Merging organocatalysis and gold catalysis: Enantioselective synthesis of tetracyclic indole derivatives through a sequential double Friedel-Crafts type reaction

Article abstract of DOI:10.1002/chem.201102793

Yet another indole miracle: The sequential combination of organocatalysis and gold catalysis on C2,C3-unsubstituted indoles provides an efficient one-pot access to tetracyclic indole derivatives in very good yields and excellent enantioselectivities (see scheme). The double Friedel-Crafts type reaction, including a rare 7-endo-dig cyclisation, opens a new entry to highly enantioenriched anticancer drugs, such as DNA intercalators. Copyright

Full text of DOI:10.1002/chem.201102793

COMMUNICATION
DOI: 10.1002/chem.201102793
Merging Organocatalysis and Gold Catalysis: Enantioselective Synthesis of
Tetracyclic Indole Derivatives through a Sequential Double Friedel–Crafts
Type Reaction
Charles C. J. Loh, Jan Badorrek, Gerhard Raabe, and Dieter Enders*[a]
Annulated indoles, fused at the C2- and C3-position, are
chemically and biologically interesting as key structural
motifs in many natural products and as pharmaceutically
active substances.[1] Furthermore, annulated, tetracyclic in-
doles containing a seven-membered ring, such as in 1
(Scheme 1), have shown anticancer activities on leukemia
and colon cell lines, as well as antiproliferative activities
through DNA intercalation.[2] However, accessing such
seven-membered-ring-containing polycycles is synthetically
challenging owing to the preferential six-membered-ring for-
mation in the cyclisation step.
The reactivities of the indole C3- and C2-position, as well
as the indole nitrogen, provide many opportunities to access
enantiopure, annulated indole derivatives. This can be ach-
ieved, for example, with an intramolecular Friedel–Crafts
type reaction[3,4] or an aza-Michael addition of the indolic
nitrogen on a suitable acceptor.[5] While reports on the
enantioselective synthesis of polycyclic indoles using various
catalytic activation modes, especially in the fields of organo-
catalysis[6] and gold catalysis,[7] are numerous, most of such
synthetic strategies required substrates containing a prefunc-
tionalised indole, either on the C3- or the C2-position
(Scheme 1).[3,5]
In view of limited precedence for the synthesis of annulat-
ed indoles from C3,C2-unsubstituted indoles 2,[8] we hypoth-
esised that chiral, polycyclic indoles could be accessed enan-
tioselectively through a single-pot tandem operation. To the
best of our knowledge, an enantioselective variant of such a
transformation is not yet known. Moreover, we envisioned
that the recent surge in utilising one-pot, multicatalytic,
tandem reactions combining distinct organocatalytic and
transition-metal cycles could be used as a viable strategy to
obtain enantiopure, annulated indoles.[9–11] This emerging
area has also spurred some efforts in utilising indole as a
key substrate in enantioselective, sequential reactions.[4k,10d]
In our synthetic planning, we were interested in combin-
ing both organocatalysis and gold catalysis, especially the
latter to access nonconventional molecular frameworks
through domino and rearrangement reactions.[7k] It is worth
noting that the pioneering studies on gold catalysis by Echa-
varren et al.[12] and Zhang et al.,[13a,b] as well as very recent
reports,[8d,13c,14] allowed complex functionalisations of indole
substrates containing an intramolecular tethered alkyne.
We now wish to report an efficient and highly enantiose-
lective one-pot, multicatalytic, C2/C3-annulation of indoles,
giving rise to tetracyclic, seven-membered-ring-containing
derivatives 1. The new protocol utilises the bifunctional
ortho-alkyne-substituted nitrostyrenes 3 as substrates, allow-
ing two sequential Friedel–Crafts type reactions. The nitro-
alkene moiety is activated through hydrogen-bonding orga-
nocatalysis, to incorporate the stereochemical information in
the first Friedel–Crafts reaction,[15]and the alkyne functional-
ity provides access to gold catalysis and its alkynophilicity,[7]
to effect the second Friedel–Crafts/ring expansion cascade.
Scheme 1. Strategy comparison between current work and known meth-
ods.
[a] C. C. J. Loh, J. Badorrek, Prof. Dr. G. Raabe, Prof. Dr. D. Enders
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: enders@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102793.
Chem. Eur. J. 2011, 17, 13409 – 13414
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To truncate the practical complexity in achieving the opti-
mal conditions for the sequential reaction, we first tested
the protocol as two separate reactions. The sequential pro-
cess would finally be developed, based on the optimised
conditions of each sequential step. First, we screened a
series of hydrogen-bonding catalysts for the Friedel–Crafts
reaction of methoxyindole 4a with the ortho-alkyne substi-
tuted nitrostyrene 5a (Table 1).
excellent yields and high enantioselectivity at À308C make
this catalyst the optimal choice for our sequential reaction.
