Visible-Light-Mediated Selective Arylation of Cysteine in Batch and Flow

Article abstract of DOI:10.1002/anie.201706700

A mild visible-light-mediated strategy for cysteine arylation is presented. The method relies on the use of eosin Y as a metal-free photocatalyst and aryldiazonium salts as arylating agents. The reaction can be significantly accelerated in a microflow reactor, whilst allowing the in situ formation of the required diazonium salts. The batch and flow protocol described herein can be applied to obtain a broad series of arylated cysteine derivatives and arylated cysteine-containing dipeptides. Moreover, the method was applied to the chemoselective arylation of a model peptide in biocompatible reaction conditions (room temperature, phosphate-buffered saline (PBS) buffer) within a short reaction time.

Full text of DOI:10.1002/anie.201706700

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Visible Light-Mediated Selective Arylation of Cysteine in Batch
and Flow
Authors: Cecilia Bottecchia, Maarten Rubens, Smita Gunnoo, Volker
Hessel, Annemieke Madder, and Timothy Noel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706700
Angew. Chem. 10.1002/ange.201706700
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10.1002/anie.201706700
Angewandte Chemie International Edition
COMMUNICATION
Visible Light-Mediated Selective Arylation of Cysteine in Batch
and Flow
Cecilia Bottecchia[a], Maarten Rubens[a], Smita B. Gunnoo[b], Volker Hessel[a], Annemieke Madder[b] and
Timothy Noёl*[a]
Abstract: A mild visible light-mediated strategy for cysteine arylation
is presented. The method relies on the use of Eosin Y as a metal-free
photocatalyst and aryldiazonium salts as arylating agents. The
reaction can be significantly accelerated in a microflow reactor, whilst
allowing the in situ formation of the required diazonium salts. The
batch and flow protocol described herein can be applied to obtain a
broad series of arylated cysteine derivatives and arylated cysteine-
containing dipeptides. Moreover, the method was applied to the
chemoselective arylation of a model peptide in biocompatible reaction
and proteins.[14] Moreover, several methodologies relying on thiol-
ene[11] (or thiol-yne[15]) reactions have been reported, often
requiring UV irradiation to generate the thiyl radical. Fewer
records in the literature describe the use of transition metals for
cysteine modification. Among them, recent developments
illustrate methodologies for cysteine arylation[16] as well as viable
protocols for cysteine arylation in proteins.[17] Inspired by these
reports, we envisioned that photoredox catalysis could serve our
purpose to obtain a mild and straightforward methodology for
conditions (room temperature, PBS buffer) within a short reaction time. cysteine arylation. Moreover, we hypothesized that highly
electrophilic benzenediazonium salts would be suitable as
arylating agents, able to easily generate aryl radicals (Ered as high
The formation of C–S bonds is of high interest in the fields of
as 0.5V vs SCE) via a SET pathway.[18] The generated aryl
organic synthesis and drug discovery.[1] However, due to the
radicals could then be trapped by the nucleophilic thiol moiety of
undesired coordination between metal catalysts and sulfur atoms,
cysteine.
traditional cross-coupling methods are often inadequate
strategies for C–S bond formation.[2] Despite this, some transition-
Thus, we commenced our investigation with the arylation of N-Ac-
L-cysteine-OMe
1a
using
4-fluorobenzenediazonium
metal catalyzed cross-coupling methods for C–S bond formation
have been reported.[3] However, these methods often rely on high
reaction temperatures and/or require stoichiometric amounts of a
strong base. A well-known strategy largely applied in industry for
C–S bond formation is the so-called Stadler-Ziegler reaction, in
which a diazonium salt is reacted with an aryl thiolate to afford the
desired thioether derivative.[4] Starting from the original conditions
reported by Stadler and by Ziegler, a plethora of methodologies
have emerged, allowing milder reaction conditions.[5] Among them,
our group reported a mild one-pot procedure for the synthesis of
arylsulfides facilitated by photoredox catalysis.[6]
In the interest of developing mild methodologies for chemical
biology purposes[7], we envisaged modifying our procedure to
achieve a visible light-induced protocol for cysteine arylation.
Specifically, we directed our attention towards the development of
a biocompatible metal-free strategy involving inexpensive organic
dyes as photoredox catalysts. In addition, due to the
incompatibility of UV light to peptides and proteins, we reasoned
that visible-light photoredox catalysis would be perfectly suited to
chemical biology applications owing to the milder reaction
conditions (e.g. room temperature and visible light).
tetrafluoroborate in acetonitrile (MeCN) under batch conditions. In
the absence of light and photocatalyst, a modest 26% of the
desired arylated product 3g was obtained within 2 hours reaction
time (Table 1, Entry 1). When exposed to a 24W compact
fluorescence light source (CFL), a similar yield of 25% was
observed, indicating that visible light alone does not significantly
increase aryl radical formation (Table 1, Entry 2). However, in the
presence of Ru(bpy)3Cl2•6H2O (1 mol %) as a benchmark
photoredox catalyst, a higher yield of 40% was obtained (Table 1,
Entry 3). In order to minimize the risks associated with the
handling of potentially explosive diazo intermediates and desiring
to simplify our protocol into a one-pot procedure, we investigated
the in situ formation of the diazonium salt starting from readily
available 4-fluoroaniline, tert-butyl nitrite (t-BuONO, 2.0 equiv.)
and catalytic amounts of tetrafluoroboric acid (HBF4, 1.5 mol %).
