AgAsF6/Sm(OTf)3 promoted reversal of enantioselectivity for the asymmetric Friedel-Crafts alkylations of indoles with β,γ-unsaturated α-ketoesters

Article abstract of DOI:10.1021/ol902587t

"Chemical Equation Presented" The first example of central metal controlled reversal of enantioselectivity in asymmetric Friedel-Crafts alkylation of indoles andβγ-unsaturated α-ketoesters has been developed. Using the same chiral starting material derive

Full text of DOI:10.1021/ol902587t

ORGANIC
LETTERS
2010
Vol. 12, No. 1
180-183
AgAsF6/Sm(OTf)3 Promoted Reversal of
Enantioselectivity for the Asymmetric
Friedel-Crafts Alkylations of Indoles
with ꢀ,γ-Unsaturated r-Ketoesters
Yanling Liu, Deju Shang, Xin Zhou, Yin Zhu, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, P. R. China
xmfeng@scu.edu.cn
Received November 8, 2009
ABSTRACT
The first example of central metal controlled reversal of enantioselectivity in asymmetric Friedel-Crafts alkylation of indoles and ꢀ,γ-unsaturated
r-ketoesters has been developed. Using the same chiral starting material derived N,N′-dioxides 1a and 1b as ligands, various indole esters
4 were obtained in good to excellent yields and enantioselectivities. The reaction also featured mild reaction conditions and remarkably low
catalyst loading (down to 0.01 mol %).
The indole framework represents a privileged structural motif
of particular value in medicinal chemistry and complex target
synthesis.1 The asymmetric Friedel-Crafts alkylation of
indole provides a direct access to the enantiomerically
enriched indole derivatives.2 Although the application of
Lewis acids as catalysts is one of the most powerful strategies
in organic chemistry,3 only a few highly enantioselective
processes based on chiral metal complexes have been
reported for the asymmetric Friedel-Crafts alkylation of
indoles with ꢀ,γ-unsaturated R-ketoesters,4 the products of
which could be functionalized readily to the corresponding
amino acids or R-hydroxy acids.5 Previous reports by
Jørgensen or Desimoni mainly focused on chiral oxazoline
complexes as catalysts, in which only one enantiomeric
ligand could be achieved easily or in low cost.6 Therefore,
(1) (a) Sundberg, R. J. In Indoles; Academic Press: San Diego, 1996.
(b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-
VCH: Weinheim, 2003. (c) Saxton, J. E. Nat. Prod. Rep. 1997, 559. (d)
Borschberg, H. J. Curr. Org. Chem. 2005, 9, 1465. (e) Kleeman, A.; Engel,
J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances, 4th ed.; Thieme:
New York, 2001.
(3) Yamamoto, H. Lewis Acids in Organic Synthesis; Wiley-VCH:
Weinheim, 2008.
(2) For recent reviews on asymmetric Friedel-Crafts reactions, see: (a)
Poulsen, T. B.; Jørgensen, K. A. Chem. ReV. 2008, 108, 2903. (b) Jørgensen,
K. A. Synthesis 2003, 1117. (c) Bandini, M.; Melloni, A.; Umani-Ronchi,
A. Angew. Chem., Int. Ed. 2004, 43, 550. (d) Bandini, M.; Melloni, A.;
Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199. (e) Bandini, M.; Cozzi,
P. G.; Melchiorre, P.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43,
84. (f) Almasi, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007,
18, 299.
(4) (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 160. (b) Desimoni, G.; Faita, G.; Toscanini,
M.; Boiocchi, M. Chem.sEur. J. 2008, 14, 3630. (c) Lyle, M. P. A.; Draper,
N. D.; Wilson, P. D. Org. Lett. 2005, 7, 901.
(5) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew.
Chem., Int. Ed. 2008, 47, 593.
(6) For the availability of both (R)- and (S)-tert-leucine, see: Be´langer,
E.; Pouliot, M.-F.; Paquin, J.-F Org. Lett. 2009, 11, 2201.
´
10.1021/ol902587t  2010 American Chemical Society
Published on Web 11/25/2009

the development of an efficient catalytic system to synthesize
both enantiomers in high optical purity, especially using a
single enantiomeric ligand available, is very challenging,
interesting, as well as demanding for this reaction.
