A diversity-oriented approach to spiroindolines: Post-ugi gold-catalyzed diastereoselective domino cyclization

Article abstract of DOI:10.1002/anie.201205052

Caught "Spiro" handed: A diversity-oriented approach comprised of an Ugi four-component reaction and a diastereoselective gold(I)-catalyzed domino cyclization for the generation of complex spiroindolines under mild conditions has been developed. Variously

Full text of DOI:10.1002/anie.201205052

Angewandte
Chemie
DOI: 10.1002/anie.201205052
Gold Catalysis
A Diversity-Oriented Approach to Spiroindolines: Post-Ugi Gold-
Catalyzed Diastereoselective Domino Cyclization**
Sachin G. Modha, Amit Kumar, Dipak D. Vachhani, Jeroen Jacobs, Sunil K. Sharma,
Virinder S. Parmar, Luc Van Meervelt, and Erik V. Van der Eycken*
Gold-catalyzed carbocyclization and heteroannulation strat-
egies have recently attracted much attention owing to the
ꢀ
selective and efficient activation of the C C bond towards
a wide range of nucleophiles that these methods provide.[1]
Domino approaches involving gold-catalysis lead to complex
heterocyclic compounds under exceedingly mild reaction
conditions.[2] Although gold-catalyzed approaches are rising
to prominence, they suffer in terms of diversity and proce-
dural length. Multistep sequences are usually required for
assembling the starting material for cyclization. We have
recently reported a concise route to indoloazocines by
a sequential Ugi/gold-catalyzed intramolecular hydroaryla-
Scheme 1. Unexpected gold-catalyzed domino cyclization.
tion approach.[3] Inspired by these findings and as a result of
our continued synthetic interest in the indole core,[4] multi-
component reactions[5] and transition metal-catalysis,[6] we
have developed a post-Ugi gold-catalyzed domino cyclization
method to generate spiroindolines.
resulting in the diastereoselective formation of tetracyclic
spiroindoline 6a in 61% yield (Scheme 1).
This observation was remarkable, as the attack on the
a-position of an alkyne conjugated with an amide is rare, and
trapping of the spiro intermediate by a sterically hindered
tert-butyl amide is rather unexpected, as was the diastereo-
selectivity observed. Spiroindolines[8] are prominent molec-
ular motifs that are frequently encountered among the large
family of alkaloids; for example, it is present in commune-
sines[8,9] and perophoramidines[8,10] (Figure 1), which display
distinct pharmacological properties.[8–10] These fused polycyc-
lic systems, which feature quaternary stereocenters, present
a nontrivial challenge for organic chemists to develop
synthetic approaches.[11]
The Ugi four-component reaction (4-CR)[7] of indole-3-
carboxaldehyde (1a) with p-methoxybenzyl amine (2a),
2-butynoic acid (3a) and tert-butyl isonitrile (4a) in methanol
at 508C gave Ugi-adduct 5a in 71% yield. When this was
treated with 5 mol% of Au[PPh3]OTf (OTf = trifluorome-
thanesulfonate) in CDCl3 at RT, the expected outcome of the
reaction was indoloazepinone 6a’ through an endo-dig
cyclization[1m,n,3] followed by rearrangement (Scheme 1).
Surprisingly, an exo-dig cyclization followed by intramolecu-
lar trapping of the spiro intermediate occurred instead,
[*] S. G. Modha, A. Kumar, D. D. Vachhani,
Prof. Dr. E. V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, KU Leuven
Celestijnenlaan 200F, Heverlee 3001, Leuven (Belgium)
E-mail: erik.vandereycken@chem.kuleuven.be
Homepage: http://chem.kuleuven.be/organ/lomac/
J. Jacobs, Prof. V. S. Parmar, Prof. Dr. L. Van Meervelt
Biomolecular Architecture, Department of Chemistry
KU Leuven
Figure 1. Naturally occurring polycyclic spiroindolines.
Celestijnenlaan 200F, Heverlee 3001, Leuven (Belgium)
A. Kumar, Prof. S. K. Sharma
Bioorganic Laboratory, Department of Chemistry
University of Delhi, Delhi-110 007 (India)
First, we optimized the conditions for this domino
