Merging visible-light photoredox and Lewis acid catalysis for the functionalization and arylation of glycine derivatives and peptides

Article abstract of DOI:10.1039/c2cc36995h

A relay catalysis protocol for the functionalization of α-amino acids and dipeptides using a combination of visible-light photoredox and Lewis acid catalysis has been developed. The Royal Society of Chemistry.

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Merging visible-light photoredox and Lewis acid catalysis for the
functionalization and arylation of glycine derivatives and peptidesw
Shaoqun Zhu and Magnus Rueping*
Received 26th September 2012, Accepted 23rd October 2012
DOI: 10.1039/c2cc36995h
A relay catalysis protocol for the functionalization of a-amino acids
and dipeptides using a combination of visible-light photoredox and
Lewis acid catalysis has been developed.
glycine derivatives and peptides as substrates has not been
reported due to the known occurrence of radical mediated
oxidations as documented for biological systems.11 The oxidation
of peptides and proteins can lead to misfolding, functional
inactivity, alteration or aging and has been associated with
diabetes, atherosclerosis and neurodegenerative diseases. Besides
side chain oxidations, peptide backbone modifications and
fragmentations involving the formation of a-carbon radicals
and their subsequent reaction with oxygen are the most often
observed transformations (Scheme 1b).11 In natural systems
these destructive reactions can be catalyzed by metals and
enzymes or may be caused by light irradiation. Thus, we were
aware that these obstacles also needed to be overcome for
visible-light photoredox catalyzed reactions employing a-amino
acids and peptides. However, such an extension would be highly
desirable as it would not only allow the functionalization of
glycine derivatives and dipeptides but more importantly it
would extend photoredox catalyzed C–H functionalizations
beyond the use of tertiary amines (Scheme 1c). In addition,
the successful accomplishment would possibly allow post-
transitional modifications of peptides and proteins. Based on
The development of highly efficient strategies for rapid access
to a-amino acid derivatives and peptides is of great importance
and remains a challenging area in organic synthesis. Classical
procedures for the construction of amino acids include the
Strecker, Ugi and Petasis reactions.1 However, catalytic methods
for the direct modification of glycine derivatives are rare and for
peptides even more so.
Li and co-workers have developed an elegant site-specific
C-functionalization of arylglycine derived peptides using CuBr
as a catalyst and TBHP as an oxidant.2 Their system can be
applied to arylglycine amides and arylglycine esters as well.
Xie and Huang reported a dual catalytic system consisting of
Cu(OAc)2 and pyrrolidine for the oxidative functionalization
of arylglycine esters with various cyclic and acyclic ketones.3
Recently, Wang and co-workers described the DDQ oxidation
of arylglycine esters to imine intermediates which are trapped
in situ with activated carbonyl nucleophiles yielding highly
functionalized products.4 The above reactions all follow a
regular synergistic pattern which requires the oxidation of
secondary amines to imines and the activation of nucleophiles
respectively (Scheme 1a). Inspired by the single electron
transfer (SET) oxidation mechanism of the above reactions,
and the SET capability of visible-light photo-catalysts in the
oxidation of tertiary amines, we questioned whether visible-
light photocatalysis is applicable to the C–H functionalization
of glycine derivatives and peptides. According to previous
studies5 as well as recent research into the field of visible light
photoredox catalyzed functionalization of tertiary amines,6–10
highly reactive iminium ion intermediates are generated in situ
and intercepted by nucleophiles to yield the corresponding
functionalized products. However, efficient photoredox mediated
reactions are hitherto limited to tertiary amines, with tetrahydro-
isoquinoline as the most frequently used substrate. The use of
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany.
E-mail: Magnus.Rueping@rwth-aachen.de;
Fax: +49 (0)241-809-2665
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc36995h
Scheme 1 Design of the relay strategy for the functionalization of
glycine derivatives by a combination of visible-light photoredox and
Lewis acid catalysis.
c
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Chem. Commun.

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our earlier work regarding the functionalization of tertiary
amines, we decided to investigate a dual catalytic protocol
combining Lewis acid and visible-light photoredox catalysis
(Scheme 1c). After photocatalytic oxidation of the secondary
amine, the Lewis acid catalyzed imine formation with concurrent
activation for subsequent nucleophilic attack should suppress the
undesired side reactions and enable the formation of the modified
amino acids and peptides.