Meanwhile, the remarkably different biological property
makes it rather essential for simultaneous preparation of both
enantiomers in catalytic asymmetric synthesis. Generally,
turning of enantioselectivity is most obviously occurred
through the use of enantiomeric ligands. However, some
chiral ligands or starting materials of chiral ligands are not
always readily or economically available in both enantiomers.
Therefore, other compensated methods such as alteration of
the reaction conditions (solvent, pressure, and additive) and
the adjustment of ligand structure with no change of the
chiral source have also been developed.7 Among them, the
introduction of different central metals to control the reaction
enantioselectivity in a specific way has attracted more and
more attention.8 The unique characteristics of metal ions in
atomic radius and electronic property altered their coordina-
tion pattern even with the same chiral ligand. This provides
the possibility of the existence of different transition states,
which offered more opportunities for modification leading
to both enantiomerically enriched products. As part of our
continuing efforts toward reactions catalyzed by N,N′-
dioxide-metal complexes,9 we report here the first example
of AgAsF6/Sm(OTf)3 controlled reversal of enantioselectivity
in asymmetric Friedel-Crafts alkylation of indoles and ꢀ,γ-
unsaturated R-ketoesters using the same chiral starting
material. Moreover, the reaction could even be carried out
with as low as 0.01 mol % catalyst loading to give the desired
products in good to excellent yields and enantioselectivities.
As novel ligands, chiral N,N′-dioxides complexed with
different metals such as In(III),9a Sc(III),9b,i La(III),9c
Ni(II),9d,f Fe(II),9g Cu(I),9e and Cu(II)9h have shown powerful
catalytic capability in various reactions. According to the
initial experiment, Sm(OTf)3 and AgOTf gave the most
promising results of 28% and 48% ee, respectively (Table
Figure 1. N,N′-Dioxide ligands evaluated.
1, entry 1 vs 2). The opposite configuration obtained
obviously proved the decisive role of central metals in
effective stereocontrol of the reaction products. Given the
rare application of Sm(III) in asymmetric catalytic reaction10
as well as the availability of L-ramiprol acid, the starting
material of the ligands 1a-1d (Figure 1), in one single
enantiomer, we decided to optimize both reaction systems
simultaneously in order to expand the utility of this reaction.
Subsequent investigation of the reaction parameters such as
ligand, temperature, substrate concentration, and catalyst
loading gave the optimal conditions: 10 mol % AgAsF6-1a
as the catalyst, -20 °C in 2.0 mL of THF for the (S)-isomer
(82% yield and 85% ee), and 0.5 mol % complex of 1b-
Sm(OTf)3 as catalyst, -20 °C in 0.6 mL of CH2Cl2 for the
(R)-isomer (96% yield and 98% eeTable 1, entries 8 and
15).11
Table 1. Catalytic Enantioselective Friedel-Crafts Reaction of
Indole 2a with ꢀ,γ-Unsaturated R-Ketoester 3a in the Presence
of Catalystsa
(7) For reviews, see: (a) Sibi, M. P.; Liu, M. Curr. Org. Chem. 2001,
5, 719. (b) Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini,
E. Chem. Soc. ReV. 2003, 32, 115. (c) Tanaka, T.; Hayashi, M. Synthesis
2008, 3361. (d) Bartók, M. Chem. ReV. 2009, DOI: 10.1021/cr9002352.
(8) For examples of metals-controlled reversal of reaction enantiose-
lectivity, see :(a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron
Lett. 1996, 37, 3815. (b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P.
J. Am. Chem. Soc. 1998, 120, 6615. (c) Sibi, M. P.; Chen, J. J. Am. Chem.
Soc. 2001, 123, 9472. (d) Yabu, K.; Masumoto, S.; Yamasaki, S.;
Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 9908. (e) Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno,
J.; Toru, T. Synlett 2004, 1703. (f) Mao, J. C.; Wan, B. S.; Zhang, Z. J.;
Wang, R. L.; Wu, F.; Lu, S. W. J. Mol. Catal. A: Chem. 2005, 225, 33. (g)
Kim, H. Y.; Shih, H.-J.; Knabe, W. E.; Oh, K. Angew. Chem., Int. Ed.
2009, 48, 7420. (h) Spangler, K. Y.; Wolf, C. Org. Lett. 2009, 11, 4724.
