Synthesis of tetrahydroisoquinocarbazoles via C-2 alkylation of indoles with 2-alkoxycyclopropanoate esters

Article abstract of DOI:10.1021/ol900937f

A concise method for the synthesis of several tetrahydroisoquinocarbazole derivatives Is reported, where the core Is prepared In six steps from tryptophol In 51% overall yield. The pentacyclic analogs are constructed via a dipolar C-2 alkylation of a 3-su

Full text of DOI:10.1021/ol900937f

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2780-2783
Synthesis of Tetrahydroisoquinocarbazoles
via C-2 Alkylation of Indoles with
2-Alkoxycyclopropanoate Esters
Barbora Bajtos and Brian L. Pagenkopf*
Department of Chemistry, The UniVersity of Western Ontario,
London, Ontario N6A 5B7, Canada
bpagenko@uwo.ca
Received April 29, 2009
ABSTRACT
A concise method for the synthesis of several tetrahydroisoquinocarbazole derivatives is reported, where the core is prepared in six steps
from tryptophol in 51% overall yield. The pentacyclic analogs are constructed via a dipolar C-2 alkylation of a 3-substituted indole with a
2-alkoxycyclopropanoate ester and a SmBr2-HMPA mediated ketyl-alkene ring closure.
Considerable synthetic attention has been directed at the
development of efficient methods toward the construction
and derivatization of indole-containing compounds, as this
important subunit constitutes the core of a plethora of
biologically active natural products.1 Our research group has
recently developed a methodology for C-2 alkylation of
3-substituted indoles with 2-alkoxycyclopropanoate esters to
give useful indole products,2 complete with ester and alkene
functional group handles for further synthetic manipulation.
Biologically active, fused indole compounds such as the
vinca alkaloids have inspired synthetic and medicinal interest
in a large class of related tetrahydroisoquinocarbazole
analogues, most of which exhibit antiarrhythmic activity.3,4
Among the most potent members of this class, RS-2135 has
attracted the most attention because of its relatively low
toxicity. In the only synthetic approach to these compounds
(2) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc.
2007, 129, 9631–9634
.
(3) (a) Simoji, Y.; Saito, F.; Tomita, K.; Morisawa, Y. Heterocycles
1991, 32, 2389–2397. (b) Simoji, Y.; Tomita, K.; Hashimoto, T.; Saito, F.;
Morisawa, Y.; Mizuno, H.; Yorikane, R.; Koike, H. J. Med. Chem. 1992,
35, 816–822. (c) Fukazawa, T.; Simoji, Y.; Hashimoto, T. Tetrahedron:
Asymmetry 1996, 7, 1649–1658. (d) Hashimoto, T.; Fukazawa, T.; Masuko,
H.; Shimoji, Y.; Koike, H.; Mizuno, H. Eur. Patent EP 415776 A2, 1991.
(e) Hiraoka, T.; Birdsall, N. J. M.; Gharagozloo, P.; Lazareno, S. U.K.
(1) Asymmetric C-3 Friedel-Craft reactions: Wang, Y.-Q.; Song, J.;
Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156–8157.
Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am.
Chem. Soc. 2005, 127, 4154–4155. Evans, D. A.; Scheidt, K. A.; Fandrick,
K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780–10781.
Allylations: Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 28, 6314–
6315. Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 4592–4593. Radical couplings: Baran, P. S.; Richter, J. M.
J. Am. Chem. Soc. 2004, 126, 7450–7451. Arylations: Deprez, N. R.;
Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972–
4973. Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127,
4996–4997. Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005,
127, 13148–13149. Michael additions: Zhou, J.; Tang, Y. J. Am. Chem.
Soc. 2002, 124, 9030–9031. C-H activation: Davies, H. M. L.; Manning,
J. R. J. Am. Chem. Soc. 2006, 128, 1060–1061. N-Arylations: Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684–11688.
Patent, GB 2 292 685 A, 1996
.
(4) (a) Lazareno, S.; Birdsall, B.; Fukazawa, T.; Gharagozloo, P.;
Hashimoto, T.; Kuwano, H.; Popham, A.; Sugimoto, M.; Birdsall, N. J. M.
Life Sci. 1999, 64, 519–526. (b) Ito, K.; Nagafuchi, K.; Taga, A.; Yorikane,
R.; Koike, H. J. CardioVasc. Pharmacol. 1996, 27, 355–361. (c) Yorikane,
R.; Hiroshi, M.; Itoh, Y.; Miyake, S.; Koike, H. J. CardioVasc. Pharmacol.
1994, 24, 28–36. (d) Sakuta, H.; Okamoto, K.; Watanabe, Y. Br. J.
Pharmacol. 1993, 109, 866–872. (e) Yorikane, R.; Sada, T.; Koike, H.
J. CardioVasc. Pharmacol. 1993, 21, 430–434. (f) Yorikane, R.; Sada, T.;
Koike, H. J. CardioVasc. Pharmacol. 1992, 20, 955–960
.
10.1021/ol900937f CCC: $40.75
Published on Web 06/09/2009
 2009 American Chemical Society