cyclization (Table 1). Whereas Au(X-Phos) with different
counter ions (X-Phos = 2-dicyclohexylphosphino-2’,4’,6’-tri-
isopropylbiphenyl) did not improve the yield, AuCl, AuCl3,
and Au(PPh3)Cl gave almost no conversion (Table 1,
entries 2–7). Reaction with Au(PPh3)SbF6 afforded an
improved yield of 75% in merely 2 h (Table 1, entry 8).
[**] Support was provided by the research fund of KU Leuven and the
FWO (Fund for Scientific Research—Flanders (Belgium)). A.K.
thanks the EMA2experts (Erasmus Mundus Action 2, Lot 11 Asia:
Experts) for providing a doctoral exchange scholarship and D.D.V.
thanks the EMECW (Erasmus Mundus External Cooperation
Window, Lot 13) for providing a doctoral scholarship. The authors
thank Ir. B. Demarsin for HRMS measurements.
À
Replacing SbF6 with other counterions, or using [MeCN
(JohnPhos)AuI]SbF6 (JohnPhos = (2-biphenyl)di-tert-butyl-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205052.
phosphine) did not give better results (Table 1, entries 9–11).
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Table 1: Optimization of the domino cyclization.[a]
entries 5
and
6).
Methyl
substitution
at
the
2-position of the indole core completely inhibited the
cyclization, and the starting material was quantitatively
recovered (Table 2, entry 10).
The application of d-(+)-1-phenylethylamine in the Ugi
reaction resulted in an inseparable 1:1 mixture of diastereo-
isomers. When subjected to the domino cyclization, two
diastereoisomeric spiroindolines 6la (35%) and 6lb (25%)
were formed in a combined yield of 79% (Table 2, entry 11).
A tosyl group on the indole nitrogen strongly diminished the
nucleophilicity of this core and hence no cyclized product
could be observed (Table 2, entry 12). The structure of
compound 6a was unambiguously assigned by X-ray crystal-
lography (Figure 2).[12]
The observed diastereoselecitivity of the reaction can be
easily explained by the mechanism (Scheme 2).[13] After the
activation of the triple bond of Ugi adduct (R)-5a by cationic
gold, the nucleophilic attack at the 3-position of the indole
can occur from two sides. If the attack occurs from the back
side of the indole core, intermediate B is formed. However,
trapping of the intermediate iminium ion in B by the
secondary amide, is sterically impossible. As a result, the
newly formed spiro-ring reopens to intermediate A. In
contrast, when the attack occurs from the front side of the
indole core, which results in spiro intermediate C, trapping of
the iminium ion is possible and spiroindoline 6a is formed,
which possesses two newly formed chiral centers (S,S;
Scheme 2).
Entry Catalyst
Solvent t [h]
% Conversion[b]
(% Yield)
1
Au(PPh3)OTf
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
3
3
100 (61)
100 (59)
40
100 (67)
0
2
3
4
5
Au(X-Phos)SbF6
Au(X-Phos)BF4
Au(X-Phos)NTf2
AuCl
20
20
20
20
20
2
20
20
20
20
20
6
AuCl3
trace
0
7
8
9
Au(PPh3)Cl
Au(PPh3)SbF6
Au(PPh3)BF4
Au(PPh3)NTf2
100 (75)
20
100 (64)
100 (62)
35
10
11
12
13
14[c]
15[d]
16[f]
17
18
19
20
[MeCN(JohnPhos)AuI]SbF6 CDCl3
AgOTf
AgSbF6
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CD2Cl2
50
100 (72)
Au(PPh3)SbF6
Au(PPh3)SbF6
Au(PPh3)SbF6
Au(PPh3)SbF6
Au(PPh3)SbF6
Au(PPh3)SbF6
Au(PPh3)SbF6
0.5
0.25 100 (58)[e]
20
3
50
100 (70)
80
CD3CN 20
[D8]THF 20
trace
MeOD
2
100 (46)[e]
Thus, the chiral center already present in the Ugi adduct,
diastereoselectively directs the domino cyclization. To the
best of our knowledge, this is the first report of the synthesis
[a] Unless otherwise noted, all reactions were run with 5a (0.1 mmol)
and a catalyst loading of 5 mol% in a screw-cap vial at RT. [b] Conversion
based on 1H NMR analysis; yields given in parentheses are yields of
isolated products. [c] Reaction at 508C. [d] Reaction at 1008C.
[e] Unidentified by-products were formed. [f] Catalyst loading of 2 mol%.
