Straightforward four-component access to spiroindolines

Article abstract of DOI:10.1039/c1cc12236c

Spiroindolines could be synthesized via a very convenient one-pot procedure combining a Ugi coupling and a new copper-catalyzed oxidative process at a peptidyl position. Due to the nature of the first step, this method offers a straightforward access to c

Full text of DOI:10.1039/c1cc12236c

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Straightforward four-component access to spiroindolinesw
a
a
b
c
Laurent El Kaım,* Laurence Grimaud,* Xavier-Frederic Le Goff, Martha Menes-Arzate
¨
´ ´
and Luis D. Miranda*d
Received 18th April 2011, Accepted 24th May 2011
DOI: 10.1039/c1cc12236c
Spiroindolines could be synthesized via a very convenient one-pot
procedure combining a Ugi coupling and a new copper-catalyzed
oxidative process at a peptidyl position. Due to the nature of the
first step, this method offers a straightforward access to complex
alkaloids with four points of molecular diversity.
Table 1 Alkyne radical cyclization of xanthate substituted Ugi
adducts
In the search for novel pharmacologic lead compounds, using
molecular frameworks that resemble natural products with
known biological activity is a good place to start.1 Given the
structural complexity and diversity of natural products, the
construction of libraries of new compounds inspired by the
structures of known natural products might be a complicated
task that slows down new drug development.1 Spiroindolenines
and spiroindolines2 are privileged motifs frequently encountered
within a large family of alkaloids that includes communesines,2,3
perophoramidines,2,4 etc. Members of this alkaloid family
display pronounced cytotoxicity and insecticidal activity.1–4 Over
the last decade, enormous efforts have been devoted to the
development of novel and practical synthetic strategies for the
construction of this molecular motif.5,6
Equiv. of
Entry Cu(OAc)2 Solvent (time, temp)
Additive Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
MeCN (5 d, rt)
MeCN (2.5 h, reflux)
CF3CH2OH (6 d, reflux) DBU
MeOH (4 d, reflux)
THF (6 h, reflux)
THF (6 h, reflux)
THF (6 h, reflux)
PhF (16 h, reflux)
—
DBU
5
11
N. R.
25
77
59
49
DBU
DBU
DBU
DBU
DBU
1
0.5
0.3
0.3
46
on the indole, this strategy could give us access to spiroindoline
or indolenine derivatives as final targets. Aerobic oxidations
constitute a vibrant research area,10 and we found the multi-
component preparation of complex natural product-like structures
under such conditions to be very appealing.
Based on our interest in radical chemistry coupled with
multicomponent processes,7 we recently reported a Mn(III)
triggered oxidative coupling of malonates with various Ugi
adducts.8 Although impressive, these transformations were
hampered by the use of manganese salts in large excess.
Wishing to identify suitable Ugi adducts that could be adapted
to catalytic oxidative couplings, we turned our attention
towards the indole core as an efficient radical trapping
moiety.9 According to the regioselectivity of the radical attack
To evaluate the feasibility of the reaction, we prepared the
Ugi adduct 1a using benzaldehyde and tryptamine as the
amine partner (Table 1). First trials were performed using
one equivalent of copper acetate in acetonitrile in the absence
of a base. The desired cyclized product was isolated in 5%
yield (Table 1, entry 1). Encouraged by this observation, we
surmised that the oxidation of the enolate should be much
more efficient. Therefore, we repeated the reaction adding one
equivalent of DBU in the mixture and achieved a slight
improvement in the yield (Table 1, entry 2). A screening
of the solvent (Table 2, entries 3–5) showed that THF was
the best choice, as the product was isolated in 77% yield
(Table 1, entry 5). Even if the product could still be obtained
using either 0.5 or 0.3 equivalents of copper salt (Table 1,
entries 6–8), the latter conditions were preferred due to their
higher efficiency.
a UMR 7652 (Ecole Polytechnique/ENSTA/CNRS),
´
´
´
Laboratoire Chimie et Procedes, Ecole Nationale Superieure des
Techniques Avancees, 32 Bd Victor, 75015 Paris, France.
´
E-mail: laurent.elkaim@ensta.fr, laurence.grimaud@ensta.fr;
Fax: +33 145528322; Tel: +33 145525537
b
´ ´ ´ ´
Laboratoire Heteroelements et Coordination, Ecole Polytechnique,
CNRS, route de Saclay, F-91128 Palaiseau Cedex, France
c Facultad Medicina, Universidad Nacional Autonoma de Mexico,
Circuito Exterior, Ciudad Universitaria, Coyoacan,
Mexico D. F. 04510, Mexico
d Instituto de Quimica, Universidad Nacional Autonoma de Mexico,
Circuito Exterior, Ciudad Universitaria, Coyoacan,
The presence of an aliphatic substituent at the peptidic
position—by use of an aliphatic aldehyde in the former Ugi
coupling—inhibited the reaction and no cyclization occurred
(Table 2, entry 1). This result is consistent with a lower acidity
of the proton, and suggested that in this reaction, the NH
Mexico D. F. 04510, Mexico. E-mail: lmiranda@servidor.unam.mx;
Fax: +52 5556162217; Tel: +52 5556224440
w Electronic supplementary information (ESI) available: Experimental
procedure and data for preparation of indoles 1, and spiroindolines 2.
CCDC 826778. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc12236c
c
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Chem. Commun., 2011, 47, 8145–8147 8145