reported thus far, Simoji and Hashimoto employed an elegant
intramolecular Diels-Alder reaction to construct the
core.3a-d Herein, we report the short syntheses of several
related tetrahydroisoquinocarbazoles (1, 2, and 3, Scheme
1) by employing the C-2 alkylation of indoles with
ester moiety in intermediate 4,2 which would be accessible
from C-2 alkylation between 3-substituted indole 5 and DA
cyclopropane 6.
The synthesis commenced with the C-2 alkylation of
commercially available tryptophol (5a) with cyclopropane
6 to give indole 4a in a moderate 70% yield (Scheme 3).5
Scheme 1
.
Application of C-2 Alkylation of Indoles with DA
Cyclopropanes
Scheme 3. C-2 Alkylation and Lactam Formation
However, closure of the D-ring with this intermediate under
basic conditions proved elusive. Acting on speculation that
the free alcohol was interfering in the lactamization process,
acylated derivative 5b was employed instead, and the C-2
alkylation product was obtained in 86% yield. The resulting
indole 4b was effectively converted to the lactam without
difficulty upon treatment with DBU. Subsequent deprotection
of the alcohol allowed access to indole 7b, thus setting the
stage to explore ring C construction.
donor-acceptor (DA) cyclopropanes and a SmBr2-HMPA
mediated reductive cyclization as key synthetic steps.
From our initial retrosynthetic analysis, we identified the
disconnection between C-12 and C-12a as being strategically
important as it simplifies the target core to indole 4, which
is readily available from our C-2 alkylation methodology
(Scheme 2). It was anticipated that ring C could be
Early approaches for ring C assembly involved elaborating
alkene 7b via hydrometalation strategies, potentially sup-
plying a collection of suitable handles (OH, halides) with
which to facilitate cyclization. Unfortunately, all attempts
at alkene functionalization with 7b led to starting material
recovery or substrate decomposition.
Scheme 2. Retrosynthetic Analysis
While initially opting for alkene elaboration prior to
cyclization, a revised strategy involved exploring radical
mediated ring closures. Selenoesters have long been recog-
nized as precursors to acyl radicals that actively participate
in inter- and intramolecular alkene addition reactions.6
Despite the usual preference for free radicals to undergo
5-exo-trig over 6-endo-trig cyclizations, Boger and co-
workers demonstrated that in some cases the latter is
favored.6
Encouraged by these reports, selenoester 8 was prepared
via a three-step sequence commencing with Swern oxidation
of alcohol 7b (Scheme 4). The resulting aldehyde was
immediately oxidized and treated with diphenyl diselenide
constructed by several strategies, including hydrometalation
of alkene 4, followed by appropriate ring-closure conditions.
The same disconnection would also allow radical cyclizations
to be explored, such as selenoester or samarium(II) iodide
mediated ring closures. The lactam bond could be constructed
via a base induced cyclization with the indole nitrogen and
(5) Identical results were obtained from either diastereotopic cyclopro-
pane or mixtures.
(6) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429–1443,
and references therein.
Org. Lett., Vol. 11, No. 13, 2009
2781