Within 2 hours, product 3g could be isolated in an improved 56%
yield (Table 1 Entry 4). Tetrafluoroborate benzenediazonium salts
are easily isolated and exhibit higher stabilities as compared to
diazonium salts bearing other counterions. However, by
implementing the in situ formation of diazonium salts, the
counterion choice appeared less restrictive (i.e. no need to use
BF4 counter-ion to afford shelf-stable diazonium salts). Instead,
we chose to use catalytic amounts of easy-to-handle para-
toluenesulfonic acid (TsOH.H2O), which gave similar results (59%,
Table 1 Entry 5). To develop a biocompatible strategy, we further
tested the possibility to employ an organic dye, Eosin Y, as
photocatalyst for our transformation. Gratifyingly, in the presence
of 1 mol% of Eosin Y, the desired product was obtained in 59%
(Table 1, Entry 6). This is in line with recent reports on the ability
of Eosin Y to be oxidatively quenched by diazonium salts, thus
generating aryl radicals.[19] Further increasing the amount of t-
BuONO to 3 equiv. did not lead to any improvement in yield (Table
1, Entry 7). Solvent screening revealed that the reaction afforded
lower yields in DMSO (15%, Table 1, Entry 8) but proceeded well
in PBS buffer (pH = 8, 46% Table 1, Entry 9), a
Novel selective chemical modifications of peptides and proteins
are of pivotal importance for the study of protein-protein
interactions and for the development of novel bioconjugates and
drug candidates.[8] Compared to other amino acids commonly
targeted for post-translational modifications, cysteine exhibits low
natural abundancy and
a
relatively high nucleophilicity.[9]
Together, these characteristics account for the generally higher
selectivity and the broad reactivity profile typical for post-
translational chemical modifications involving cysteine residues.
Some of the most widespread strategies for cysteine
bioconjugation include disulfide formation,[10] thiol-maleimide
reactions,[11] and alkylation with haloalkyl reagents.[12] Other
strategies use cysteine as precursor for the formation of
dehydroalanine[13] (Dha), or as a handle for nucleophilic aromatic
substitution allowing access to perfluorinated staples in peptides
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10.1002/anie.201706700
Angewandte Chemie International Edition
COMMUNICATION
Table 1: Optimization of Reaction Conditions in Batch for Cysteine Arylationa
increase in product yields can be attributed to the optimal
irradiation of the reaction mixture.[20a]
With optimized conditions in hand, we evaluated the scope of our
protocol both in batch and in continuous flow (Scheme 1). The
arylation reaction tolerated a wide variety of substituents on the
aniline coupling partner. Anilines bearing alkyl substituents
reacted in modest yields in batch to give the corresponding
arylated cysteine derivatives (3a to 3c) and improved yields were
obtained in flow for compounds 3a and 3b. Notably, compound
3d (49% batch vs 61% flow) bearing an alkyne moiety could be of
use for further functionalization of biomolecules through copper-
catalyzed alkyne-azide cycloaddition methods (CuAAC).[23]
Anilines bearing both ortho and para substituents also reacted in
modest to good yields to give the desired arylated derivatives 3e
and 3f (28% and 66% batch vs 73% in flow for 3f). In general, we
observed that electron-deficient anilines gave higher yields as
compared to the electron-rich anilines. This can be attributed to
the difference in reactivity of their corresponding diazonium salts.
In fact, electron-deficient aryldiazonium salts are less stable and
therefore more prone to reduction via SET.[18b] Moreover, a series
of fluorinated derivatives was obtained in good to excellent yields
(3g to 3m). Specifically, para- and ortho-fluoro (3g 59% batch,
82% flow, 3h 70% batch), para- and meta-trifluoromethyl- (3k
60% batch, 89% flow and 3l 81% flow) and trifluoromethoxy- (3m
62% flow) arylated cysteine derivatives were all prepared in good
yields. Additionally, perfluoroarylated derivatives 3i (flow 40%)
and 3j (batch 42%, flow 45%) were synthesized in satisfactory
yields. Similar perfluoroarylated cysteine derivatives have been
reported by Pentelute and co-workers as convenient
intermediates for peptide stapling.[14a, 14b]
Next, we explored the potential of our methodology for Cl, Br and
I containing anilines, as all halogenated derivatives could
represent useful synthetic handles for further peptide
functionalization. Both ortho- and para-Cl derivatives were
obtained in satisfactory yields (3o 78%, 3p 62%) as well as the
ortho-Br derivative 3n (79%). Moreover, para- and meta-I
derivatives were synthesized (3q 35%, 3r 41%) albeit in slightly
diminished yields. The lower yields observed in the presence of
an iodine atom could be explained by considering that iodoarene
moieties are prone to iodine transfer to aryl radicals, thus affording
1,4-diiodobenzene, which we did observe as a significant side
product in our reaction (detected in GC-MS).[19e] Additionally, we
explored the possibility of employing keto- and ester-containing
anilines, thus obtaining para-methyl ketone and ortho-methoxy
ester derivatives 3s (78%) and 3t (75%) in good yields. Finally,
we probed the reactivity of the heterocycle 3-amino-5-Cl pyridine
towards our transformation. Gratifyingly, the pyridine-containing
cysteine derivative 3u was obtained in 69% yield in flow.
