Friedel-Crafts-type alkylation in aqueous media using resin-supported peptide catalyst having polyleucine

Article abstract of DOI:10.1016/j.tetlet.2009.07.071

The asymmetric Friedel-Crafts-type alkylation in aqueous media was realized by the resin-supported N-terminal prolyl peptide catalyst having a polyleucine tether. The hydrophobic polyleucine chain in the peptide catalyst was essential for the reaction eff

Full text of DOI:10.1016/j.tetlet.2009.07.071

Tetrahedron Letters 50 (2009) 5602–5604
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Tetrahedron Letters
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Friedel–Crafts-type alkylation in aqueous media using resin-supported
peptide catalyst having polyleucine
Kengo Akagawa a, Takuhiro Yamashita a, Seiji Sakamoto b, Kazuaki Kudo a,
*
a Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
b Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric Friedel–Crafts-type alkylation in aqueous media was realized by the resin-supported
N-terminal prolyl peptide catalyst having a polyleucine tether. The hydrophobic polyleucine chain in
the peptide catalyst was essential for the reaction efficiency and enantioselectivity. The resin-bound pep-
tide catalyst could be reused at least for five times.
Received 19 June 2009
Revised 15 July 2009
Accepted 16 July 2009
Available online 18 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Chiral indole derivatives constitute a class of important struc-
tural units for natural products and pharmaceuticals.1 Because the
Friedel–Crafts-type alkylation of indole rings is a powerful way of
obtaining optically active indole compounds, many kinds of asym-
metric catalysts for Friedel–Crafts reactions of indoles have been
developed to date.2 After MacMillan and Austin reported the
(1)
Pro D-Pro Aib Trp Trp (Leu)25.4
hydrophobic chain
= -HN-CH2-CH2-PEG-PS
amphiphilic resin
catalytically active site
Figure 1. Resin-supported peptide catalyst.
In our previous study, it was revealed that (1) the polyleucine
moiety in the peptide chain plays important roles both in the effi-
ciency and in the stereoselectivity of catalysis in aqueous media,
and (2) amphiphilic polyethyleneglycol-grafted cross-linked poly-
styrene (PEG-PS) resin support is essential for avoiding aggregation
and sedimentation of a hydrophobic peptide catalyst. Accordingly,
we first tried the reaction of 4-nitrocinnamaldehyde with N-
methyl indole using trifluoroacetic acid (TFA) salt of the PEG-PS-
Michael-typeadditionofindolestoa,b-unsaturatedaldehydesusing
an imidazolidin-4-one catalyst,3 considerable attention has been
paid to organocatalytic Friedel–Crafts-type alkylations for synthe-
sizing indole derivatives.4,5 Among them, those catalyzed by chiral
amines have been well studied. Substrate enals are condensed with
the catalysts to form iminium ion intermediates, which control the
facial selectivity of the addition. So far, several types of chiral amines
such as imidazolidinones,3,6 proline derivatives,7 aziridinyl metha-
nol,8 and cinchona alkaloid derivatives9 have been employed for
the catalytic enantioselective Friedel–Crafts-type alkylation
through the iminium activation. Although peptide catalysts are also
promisingcandidatesfor enantioselectiveorganocatalysis,10 thereis
no report on a Friedel–Crafts reaction using a peptide-based catalyst.
Compared with relatively simple organocatalysts, peptide catalysts
are easy to be optimized through the tuning of the sequence/number
of the amino-acid residues.
Table 1
Friedel–Crafts-type alkylation in aqueous media using prolyl catalyst having
polyleucine chain
Me
3 equiv
N
CHO
20 mol% TFA catalyst
solvent, rt, 24 h
NaBH4
+
O2N
OH
N
Recently, as a catalyst for an asymmetric transfer hydrogena-
tion in aqueous media, we have developed the resin-supported
Me
2a
Catalyst
O2N
3a
N-terminal prolyl peptide
1 having a hydrophobic tether
Entry
1
Solvent
THF
Conversiona (%)
eeb (%)
—
(Fig. 1).11 Because development of catalytic reactions in aqueous
media has received increasing attention, we have tried to extend
this peptide catalyst to other reactions, especially to C–C bond
formations. Herein, we report the Friedel–Crafts-type reaction of
indoles with enals under aqueous conditions using the resin-sup-
ported N-terminal prolyl peptide catalyst.
Pro (Leu)25.4
(4)
0
2
3
4
5
4
4
4
Pro
THF/H2O = 2/1
THF/H2O = 1/1
THF/H2O = 1/2
THF/H2O = 1/2
11
44
59
8
24
28
22
<1
6
Proline
THF/H2O = 1/2
5
<1
a
Estimated by 1H NMR of the crude mixture.
Determined by chiral HPLC analysis using Chiralcel IA.
* Corresponding author. Tel.: +81 3 5452 6357; fax: +81 3 5452 6359.
E-mail address: kkudo@iis.u-tokyo.ac.jp (K. Kudo).
b
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.071