Scheme 4
.
Selenoester Cyclization Approach
Table 1. Optimization Data for SmI2 Cyclization with Additives
entry
additives (equiv)a
ratio of 3:7b
yield (%)b
1
2
3
4
5
6
none
HMPA (8.8)
H2O (22)
MeOH (22)
LiBr (8.8)
1.2:1.0
2.0:1.0
>99:1
>99:1
1.4:1.0
80
85
33
42
91
78
LiBr (8.8), HMPA (110)
>99:1
a Relative to aldehyde 10, with 2.2 equiv of 0.1 M SmI2 in each reaction.
b Combined isolated yield of 3 and 7b, for both steps starting from alcohol
7b.
mediated reactions.7 According to Flowers and co-workers,
the oxidation potential of SmI2 alone is -1.33 V (vs Ag/
AgNO3 in THF) and was found to increase to a maximum
of -2.05 V with 4 equiv of added HMPA.9 When these
conditions were applied to the intramolecular coupling
reaction, an increase in selectivity toward cyclization over
aldehyde reduction was observed (Table 1, entry 2).
Protic additives such as water and methanol have also been
shown to influence similar radical processes,7 as they likely
activate the reagent through metal coordination and protonate
anionic intermediates.10 Although these proton sources
improved selectivity for the cyclization product 3 over
aldehyde reduction, significantly lower yields were ac-
companied with considerable decomposition (Table 1, entries
3 and 4).
Inorganic salts such as LiBr have been shown to participate
in displacement reactions with SmI2, producing soluble
SmBr2.11 Cyclizations with the soluble SmBr2 reducing agent
provided an unfavorable mixture of 3 and 7a, although in
excellent combined yield (Table 1, entry 5). Flowers also
found that the addition of 50 equiv of HMPA significantly
improved the reducing ability of SmBr2 (-2.07 V for SmBr2
versus -2.63 V for SmBr2-HMPA).11 Optimal results were
achieved by a combination of several known additives,
specifically, LiBr and HMPA (Table 1, entry 6). The
and tributylphosphine, providing cyclization precursor 8 in
81% yield over three steps. An acyl radical was then
generated from selenoester 8, but regrettably, a stabilized
radical is formed after rapid decarbonylation, ultimately
giving 3-methyl indole 9 as the exclusive product.
Operating through the aldehyde oxidation state appeared
to be an attractive means to further explore a radical
cyclization strategy while precluding the undesired decar-
bonylation. In this regard, both inter- and intramolecular
carbonyl-alkene/alkyne reductive coupling reactions mediated
by samarium(II) iodide are well documented.7 Both alde-
hydes and ketones participate as coupling partners, but a large
majority of these radical induced cyclizations with aldehydes
employ electrophilic R,ꢀ-unsaturated esters or allylic leaving
groups including halides, sulfides, and sulfones.8
The aldehyde cyclization precursor was efficiently pre-
pared by Swern oxidation of alcohol 7b, which was im-
mediately treated with 2.2 equiv of 0.1 M SmI2 in THF
(Scheme 5). Two major reaction products were obtained
Scheme 5. Completion of Several Tetrahydroisoquinocarbazoles
(7) (a) Kagan, H. B. J. Alloys Compd. 2006, 408-412, 421–426. (b)
Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371–
3403. (c) Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 17, 3393–
3403. (d) Kagan, H. B. Tetrahedron 2003, 59, 10351–10372. (e) Molander,
G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321–3354. (f) Skrydstrup, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 345–347. (g) Molander, G. A.;
Harris, C. R. Chem. ReV. 1996, 96, 307–338. (h) Molander, G. A. Chem.
ReV. 1992, 92, 29–68.
(8) R,ꢀ-Unsaturated esters: Villar, H.; Guibe, F. A. Tetrahedron Lett.
2002, 43, 9517–9520. Johnston, D.; Francon, N.; Edmonds, D. J.; Protor,
D. J. Org. Lett. 2001, 3, 2001–2004. Johnston, D.; McCusker, C. F.; Muir,
K.; Protor, D. J. J. Chem. Soc., Perkin Trans. 1 2000, 681–695. Enholm,
E. J.; Satici, H.; Trivellas, A. J. Org. Chem. 1989, 54, 5841–5843. Enholm,
E. J.; Trivellas, A. J. Am. Chem. Soc. 1989, 111, 6463–6465. Allylic halides:
Matsuda, F.; Sakai, T.; Okada, N.; Miyashita, M. Tetrahedron Lett. 1998,
39, 863–864. Souppe, J.; Namy, J. L.; Kagan, H. B. Tetrahedron Lett. 1982,
23, 3497–3500. Sulfides and sulfones: Kan, T.; Nara, S.; Ito, S.; Matsuda,
F.; Shirahama, H. J. Org. Chem. 1994, 59, 5111–5113. Kan, T.; Hosokawa,
S.; Oikawa, M.; Ito, S.; Matsuda, F.; Shirahama, H. J. Org. Chem. 1994,
59, 5532–5534.
under these conditions, including the desired secondary
alcohol 3 and 7b from aldehyde reduction in a 1.2:1.0 ratio
(Table 1, entry 1).
Efforts to optimize this cyclization involved exploring
various additives such as Lewis bases (HMPA), proton
sources (H2O, MeOH), and inorganic salts (LiBr), all of
which have been documented to profoundly affect SmI2
(9) Shabangi, M.; Flowers II, R. A. Tetrahedron Lett. 1997, 38, 1137–
1140.
(10) (a) Kagan, H. B.; Namy, J. L. In Lanthanides: Chemistry and Use
in Organic Synthesis; Kobayashi, S., Ed.; Springer: New York, 1999. (b)
Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008–5010.
(11) Knettle, B. W.; Flowers, R. A., II. Org. Lett. 2001, 3, 2321–2324.
2782
Org. Lett., Vol. 11, No. 13, 2009

