6, 7.2
and 0.8 Hz), 7.05 (dd, 1H, 7.6 and 1.2 Hz), 7.16 (ddd, 1H, 8.0,
7.2, and 1.2 Hz), and 7.85 (brs, 1H); 13C NMR (CD3CN, 100
MHz) δ -4.3, -3.9, 18.8, 22.4, 25.1, 26.1, 26.3, 26.4, 35.6, 40.0,
48.6, 68.4, 70.7, 106.9, 117.6, 121.6, 125.3, 129.0, 135.9, 139.6,
144.1, 170.8, and 172.5; HRMS calcd for C25H33N2O3Si 438.2339,
found 438.2334.
7-Acet yl-3-a llyl-6-(ter t-d im et h yl-sila n yloxy)-5,6,6a ,7-
tetr a h yd r o-3H-p yr r olo-[2,3-d ]ca r ba zol-2-on e (47). To a
solution of 0.5 g (1.5 mmol) of the tetracyclic ketone 40 in 40
mL of EtOH was added 0.06 g (1.5 mmol) of NaBH4. The
reaction mixture was stirred for 10 min at room temperature;
H2O was added, and this was followed by extraction with CH2-
Cl2. The combined organic layers were washed with H2O and
dried over MgSO4. After removing the solvent under reduced
pressure, the resulting residue was dissolved with 20 mL of
CH2Cl2 and cooled to 0 °C. To this mixture was added 0.35
mL (3.0 mmol) of 2,6-lutidine, followed by the addition of 0.5
mL (2.3 mmol) of TBSOTf via syringe. After stirring for 20
min, the reaction mixture was warmed to 25 °C and stirred
for an additional 2 h. The reaction was quenched by the
addition of water, and the mixture was extracted with CH2-
Cl2. The combined organic layers were washed with 0.1 N HCl,
water, and brine, respectively. The solution was dried over
MgSO4 and concentrated under reduced pressure. The result-
ing residue was subjected to flash silica gel chromatography
using a 5% ethyl acetate-hexane mixture to give 0.43 g (60%)
of 47 as a pale yellow oil: IR (neat) 1726, 1677, 1395, and 751
cm-1; 1H NMR (CD3CN, 400 MHz) δ 0.06 (s, 3H), 0.09 (s, 3H),
0.83 (s, 9H), 1.78 (ddd, 1H, J ) 15.0, 9.6, and 3.2 Hz), 2.22
(dddd, 1H, J ) 15.0, 7.6, 4.4, and 0.8 Hz), 2.27 (s, 3H), 2.48 (d,
1H, J ) 17.0 Hz), 2.97 (d, 1H, J ) 17.0 Hz), 4.06-4.13 (m,
2H), 4.26 (ddt, 1H, J ) 16.0, 5.2, and 1.6 Hz), 4.70 (d, 1H, J )
5.6 Hz), 4.97 (dd, 1H, J ) 7.6 and 3.2 Hz), 5.44 (dq, 1H, J )
10.6 and 1.6 Hz), 5.30 (dq, 1H, 17.0 and 1.6 Hz), 5.83-5.93
(m, 1H), 6.97-7.01 (m, 2H), 7.17-7.24 (m, 1H), and 7.89 (brs,
1H); 13C NMR (CD3CN, 100 MHz) δ -3.9, -3.7, 19.0, 25.5,
26.6, 30.7, 43.5, 47.1, 49.8, 68.4, 71.2, 96.6, 117.4, 118.6, 121.9,
125.6, 129.4, 133.2, 138.8, 144.3, 144.5, 171.2, and 173.5;
HRMS calcd for [(C25H34N2O3Si) + Li]+ 445.2499, found
445.2513.
7-Acetyl-3-a llyl-4-br om o-6-(ter t-d im eth yl-sila n yloxy)-
5,6,6a ,7-tetr a h yd r o-3H-p yr r olo[2,3-d ]ca r ba zol-2-on e (48).
