A novel one-pot approach of hexahydropyrrolo[2,3-b ]indole nucleus by a cascade addition/cyclization strategy: Synthesis of (±)-esermethole

Article abstract of DOI:10.1021/ol101527j

A practical and efficient synthesis of 3-substituted hexahydropyrrolo[2,3- b]indole is described. The addition/cyclization of 3-substituted indoles with α,β-dehydroamino esters in the presence of a Lewis acid provides hexahydropyrrolo[2,3-b]indole adducts in good yields and stereoselectivities. This approach has been applied to the concise synthesis of esermethole employing an appropriately substituted indole and an N-acyl dehydroamino ester.

Full text of DOI:10.1021/ol101527j

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3844-3847
A Novel One-Pot Approach of
Hexahydropyrrolo[2,3-b]indole Nucleus
by a cascade addition/cyclization
strategy: Synthesis of (()-Esermethole
Simone Lucarini, Francesca Bartoccini, Flavia Battistoni, Giuseppe Diamantini,
Giovanni Piersanti,* Marika Righi, and Gilberto Spadoni
Department of Drug and Health Sciences, UniVersity of Urbino “Carlo Bo”,
Piazza del Rinascimento 6, 61029 Urbino (PU), Italy
gioVanni.piersanti@uniurb.it
Received July 3, 2010
ABSTRACT
A practical and efficient synthesis of 3-substituted hexahydropyrrolo[2,3-b]indole is described. The addition/cyclization of 3-substituted indoles
with r,ꢀ-dehydroamino esters in the presence of a Lewis acid provides hexahydropyrrolo[2,3-b]indole adducts in good yields and
stereoselectivities. This approach has been applied to the concise synthesis of esermethole employing an appropriately substituted indole
and an N-acyl dehydroamino ester.
The hexahydropyrrolo[2,3-b]indole1 framework (1) having
a quaternary center at the C-3a site occurs frequently in many
alkaloids isolated from a variety of natural sources.2 The
best known members of this group are alkaloids found in
seeds of the African calabar bean Physostigma Venenosum,
such as (--)-physostigmine (2).3 Some other representative
examples include flustramine B (5),4 (-)-pseudophrynaminol
(6),5 and polycyclic minfiensine compounds6 (Figure 1).
Various biological activities are associated with 3a-substi-
tuted pyrrolidinoindolines as exemplified by (-)-physostig-
(1) For recent reviews, see: (a) Crich, D.; Banerjee, A. Acc. Chem. Res.
2007, 40, 151. (b) Schmidt, M. A.; Movassaghi, M. Synlett 2008, 313.
(2) (a) Anthoni, U.; Christophersen, C.; Nielsen, P. H. In Alkaloids:
Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New
York, 1999; Vol. 13, p 163. (b) Takano, S.; Ogasawara, K. In The Alkaloids;
Brossi, A., Ed.; Academic: San Diego, CA, 1989; Vol. 36, p 225. (c)
Figure 1. Representative hexahydropyrrolo[2,3-b]indole alkaloids
Chemistry and reactions of cyclic tautomers of tryptamines and tryptophans:
Hino, T., Nakagawa, M. In The Alkaloids: Chemistry and Pharmacology;
Brossi, A., Ed.; Academic Press: New York, 1989; Vol. 34, pp 1-75.
(3) Jobst, J.; Hesse, O. Justus Liebigs Ann. Chem. 1864, 129, 115–118.
(4) Carle, J. S.; Christophersen, C. J. Am. Chem. Soc. 1979, 101, 4012–
4013.
having a quaternary center at C3a.
mine (2) and (-)-phenserine (3), which are used to treat
(5) Spande, T. F.; Edwards, M. W.; Pannell, L. K.; Daly, J. W.;
Erspamer, V.; Melchiorri, P. J. Org. Chem. 1988, 53, 1222–1226.
glaucoma and Alzheimer’s disease.7
10.1021/ol101527j  2010 American Chemical Society
Published on Web 08/12/2010

