Small peptide diversification through photoredox-catalyzed oxidative C-terminal modification

Article abstract of DOI:10.1039/d0sc06180h

A photoredox-catalyzed oxidative decarboxylative coupling of small peptides is reported, giving access to a variety ofN,O-acetals. They were used as intermediates for the addition of phenols and indoles, leading to novel peptide scaffolds and bioconjugates. Amino acids with nucleophilic side chains, such as serine, threonine, tyrosine and tryptophan, could also be used as partners to access tri- and tetrapeptide derivatives with non-natural cross-linking.

Full text of DOI:10.1039/d0sc06180h

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Small peptide diversification through photoredox-
catalyzed oxidative C-terminal modification†
Cite this: Chem. Sci., 2021, 12, 2467
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Eliott Le Du, ‡ Marion Garreau‡ and Jerome Waser
´ ˆ
A photoredox-catalyzed oxidative decarboxylative coupling of small peptides is reported, giving access to
a variety of N,O-acetals. They were used as intermediates for the addition of phenols and indoles, leading to
novel peptide scaffolds and bioconjugates. Amino acids with nucleophilic side chains, such as serine,
threonine, tyrosine and tryptophan, could also be used as partners to access tri- and tetrapeptide
derivatives with non-natural cross-linking.
Received 9th November 2020
Accepted 22nd December 2020
DOI: 10.1039/d0sc06180h
rsc.li/chemical-science
Moest in 1902.6 Seebach and coworkers later applied this
method to amino acids and small peptides.7 In the presence of
1. Introduction
methanol or acetic acid, N,O-acetals were generated. Activation
of the N,O-acetals to give versatile N-acyliminium intermediates
I8 then allowed the addition of different nucleophiles (Grignard
Bioactive peptides have gained a lot of attention in the past
decade as therapeutic compounds interacting with receptors or
inhibiting protein–protein interactions. The biological activity
and metabolic stability of native peptides is usually improved by
the introduction of unnatural amino-acids (UAA) and rigid-
ifying elements.1 Moreover bioconjugation between peptides
and other types of synthetic or natural bioactive molecules
opens access to a broader chemical space. This is particularly
interesting for drug discovery as it allows combining the best of
two worlds, such as the higher target affinity of peptides and the
better membrane permeability of small non polar synthetic
compounds.2 This strategy can be used to nely tune the
pharmacological properties of drugs.3 With the ambition to
develop an efficient method for the structural diversication of
peptides, we were interested in the functionalization of the C-
termini of peptides, which can have a fundamental inuence
on their bioactivity.4 In addition, as the C-terminus is unique
and free in most peptides, such an approach would be at the
same time general and selective. Most methods for the modi-
cation of native peptides rely on the specic reactivity of
nucleophilic residues present in amino acids such as cysteine
and lysine, and examples of functionalization of the C-terminus
remain scarce.5
Recently, decarboxylative coupling has emerged as a method
of choice to reach this goal, either via one or two-electron
processes (Scheme 1A). Concerning the latter, the oxidative
decarboxylative conversion of carboxylic acids to alcohols under
electrochemical conditions was already reported by Hofer and
´
Laboratory of Catalysis and Organic Synthesis, Institut des Sciences et Ingenierie
´ ´
Chimique, Ecole Polytechnique Federale de Lausanne, Lausanne, CH-1015,
Switzerland. E-mail: jerome.waser@ep.ch
† Electronic supplementary information (ESI) available: Experimental data. See
DOI: 10.1039/d0sc06180h. Raw data for NMR IR and MS is available at
https://zenodo.org, DOI: 10.5281/zenodo.4384417.
Scheme 1 (A) Decarboxylative functionalization of peptides; (B) our
‡ These authors contributed equally.
photoredox strategy for the synthesis of bioconjugates.
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reagents, phosphites, allylsilanes, terminal alkyne or TMSCN). serine, threonine, tyrosine and tryptophan, giving access to new
In 2020, the Malins group reported an extension of this types of peptide cross-linking for the synthesis of non-natural
approach to more complex peptides for the total synthesis of tri- and tetrapeptides.
analogues of Biseokeaniamides A–C.9
The formation of N,O-acetals could also be achieved using
chemical oxidants, in particular hypervalent iodine reagents.