To a solution of 0.43 g (1.0 mmol) of 47 in 25 mL of CH2Cl2
was added 0.19 g (1.0 mmol) of NBS at 25 °C. After stirring
for 2 h, the reaction mixture was quenched with H2O and
extracted with CH2Cl2. The combined organic layers were
washed with H2O, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was subjected to flash
silica gel chromatography using a 5% ethyl acetate-hexane
mixture to afford 0.37 g (66%) of 48 as a clear oil: IR (neat)
1725, 1667, 1215, and 769 cm-1; 1H NMR (CD3CN, 400 MHz)
δ -0.04 (s, 3H), -0.06 (s, 3H), 0.71 (s, 9H), 2.27 (s, 3H), 2.38
(d, 1H, 16.0 Hz), 2.40 (dd, 1H, 16.2 and 7.2 Hz), 2.68 (dd, 1H,
16.2 and 3.6 Hz), 2.97 (d, 1H, 16.0 Hz), 4.31 (ddd, 1H, 7.2, 5.2
and 3.6 Hz), 4.63 (dt, 2H, 5.6, and 1.6 Hz), 4.65 (brs, 1H), 5.28
(dq, 1H, 10.0, and 1.6 Hz), 5.78 (dq, 1H, 16.8, and 1.6 Hz),
6.02-6.12 (m, 1H), 6.95-7.02 (m, 2H), 7.20 (ddd, 1H, 7.8, 7.4,
and 2.0 Hz), and 7.86 (brs, 1H); 13C NMR (CD3CN, 150 MHz)
δ -4.6, -4.1, 18.7, 24.8, 26.2, 44.0, 45.1, 47.8, 53.7, 67.6, 70.5,
91.6, 117.7, 118.5, 121.3, 125.4, 129.6, 134.7, 138.1, 139.1,
144.1, 170.5, and 174.2.
Meth yl 3-((N-(F u r a n -2-yl)-N-((Z)-2-iod obu t-2-en yl)ca r -
ba m oyl)m eth yl)-1H-in d ole-1-ca r boxyla te (53). To a solu-
tion containing 0.3 g (1.0 mmol) of 2-amidofuran 30 and 15
mL of a 4:1 DMF/THF mixture at room temperature was added
0.7 g (2.1 mmol) of cesium carbonate. The reaction mixture
was stirred at room temperature for 30 min, and 0.5 g (2.1
mmol) of (Z)-1-bromo-2-iodobut-2-ene was added in one por-
tion. The reaction mixture was heated at 80 °C for 2 h and
then cooled to room temperature, quenched with H2O, and
extracted with EtOAc. The organic layer was washed with
H2O, dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography using a 5% ethyl acetate-hexane mixture to
provide 0.34 g (76%) of methyl 3-((N-(furan-2-yl)-N-((Z)-2-
iodobut-2-enyl)carb-amoyl)methyl)-1H-indole-1-carboxylate (53)-
as a pale yellow oil: IR (neat) 1734, 1689, 1456, 1257, and
1
735 cm-1; H NMR (CDCl3, 400 MHz) δ 1.70 (d, 3H, J ) 6.4
Hz), 3.62 (s, 2H), 4.01 (s, 3H), 4.59 (s, 3H), 4.72 (q, 1H, J )
6.4 Hz), 6.19 (d, 1H, J ) 2.4 Hz), 6.38 (dd, 1H, J ) 3.6 and 2.4
Hz), 7.23 (t, 1H, J ) 7.6 Hz), 7.30-7.34 (m, 2H), 7.45 (d, 1H,
J ) 7.6 Hz), 7.47 (s, 1H), and 8.14 (brs, 1H); 13C NMR (CDCl3,
100 MHz) δ 21.8, 30.9, 53.8, 103.0, 106.2, 111.4, 115.2, 119.3,
122.9, 124.0, 124.8, 130.2, 134.0, 135.4, 140.4, 147.3, 151.4,
and 171.1; HRMS calcd for [(C20H19IN2O4) + Li]+ 485.0550,
found 485.0547.