The unique structural arrays and interesting biological
activities displayed by these alkaloids makes them a par-
ticularly appealing target for total synthetic efforts as well
as the design of new reaction methods that enable the simple
and rapid construction of many of these complex alkaloids.
The construction of the hexahydropyrrolo[2,3-b]indole struc-
tural motif has been classically carried out by electrophilic
attack on a tryptophan or tryptamine (8) unit at the indole
C-3 position, followed by cyclization onto the resulting C-2
iminium ion by the side-chain nitrogen (Figure 2, biomimetic
tryptophan and related amino acid derivatives.10 To extend
the methodology developed, we now describe a conceptually
different approach to the hexahydropyrrolo[2,3-b]indole core,
in which the tricyclic pyrrolidinoindoline ring system is
constructed in a single-step one-pot reaction by reacting
readily available 3-substituted indoles (10) and N-acylated
R,ꢀ-dehydroamino esters (11) through the domino addition-
cyclization approach outlined in Figure 2. Besides the
simplicity of employing commercially or readily available
precursors, this novel and concise approach to the pyrroli-
dinoindoline core structure potentially could allow a wide
variety of substituents to be incorporated at C-3a, including
those not readily introduced through other methods. Interest-
ingly, the proposed pyrroloindoline ring formation involves
a two step reaction: carbon-carbon bond formation that leads
to dearomatization of the indolyl system with concomitant
formation of a quaternary stereocenter and subsequent
carbon-nitrogen bond formation. Both reactions occur under
the influence of the same Lewis acid.
We report herein the first examples of Lewis acid mediated
diastereoselective one-pot pyrrolidinoindoline formation from
3-substituted indoles and R-amidoacrylates and application
of this methodology for the synthesis of (()-esermethole.
To achieve this goal, we first examined the addition of
3-methylindole (10a) to commercially available N-acetami-
doacrylate (11) in the presence of ethylaluminum dichloride;
the desired tricyclic hexahydropyrroloindole 12 was obtained
in good yield and high exo-diastereoselectivity (Table 1, entry
Figure 2. Retrosynthetic approaches.
approach).8 Although this retrosynthetic disconnection has
been realized, it is highly sensitive to the nature of the
electrophile and the indole substrate. Yields are often poor,
versatility is low, and many total syntheses have adopted
less direct solutions for the construction of this skeleton.
Alternatively, the hexahydropyrrolo[2,3-b]indole core can be
attained through alkylation of a suitable 2-oxoindole (9)
followed by a sequence of functional group interconversions
that allows the final cyclization under reductive conditions.9
(Figure 2, oxoindole approach).
Table 1. Optimization of Reaction Conditions
entry
solvent
MXn (2 equiv)
yielda (%) (exo/endo)b
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
iPrOH
CH3CN
dioxane
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtAlCl2
ZrCl4
TiCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
63 (9/1)
75 (9/1)
58 (8/1)
n.r.
16 (8/1)
10 (8/1)
11 (9/1)
65 (9/1)
n.r.
Recently, we have reported the Michael-type Friedel-Crafts
(FC) alkylations of various 3-unsubstituted indoles with
acylated R,ꢀ-dehydroamino esters for the preparation of
8c
9d
10e
11f
(6) Pettit, G. R.; Tan, R.; Herald, D. L.; Cerny, R. L.; Williams, M. D.
J. Org. Chem. 1994, 59, 1593.
(7) Sorbera, L. A.; Castaner, J. Drugs Future 2003, 28, 18–25 and
references cited therein.
71 (9/1)
55 (9/1)
(8) (a) Taniguchi, M.; Gonsho, A.; Nakagawa, M.; Hino, T. Chem.
Pharm. Bull. 1983, 31, 1856. (b) Bourne, G. T.; Crich, D.; Davies, J. W.;
Horwell, D. C. J. Chem. Soc., Perkin Trans. 1 1991, 1693. (c) Bruncko,
M.; Crich, D.; Samy, R. Heterocycles 1993, 36, 1735. (d) Bruncko, M.;
Crich, D.; Samy, R. J. Org. Chem. 1994, 59, 5543. (e) Marsden, S. P.;
Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 143. (f)
Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218. (g) Kawahara, M.;
Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675. (h) Tan, G. H.; Zhu,
X.; Ganesan, A. Org. Lett. 2003, 5, 1801. (i) Lo´pez-Alvarado, P.; Caballero,
E.; Avendan˜o, C.; Mene´ndez, C. J. Org. Lett. 2006, 8, 4303. (j) Austin,
J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5482. (k) Movassaghi, M.; Schmidt, M. A.
Angew Chem., Int. Ed. 2007, 46, 3725. (l) Newhouse, T.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 10886. (m) He, B.; Song, H.; Du, Y.; Qin, Y. J.
Org. Chem. 2009, 74, 298. (n) Kim, J.; Ashenhurst, J. A.; Movassaghi, M.
Science 2009, 324, 238.
a Isolated yield. b Determined by HPLC. c The reaction was conducted
at 40 °C. d Catalytic amount of ZrCl4; e 2.4 equiv of ZrCl4; f 0.8 equiv of
DHA.
1). We then examined the effect of the Lewis acid on the
reaction, starting from metal salts that in previous studies
allowed 11 to behave as an electron-deficient olefin in the
FC alkylation. The best results in terms of yield and
selectivity were obtained by employing 2 equiv of zirconium
chloride with respect to the electrophile (Table 1, entry 2).
Org. Lett., Vol. 12, No. 17, 2010
3845