(9) (a) Yu, Z. P.; Liu, X. H.; Dong, Z. H.; Xie, M. S.; Feng, X. M.
Angew. Chem., Int. Ed. 2008, 47, 1308. (b) Shang, D. J.; Xin, J. G.; Liu,
Y. L.; Zhou, X.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2008, 73, 630. (c)
Yang, X.; Zhou, X.; Lin, L. L.; Chang, L.; Liu, X. H.; Feng, X. M. Angew.
Chem., Int. Ed. 2008, 47, 7079. (d) Wang, L. J.; Liu, X. H.; Dong, Z. H.;
Fu, X.; Feng, X. M. Angew. Chem., Int. Ed. 2008, 47, 8670. (e) Tan, C.;
Liu, X. H.; Wang, L. W.; Wang, J.; Feng, X. M. Org. Lett. 2008, 10, 5305.
(f) Zheng, K.; Shi, J.; Liu, X. H.; Feng, X. M. J. Am. Chem. Soc. 2008,
130, 15770. (g) Chang, L.; Shang, D. J.; Xin, J. G. J.; Liu, X. H.; Feng,
X. M. Tetrahedron Lett. 2008, 49, 6663. (h) Shang, D. J.; Liu, Y. L.; Zhou,
X.; Liu, X. H.; Feng, X. M. Chem.sEur. J. 2009, 15, 3678. (i) Liu, Y. L.;
Shang, D. J.; Zhou, X.; Liu, X. H.; Feng, X. M. Chem.sEur. J. 2009, 15,
2055. (j) Chen, S. K.; Hou, Z. R.; Zhu, Y.; Wang, J.; Lin, L. L.; Liu, X. H.;
Feng, X. M. Chem.sEur. J. 2009, 15, 5884.
entry
L
metal
solvent x (mol %) yield (%)b ee (%)c
1
2
3
4
5
6
7
1a Sm(OTf)3 THF
10
10
10
10
10
10
10
10
10
10
10
10
10
10
91
53
60
59
47
47
61
82
99
99
86
83
98
93
96
28 (R)
48 (S)
64 (S)
70 (S)
49 (S)
29 (S)
42 (S)
85 (S)
62 (R)
90 (R)
81 (R)
65 (R)
98 (R)
94 (R)
98 (R)
1a AgOTf
1a AgSbF6
1a AgAsF6
1b AgAsF6
1c AgAsF6
1d AgAsF6
1a AgAsF6
1a Sm(OTf)3 CH2Cl2
1b Sm(OTf)3 CH2Cl2
1c Sm(OTf)3 CH2Cl2
1d Sm(OTf)3 CH2Cl2
1b Sm(OTf)3 CH2Cl2
THF
THF
THF
THF
THF
THF
THF
8d e
,
9
10
11
12
13d
14d f 1b Sm(OTf)3 CH2Cl2
,
15d g 1b Sm(OTf)3 CH2Cl2
0.5
,
a Unless otherwise noted, reactions were carried out with ligand (10 mol
%), metal (10 mol %), 2a (0.25 mmol), and 3a (0.25 mmol) in solvent (0.3
mL) at 0 °C for 24 h. b Isolated yield. c Determined by chiral HPLC analysis.
The absolute configuration was determined by comparing with literature data.4
d Reaction was carried out at -20 °C. e The solvent was 2.0 mL. f The solvent
was 1.0 mL. g 0.5 mmol 3a and 0.6 mL CH2Cl2 were used.
Org. Lett., Vol. 12, No. 1, 2010
181

Under the optimal conditions, the substrate scope for the
(S)-enantiomer of indole R-ketoesters 4 was investigated
using 10 mol % complex of AgAsF6-1a as catalyst. As
presented in Table 2, the catalytic enantioselective Friedel-
Crafts alkylation reaction proceeded well for many differently
substituted ꢀ,γ-unsaturated R-ketoesters and indoles, inde-
pendent of the electron-donating or electron-attracting char-
acter of the substituents (up to 90% ee). Moreover, heteroar-
omatic and fused ring substrates were also applicable, giving
the desired indole esters with the same enantioselectivity of
84% ee (Table 2, entries 7 and 8).
influence on the reaction:, 86% yield and 93% ee could be
obtained (Table 3, entry 15). Just like the AgAsF6 system,
indoles with either electron-withdrawing or electron-donating
substituents at different positions were also competent
substrates, providing the Friedel-Crafts alkylation products
with up to 99% yield and 98% ee (Table 3, entries 16-22).