Met h yl 2,3,9,10-Tet r a h yd r o-1-((Z)-2-iod ob u t -2-en yl)-
2,9-d ioxo-1H -p yr r olo[2,3-d ]ca r b a zole-8-(8a H )-ca r b oxy-
la te (54). A solution of 0.3 g (0.6 mmol) of amide 53 in 1 mL
of toluene was heated at 200 °C for 2 h, cooled to room
temperature, and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography using
a 5% ethyl acetate-hexane mixture to provide 0.26 g (87%) of
ketone 54 as a pale yellow oil: IR (neat) 1728, 1685, 1477,
1386, and 731 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.79 (d, 3H,
J ) 6.6 Hz), 2.58 (d, 1H, J ) 16.8 Hz), 2.89 (dd, 1H, J ) 19.8
and 3.0 Hz), 2.94 (d, 1H, J ) 16.8 Hz), 2.98 (dd, 1H, J ) 19.8
and 5.4 Hz), 3.84 (s, 3H), 4.47 (d, 1H, J ) 16.2 Hz), 4.62 (d,
1H, J ) 16.2 Hz), 4.72 (brs, 1H), 5.11 (dd, 1H, J ) 5.4 and 3.0
Hz), 5.96 (q, 1H, J ) 6.6 Hz), 6.95 (t, 1H, J ) 7.8 Hz), 7.22 (t,
2H, J ) 7.8 Hz), and 7.78 (brs, 1H); 13C NMR (CDCl3, 150
MHz) δ 21.9, 36.6, 46.3, 50.4, 52.2, 53.2, 70.9, 88.5, 95.9, 101.4,
116.1, 122.0, 124.3, 129.7, 134.5, 140.2, 140.5, 154.0, 171.9,
and 201.9.
P r ep a r a tion of Ca r ba m a te 57. To the solution of 0.05 g
(0.1 mmol) of ketone 54 in 1 mL of MeOH was added 4.5 mg
(0.1 mmol) of NaBH4. The reaction was stirred at room
temperature for 5 min, quenched with H2O, and extracted with
EtOAc. The combined organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography using a 5% ethyl
acetate-hexane mixture to provide 0.04 g (93%) of 57 as a
6-Acetyl-5-(ter t-dim eth yl-silan yloxy)-2,3,4,5,5a ,6-h exah y-
d r o-1H-6,12a -d ia za -in d en o[7,1-cd ]flu or en -12-on e (50). To
a solution of 0.2 g (0.39 mmol) of 48 in 40 mL of anhydrous
benzene were added 0.18 g (0.6 mmol) of Bu3SnH and 7 mg
(0.039 mmol) of AIBN. The resultant mixture was placed in a
1
clear oil: IR (neat) 1770, 1673, 1275, 1001, and 729 cm-1; H
NMR (CDCl3, 600 MHz) δ 1.77 (d, 3H, J ) 6.6 Hz), 1.83-1.89
(m,1H), 2.58-2.63 (m, 1H), 2.90 (s, 2H), 4.33 (d, 1H, J ) 15.6
Hz), 4.66 (d, 1H, J ) 15.6 Hz), 4.77 (dt, 1H, J ) 10.8 and 6.0
3744 J . Org. Chem., Vol. 69, No. 11, 2004

New Strategy toward Indole Alkaloids
Hz), 4.81 (d, 1H, J ) 6.0 Hz), 4.89 (dd, 1H, J ) 7.8 and 3.0
Hz), 4.93 (q, 1H, J ) 6.6 Hz), 7.08 (t, 1H, J ) 7.8 Hz), 7.29 (d,
1H, J ) 7.8 Hz), 7.30 (t, 1H, J ) 7.8 Hz), and 7.42 (d, 1H, J )
7.8 Hz); 13C NMR (CDCl3, 150 MHz) δ 22.0, 26.0, 29.9, 47.1,
47.5, 51.8, 67.5, 94.1, 101.4, 114.2, 123.2, 125.5, 129.9, 134.6,
136.8, 141.9, 143.2, 158.4, and 172.3.