No reactivity was observed when the reaction was carried
out using catalytic amounts or less than 1 equiv of the Lewis
acid (Table 1, entry 9). Low conversion was observed when
1 equiv was used. To further optimize the process, examina-
tion of the reaction medium led to the selection of dichlo-
romethane as the best solvent. Reactions performed in
ethereal solvents such as THF, ether, dioxane, methyl tert-
butyl ether (MTBE), and 1,2-dimethoxyethane (DME) gener-
ally afforded worse results in terms of reaction yield and
diastereoselectivity, and no reaction occurred in polar
solvents such as DMF, CH3CN, or water. Less promising
results were also obtained in nonpolar solvents such as 1,2-
dichloroethane (DCE), chloroform, and toluene. These results
are consistent with previous reports that nonpolar and
noncoordinating solvents are generally optimal in these types
of reaction systems. The reaction temperature also has an
important effect on the reaction. In general, lowering the
temperature resulted in a decreased reaction rate but slightly
increased the yield (Table 1, entry 8). The reaction proceeds
with high exo-selectivity.11 At this point, it is difficult to
offer a mechanistic proposal to rationalize this stereochemical
preference in light of a known thermodynamic bias for the
endo-diastereomer. However, the reaction of tryptophan or
tryptamine with a number of electrophiles has shown a
similar stereochemical outcome.8 It is also evident that the
preference of ester substituent for the exo- over the endo
position holds under acidic reaction conditions (ZrCl4 in
CH2Cl2), as endo-13a undergoes inversion. Clearly, exo-12a
becomes the more stable endo form upon treatment with
sodium tert-butoxide in DMF at 80 °C for 16 h. Thus, the
use of ZrCl4 (2 equiv) and a 1:1.1 ratio of indole/N-
acetamidoacrylate in CH2Cl2 at room temperature for 24 h
became our standard conditions.
Having established the optimal conditions for the tandem
addition/cyclization reaction, the generality of the reaction
was then examined in detail using various substituted indoles
(Table 2). The corresponding 3-substituted hexahydropyr-
rolo[2,3-b]indoles were obtained, albeit in lower yields and
diastereoselectivities (entries 1-8). When 1,3-dimethyl in-
dole was prepared and treated with N-acetamidoacrylate, the
reaction occurred demonstrating that the H atom on the N
atom is not crucial for the cascade reaction. However,
N-acetyl, N-sulfonyl, and N-BOC-indole did not afford the
desired products, clearly showing the importance of the
nucleophility of the indole. The size of the 3-alkyl group
plays an important role in the reaction (entries 2, 4, and 8).
While acceptable yields were obtained with cyclopentyl in
this position, the reaction did not proceed with the more
Table 2. Scope of the Reaction
indole
entry
R1
R2
R3
R4
yielda (%) (exo/endo)b
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
H
CH3
H
H
H
H
CH3
H
H
H
H
H
CH3
CH3
H
H
H
H
75 (9/1)
46 (6/1)
72 (4/1)c
69 (7/1)c
45 (3/1)
84 (4/1)
68 (3/1)
62 (6/1)
trace
CH3 CH3
CH2CH2CH2
CH3
H
H
H
H
H
H
Br
CH3
CH3
cyclopentyl
C6H5
CHdCH2
OCH3
OCH3
H
H
H
9
10
j
n.r.
a Isolated yield. b Determined by HPLC. c Exo/endo ratio was determined
1
by H NMR.
bulky γ-prenyl substituent.12 This was not unexpected as the
dehydroamino acid was likely coordinated to the bulky
zirconium metal during the reaction and would try to
minimize steric interactions by steering the large substituent
away from the metal. Translation of these conditions to the
reaction with 3-vinylindole, however, was not possible. This
more electron-rich olefin was in fact found to be much more
sensitive to the acidic catalyst, resulting mainly in decom-
position and giving a very poor product yield. The alkylation
reaction was also highly regio- and chemoselective. Indeed,
although N- and C2-electrophilic substitution of 3-substituted
indoles have been reported,13 neither N- nor C2-adducts were
detected under the reaction conditions utilized. Suitably
encouraged by these results, we commenced our investigation
using 2,3-disubstituted indoles. Gratifyingly, the domino
reaction occurred and the corresponding 2,3-disubstituted
hexahydropyrrolo[2,3-b]indoles were obtained in satisfactory
yields and diastereselectivities both with 2,3-dimethylindole
and cyclopentane-fused indole. These are notable results
because the direct C3-functionalization of 2,3-disubstituted
indoles represents a great synthetic challenge. Moreover, it
represents an easy approach to C2-substituted hexahydro-
pyrrolo[2,3-b]indole analogues, difficult to obtain by the
oxyindole approach and never reported by biomimetic or
other approaches.
(9) (a) Matsuura, T.; Overman, L. E.; Poon, D. J. Am. Chem. Soc. 1998,
120, 6500. (b) Overman, J. L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem.
Soc. 1999, 121, 7702. (c) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
(d) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004,
126, 14043. (e) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128,
4590. (f) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.sEur. J. 2007, 13,
961.
To illustrate the synthetic utility of this methodology and
further confirm the relative stereochemistry of this reaction,
we undertook the total synthesis of (()-esermethole, the
(12) For a comprehensive review on selective catalytic indole function-
alization, see: Bandini, M.; Eichholzer, A. Angew Chem. Int. Ed. 2009, 48,
9608. For specific examples, see: (a) Lin, Y. D.; Kao, J. Q.; Chen, C. T.
Org. Lett. 2007, 9, 5195. (b) Leitch, S.; Addison-Jones, J.; McCluskey, A.
Tetrahedron Lett. 2005, 46, 2915.
(10) Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti,
G. J. Org. Chem. 2008, 73, 5654.
1
(11) The exo/endo ratio is readily established by H NMR due to the
characteristic methyl ester resonance of both diastereoisomers. The endo-
isomer shows a remarkably upfield signal at δ 3.1 ppm, whereas the exo-
isomer shows a more common resonance at δ <3.7 ppm.
(13) For an interesting report on C-3a-prenylated pyrroloindoles, see:
Lindel, T.; Bra¨uchle, L.; Golz, G.; Bo¨hrer, P. Org. Lett. 2007, 9, 283.
3846
Org. Lett., Vol. 12, No. 17, 2010

