Gold-catalyzed intramolecular regio- and enantioselective cycloisomerization of 1,1-bis(indolyl)-5-alkynes

Article abstract of DOI:10.1002/anie.201302632

Bis(indole) alkaloids analogues were prepared under mild conditions and in high yields through a gold-catalyzed cycloisomerization of 1,1-bis(indolyl)-5- alkynes (see scheme). The enan Copyright

Full text of DOI:10.1002/anie.201302632

Angewandte
Chemie
DOI: 10.1002/anie.201302632
Cyclisation
Gold-Catalyzed Intramolecular Regio- and Enantioselective
Cycloisomerization of 1,1-Bis(indolyl)-5-alkynes**
Long Huang, Hai-Bin Yang, Di-Han Zhang, Zhen Zhang, Xiang-Ying Tang, Qin Xu,* and
Min Shi*
Indole is one of the most intensively investigated aromatic
heterocycle, because its derivatives are abundant in nature
and possess various biological activities.[1] Among the large
number of indoles, bis(indole) alkaloids, such as hamacan-
thins, nortopsentins, and dragmacidins (Scheme 1), are par-
carbophilic p-acids, which are widely employed in the
activation of alkynes, allenes, and alkenes. However, in
contrast to gold-catalyzed enantioselective transformations
involving allenes, there are relatively few examples involving
alkynes.[3–6] Echavarren and co-workers reported an elegant
gold-catalyzed intramolecular reaction of indoles with
alkynes, which proceeded through 6-endo-dig, 6-exo-dig, 7-
exo-dig, and 8-endo-dig cyclizations and were highly depen-
dent on the oxidation state of the gold catalyst. Further
investigations by this group indicated that similar spirocyclic
intermediates were probably involved in cyclizations of
various other substrates [Scheme 2, Eq. (1)].[7] Recently,
Scheme 1. Examples of naturally occurring and pharmacologically
active bis(indole) alkaloids.
ticularly abundant in marine sponges. In bis(indole) alkaloids,
two indole moieties are connected to various heterocyclic
units. Compounds with this structural motif exhibit a wide
spectrum of pharmacological activities, including antibacte-
rial, antiviral, and cytotoxic activities, which make bis(indole)
alkaloids and their analogues attractive targets for biomedical
and synthetic studies.[2]
Gold catalysis, which is currently a hot topic in homoge-
neous catalysis, can be well understood with the concept of
[*] L. Huang, H.-B. Yang, D.-H. Zhang, Z. Zhang, Dr. X.-Y. Tang,
Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
E-mail: Mshi@mail.sioc.ac.cn
Dr. Q. Xu, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology
130 Mei Long Road, Shanghai 200237 (China)
Scheme 2. Intramolecular cycloaddition reactions of indole and alkyne.
[**] We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), the National Basic Research Program of
China ((973)-2010CB833302), and the National Natural Science
Foundation of China (21072206, 20472096, 20872162, 20672127,
21121062, 21102166, and 20732008) for financial support.
tremendous efforts have been made toward the formation
of useful aza-heterocyclic structures through the versatile
intramolecular cyclization of indoles with alkynes.[8] Most of
these efforts focused on the construction of indole-fused
scaffolds, and Bandini and co-workers reported the only
asymmetric variant in 2012.[8j] We developed an efficient
protocol for the preparation of 1,1-bis(indolyl)-5-alkynes
Supporting information for this article (including spectroscopic and
HPLC data of the products shown in Tables 1–4) is available on the
WWW under http://dx.doi.org/10.1002/anie.201302632.
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Table 1: Substrate scope of gold(I)-catalyzed intramolecular cycloiso-
through an acid-catalyzed intermolecular reaction of 5-
alkynals with indoles (see Table S1 in the Supporting
Information for details).[9e] Upon treatment of 1,1-bis-
(indolyl)-5-alkyne with a gold catalyst, a bis(indole) cyclo-
adduct was obtained [Scheme 2, Eq. (2)],[10] stemming from
a gold-catalyzed 6-endo-dig cyclization and a pseudo 1,5
merization of various 1,1-bis(indolyl)-5-hexynes.[a]
ꢀ
migration of the nucleophilic indole moiety (C C bond
cleavage) followed by nucleophilic attack of the in situ
generated alkenyl–gold complex.[11] It also provided us with
a strategy for the synthesis of six-membered rings from 5-
alkynals with two indole moieties, rather than indole-fused
cycloadducts (as reported previously), playing a key role in
the annulation process.
