Asymmetrie construction of polycyclic indoles through olefin cross-metathesis/intramolecular friedel-crafts alkylation under sequential catalysis

Full text of DOI:10.1002/anie.200903462

Communications
DOI: 10.1002/anie.200903462
Asymmetric Catalysis
Asymmetric Construction of Polycyclic Indoles through Olefin Cross-
Metathesis/Intramolecular Friedel–Crafts Alkylation under Sequential
Catalysis**
Quan Cai, Zhuo-An Zhao, and Shu-Li You*
The combination of mechanistically distinct organo-
catalysis and transition-metal catalysis has enabled
novel transformations beyond those possible with
single catalytic systems.[1] Sequential catalysis involv-
ing a binary catalytic system often reduces labor and
waste and enables the use of more readily available
starting materials for a given transformation.[2] Chiral
Brønsted acids have been shown to be efficient
catalysts for asymmetric Friedel–Crafts reactions.[3,4]
In particular, intramolecular Friedel–Crafts-type
reactions provide a direct route to polycyclic indoles,
Scheme 1. Cascade reaction involving cross-metathesis and an asymmetric
such as tetrahydropyrano[3,4-b]indoles (THPIs) and
Friedel–Crafts alkylation. Boc=tert-butoxycarbonyl.
tetrahydro-b-carbolines (THBCs),[5,6] which are fre-
quently encountered in biologically active natural
products and pharmaceuticals.[7] Despite considera-
ble efforts devoted to asymmetric intramolecular Friedel–
Crafts-type Michael addition reactions, there are few suc-
cessful examples.[8] Most notably, the tedious procedure for
the preparation of substrates for the intramolecular Friedel–
Crafts reaction limits its synthetic applications.
thermore, the Friedel–Crafts reaction should accelerate the
CM reaction by converting the metathesis product into an
alkylation product. Herein, we report our preliminary results
on an enantioselective intramolecular Friedel–Crafts alkyla-
tion based on sequential catalysis.
Xiao et al. recently demonstrated an elegant ruthenium-
catalyzed tandem cross-metathesis (CM)/intramolecular
hydroarylation sequence for the efficient synthesis of poly-
cyclic indoles.[9] The Lewis acidic ruthenium species gener-
ated in situ catalyzes the Friedel–Crafts alkylation reaction.
As part of our research program towards the development of
enantioselective Friedel–Crafts reactions,[10] we envisaged
that sequential olefin cross-metathesis and asymmetric intra-
molecular Friedel–Crafts alkylation reactions might be used
to construct enantiomerically pure polycyclic indoles
(Scheme 1). Chiral phosphoric acids were chosen as catalysts
for the asymmetric Friedel–Crafts reaction because of their
strong activation of unsaturated carbonyl compounds. We
hoped that these catalysts would suppress the racemic
reaction caused by Lewis acidic ruthenium species.[9] Fur-
When we began our study, no efficient enantioselective
Friedel–Crafts alkylation of indolyl enones was known.[11] We
chose the indolyl enone 1a as the model substrate and
explored the use of chiral Brønsted acid catalysts for this
transformation. With chiral phosphoric acids 5 (5 mol%) in
toluene at À208C, the desired reaction proceeded smoothly to
give 2a with 59–96% ee (Table 1). The chiral phosphoric acid
5h bearing 9-phenanthryl groups afforded 2a with greater
than 95% conversion and 96% ee and thus proved to be the
optimal catalyst (Table 1, entry 8). Further examination of the
reaction conditions revealed that the reaction proceeded with
optimal enantioselectivity (98% ee) at 08C in toluene
(Table 1, entry 13).
Various substituted indolyl enones were subjected to the
intramolecular Friedel–Crafts alkylation under these opti-
mized reaction conditions to examine the generality of the
reaction (Table 2). The phosphoric acid catalyzed intramo-
lecular Friedel–Crafts alkylation was found to be effective
with a wide range of substrates. Indolyl phenyl enones 1b–f,
which contain either an electron-donating group or an
electron-withdrawing group at the 5- or 6-position of the
indole, were good substrates; the desired products were
formed in 97–99% yield with 90–97% ee (Table 2, entries 2–
6). When the protecting group on the N atom of the indole
ring was changed from methyl to benzyl, the reaction
proceeded relatively slowly, but the yield and enantioselec-
tivity were satisfactory (97% yield, 95% ee; Table 2, entry 7).