2. Results and discussions
2.1. Discovery and optimization of the reaction
´
The Suarez group investigated the decarboxylative hydroxyl-
We started our study by exploring the oxidative decarboxylation
of Cbz–Gly–Pro (1a) in presence of methanol as the model
reaction (Table 1). The hypervalent iodine reagent acetox-
ybenziodoxolone (BI-OAc, 2a) was selected as oxidant for the
optimization, due to its recent success in oxidative decarbox-
ylative reactions.30
Based on our work on the alkynylation of peptides using
organic photoredox catalysts,17 4CzIPN (2,4,5,6-tetra(9H-
carbazol-9-yl)isophthalonitrile, 3a) was selected as photo-
catalyst and K2HPO4 as base. To our delight the desired
ation of proline derivatives under visible light using phenyl-
iodine(III) diacetate (PIDA) as oxidant.10 The strategy was later
used by Kita and coworkers on non-cyclic amino-acids, but
using heating instead of light to initiate the oxidation step.11
This method, oen coupled with in situ functionalization of the
acetals, was then applied to amino acids and small peptides.12
The advent of photoredox catalysis contributed to the
development of new strategies for bioconjugation via one–
electron processes (Scheme 1A).13 Starting from native peptides,
C-terminal decarboxylative arylation,14 reduction,15 allylation,16
alkynylation,17 cyanation,18 azidation19 and Giese coupling20
have been described. Decarboxylative coupling reactions can
alternatively be performed by activation of the carboxylic acid
via the formation of a redox-active ester (RAE). Single Electron
Transfer (SET) from a metal complex or from a photocatalyst
then induces the decarboxylation.13d Using nickel complexes,
the Baran group elegantly functionalized peptides through
decarboxylative alkylation,21 alkenylation,22 alkynylation,23
Giese coupling24 and borylation.25 Moreover, photoredox cata-
lyzed decarboxylative arylation,26 thio-27 and selenoarylation28
were also reported. The generation of an a-aminyl radical
intermediate II was involved in all these processes. However, in
the case of the cyanation methodology involving a hypervalent
iodine reagent, computation indicated that the radical was
further oxidized to form an iminium intermediate, constituting
one of the rare cases of two-electron oxidation under photo-
redox catalysis.18
Table 1 Optimization of the oxidative decarboxylation of dipeptides
Decarboxylative photoredox catalyzed C–O bonds formation
has been described only in a few examples of protected amino
acids, and is oen associated with overoxidation to give
amides.29 To the best of our knowledge, the generation of
peptide derived N,O-acetals from free carboxylic acids has never
been reported using photoredox conditions. When considering
that photocatalysis can proceed under milder conditions (room
temperature, visible light, weaker oxidants) and requires less
technical know-how than electrochemistry, such a method
would be highly useful for synthetic and medicinal chemists
requiring modied peptides. Furthermore, the method would
be complementary to existing one-electron approaches: func-
tional group tolerance would be lower, but access to versatile
iminium intermediates would allow extensive diversication of
the products with nucleophiles, leading to different types of
bond formations.
Base
(2 equiv.)
HPLC yielda
(%)
Entry
Solvent
Catalyst
x
1b
2b
3b
4
5
6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
MeCN
DCE
4CzIPN (3a)
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Eosin Y
Rhodamine B
Rose bengal
4DPAIPN (3b)
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
50
50
10
10
5
2
5
5
5
5
5
5
5
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
None
46 (18)c
59
78
82
>95
>95
17
27
35
7
8d
9d
10d
11
12
13
14e
45
Herein, we report
a photoredox catalyzed oxidative-
>95
decarboxylative coupling of small peptides (Scheme 1B). This
methodology allowed the synthesis of modied peptides with
N,O-acetals at the C-terminus, which served as intermediates to
introduce phenols and indoles via Friedel–Cras reactions. The
scope of nucleophiles included alcohols and electron-rich
aromatic residues present in natural amino acids such as
>95 (68)c
>95
None
None
MeCN
0
>95 (75)c
a
b
Ratio of integration at 214 nm by RP-HPLC. Concentration 10 mM.
c
d
e
Isolated yield on 0.3 mmol. Green LEDs. BI-OMe (2b) instead of
BI-OAc (2a).
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methanol N,O-acetal 4a was formed with 50 equivalents of working with methoxybenziodoxolone (BI-OMe, 2b) and the
MeOH in DMF in 46% HPLC yield and 18% isolated yield (entry corresponding N,O-acetal 4a was obtained in 75% isolated yield
1). Changing the photocatalyst to Ru(bpy)3Cl2 slightly increased (entry 14). A slightly higher yield was obtained with 2b but the
the yield (entry 2).31 Decreasing the amount of MeOH in the necessity to pre-form the hypervalent iodine reagent prior to the
reaction mixture and increasing the concentration had a bene- reaction is not desirable for more complex alcohols. Finally,
cial impact on the yield (entries 3 and 4). Full conversion was control experiments were carried out and only traces of the
observed with either 5 or 2 equivalents of methanol (entries 5 desired product were observed in the absence of light or
and 6). For practical reasons, 5 equivalents of methanol were catalyst.
employed for the rest of the optimization, but 2 equivalents only
of alcohols will be used during the investigation of the scope of
2.2. Scope of the oxidative decarboxylation reaction
the reaction.