In the separate screening of transition metals to effect the
second Friedel–Crafts type reaction, common gold catalysts,
such as [AuACHTUGTNRENNUG(PPh3)]NTf2, [AuCAHTUNGTRNEN(UGN PPh3)]SbF6 and [Au-
AHCTUNGRTEG(NNUN PPh3)]OTf, generally led to almost quantitative yields of
the cyclised product. Other transition-metal catalysts, such
as PdCl2, AgOTf, CuOTf and InCl3, gave no desired prod-
ucts (see Supporting Information for more details). While a
wide variety of gold(I) catalysts were effective, [Au-
AHCTUNTGRENGUN(N PPh3)]NTf2 was the catalyst of choice in our sequential re-
Table 1. Screening of organocatalysts.[a]
action development, because gold complexes containing the
NTf2 counterion show greater air and thermal stability com-
pared to other counterions,[17] which makes it more tenable
to varying reaction conditions.
With suitable catalysts for both the organo- and gold-cata-
lysed steps in hand, we proceeded with the combination of
catalyst 6c and [AuACHTNUTRGNEUNG(PPh3)]NTf2 in a one-pot tandem se-
quence. Initial tests without additives yielded only traces of
product (Table 2, entry 1). This observation was in line with
Table 2. Additive optimisation of the one-pot sequential reaction.[a]
[Au
E
N
Additive
Yield
[%][b]
ee
[%][c]
1[d]
2[d]
3[e]
4[e]
5[e]
6[e]
7[e]
8[e]
10
10
10
10
10
10
10
0
–
–
–
25% p-TSA
50% p-TSA
50% DPP
75% p-TSA
100% p-TSA
1.5 equiv tBuOH
75% p-TSA
40
50
42
99
80
–
95
96
93
97
97
–
Catalyst
Cat. Loading
[%]
t
T
[8C]
Yield
[%][b]
ee
[d]
[%][c]
–
–
1
2
3
4
5
6
6a
6b
6c
6c
6d
6e
20
20
10
10
20
20
8
9
1
23
23
23
48
45
93
91
55
55
33
39
89
95
45
0
[a] All reactions were conducted on a 0.2 mmol scale of nitroalkene 5a
with indole 4a. [b] Yields isolated after flash column chromatography.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] The
reaction was conducted at room temperature to 408C. [e] Reaction was
conducted at room temperature to reflux.
1
À30
10
12
23
23
[a] All reactions were conducted on a 0.2 mmol scale of nitroalkene 5a
with indole 4a. [b] Yields isolated after flash column chromatography.
[c] Determined by HPLC analysis on a chiral stationary phase.
reports from other research groups,[10c,f,g] indicating that a
gold catalyst deactivation by the amine-containing 6c is pos-
sible. Hence, a screening was conducted to determine an ap-
propriate additive to regenerate the active AuI species.[10c,f,g]
A series of additives was tested to determine the optimal
combination (Table 2). While protic additives, such as
tBuOH, did not have a measurable effect on the reaction,
strong Brønsted acid additives, such as p-toluenesulfonic
acid hydrate (p-TSA) and diphenylphosphate (DPP),
showed increased yields for product 8a with excellent enan-
tioselectivities (Table 2, entries 2–6). The optimised condi-
tion was observed, when 0.75 equivalents of p-TSA were
In the series of catalysts tested for the organocatalytic
Friedel–Crafts alkylation with 5a,[16] the thiourea-based or-
ganocatalysts 6a, 6b, 6d, and 6e generally resulted in slug-
gish reactions at room temperature. Moreover, such cata-
lysts gave only moderate yields with low to moderate enan-
tiomeric excesses. With all the hydrogen-bonding catalysts
screened for the organocatalytic first step, catalyst 6c, devel-
oped by Seidel et al.,[16d] provided the best enantioselectivity
of up to 95% (Table 1, entry 4). The faster reaction times,
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Synthesis of Tetracyclic Indole Derivatives
COMMUNICATION
used in combination with both catalyst 6c and [Au-
ACHTUNGTRENNUNG(PPh3)]NTf2 (Table 2, entry 5).