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Table 2 Scope of the oxidative process
Entry Ugi adduct (yields)
Cyclized product (yields)
1
2
3
4
5
1b R = Et 89%
N.R.
1c R = 4-ClC6H4 89%
1d R = 4-MeOC6H4 83%
1e R = 4-HOC6H4 93%
1f R = 4-NO2C6H4 90%
2c R = 4-ClC6H4 64%
2d R = 4-MeOC6H4 53%
2e R = 4-HOC6H4 62%
2f R = 4-NO2C6H4 76%
Fig. 1 X-Ray analysis of 2f.
6
7
8
1g X = H 93%
1h X = Cl 88%
1i X = OMe 83%
2g X = H 66%
2h X = Cl 75%
2i X = OMe 59%
Scheme 1 Proposed radical mechanism.
9
10
1j R1 = Me, R2 = t-Bu 94% 2j R1 = Me, R2 = t-Bu 66%
1m R1 = Ph, R2 = Cy 90% 2m R1 = Ph, R2 = Cy 60%
modern technologies. Several elegant C-3 selective Pd- and
Ir-catalyzed allylations of indoles using different sources of
allylic cations have been reported to construct a range of
indolenine and indoline derivatives bearing quaternary stereo-
centers.12 Less studied have been the free radical-mediated C-3
spirocyclization processes of indole derivatives leading in our
case to a radical analogue of a Pictet–Spengler cyclization.6,9b
The reaction mechanism probably involves the oxidative
generation of a peptidyl radical triggered by copper(II) salts.
A 5-exo-dig cyclization, followed by a further oxidation of the
a-aminoalkyl radical forms an iminium trapped by the vicinal
amide moiety (Scheme 1). This mechanism is supported by
known radical additions onto the indole core9 as well as recent
oxidative couplings of radicals generated from enolates.13 The
reaction shares some relationship with the anionic couplings
reported by the Baran group.14 In our case, the choice of an
aryl activating group in the peptidyl position allowed a
coupling under mild basic conditions.15 We were able to
eliminate the possibility of alternative mechanistic paths starting
from an oxidation of the indole core based on the reactivity of
1f under neutral conditions compared to the unproductive
coupling of 1a in the absence of a base.16
1k R1 = 2-pyridyl,
R2 = Cy 90%
2k R1 = 2-pyridyl,
R2 = Cy 46%
11
12
1l R1 = 2-pyridyl,
R2 = Cy 93%
2l R1 = 2-pyridyl,
R2 = Cy 37%
should be much more acidic. However, aromatic substituents
bearing either electron-donating or electron-withdrawing
groups were introduced successfully at this position. The
reaction proceeded efficiently with various amide substituents,
even hindered ones.
It is worth noting that, probably due to an easier enolization,
compound 1f (with a nitro group) could be oxidized under
non-basic and even acidic conditions. Indeed, when treated
with one equivalent of copper diacetate in acetic acid at reflux
for 20 h, the corresponding 2f was obtained in 54% yield. The
reaction was even more efficient in acetonitrile, with 2f being
formed in 80% isolated yield after 8 h at room temperature.
The structures of compounds 2 were confirmed by an X-ray
analysis of 2f (Fig. 1).
Considering the high level of diversity offered by this
oxidation–cyclization process, we were eager to adapt the
procedure and transform it into a one-pot process. Although
we were unable to identify a solvent applicable for both
steps, we were delighted to find that the oxidation could be
performed directly after the Ugi reaction without any inter-
mediate purification. The best yields were obtained by simply
evaporating the methanol. More conveniently, the first step
may be performed in a more concentrated medium, followed
by direct addition of THF, base and copper (Scheme 2).
Most synthetic strategies for spiroindolines rely on a
spirocyclization process onto the C-3 of the indole nucleus
via a dearomatization process.6,11,12 Since the pioneering work
of a C-3 iminium-mediated spirocyclization of tryptamine
derivatives to obtain spiroindolenines, as reported by
Van Tamelen et al.,11 the process has been expanded with
c
8146 Chem. Commun., 2011, 47, 8145–8147
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Scheme 2 One-pot conditions for the preparation of spiroindolines.
In conclusion, we have disclosed a new copper-catalyzed
spirocyclization. The reaction probably involves radicals
generated from enolates by a copper(II)-triggered oxidation.
This simple procedure produces remarkably complex final
structures. In these one-pot reactions, the four-component
nature of the first Ugi step contributes to the formation
of complex alkaloid-like structures with high diversity. The
programmed combination of this multi-component reaction
with sequential secondary transformations has already been
recognized as a powerful approach to reach high molecular
complexity. Indeed, many cycloadditions, cyclocondensations
or organometallic couplings have been reported as Ugi post-
condensations. In contrast, radical cyclizations still remain
underutilized.7,17 This new synthesis of complex indolines in
one step underscores the potential of such synthetic approaches.
This work was made possible by a grant from CONACYT.
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15 The fact that the reaction only gives one diastereomer is rather
surprising for the cyclization of a radical species. It may be
explained either by a degradation of the isomer unable to cyclize
with the pendant amide or by a ring-opening of the spiro iminium
A leading to an epimerization of the peptidyl position.
16 1f is probably oxidized via its enol tautomer.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8145–8147 8147