We first attempted the cyclization with 1,1-bis(indolyl)-5-
hexyne 1a as the model substrate, which was easily prepared
from the reaction of 5-alkynal with indole using BF3·Et2O as
the catalyst. The initial results and subsequent optimization of
the reaction conditions are summarized in Table S2 in the
Supporting Information. Cycloadduct 2a was exclusively
produced in 97% yield within 10 minutes (Scheme 3), when
a gold complex with the electron-rich phosphine ligand
Me4tBuXPhos was employed as the catalyst.
Ent.
1
X
R1
R2
t [min]
2
Yield [%][b]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
H
H
H
2-Me
4-Cl
5-Cl
5-Br
5-Me
H
Bn
allyl 120
Me
Me
Me
Me
Me
30
ꢁ5
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
90[c]
ꢂ99
ꢂ99
ꢂ99
90
10
10
10
10
10
10
10
60
10
10
ꢁ5
10
ꢂ99
98
95
97
ꢂ99
ꢂ99
89
97
97
91
9
1j
1k
1l
5-OMe Me
10
11
12
13
14
15
6-F
7-Me
H
H
H
Me
Me
Me
Me
Me
Me
1m NBs
1n
1o
1p
NNs
CH(CO2Et)2
O
H
[a] All reactions were carried out using 1 (0.1 mmol) in the presence of
catalyst (2.5 mol%) in toluene (1.0 mL) unless otherwise specified.
[b] Yield of isolated product. [c] 2:3=15:1, determined by 1H NMR
analysis of the crude product using 1,3,5-trimethoxybenzene as internal
standard. [d] Ts=4-toluenesulfonyl, Ns=4-nitrobenzenesulfonyl,
Bs=4-bromobenzenesulfonyl.
Scheme 3. Optimized reaction conditions for the intramolecular cyclo-
isomerization of 1,1-bis(indolyl)-5-hexyne 1a.
yields, respectively, (Table 1, entries 14 and 15), thus indicat-
ing the broad substrate scope of this reaction.
Having established the optimal reaction conditions for the
formation of 2a as the major product, we surveyed the
substrate scope of the reaction by using variously substituted
bis(indolyl)alkynes 1 (Table 1). Among tosylamide-linked
substrates 1b–1l (X = NTs), a variety of N-substituted indole
moieties were well-tolerated, including those substituted with
N-benzyl and N-allyl groups. The use of indoles 1c and 1d as
nucleophiles provided the products in better yields and
regioselectivities compared with N-nonsubstituted indole 1b
(Table 1, entries 1–3). Next, we found that substituents at
positions 2, 4, 5, 6, and 7 of the N-methylindole backbone
were also well tolerated, regardless of whether they were
electron-donating or electron-withdrawing, furnishing the
desired products in high yields and excellent regioselectivities
(Table 1, entries 4–11). In the case of other N-sulfonated
amines (X = NBs or NNs), the reactions also proceeded
smoothly to give the desired products 2m and 2n in 89% and
97% yield, respectively (Table 1, entries 12 and 13). Sub-
strates with gem-diester and oxygen atom linkers efficiently
gave the desired cycloadducts 2o and 2p in 97% and 91%
AuI-catalyzed cyclizations of 1,1-bis(indolyl)-5-alkynes
1q–1u were also explored under similar conditions
(Table 2). The reactions of substrates 1q and 1s, which both
bear an ester group at the alkyne moiety, proceeded smoothly
to give the corresponding products 2q and 2s in good yields
and excellent regioselectivities under identical conditions as
those employed in Table 1 (Table 2, entries 1 and 3). The
cyclization of 1r was sluggish using Me4tBuXPhosAuCl/
AgOTf as the catalyst system, but was successfully catalyzed
by [(PPh3)AuCl]/AgOTf, giving 2r in 78% yield and in a ratio
of 4:1 with the corresponding regioisomer 3r (Table 2,
entry 2). The structures of 2r and 3r were unambiguously
determined by X-ray diffraction (see the Supporting Infor-
mation). Moreover, the previously employed reaction con-
ditions were not suitable for the less reactive substrates 1t and
1u. According to recent investigations on ligand effects in
gold catalysis, the use of an electron-poor ligand would favor
the electronic activation of the alkyne in reactions, in which
ꢀ
the activation of an unsaturated C C bond is the rate-
determining step.[6b] Further investigations revealed that both
substrates produced the corresponding products 2t and 2u in
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Table 2: Substrate scope of gold(I)-catalyzed intramolecular cycloiso-
Table 3: Selected optimization experiments of AuI-catalyzed enantiose-
lective cycloisomerization with 1,1-bis(indolyl)-5-alkyne 1a.[a]
merization of various internal 1,1-bis(indolyl)-5-alkynes.[a]
Ent. Cat. (mol%)
T
t
2a:3a[b] Yield ee
R1
H
R3
CO2Et [(Me4tBuXPhos)AuCl]
Catalyst
t [h]
2
Yield [%][b]
[%][c] [%][d]
Ent.