TSA in this reaction, two control experiments of the tandem
reaction with and without p-TSA were performed in CDCl3
and studied by using 31P NMR spectroscopy (see Supporting
Information). The NMR studies revealed that only one 31P
peak at d=34.2 ppm was observed for both control reac-
tions at room temperature, albeit with extremely low prod-
uct formation for the reaction containing p-TSA. This d=
34.2 ppm resonance is consistent with a separate 31P experi-
ment on a sample containing only catalyst 6c and [Au-
To exclude any uncertainty that the gold-catalysed cyclisa-
tion might be effected by the presence of p-TSA,[18] a con-
trol experiment was performed using the exact conditions
without [AuACHTUNGTRENNUNG(PPh3)]NTf2 (Table 2, Entry 8). This control ex-
periment revealed that no product was detected in the ab-
sence of the gold catalyst.
Having achieved the optimised conditions through the ad-
ditive screening, we turned our attention to develop the
scope of this novel, catalytic, asymmetric synthesis of phar-
maceutically interesting tetrayclic indole derivatives
(Table 3). In general, this one-pot, sequential, catalytic reac-
A
A
separate experiment on pure [Au-
AHCTUNGTRENNUNG
resonating at d=46.2 and 34.2 ppm were observed for both
control experiments, when the reactions were heated to
1
reflux. Simultaneous H NMR studies on the same reaction
mixtures revealed that only the addition of p-TSA resulted
in product formation.
Table 3. Substrate scope of the methodology.[a,b]
We believe that the same deactivation effect on the AuI
catalyst is present, regardless of the presence of p-TSA. This
is exemplified by the downfield shift of the 31P peak to d=
34.2 ppm at room temperature, which corresponds to the
low-reactive adduct formed between AuI and the organoca-
talyst 6c. Upon heating, the new 31P peak, observed at d=
À
46.2 ppm, might indicate the formation of covalent Au C
bonds.[20] The role of p-TSA seems to be the regeneration of
the active AuI species to re-enter the catalytic cycle; howev-
er, apparently this is more effective at elevated tempera-
tures.
The absolute configuration and molecular structure of 8l
was unambiguously determined by X-ray crystallography
(Figure 1).[21] This is also consistent in analogy with the ab-
solute configuration reported by Ricci et al. using catalyst
6a[16a] and double confirmed by comparing the stereochemi-
cal outcome with HPLC obtained with both catalysts 6a and
6c (Table 1, entries 1 and 4).
8
R1
R2
R3
t[c]
[h]
Yield[d]
[%]
ee[e]
[%]
a
b
c
d
e
f
g
h
i
5-OMe
5-Me
H
7-Me
5-OMe
5-Me
H
7-Me
5-OMe
5-Me
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3-tolyl
3-tolyl
3-tolyl
3-tolyl
H
H
H
H
F
F
F
F
H
H
H
H
24+19
36+30
48+38
37+31
22+20
16+29
21+25
21+25
18+42
27+15
25+67
25+41
78
92
51
70
67
96
81
78
80
94
79
60
97
97
97
98
97
95
98
99
97
98
97
98
j
k
l
To demonstrate further possible transformations of the
tetracyclic indole targets, the nitro group of 8b was reduced
7-Me
[a] All reactions were conducted on a 0.8 mmol scale of 5a–c and indole
4a–d. [b] Absolute configurations are deduced by analogy to the crystal
structure of 8l. [c] Times for organocatalytic step + gold catalysed cycli-
sation. [d] Yields isolated after flash column chromatography. [e] Deter-
mined by HPLC analysis on a chiral stationary phase.
tion tolerates a variety of substrates, with varying functional-
ities on the indole 4, as well as the alkyne nitrostyrene com-
ponent 5. 5-Methyl indole performed excellently in this
tandem reaction (Table 3, 8b, 8 f and 8j) with yields of over
90%. Other indoles, such as 5-methoxyindole, 7-methylin-
dole and unsubstituted indoles, also gave good to excellent
yields.[19]
To ensure the industrial applicability of this novel, multi-
catalytic protocol, a 4 g scale reaction was conducted to pro-
vide convincing evidence of its scalability. This system pro-
ceeded smoothly on a multigram scale at significantly lower
catalyst loading (3 mol% of 6c and 5 mol% of [Au-
ACHTUNGTRENNUNG(PPh3)]NTf2) with still excellent enantioselectivity (93% ee)
and yield (93%) comparable to those of the small-scale re-
action (Table 3, 8b). To further understand the role of p-
Figure 1. X-ray crystal structure of (R)-8l.
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D. Enders et al.
to the corresponding primary amine (86%), which in turn
was converted by acylation into a camphanic amide and a p-
bromobenzamide in good yields and without racemisation
(for details on compounds 9–11, see Supporting Informa-
tion).