K. Akagawa et al. / Tetrahedron Letters 50 (2009) 5602–5604
5603
Table 2
Effect of catalyst structure
namaldehyde proceeded smoothly and afforded the product in
good yield and enantioselectivity (entries 1 and 6). Although the
addition to 4-chlorocinnamaldehyde was relatively slow (the con-
version was 61% after 168 h), good selectivity was achieved (entry
2). The reaction between 2-nitrocinnamaldehyde and N-methyl in-
dole was sluggish probably owing to steric hindrance (after 120 h,
21% yield with 61% ee in THF/H2O = 1/2, 30% yield with 52% ee in
H2O). An aliphatic aldehyde could be used as an acceptor, though
the yield and enantioselectivity were moderate (entry 3). Unsub-
stituted indole and N-methyl pyrrole could also be employed for
the present alkylation with good enantioselectivity (entries 4 and
5). Since a solid-supported catalyst can be easily separated from
the reaction mixture, the present resin-bound peptide might have
an advantage for recycling.14 The reusability of the catalyst, which
was recovered after the reaction by filtration, was examined.
Although the isolated yield decreased to some extent, the catalyst
could be reused without losing enantioselectivity at least for five
times (entries 7–11). It is also worth noting that the reaction
Me
3 equiv
N
CHO
+
20 mol% TFA catalyst
THF/H2O = 1/2, rt, 72 h
NaBH4
O2N
O2N
OH
N
Me
2a
3a
Entry
Catalyst
Yielda (%)
eeb (%)
Pro
Pro
Pro
Pro
D
-Pro Aib Trp Trp (Leu)25.4
(1)
1
2
3
4
85
19
81
87
88
30
43
41
D
-Pro Aib Trp Trp
(5)
D-Trp
D
-Pro Aib
Trp (Leu)24.4
-Trp (Leu)24.4
D
-Pro Aib Trp
D
a
Isolated yield.
Determined by chiral HPLC analysis using Chiralcel IA.
b
supported prolyl peptide having the polyleucine tether (4) as a cat-
alyst (Table 1). When THF was used as a sole solvent, reaction did
not proceed (entry 1). Upon addition of water to the solvent, the
Friedel–Crafts reaction was promoted. Increasing the ratio of water
in the solvent system enhanced the reaction rate (entries 2–4).12
Similar solvent effect has been observed in our previous study on
the transfer hydrogenation.11 This acceleration effect is probably
due to the intensified hydrophobic interaction between substrates
and the catalyst. When the catalyst having no polyleucine chain
was employed, the efficiency was very low (entry 5). Simple pro-
line TFA salt also failed to catalyze the reaction (entry 6). These re-
sults indicate that the polyleucine moiety in peptide 4 provides a
hydrophobic environment in aqueous media in which the reaction
proceeded efficiently.
Table 3
Substrate scope and reusability of catalyst
3 equiv
Ar-H
Ar
20 mol% TFA 1
NaBH4
CHO
+
R
∗
R
OH
THF/H2O = 1/2, rt
2
3
Entry
1
3
Time (h)
Yielda (%)
eeb (%)
87
Me
N
b
O2N
72
73
OH
We then tried the peptide catalyst 1 having a b-turn inducing D-
Pro-Aib unit (Table 2, entry 1). A high degree of asymmetric induc-
tion was realized at room temperature. This is in sharp contrast
with the imidazolidinone catalyst which requires quite low tem-
perature to obtain a product with high enantioselectivity.3 With
catalyst 5 having no polyleucine chain, the reaction rate and selec-
tivity drastically decreased (entry 2). In the previous paper on the