penultimate intermediate to physostigmine and phenserine.2b
By reacting 5-methoxy-3-methyl-N-methylindole (10g), readily
available in one step from 4-methoxy-N-methylaniline and
chloroacetone,14 under standard reaction conditions, it was
possible to prepare tricycles 12g/13g in multigram quantities
(Scheme 1). Under optimal reaction conditions, treatment
amine 15g in 99% yield. N-Methylation of the secondary
amine group using formalin and sodium triacetoxyborohy-
dride provided racemic esermethole in 87% yield. The
spectral data of the compound obtained were identical with
the reported data for esermethole.15
In summary, we have demonstrated a one-pot, novel, and
simple approach to the hexahydropyrrolo[2,3-b]indole nucleus
using a tandem addition/cyclization reaction of three sub-
stituted indoles and dehydroamino acids. The tandem reaction
was general with respect to indoles and provided the desired
products bearing a chiral quaternary center at C3 in good
yield. This chemistry allows the formation of both the
carbon-carbon bond and the carbon-nitrogen bond of the
hexahydropyrrolo[2,3-b]indole substructure and offers the
shortest synthesis of these alkaloids from commercial materi-
als. It is to be noted that this synthetic strategy requires only
minor variations to be adapted for the synthesis of hexahy-
dropyrrolo[2,3-b]indoles, which differ mainly by a substituent
at the C-3a position. The application of this chemistry for
the concise synthesis of racemic esermethole is also de-
scribed. Further investigations of the scope and synthetic
utility of this chemistry are underway, and the results will
be reported in due course.
Scheme 1. Synthesis of Esermethole
Acknowledgment. This work was partially supported by
the Italian MIUR (Ministero dell’Istruzione, dell’Universit
e della Ricerca). We thank Prof. Cesarino Balsamini,
Department of Drug and Health Sciences, University of
Urbino “Carlo Bo”.
of esters 12g/13g with a mixture of methanol and aqueous
potassium hydroxide at room temperature for 1 h provided
the corresponding carboxylic acid in 92% yield. Decarboxy-
lation was achieved by the Barton reaction through sequential
conversion to the thiohydroxamic ester, followed by treat-
ment with Bu3SnH in benzene, to afford tricycle 14g in
almost quantitative yield. At this point, strong acidic condi-
tions for the removal of the acetyl group of 14g led to
decomposition, whereas a methanolic solution of amide 14g
and sodium hydroxide at 80 °C for 16 h afforded the desired
Supporting Information Available: Experimental pro-
cedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101527J
(15) Selected previous syntheses of esermethole: (a) Reddy, V. J.;
Douglas, C. J. Org. Lett. 2010 12, 952. (b) Nakao, Y.; Ebata, S.; Yada, A.;
Hiyama, T.; Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874.
(c) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314. (d)
Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 1049.
(e) Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. Tetrahedron: Asymmetry
1994, 5, 363.
(14) Underwood, R.; Prasad, K.; Repic, O.; Hardtmann, G. E. Synth.
Commun. 1992, 22, 343.
Org. Lett., Vol. 12, No. 17, 2010
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