Based on our empirical data, as well as previously report-
ed studies,[7g,12,13,22] a mechanism is proposed to explain this
multicatalytic system (Scheme 2). Starting from C3,C2-un-
substituted indoles and ortho-alkyne-substituted nitrostyr-
Scheme 3. Indirect mechanistic evidence for the formation of spirocyclic
intermediates.
to effect an expansion from a
six- to a seven-membered ring
(15).[23] The final driving force
towards 16 lies in the indole
rearomatisation and protodeau-
ration step. It is worth noting
that our methodology allows a
three-carbon tether between
the C3 atom of indole and the
alkyne to undergo
a seven-
membered-ring formation by a
formal 7-endo-dig cyclisation.[8d]
This is in contrast to previous
reports, in which an intramolec-
ular Friedel–Crafts attack on a
three-carbon, aliphatic tether
resulted in six-membered rings,
formed by a formal 6-exo-dig
reaction.[12–14] One possible ex-
planation is that the presence
of a fused phenyl group on the
Scheme 2. Proposed mechanism of the sequential organo- and gold-based catalysis.
tether might stabilise the endo-
cyclic olefin better than an exo-
enes, 6c serves as a bifunctional organocatalyst, similar to a
thiourea catalyst, forming a tight transition state TS12,
which is stabilised by multiple hydrogen-bonding interac-
cyclic one, suggesting that thermodynamic factors could be
responsible for the observed regioselectivity.
In conclusion, we have developed a new methodology to
access tetracyclic indole derivatives enantioselectively by
merging organo- and gold-based catalysis through two se-
quential Friedel–Crafts type reactions. It is remarkable that
this one-pot protocol allows insertion of a stereogenic
centre into a highly conjugated, tetracyclic system, without
compromising the stereogenic integrity of the dibenzylic po-
sition. Moreover, a rare 7-endo-dig cyclisation provides
deeper insights into gold catalysis on indoles. As some ques-
tions regarding the exact dependence of the tethering bridge
and the mode of cyclisation remain unsolved, further mech-
anistic studies are currently ongoing in our laboratories.
À
tions with the nitroolefin and the N H of the attacking
indole nucleophile. This locks the reacting partners in fa-
vouring an indole Si-attack and explains the high enantiose-
lectivity and (R)-configuration in the first Friedel–Crafts
type reaction. Subsequently, the C3-substituted intermediate
13 is activated by the p-acidic [AuACTHNUTRGNEUNG(PPh3)]NTf2, owing to the
presence of the auraphilic alkyne. The alkyne activation
allows the C3 of indole to undergo a second Friedel–Crafts
type reaction in a 6-endo-dig fashion, forming a spirocyclic
intermediate 14.[12,13,22] A mechanistic test was conducted by
using our protocol on a C2-substituted indole (Scheme 3).
Indeed, a small amount of the spirocyclic product 18 was
isolated, albeit in low yield, possibly owing to the formation
of a highly congested quartenary centre. Nevertheless, the
successful isolation of this compound provides a plausible
evidence that spirocyclic intermediates, such as 14, could be
involved in the catalytic cycle. With the known character of
gold catalysis to engage in nonclassical cationic-type casca-
des,[7b,l] the intermediate 14 can rearrange through a 1,2-shift
Experimental Section
General procedure: Trifluomethanesulfonic acid (7.1 mL, 0.08 mmol,
0.1 equiv) was added under air to a Schlenk tube, containing a solution
of 6c (0.08 mmol, 0.1 equiv) in CHCl3 (4 mL). Then, NaBArF24
(0.08 mmol, 0.1 equiv) was added to the reaction mixture, which was
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Synthesis of Tetracyclic Indole Derivatives
COMMUNICATION
stirred for a further 10 min. The corresponding nitrostyrene alkyne 5a–c
(0.8 mmol, 1 equiv), dissolved in CHCl3 (4 mL), was then added and the
reaction mixture was cooled to À308C. Indole 4a–d (1.2 mmol,
1.5 equiv), dissolved in CHCl3 (2 mL), was subsequently added and the
reaction was monitored by TLC, until full conversion of the first tandem
step was observed. The reaction was warmed to room temperature over
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30 min, and p-TSA (0.6 mmol, 0.75 equiv) and [AuACTHNUTRGNE(UNG PPh3)]NTf2
(0.08 mmol, 0.1 equiv) were transferred to the reaction mixture sequen-
tially. The reaction mixture was heated under reflux and monitored by
TLC, until no further changes were observed. The product was then di-
rectly purified by flash column chromatography.
Keywords: gold · indoles · multicatalysis · one-pot reaction ·
organocatalysis
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Received: September 7, 2011
Published online: October 24, 2011
13414
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Chem. Eur. J. 2011, 17, 13409 – 13414