1
1
2
3
4
5
6
1q
3
1
2q 86[c]
2r 78[d]
2s 77
2t 71
2u 90
2u 82
1
2
3
4
5
6
[LAu2Cl2] (2.5)/AgOTf (5)
08C 30 min 2.5:1
08C 5 h 5:1
08C 30 min 12:1
08C 1 h
08C 10 h
60
74
67
66
41
71
–
25
31
30
44
19
53
–
1r 4-Cl CO2Et [(PPh3)AuCl]
1s
1t
1u
1u
[LAu2Cl2] (2.5)/AgBF4 (5)
[LAu2Cl2] (2.5)/AgNTf2 (5)
[LAu2Cl2] (2.5)/AgSbF6 (5)
[LAu2Cl2] (2.5)/AgOTs (5)
[LAu2Cl2] (5)/AgSbF6 (5)
H
H
H
H
CO2Ph [(Me4tBuXPhos)AuCl] 12
Me
Ph
Ph
[(JackiePhos)AuCl]
[(JackiePhos)AuCl]
[(IPr)AuCl]
12
6
3
8:1
1.4:1
08C 30 min 19:1
RT 7 days
7[e] [LAu2Cl2] (2.5)/AgOBz (5)
–
[a] The were carried out using 1 (0.1 mmol) in the presence of catalyst
(5 mol%) and AgOTf (5 mol%) as co-catalyst in (CH2Cl)2 (1.0 mL).
[b] Yield of isolated product. [c] 2:3=19:1. [d] 2:3=4:1. Ratios of 2:3
8
[LAu2Cl2] (2.5)/AgODNB (5) RT 7 days 6:1
50
72
81
68
80
88
81
82
88
88
85
91
9[e] [LAu2Cl2] (5)/AgODNB (10) RT 24 h
4:1
7:1
10[e] [L(AuODNB)2] (5)
11[e] [L(AuOPNB)2] (5)
12[e] [L(AuOONB)2] (5)
13[e] [L(AuODTfB)2] (5)
RT 2 h
RT 2 days 9:1
RT 3 h
RT 12 h
1
determined by H NMR analysis of the crude product using 1,3,5-
trimethoxybenzene as internal standard. JackiePhos=2-{bis[3,5-bis(tri-
fluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-
biphenyl.
5:1
8:1
[a] The reactions were carried out with 1a (0.1 mmol) and catalyst in
(CH2Cl)2 (1.0 mL), unless otherwise specified. [b] Ratio determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.
[c] Yield of isolated product 2a. [d] ee value of product 2a, determined by
HPLC on a chiral stationary phase. [e] In 0.5 mL (CH2Cl)2. ODNB=3,5-
dinitrobenzoate, OPNB=4-nitrobenzoate, OONB=2-nitrobenzoate,
ODTfB=3,5-di(trifluoromethyl)benzoate.
good yields and excellent regioselectivities by employing the
electron-poorer phosphine ligand JackiePhos (Table 2,
entries 4 and 5). The use of [(IPr)AuCl]/AgOTf as the catalyst
system gave 2u also in good yield (Table 2, entry 6).