transfer hydrogenation, we had clarified that (1) the N-terminal
five-residue part of peptide catalyst 1 takes b-turn conformation
with the aid of the polyleucine chain under aqueous conditions,
and (2) high enantioselectivity arose from the effective shielding
of one stereotopic face of the iminium ion intermediate by the rigid
peptide framework.11 It might be reasonable to mention that the
present alkylation underwent through the essentially same mech-
anism as above. The stereochemical outcome of this Friedel–Crafts-
type reaction can be accounted for by the attack of the nucleophile
from less shielded Si face of (E)-anti iminium ion (Fig. 2). Replace-
Me
N
2
3
4
5
6
168
72
56
82
c
OH
Cl
Me
N
52c
d
44
OH
HN
48
84
87
e
f
OH
O2N
ment of one of the two L-Trp residues with D-Trp brought about a
N
dramatic decrease in enantioselectivity (entries 3 and 4). This
might be because the inversion of the asymmetric carbon of the
Trp residue significantly affected the three-dimensional structure
of the whole peptide.
With peptide catalyst 1, the substrate scope of the asymmetric
Friedel–Crafts-type alkylation in aqueous media was investigated
(Table 3).13 The addition of N-methyl indole to 4- or 3-nitrocin-
Me
48
57
77
OH
O2N
Me
N
72
85 (88)d
88 (94)d
a
OH
O2N
7
8
9
10
11
(1st reuse of catalyst)
(2nd reuse of catalyst)
(3rd reuse of catalyst)
(4th reuse of catalyst)
(5th reuse of catalyst)
72
72
72
72
72
74
76
70
70
71
89
90
90
90
88
peptide
N
Ar
a
Isolated yield.
N
b
c
Determined by chiral HPLC analysis using Chiralcel IA unless otherwise noted.
Determined by chiral HPLC analysis using Chiralcel OJ.
Values in parentheses are the results of the reaction performed in H2O.
Me
d
Figure 2. Schematic illustration of the enantiocontrol for the addition.

5604
K. Akagawa et al. / Tetrahedron Letters 50 (2009) 5602–5604
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proceeded even in the absence of THF, an organic co-solvent (entry
6 in parentheses).
In conclusion, the asymmetric Friedel–Crafts-type alkylation in
aqueous media was realized by the N-terminal prolyl peptide cat-
alyst having a polyleucine tether. The hydrophobic polyleucine
chain in the peptide catalyst was essential for the reaction effi-
ciency and enantioselectivity. Because the peptide catalyst used
in this study was effective for the asymmetric transfer hydrogena-
tion we had previously reported, this type of peptide is expected to
have the extendibility to other reactions in aqueous media. A re-
search from such a viewpoint is now underway in this laboratory.
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Acknowledgment
This work was supported in part by Global COE Program, Chem-
istry Innovation through Cooperation of Science and Engineering,
MEXT, Japan.
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Supplementary data
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12. The reaction proceeded smoothly even in water (86% conversion and 21% ee
under the same reaction conditions).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.071.
13. Typical experimental procedure for Friedel–Crafts-type alkylations: To a mixture
References and notes
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