In general, electron-rich indolyl enones (Table 2, entries 2
[*] Q. Cai, Z.-A. Zhao, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-5492-5087
E-mail: slyou@mail.sioc.ac.cn
[**] We thank the National Natural Science Foundation of China
(20732006, 20821002), the National Basic Research Program of
China (973 Program 2009CB825300), and the Chinese Academy of
Sciences for generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903462.
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Table 1: Optimization of the reaction conditions for the enantioselective
11). Single-crystal X-ray analysis of enantiomerically pure 2d
Friedel–Crafts reaction.[a]
revealed the absolute configuration to be R.[12,13]
Following the success of the asymmetric intramolecular
Friedel–Crafts alkylation, we investigated the sequential
catalysis of olefin cross-metathesis and asymmetric Friedel–
Crafts alkylation. Optimization of the reaction conditions led
to efficient sequential catalysis:[13] When the indolyl allyl
ether 3a and the phenyl enone 4a (1.5 equiv) were combined
and heated in toluene at 408C with 5h (5 mol%) and the Ru
catalyst 6 (5 mol%), the desired product 2a was obtained in
85% yield with 94% ee (Table 3, entry 1). Notably, the
Entry 5, R
Solvent
T [8C] Conv. [%][b] ee [%][c]
1
2
5a, phenyl
5b, 9-anthryl
toluene
toluene
toluene
toluene
toluene
toluene
À20
À20
À20
À20
À20
À20
À20
À20
À20
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
59
81
89
84
61
87
63
96
96
96
96
97
98
96
3
4
5
6
5c, 2-naphthyl
5d, 4-biphenyl
5e, 4-NO2-C6H4
5 f, 1-naphthyl
Table 3: Scope of the cross-metathesis/Friedel–Crafts cascade
reaction.[a]
7
8
9
5g, 3,5-(CF3)C6H3 toluene
5h, 9-phenanthryl toluene
5h, 9-phenanthryl CH2Cl2
10
11
12
13
14
5h, 9-phenanthryl CH2ClCH2Cl À20
5h, 9-phenanthryl toluene
5h, 9-phenanthryl toluene
5h, 9-phenanthryl toluene
5h, 9-phenanthryl toluene
À40
RT >95
Entry 3, R1, R3, X
4, R2
T
2, yield
ee[b]
0
40
>95
>95
[8C] [%]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3a, H, Me, O
3a, H, Me, O
3b, 6-OMe, Me, O 4a, C6H5
4a, C6H5
4a, C6H5
40
60
40
60
40
60
40
60
60
60
60
60
60
2a, 85
94
92
90
90
92
88
92
91
91
93
92
89
92
90
[a] Reaction conditions: (S)-5 (5 mol%), 1a (15 mg), solvent (0.5 mL).
[b] The conversion was determined by 1H NMR spectroscopy. [c] The
ee value was determined by HPLC analysis on a chiral stationary phase
(Daicel Chiralpak AD-H).
2a, 94
2b, 43
2c, 89
2d, 78
2d, 90
2e, 75
2e, 84
2 f, 96
2g, 97
2i, 91
2j, 90
2k, 93
2l, 96
3c, 5-Me, Me, O
3d, 6-Br, Me, O
3d, 6-Br, Me, O
3e, 5-F, Me, O
3e, 5-F, Me, O
3 f, 5-Br, Me, O
3g, H, Bn, O
3a, H, Me, O
3a, H, Me, O
3a, H, Me, O
3a, H, Me, O
3a, H, Me, O
3a, H, Me, O
3a, H, Me, O
3h, H, Me, NBoc
4a, C6H5
4a, C6H5
4a, C6H5
4a, C6H5
4a, C6H5
4a, C6H5
4a, C6H5
4b, 4-Cl-C6H5
4c, 4-BrC6H5
4d, 4-MeC6H5
Table 2: Scope of the intramolecular Friedel–Crafts alkylation.[a]
4e, 4-MeOC6H5 60
4 f, 4-NO2C6H5
4g, 2-naphthyl
4 f, 2-furyl
60
60
60
60
2m, 91 87
2n, 88
2o, 64
2p, 90
91
80
83
Entry
1, R1, R2, R3
t [min]
2, yield [%]
ee [%][b]
4a, C6H5
1
2
3
4
5
6
7
8
9
1a, H, C6H5, Me
3
6
3
15
13
15
180
10
5
2a, 99
2b, 99
2c, 98
2d, 99
2e, 99
2 f, 98
2g, 97
2h, 97
2i, 98
2j, 97
2k, 99
98
97
96
[a] Reaction conditions: 3 (0.1 molLÀ1), 4 (1.5 equiv), (S)-5h (5 mol%),
6 (5 mol%), toluene (2 mL). [b] The ee value was determined by HPLC
analysis on a chiral stationary phase. Mes=2,4,6-trimethylphenyl.