The results of our examination of the enantioselective
cyclization of 1,1-bis(indolyl)-5-hexyne (1a) are shown in
Table 3. Among the commonly used chiral phosphine ligands,
use of (R)-DM-SEGPHOS resulted in the best enantioselec-
tivity (see Tables S3–S5 in the Supporting Information for
details). The examination of silver salts by carrying out the
reaction in dichloroethane at 08C showed that AgSbF6 was
the better co-catalyst compared with a range of other silver
salts (Table 3, entries 1–5). Changing the ratio of [LAu2Cl2]/
AgSbF6 to 1:1 (5 mol% each, L = (R)-DM-SEGPHOS)
improved the ee value to 53% (Table 3, entry 6). This
increase in enantioselectivity led us to believe that the
intact coordination of the counterion was crucial for stereo-
induction (one counterion is Cl and the other is SbF6).
Inspired by a report of Toste and co-workers, we next
investigated the cyclization using silver salts with benzoate
counterions, because the catalyst systems could be easily
modified both electronically and sterically by careful choice
of these counterions.[5h] Use of silver benzoate did not lead to
any product (Table 3, entry 7). We found a dramatic improve-
ment on the ee value when silver 3,5-dinitrobenzoate was
employed as the co-catalyst at room temperature, although
the yield was only 50%, even after extending the reaction
time (Table 3, entry 8). When the reaction was performed
with an increased catalyst loading of 5 mol% and an
increased concentration (0.5 mL of solvent) at room temper-
ature, 2a was obtained in 72% yield and 82% ee (Table 3,
entry 9). Next, we synthesized [L(AuODNB)2] and directly
used it in this asymmetric gold catalysis, affording 2a in 81%
yield and 88% ee within 2 h (Table 3, entry 10). Further
optimizations indicated that 3,5-di(trifluoromethyl)benzoate
was the best counterion, producing 2a in 88% yield with
91% ee and an 8:1 ratio of regioisomers (Table 3, entries 11–
13).
During the exploration of the substrate scope, we realized
that in some cases, the reaction should be performed in
dichloromethane and in the presence of 5 mol% [L-
(AuODNB)2] (L = (R)-DM-SEGPHOS), because some sub-
strates are not soluble in dichloroethane and the reaction
proceeds more quickly in the presence of [L(AuODNB)2].[12]
Thus, we developed two sets of reaction conditions for this
enantioselective gold(I)-catalyzed 6-endo-dig cyclization:
A) 5 mol% [L(AuODTfB)2], 0.5 mL dichloromethane, and
B) 5 mol% [L(AuODNB)2], 0.5 mL dichloromethane. With
these two sets of reaction conditions in hand, the substrate
scope of the reactions was examined. Reactions of N-
benzylated or N-allylated indole derivatives 1c and 1d
provided the desired products 2c and 2d, respectively, in
moderate yields and good enantio- and regioselectivities
(Table 4, entries 1 and 2, respectively). A range of substitu-
ents at positions 4, 5, 6, and 7 of the indole moieties were well
tolerated, affording the desired products in 65–90% yields
with 60–96% ee, regardless of whether they were electron-
donating or electron-withdrawing groups (Table 4, entries 3–
9). Substrates with NBs and NNs linkers gave the desired
products 2m and 2n, respectively, in 65–69% yields with 83–
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Table 4: Substrate scope of enantioselective AuI-catalyzed cycloisomerization with
various 1,1-bis(indolyl)-5-hexynes.
84% ee and regioisomers in ratios of 4:1–5:1
(Table 4, entries 10 and 11). Substrate 1o, which
has a gem-diester linker, gave the corresponding
product 2o in 80% yield with 48% ee (Table 4,
entry 12). It should be noted that the electron density
and steric hindrance associated with the indole rings
as well as the linker of 1,1-bis(indolyl)-5-hexyne
were essential to the outcome of the reactions with
regard to yields, enantioselectivities, and regioselec-
tivities.[13]
Ent.