A robustness test with different protected amino acids present
in the reaction mixture showed a moderate functional group
tolerance,36 setting the basis for the investigation of the scope
(Scheme 2). Previous works based on electrochemistry or
chemical oxidation had focused mostly on the incorporation of
simple alcohols as solvents.7 Our method was already efficient
with only two equivalents of methanol, as well as allyl, propargyl
and benzyl alcohols, to give N,O-acetals 4b–d in 64–98% yield
(Scheme 2A). Functional groups such as cyanide, chloride and
azide were well tolerated and the corresponding N,O-acetals 4e–
g were obtained in 47–91% yield. The introduction of bio-
orthogonal terminal alkyne or azido groups is highly valuable as
it allows to further functionalize the products. The more steri-
cally hindered secondary alcohol (L)-menthol gave the N,O-
acetal 4h in 35% yield.
With those conditions in hand we decided to screen some
organic dyes to accomplish a metal-free process. We thus
selected organophotocatalysts with similar oxidative properties
in the excited state as Ru(bpy)3Cl2 (RuII*/RuI: +0.77 V vs. SCE).32
However, neither Eosin Y (EY*/EYcÀ: +0.83 V vs. SCE),33 rhoda-
mine B (RhB*/RhBcÀ: +0.84 V vs. SCE)34 nor rose bengal (RB*/
RBcÀ: +0.81 V vs. SCE)34 were suitable for the transformation
and degradation of the dyes was observed (entries 7–9). Simi-
larly, despite its promising redox properties, 4DPAIPN (2,4,5,6-
tetrakis(diphenylamino)isophthalonitrile,
3b)
(4DPAIN*/
4DPAINcÀ: 0.90 V vs. SCE)17 only afforded the desired product in
45% yield (entry 10). Unfortunately DMF was not a suitable
solvent for further functionalization of the N,O-acetals. Based
on the reported use of N,O-acetals to generate N-acyliminiums
in MeCN,35 we tested this solvent and full and clean conversion
was observed (entry 11). A control experiment without base was
attempted and full conversion to product 4a was also observed
(entry 12). Under these conditions, N,O-acetal 4a could be iso-
lated in 68% yield on a 0.3 mmol scale. A similar result was
obtained in DCE (entry 13). Interestingly, the reaction was also
The method could be extended to the alcohol-containing
amino acids serine and threonine allowing to access a new
type of cross-linked peptides 4i and 4j in 42% and 38% yield,
respectively (Scheme 2B). Finally the conditions were success-
fully applied to other dipeptides (Cbz–Ala–Ala (1b), Cbz–Gly–
Phe (1c) and Cbz–Pro–Val (1d)) with various alcohols and the
Scheme 2 Scope of obtained N,O-acetals. Reactions performed on 0.3 mmol scale. Yields of isolated products are given. aCompound obtained
with a low diastereoselectivity that could not be determined exactly due to the presence of rotamers.
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N,O-acetals 4k–m were formed in 46–68% yields as mixtures of their reactivity for the direct reaction with nucleophiles
diastereoisomers in the case of 4k and 4m (Scheme 2C).
(Scheme 3).
Based on the report of White and coworkers,37 we examined
the addition of p-cresol in presence of BF3$Et2O as Lewis acid.
While only degradation was observed in MeCN, we were pleased
to observe full conversion of Cbz–Gly–Pro (1a) to Friedel–Cras
product 5a in DCE (Scheme 3A(1), conditions A). Aer the one-
pot two steps procedure 5a could be obtained in 62% yield with
2.3. Functionalization of the N,O-acetals
During our studies on the formation of N,O-acetals we observed
that in absence of alcohol the reaction was still taking place and
N,OAc-acetals were generated. As we could not isolate these
compounds, we wondered whether we could take advantage of
Scheme 3 Scope of the one-pot arylation of dipeptides with phenols and indoles. Reactions performed on 0.3 mmol scale. Yields of isolated
products are given. aCompound obtained with a low diastereoselectivity that could not be determined exactly due to the presence of rotamers.
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complete selectivity for the ortho position. Similarly, electron- substituent in C6 position and a triuoromethyl substituent in
rich para-methoxyphenol could be added to give 5b in 78% C7 position were tolerated and led to the formation of the
yield. Estrone was also compatible with the reaction conditions: desired products 6b and 6c in 66% and 50% yield respectively.
a 7 : 3 mixture of two regioisomers of 5c was obtained in 63% 2-Methylindole could be introduced in 49% yield onto dipeptide
yield with a preference for the position in para to the alkyl 1a. When C3-substituted indoles were employed, N-addition
donating group. Para-methoxyphenol was successfully was the major outcome. For instance, 3-methylindole led to
employed for the arylation of other dipeptides (Cbz–Gly–Phe the formation of 6e in 43% yield. C2-addition was also detected
(1c), Cbz–Pro–Val (1d) and Cbz–Ala–Ala (1b)) to give products in the crude mixture (ratio N/C2-addition 2 : 1), but the corre-
5d–f in 49–64% yield. Cbz–Pro–Gly (1e) could also be arylated at sponding product could not be isolated in pure form. Interest-
the C-terminal position. Electron-withdrawing groups such as ingly, melatonin, which is a hormone helping to regulate the
bromine and uorine were tolerated on the phenol with this sleep–wake cycle and which can be used for short-term treat-
more reactive iminium and the corresponding products 5g and ment of insomnia, was compatible with the reaction conditions.