Table 3. Sm(OTf)3 Promoted Alternative Enantioselective
Frediel-Crafts Reaction of indoles 2 with ꢀ,γ-Unsaturated
R-Ketoesters 3a
Table 2. AgAsF6 Catalyzed Enantioselective Frediel-Crafts
Reaction of Indoles 2 with ꢀ,γ-Unsaturated R-Ketoesters 3a
entry
R1
R2
R3
time
yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
15 min
20 min
15 h
22 h
3 h
96
98
99
94
96
99
90
77
92
91
93
96
83
87
86
99
83
90
82
99
99
99
98 (R)f
98
95
97
93
3-BrC6H4
2-ClC6H4
2,4-Cl2C6H3
4-ClC6H4
4-FC6H4
4-BrC6H4
4-NO2C6H4
4-CNC6H4
4-PhC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
2-thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
entry
R1
R2
time (h) yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
5-Me
5-F
5-Cl
5-Br
68
51
64
51
51
51
93
93
64
64
68
68
82
75
91
94
77
73
51
62
70
68
80
75
85 (95)d (S)e
86 (92)d
90
22 h
3 h
96
92 (R)f
90
3-BrC6H4
2-ClC6H4
2,4-Cl2C6H3
4-FC6H4
4-BrC6H4
2-thienyl
2-naphthyl
Ph
39 h
15 h
15 h
36 h
22 h
23 h
36 h
88
9
95
90
96
96
97
98
93
98
92
95
90
95
98
96
85 (91)d
83 (99)d (S)e
84
10
11
12
13d
14
15
16
17e
18
19
20
21
22
84 (90)d
81
9
10
11
12
Ph
Ph
Ph
85
Me 1 h
85 (96)d
85 (90)d
2-Me
4-OMe
5-F
H
H
H
H
H
H
H
1 h
1 h
a Unless otherwise noted, reactions were carried out with 1a (10 mol
%), AgAsF6 (10 mol %), 2 (0.25 mmol), and 3 (0.25 mmol) in THF (2.0
mL) at -20 °C. See Supporting Information for details. b Isolated yield.
c Determined by chiral HPLC analysis. See Supporting Information for
details. d After a single recrystallization. e The absolute configuration was
determined by comparing with literature data.4
58 h
58 h
30 min
27 h
10 h
5-Cl
6-OMe
7-Me
7-Et
a Unless otherwise noted, reactions were carried out with 1b (0.5 mol
%), Sm(OTf)3 (0.5 mol %), 2 (0.5 mmol), and 3 (0.5 mmol) in CH2Cl2 (0.6
mL) at -20 °C. See Supporting Information for details. b Isolated yield.
c Determined by chiral HPLC analysis. See Supporting Information for
details. d The catalyst was 1 mol %. e 0.3 mL of CH2Cl2 was used. f The
absolute configuration was determined by comparing with literature data.4
We then turned our attention to the preparation of (R)-R-
ketoester isomers 4 in the presence of 0.5 mol % Sm(OTf)3-
1b. Various indoles and ꢀ,γ-unsaturated R-ketoesters were
also evaluated, giving the corresponding antipodes with
excellent enantioselectivities (up to 98% ee). As shown in
Table 3, the enantioselectivity of the reaction was found to
be insensitive to both the steric and electronic properties of
substituents on the phenyl ring (Table 3, entries 1-13), and
different substituted R-ketoesters 4 were isolated in good
yields and excellent enantiomeric ratios. In addition, het-
eroaromatic R-ketoester also reacted well with indole to
deliver the desired product in 87% yield with 98% ee (Table
3, entry 14). The methyl protected indole exhibited little
On the basis of the previous excellent works on Ag(I)
complexes, as well as the low coordination number of
Ag(I),12 we consider that the bidentate coordination of Ag(I)
with two oxygen atoms of N-oxide is preferred for the
AgAsF6-1a complex. As shown in TS-1, indole attacked the
ꢀ-si face of the ester leading to the desired product with S
configuration. However, a different transition state was
proposed according to our previous study on the X-ray single
crystal structure of N,N′-dioxide-Sc(III) complex.9i As rare
earth metals bear similar coordination patterns,13 it is
(10) (a) Nemoto, T.; Kakei, H.; Gnanadesikan, V.; Tosaki, S.; Ohshima,
T.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544. (b) Kinoshita, T.;
Okada, S.; Park, S.-R.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int.