1
X
R1
R2
Cond.[a]
t
2:3[b]
2
Yield ee
[days]
[%][c] [%][d]
In summary, we have developed a novel gold(I)-
catalyzed 6-endo-dig cyclization of various 1,1-bis-
(indolyl)-5-alkynes to give bis(indole) alkaloid ana-
logues in good yields through a pseudo 1,5 migration
of an indole moiety. This reaction is not only
applicable to a wide range of terminal alkyne
substrates, but also to various internal alkyne sub-
strates by adjusting the electronic property of the
catalyst through the choice of the phosphine ligands.
Moreover, the use of chiral phosphine/gold(I) com-
plexes [L(AuODTfB)2] or [L(AuODNB)2] (L = (R)-
DM-SEGPHOS) enabled enantioselective 6-endo-
dig cyclizations, affording the corresponding bis-
(indole) alkaloid analogues in moderate to excellent
yields (55–90%) and with moderate to good ee val-
ues (48–96%) together with satisfactory regioselec-
tivities (3.5:1!20:1).
1
2
3
4
5
6
7
8
1c NTs
1d NTs
1 f NTs
1g NTs
1h NTs
1i NTs
1j NTs
1k NTs
1l NTs
1m NBs
1n NNs
1o C(CO2Et)2
H
H
4-Cl
5-Cl
5-Br
5-Me
Bn
B
A
B
B
A
B
B
A
A
A
A
A
1
4
1
0.5
3
1
0.5
2
2
3
7:1 2c 69
6:1 2d 55
6:1 2 f 74
>20:1 2g 90
>20:1 2h 85
4:1 2i 75
3.5:1 2j 68
3:1 2k 65
5:1 2l 75
5:1 2m 65
4:1 2n 69
4:1 2o 80
72
81
60
96
96
82
83
90
90
83
84
48
allyl
Me
Me
Me
Me
5-MeO Me
6-F
7-Me
H
H
H
Me
Me
Me
Me
Me
9
10
11
12
2
3
[a] Conditions A: 1 (0.1 mmol), [L(AuODTfB)2] (5 mol%), (CH2Cl)2 (0.5 mL);
conditions B: 1 (0.1 mmol), [L(AuODNB)2] (5 mol%), CH2Cl2 (0.5 mL). [b] Ratio
determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as internal
standard. [c] Yield of isolated product. [d] Determined by HPLC on a chiral stationary
phase. Ts=4-toluenesulfonyl, Ns=4-nitrobenzenesulfonyl, Bs=4-bromobenzene-
sulfonyl.
1
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Experimental Section
General procedure for gold(I)-catalyzed cycloisomerization of 1,1-
bis(indolyl)-5-alkynes: [(Me4tBuXPhos)Au]SbF6 (2.5 mol%) was
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added to
a solution of 1,1-bis(indolyl)-5-alkyne 1 (0.1 mmol,
1.0 equiv) in (CH2Cl)2 (1.0 mL) in an Schlenk tube. The mixture
was stirred at room temperature until the reaction was completed
(monitored by TLC). The solvent was removed under reduced
pressure and the residue was purified by flash column chromatog-
raphy (SiO2, eluent: petroleum ether/ethyl acetate = 8/1!4/1) to give
the corresponding products 2 in moderate to excellent yields.
Received: March 29, 2013
Published online: May 13, 2013
Keywords: bis(indoles) · cycloisomerization ·
.
enantioselectivity · gold · regioselectivity
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[12] During the course of our studies on the effect of the counterion
on this enantioselective gold(I)-catalyzed 6-endo-dig cyclization,
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increased acidity of the employed benzoates. pKa values of
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[13] Using conditions B, the corresponding bis(indole) alkaloid
analogues 2b and 2e were obtained in 23% ee and 10% ee,
respectively. As for substrate 1b, we posited that the coordina-
tion of chiral gold(I)–benzoate complexes could be impacted by
ꢀ
the exposed indole N H, whereas the coordinated counterions
were crucial to increase the transmission of chiral information.
As for substrate 1e, the chiral catalyst was too far away from the
electrophilic site to induce chirality, because of the steric
hindrance between the methyl group at position 2 of the iminium
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[14] CCDC 874179 (1q), 877836 (2r), and 878653 (3r) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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