Table 2 Scope of indoles and glycine esters
Entrya R1
R2
R3
R4
3
Yieldb (%)
In order to validate our hypothesis and to explore the
feasibility of the dual catalytic procedure, initial reactions
concentrated on the modification of glycine derivatives using
indoles as nucleophiles. The effect of different Lewis acids was
investigated and the results are summarized in Table 1.12 When
Sc(OTf)3, Bi(OTf)3 and copper salts were used, only traces of the
desired product 3a were obtained or no reaction was observed
(Table 1, entries 2–7). A satisfactory yield of 72% was obtained
when 10 mol% Zn(OAc)2 was used (Table 1, entry 14). In some
cases, the double Friedel–Crafts/dehydration product 4a was
observed which is similar to what we previously described for
the addition of indoles to b,g-unsaturated a-keto esters.13 Different
solvents and different light sources (Table 1, entries 15 and 16)
were also tested, however, no improvement was observed.14
With the best reaction conditions established, we next
investigated the scope of this protocol by employing a variety
of glycine derivatives 1 and indoles 2 (Table 2). Initially,
different ester groups (OMe, OEt, OiPr, OtBu and OBn) were
tested and proved to give the corresponding products in good
yields (Table 2, entries 1–5, 45–83%). Interestingly, when the
ester group was replaced by a keto group the desired product
was not obtained (Table 2, entry 6). Furthermore, different
electron-donating (Me and OMe) and electron-withdrawing
groups (Cl and Br) on the aromatic ring of the arylglycine
esters were tested and proved to be compatible under the
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-Cl
H
OEt
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
—
72
71
73
45
83
—
67
75
56
65
82
70
50
OMe
OiPr
OtBu
OBn
Ph
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
5-CO2Me 3f
5-CN
5-F
2-Ph
6-Me
5-Me
2-Me
7-Me
5-I
5-OMe
5-Br
H
H
H
H
5-Br
H
H
H
—
3g
3h
3i
3j
3k
3l
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
27
28
3m 86
3n
3o
3p
3q
3r
52
69
54
42
60
55
68
68
76
74
76
71
—
—
H
TBS
Me
Me
OEt
OBn
3s
3t
OtBu Me
OMe Me
3u
3v
3w
3x
3y
—
—
OEt
OEt
H
H
H
—
4-OMe OEt
Me
Me
Me
OMe
OMe COPh
OMe COMe
H
H
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [Ir(ppy)2bpy]PF6
1 mol%, Zn(OAc)2 10 mol%, 11 W fluorescent bulb, MeCN (2.0 mL),
b
c
30–72 h. Yield of the isolated product. 1,3,5-Trimethoxybenzene
was used instead of indoles.
Table 1 Evaluation of different Lewis acids in the photoredox
catalyzed functionalization of ethyl 2-(p-tolylamino)acetate
applied conditions. Indoles with various substituents at different
positions could also be applied under the standard conditions
(Table 2, entries 7–25). In contrast to the free 1H-indoles, and
N-Me and N-TBS derivatives, which gave the corresponding
products in good yields (Table 2, entries 16–22), indoles bearing
electron-withdrawing groups (COMe and COPh) on the nitrogen
failed to give the corresponding products (Table 2, entries 27
and 28). This can be attributed to the decrease in nucleophilicity
of indoles due to electron-withdrawing substituents on the
nitrogen. As an electron-rich aromatic nucleophile, 1,3,5-tri-
methoxybenzene was tested and gave the corresponding product
in 71% yield (Table 2, entry 26).
Entrya
Lewis acid
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
CuBr
CuCl
CuI
Cu(OAc)2
Cu(OTf)2
Sc(OTf)3
Bi(OTf)3
ZnCl2
48
48
48
48
48
48
48
48
24
48
24
48
48
48
48
48
Trace
Trace
Trace
—
Trace
Trace
—
Trace
57% 3a, 33% 4a
31% 4a
64% 3a
10% 3a, 67% 4a
Trace
72% 3a
64% 3a
61% 3a
To extend the scope of our protocol further, we next turned
our attention to dipeptides, which are typically difficult to
modify and are prone to oxidative cleavage (Scheme 1b).