1b, 6-MeO, C6H5, Me
1c, 5-Me, C6H5, Me
1d, 6-Br, C6H5, Me
1e, 5-F, C6H5, Me
1 f, 5-Br, C6H5, Me
1g, H, C6H5, Bn
1h, H, 3-MeOC6H4, Me
1i, H, 4-ClC6H4, Me
1j, H, 4-BrC6H4, Me
1k, H, 4-MeC6H4, Me
97 (R)[c]
96
90
95
97
97
96
98
reaction of 1a with 5h (5 mol%) at 408C in toluene led to
2a with 96% ee (Table 1, entry 14); thus, there was almost no
erosion in enantioselectivity during sequential catalysis.
To ascertain the generality of the cascade reaction, we
examined various substituted indolyl allyl ethers and enones
(Table 3). In most cases, the reactions proceeded smoothly to
afford the desired products in good yields and with good
enantioselectivity (43–97% yield, 80–94% ee; Table 3,
entries 1–17). In general, the products were formed in
higher yield but with slightly lower enantioselectivity at
608C than at 408C. Not only substituted phenyl enones, but
also 2-naphthyl and 2-furyl enones were suitable substrates
for the cascade reaction (entries 16 and 17, Table 3). This
methodology could also be used to construct the THBC ring
10
11
5
10
[a] Reaction conditions: 1 (0.1 molLÀ1), (S)-5h (5 mol%), toluene
(2 mL). [b] The ee value was determined by HPLC analysis on a chiral
stationary phase. [c] The absolute configuration of 2d was determined by
single-crystal X-ray diffraction. Bn=benzyl.
and 3) were more reactive than electron-deficient substrates
(Table 2, entries 4–6). Excellent yields and enantioselectiv-
ities were observed for aryl indolyl enones with a variety of
aryl groups (97–99% yield, 96–98% ee; Table 2, entries 8–
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system: the reaction between 3h (X = NBoc) and 4a led to
Experimental Section
the cyclized product in 90% yield with 83% ee (Table 3,
entry 18). Sequential catalysis overcomes the low-yielding
and time-consuming synthesis of substrates 1. Moreover,
some substrates 1 are very reactive, and the cyclized products
were formed during their purification. Thus, sequential
catalysis avoids problematic separation processes.
The proposed method based on sequential catalysis
involves two distinct catalytic processes: olefin cross-meta-
thesis of 3 and 4 catalyzed by a Ru complex, followed by an
intramolecular Friedel–Crafts alkylation catalyzed by a chiral
phosphoric acid. In the presence of the Ru catalyst, cross-
metathesis of 3 and 4 occurs to afford the indolyl enone 1 and
a Lewis acidic Ru complex I (Scheme 2).[9] The activation of
enone 1 by the Ru complex I would lead to a racemic product;
General procedure: The indolyl allyl ether 3 (0.2 mmol) and enone 4
(0.3 mmol) were dissolved in toluene (2 mL) under argon in a dry
Schlenk tube. The resulting solution was heated to 40 or 608C, and
then the chiral phosphoric acid (0.01 mmol) and Ru catalyst
(0.01 mmol) were added together in one portion. When the reaction
(monitored by TLC or 1H NMR spectroscopy) was complete, the
solvent was evaporated under reduced pressure, and the residue was
purified by flash chromatography (ethyl acetate/petroleum ether
1:13–1:6) to afford the product.
Received: June 26, 2009
Published online: September 8, 2009
Keywords: asymmetric catalysis · chiral Brønsted acids ·
.
Friedel–Crafts alkylation · indoles · sequential catalysis
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yield.
In summary, we have developed an efficient procedure for
the sequential catalysis of olefin cross-metathesis and a
Friedel–Crafts alkylation to construct the THPI and THBC
ring systems in excellent yields and with excellent enantiose-
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readily available starting materials and makes the synthesis of
the THPI and THBC systems more practical and economical.
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