1-(Bu t-2-yn yl)-8,8a -d ih yd r o-1H-p yr r olo[2,3-d ]ca r ba zol-
2(3H)-on e (59). To a solution of 0.03 g (0.09 mmol) of the
above alkyne 58 in 1 mL of toluene was added 0.5 mL of DBU.
The reaction mixture was heated at reflux for 12 h, quenched
with water, and extracted with EtOAc. The combined organic
layer was dried over MgSO4 and concentrated under reduced
pressure to give 0.02 g (70%) of 59 as a pale yellow oil: 1H
NMR (CDCl3, 600 MHz) δ 1.80 (t, 3H, J ) 2.4 Hz), 2.55 (d,
1H, J ) 16.8 Hz), 2.72 (d, 1H, J ) 16.8 Hz), 3.90 (brs,1H),
4.20 (dq, 1H, J ) 16.8 and 2.4 Hz), 4.53 (dq, 1H, J ) 16.8 and
2.4 Hz), 5.54 (m,1H), 5.20 (dd, 1H, J ) 9.6 and 2.4 Hz), 5.33
(d, 1H, J ) 6.0 Hz), 5.97 (ddd, 1H, J ) 9.6, 6.0, and 2.4 Hz),
6.70 (d, 1H, J ) 7.8 Hz), 6.71 (t, 1H, J ) 7.8 Hz), 6.92 (dd, 1H,
J ) 7.8 and 1.2 Hz), and 7.07 (td, 1H, J ) 7.8 and 1.2 Hz).
P r ep a r a tion of Alk yn e 58. To a solution of 0.1 g (0.2
mmol) of carbamate 57 in 3 mL of toluene was added 0.07 mL
(1.2 mmol) of DBU. The mixture was heated at reflux for 12
h, cooled to room temperature, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography using a 5% ethyl acetate-hexane mixture to
provide 0.06 g (78%) of 58 as a white solid: mp 210-212 °C;
1
IR (neat) 1770, 1727, 1675, and 752 cm-1; H NMR (CDCl3,
600 MHz) δ 1.78 (t, 3H, J ) 2.4 Hz), 1.89-1.94 (m,1H), 2.66-
2.71 (m, 1H), 2.83 (d, 1H, J ) 16.8 Hz), 2.88 (d, 1H, J ) 16.8
Hz), 4.24 (dq, 1H, J ) 16.8 and 2.4 Hz), 4.36 (dq, 1H, J ) 16.8
and 2.4 Hz), 4.81 (d, 1H, J ) 6.0 Hz), 4.83 (dt, 1H, J ) 12.0
and 6.0 Hz), 5.06 (dd, 1H, J ) 7.8 and 3.0 Hz), 7.06 (d, 1H, J
) 7.8 Hz), 7.08 (t, 1H, J ) 7.8 Hz), 7.31 (t, 1H, J ) 7.8 Hz),
and 7.44 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 150 MHz) δ
3.7, 26.0, 30.1, 46.9, 47.7, 67.2, 71.8, 77.6, 80.4, 93.9, 114.3,
122.2, 125.6, 130.0, 137.0, 141.9, 142.7, 158.5, and 171.5. Anal.
Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C,
71.08; H, 5.06; N, 8.72.
Ack n ow led gm en t. This research was supported by
the National Science Foundation (Grant CHE-0132651).
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
experimental procedures for compounds 20, 21, 31, 38, 45, and
46 and 1H and 13C NMR spectra for new compounds lacking
elemental analyses. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O049808I
J . Org. Chem, Vol. 69, No. 11, 2004 3745