JohnPhos=(2-biphenyl)di-tert-butylphosphine, Tf=trifluoromethane-
sulfonyl, X-Phos=2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.
of spiroindolines by
“branched-handed”
(Figure 3).[2,11]
a
domino cyclization involving
pre-cyclization architecture
a
In conclusion, we have developed a diversity-oriented
approach to the synthesis of complex spiroindolines from
readily available starting materials. The first step, the Ugi-
4CR, generates diversity, and the second step, an efficient
Experiments with AgOTf and AgSbF6 resulted
in only moderate yields (Table 1, entries 12 and
13). Reaction with the hitherto best catalyst
system, Au(PPh3)SbF6, at 508C reduced the time
for reaction completion to 30 min with a slightly
diminished yield, whereas increasing the temper-
ature to 1008C decreased the yield to 58%
(Table 1, entries 14 and 15). A lower catalyst
loading of 2 mol% resulted in only 50% conver-
sion after 20 h. Changing the solvent did not give
better results (Table 1, entries 16–20).
To evaluate the scope and limitations of our
optimized method (Table 1, entry 8), different Ugi
adducts were synthesized from indole-3-carboxal-
dehyde in good to excellent yields, and subjected to
the domino cyclization reaction (Table 2). Various
substituents on the alkyne, isonitrile, indole, and
amine groups are tolerated (Table 2, entries 1–4, 7–
9). In the case of bulky substituents on the alkyne,
such as p-methoxyphenyl and iso-propyl, the yields
Figure 2. Crystal structure of compound 6a. Thermal ellipsoids set at 50%
decreased to 50% and 57%, respectively (Table 2, probability.[12]
2
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Table 2: Scope and limitations of domino cyclization to form spiroindolines.[a]
Entry
Ugi adduct 5
Spiroindolines (Æ)-6
Entry
7
Ugi adduct 5
Spiroindolines (Æ)-6
1
2
3
8
9
4
5
10
11
6
12
[a] All reactions were run with 5 (0.2 mmol) in a screw-cap vial at RT. [b] Inseparable mixture of diastereoisomers. [c] Yield of pure diastereoisomer. The
combined yield was 79% (d.r.=1:1). Bn=benzyl, Cy=cyclohexyl, PMB=p-methoxybenzyl, PMP=p-methoxyphenyl, Ts=p-toluenesulfonyl.
gold(I)-catalyzed diastereoselective domino cyclization under
mild reaction conditions, results in the formation of the
spiroindolines. The unprecedented application of “branched-
handed” pre-cyclization architecture, the unexpected selec-
Scheme 2. Proposed mechanism for the diastereoselective domino
cyclization to spiroindolines. PMB=p-methoxybenzyl.
Figure 3. “Branched-handed” pre-cyclization architecture.
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tive exo-attack of the indole on the propargylic amide, and the
unique diastereoselectivity (control of three chiral centers)
are the merits of this protocol. Further studies on ring
expansion[14] and the application of this method to the
synthesis of naturally occurring spiroindolines are currently
under investigation.
Received: June 27, 2012
Published online: && &&, &&&&
Keywords: alkynes · gold · indoles · spiroindolines · Ugi
.
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4
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These are not the final page numbers!

Angewandte
Chemie
Communications
Gold Catalysis
S. G. Modha, A. Kumar, D. D. Vachhani,
J. Jacobs, S. K. Sharma, V. S. Parmar,
L. Van Meervelt,
E. V. Van der Eycken*
&&&& — &&&&
A Diversity-Oriented Approach to
Spiroindolines: Post-Ugi Gold-Catalyzed
Diastereoselective Domino Cyclization
Caught “Spiro” handed: A diversity-ori-
ented approach comprised of an Ugi four-
component reaction and a diastereose-
lective gold(I)-catalyzed domino cycliza-
tion for the generation of complex spi-
roindolines under mild conditions has
been developed. Variously substituted
spiroindolines were synthesized in good
to excellent yields and with complete
diastereoselectivity.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!