Therefore, we were most delighted to see that the reaction of
ethyl 2-(2-(p-tolylamino)acetamido)acetate 5a with indoles
under the above conditions provided the desired product 6a.14
In order to improve the conversion and the yield, the reaction
parameters were optimized by testing other Lewis acids and
varying the catalyst loading. However, the various copper and
zinc Lewis acids (10 mol%) tested failed to increase the yield.
Nevertheless, with 1.0 equivalent of Zn(OAc)2 the corresponding
9
10
11
12
13
14
15c
16d
ZnBr2
ZnI2
Zn(NO3)2
Zn(OTf)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Ir(ppy)2bpy]PF6
1 mol%, Lewis acid 10 mol%, 11 W fluorescent bulb, MeCN (2.0 mL).
b
c
Yield of the isolated product. 5 W fluorescent bulb. 2.4 W blue LED.
d
c
Chem. Commun.
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Table 3 Scope of indoles and glycine derived dipeptides
amino acids and peptides. Further studies, employing different
peptides and nucleophiles in this new combined photoredox and
Lewis acid catalysis protocol, are currently in progress.
S.-Q. Zhu is grateful to the CSC (Chinese Scholarship
Council) for a fellowship.
Notes and references
Entrya
R3
R4
R5
6
Yieldb (%)
1 (a) A. Strecker, Ann. Chem. Pharm., 1850, 75, 27–45; (b) I. Ugi,
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1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
H
Me
Me
TBS
H
H
H
2-Ph
6-Me
7-Me
2-Ph
5-Br
5-Br
H
Et
Me
iPr
Et
6a
6b
6c
6d
6e
6f
6g
6h
6i
60
66
63
52
62
76
50
55
51
68
Et
Et
iPr
Et
iPr
Et
6j
a
Reaction conditions: 7 (0.2 mmol), 2 (0.3 mmol), [Ir(ppy)2bpy]PF6
(1 mol%), Zn(OAc)2 1.0 equiv., MeCN (2.0 mL), 11 W fluorescent
b
bulb 48 h. Yield of the isolated product.
8 (a) M. Rueping, C. Vila, R. M. Koenigs, K. Poscharny and
D. C. Fabry, Chem. Commun., 2011, 47, 2360–2362; (b) M. Rueping,
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9615–9617; (d) M. Rueping, S. Zhu and R. M. Koenigs, Chem.
Commun., 2011, 47, 12709–12711; (e) M. Rueping, R. M. Koenigs,
K. Poscharny, D. C. Fabry, D. Leonori and C. Vila, Chem.–Eur. J.,
2012, 18, 5170–5174.
Scheme 2 Proposed mechanism for the relay catalysis.
product was isolated in 60% yield. In addition, various
substituted glycine derived dipeptides 5 and indoles 2 were
subjected to the optimized conditions and the corresponding
arylated dipeptides were obtained in moderate to good yields
(Table 3). It is worth mentioning that no peptide degradation
has been observed with this combined catalysis protocol.
A catalytic cycle for the present transformation is proposed
in Scheme 2. Upon irradiation, IrIII+ is excited to IrIII+* and
reductively quenched by A to produce IrII+ and radical cation
B via SET oxidation. Subsequently, the radical amine cation B
is converted into intermediate C, an a-carbon hydroperoxide
or hemi aminal, which under the influence of the Lewis acid
catalyst forms the activated electrophile D. Reaction with the
nucleophile gives the functionalized product E. In addition A
can also react with the generated superoxide anion to give C.
In conclusion, we have developed for the first time a relay
catalysis protocol for the C–H functionalization of glycine deriva-
tives and glycine derived dipeptides by combining visible-light
photoredox catalysis and Lewis acid catalysis. Importantly the
generation and activation of the imine intermediates can only be
achieved by applying this combined catalysis approach and neither
over oxidation to a-oxo esters nor peptide fragmentation has been
observed. The results reported not only demonstrate the use of
secondary amines in photoredox catalysis but also pave the way for
the use of other nucleophiles for direct a-amino acid and peptide
modification. The operational simplicity and practicability, as well
as the mild reaction conditions using visible light as the energy
source promote the protocol as an attractive way to functionalize
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10 For latest reviews on photoredox catalysis directed towards
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12 In the absence of Lewis acid, the oxidized glycine was the major
product. See also copper catalyzed oxidations: J.-C. Wu,
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Angew. Chem., Int. Ed., 2012, 51, 3453–3457.
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14 see ESIw.
c
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Chem. Commun.