SmBr2-HMPA reductant prepared under Flowers’ conditions
displayed excellent selectivity for cyclization to 3 in 78%
yield. The relative stereochemistry of 3 was established by
extensive NMR analysis.12
To further illustrate the utility of this approach additional
modifications were made to the functionalized core (Scheme
5). Oxidation of alcohol 3 with IBX proceeded smoothly to
afford ketone 2, which was advanced to amine 1 after
reductive amination. Presumably, other functionalized cores
can be accessed by elaboration of the starting indole or
cyclopropane.
the first time the synthetic utility of the dipolar C-2 alkylation
of 3-substituted indoles with 2-alkoxycyclopropanoate esters
and provides an attractive route to other biologically active
members of this class, including RS-2135. The synthesis also
features a selective SmBr2-HMPA promoted ring closure
of an aldehyde onto a sterically congested trisubstituted
alkene.
Acknowledgment. We thank NSERC and the University
of Western Ontario for financial assistance. B.B. thanks
NSERC for a CGS M fellowship.
In summary, we have reported the most efficient and
highest yielding route to several tetrahydroisoquinocarba-
zoles, where the core (3) was prepared in six steps from
tryptophol in 51% overall yield. This work highlights for
Supporting Information Available: General experimental
procedures and characterization of all new compounds, and
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) 1H NMR, 13C NMR, gCOSY, gHSQC, and NOESY spectra for 1,
2, and 3 can be found in Supporting Information.
OL900937F
Org. Lett., Vol. 11, No. 13, 2009
2783