5h were obtained in 47% and 57% yield respectively. To our Product 6f was obtained in 64% yield. Cbz–Gly–Phe (1c) and
delight phenols in tyrosine were compatible with our method Cbz–Pro–Val (1d) could also be arylated with 1H-indole and the
(Scheme 3A(2)). The addition of Cbz–Tyr–OMe and Cbz–Ala– corresponding products 6g and 6h were obtained in 58% and
Tyr–OMe led to the formation of unprecedented unnatural tri- 64% yields respectively. The tryptophan indoles of Cbz–Trp–
and tetrapeptides 5i and 5j in 37% and 40% yield respectively. OMe and Cbz–Val–Trp–OMe reacted via C–N bond formation to
We were then interested in adding indoles, which are also give the unprecedented unnatural tri- and tetrapeptides 6i and
proteinogenic nucleophiles present in tryptophan. Wang and 6j in 57% and 50% yield respectively (Scheme 3B(2)).
coworkers recently reported an asymmetric Friedel–Cras
Finally, we investigate the extension of our methodology to
reaction between indoles and N-acyl iminiums generated in situ larger peptides (Scheme 4). Ac–Ala–Phe–Gly–Ala (7a) was
by decarboxylation of RAE derived from amino acids.38 selected as model substrate. By increasing the amount of
However, this transformation was not extended to peptides and oxidant and photocatalyst, indole could be added successfully
prefunctionalization of the carboxylic acids was needed. to 7a. The desired modied tetrapeptide 8a was the only
Inspired by conditions reported by our group,35 a one-pot two product observed by HPLC and was obtained in 66% yield (See
steps arylation procedure directly from free carboxylic acids was ESI† for more details). Serine was also tolerated at the C-
developed using a slight excess of indoles and one equivalent of terminus and full conversion towards 8b was observed. A pro-
TFA (Scheme 3B(1), conditions B). Using Cbz–Gly–Pro (1a) as tected amide from asparagine and a protected amine from
model substrate several indoles reacted preferentially at the C3- lysine were moderately tolerated leading to products 8c and 8d.
position. 1H-indole afforded 6a in 66% yield. A chlorine Moreover, more complex unnatural peptides could be obtained
Scheme 4 Preliminary results towards arylation of tetrapeptides. Reactions performed on 1 mmol scale. Relative HPLC ratios of the area of the
product over remaining starting material and peptide side-products at 214 nm are given. Average of 3 independent trials. aCalibrated yield, see SI
for details. bCompound 8c could not be fully separated from a side product by HPLC.
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by reaction with proteinogenic indoles from Cbz–Trp–OMe and
Cbz–Val–Trp–OMe. For instance 8e and 8f were formed in
moderate to good HPLC ratios. Protected aspartic acid, histi-
dine and arginine were also submitted to the reaction condi-
tions and led to the formation of arylated peptides but with
lower HPLC ratios (<25%, see SI for more details).39 Unfortu-
nately, the current conditions for phenols were not compatible
with tetramers and would require further optimization .
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In summary, we have developed a photoredox-catalyzed oxida-
tive decarboxylative strategy towards the introduction of diverse
functional groups on peptides. Under the developed conditions,
valuable alcohols were successfully introduced leading to
structurally diverse N,O-acetals. Moreover, the N,O-acetals were
also employed as key reactive intermediates for arylation with
phenols and indoles. Bioconjugation of bioactive compounds
such as estrone or melatonin with dipeptides was possible.
Additionally, serine, threonine, tyrosine and tryptophan deriv-
atives could be used as nucleophilic partners to give new types
of cross-linked peptides. As a proof of concept for the arylation
of larger peptides, indole and two tryptophan derivatives were
successfully added to several tetrapeptides.
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Acknowledgements
This work is supported by the Swiss National Science Founda-
tion (Grant No. 200020_182798), the NCCR Chemical Biology of
the Swiss National Science Foundation and EPFL. The MS
service from EPFL-ISIC is acknowledged for their support.
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39 A mass corresponding to an enamide obtained from
deprotonation of the iminium intermediate was oen
observed in case of lower yields, but further studies will be
needed to conrm this structural assignment and to
identify other side products.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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