Ed. 2003, 42, 4680. (c) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2003, 125,
10162. (d) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki,
M. J. Am. Chem. Soc. 2004, 126, 7559. (e) Handa, S.; Gnanadesikan, V.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900.
(11) See Supporting Information for details.
(12) (a) Momiyama, N.; Yamamoto, H. J. Am. Soc. Chem. 2004, 126,
5360. (b) Ohkouchi, M.; Masui, D.; Yamaguchi, M.; Yamagishi, T. J. Mol.
Catal. A: Chem. 2001, 170, 1. (c) Wieland, L. C.; Vieira, E. M.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Soc. Chem. 2009, 131, 570. For silver-
catalyzed asymmetric reactions, see the following review: (d) Naodovic,
M.; Yamamoto, H. Chem. ReV. 2008, 108, 3132.
182
Org. Lett., Vol. 12, No. 1, 2010

suggestedthattheuseof1bandSm(OTf)3 intheFriedel-Crafts
reaction is likely to generate a hexacoordinate Sm(OTf)3-
derived transition state, in which not only the oxygens of
N-oxide but also carbonyl oxygens coordinated with Sm(III)
in a tetradentate manner (Figure 2, TS-2). Moreover, one
N-oxide is located trans to the carbonyl oxygen of the ester,
while other oxygens such as the two carbonyl oxygens of
amides, another N-oxide, and the one at the R position of
the ester are accommodated in the same plane. This arrange-
ment resulted in the attack of indole to the ꢀ-re face of the
Michael acceptor, which provides the access to R-configured
indole derivatives.
g, Scheme 1). As far as we know, this is to date the lowest
catalyst loading reported for the Friedel-Crafts alkylations
of indoles, thus demonstrating one of the advantages for this
catalyst system.
Scheme 1. Scaled-up Version of Friedel-Crafts Alkylation of
Indole 2a with ꢀ,γ-Unsaturated R-Ketoester 3a
In summary, we have developed an efficient catalytic
enantioselective Friedel-Crafts alkylation of indole and ꢀ,γ-
unsaturated R-ketoester. Just through changing the central
metals, the reversal of enantioselectivity in the Friedel-Crafts
alkylation of different indoles with a variety of ꢀ,γ-
unsaturated R-ketoesters has been achieved using ligands 1a
and 1b derived from the same chiral starting material. Both
enantiomers can be obtained in good to excellent enantiose-
lectivities. Furthermore, it should be highlighted that this
catalytic procedure allows the lowering of catalyst loading
to 0.01 mol % of Sm(OTf)3-1b without considerable loss in
reactivity and enantioselectivity. Further investigations on
the mechanism of this catalytic system are still in progress.
Figure 2. Proposed transition states for AgAsF6-1a and Sm(OTf)3-
1b.
To exploit the potential of the current catalyst system, the
reaction was scaled up to 25 mmol of the starting material
only in the presence of 0.01 mol % of complex Sm(OTf)3-
1b as the catalyst. The corresponding product (R)-4a could
also be isolated in a remarkable yield of 93% (7.12 g) with
84% ee. After a simple recrystallization,11,14 the enantiose-
lectivity could be increased to 98% ee with 82% yield (5.82
Acknowledgment. We appreciate the National Natural
Science Foundation of China (no. 20732003) and PCSIRT
for financial support and Sichuan University Analytical &
Testing Centre for NMR analysis and the State Key Labora-
tory of Biotherapy for HRMS analysis.
Supporting Information Available: Experimental pro-
cedures, spectral and analytical data for the reaction products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187.
(b) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV.
2002, 102, 2227.
(14) Recrystallization was carried out in CH2Cl2 and petroleum ether
(CH2Cl2/petroleum ether ) 1:4).
OL902587T
Org. Lett., Vol. 12, No. 1, 2010
183