Changes from
optimized conditions Yield (%)
Isolated
Entry Light source
Catalyst
1
2
3
No light
CFL
none
none
Pre-made diazonium
Pre-made diazonium
Pre-made diazonium
26
25
40
CFL
Ru(bpy)3Cl2
In situ formation,
HBF4
4
CFL
Ru(bpy)3Cl2
56
In situ formation,
PTSA
5
6
7
CFL
CFL
CFL
Ru(bpy)3Cl2
Eosin Y
59
59
None
In situ formation,
3 eq. tBuONO
Eosin Y
52b
8
9
CFL
CFL
Eosin Y
Eosin Y
Eosin Y
DMSO
PBS
15
46
10
White LEDs
Continuous flow f 79 (92b)
(1a), 4-
aStandard reaction conditions: 0.5 mmol N-Ac-L-cysteine-OMe
fluoroaniline (1.3 equiv), t-BuONO (2.0 equiv), 1.5 mol% TsOH∙H2O and 1 mol%
Eosin Y in 5 ml MeCN (0.1 M), white CFL, 2 hours reaction time. For pre-made
diazonium salts: 4-fluorobenzenediazonium tetrafluoroborate was used in
absence of t-BuONO and TsOH∙H2O. bYield determined by GC-MS with n-
f
decane as internal standard. For detailed flow conditions, see Scheme 1 and
ESI.
commonly used solvent for peptide and protein modifications.
One of the major limitations of photocatalytic reactions conducted
in batch is the inefficient irradiation of the reaction mixture, often
resulting in sub-optimal yields and difficulty of scale-up.[20] In order
to circumvent these issues, we translated our arylation protocol
into a micro-flow procedure. We developed a photomicroreactor
assembly consisting of a 3D-printed holder equipped with 0.45 mL
PFA microcapillary tubing (500 µm ID) and 3.12 W white LEDs
(see ESI for microreactor details).[21] Remarkably, within only a 30
second residence time, 79% of compound 3g was obtained
(Table 1, Entry 10). Due to the evolution of nitrogen gas
(consistent with the reduction of diazonium salts), the formation of
a slug flow was observed, which ensured optimal mixing
efficiency.[22] The significant acceleration of reaction kinetics and
Owing to the ease of scalability, our flow protocol could be easily
employed to obtain arylated cysteine derivatives on gram scales.
Consequently, this notable feature allows one to prepare
sufficient quantities for use in automated solid phase peptide
synthesis (SPPS). As an example, we performed a continuous-
flow scale-up experiment with N-Ac-L-cysteine-OMe 1a (5 mmol)
and 3-trifluoromethylaniline. Within approximately two hours of
operation time, 1.16 g (72%) of derivative 3l was obtained.
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10.1002/anie.201706700
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COMMUNICATION
Scheme 1. Scope of cysteine arylation in batcha and flowb. aReaction conditions batch: 1.0 mmol N-Ac-Cys-OMe (1a), aniline (1.3 eq), t-BuONO (2 mmol),
1.5mol %TsOH∙H2O and 1mol% Eosin Y in 10 ml ACN (0.1 M), white CFL, 2 h reaction time; bReaction conditions flow: 2.0 mmol N-Ac-Cys-OMe (1a), aniline (1.3
eq), t-BuONO (2 mmol), 4 mol %TsOH∙H2O and 1mol% Eosin in 40 ml ACN (0.05 M), white LED light, 30 seconds residence time; Reported yields are isolated
yields [average of two runs]; c60 seconds residence time, d150 seconds residence time. eGram scale experiment in continuous flow (5 mmol scale)
Encouraged by the results obtained for the arylation of N-Ac-L-
Cys-OMe, we prepared a small array of cysteine-containing
dipeptides to test the compatibility of our methodology with simple
model peptides. Therefore, four dipeptides (4 N-Boc-L-Ala-L-Cys-
OMe, 5 N-Boc-L-Leu-L-Cys-OMe, 6 N-Boc-L-Trp-L-Cys-OMe and
7 N-Boc-L-Phe-L-Cys-OMe) were prepared in solution via native
chemical ligation, and were subjected to our arylation protocol
(Scheme 2).[24] Satisfyingly, N-Boc-L-Ala-L-Cys-OMe afforded the
corresponding arylated dipeptides 8a (60%), 8b (56%) and 8c
(42%) in good yields. Similarly, good yields were obtained with N-
Boc-L-Leu-L-Cys-OMe for derivatives 9a to 9d. A remarkable
acceleration and increase in yield was observed when the
arylation of N-Boc-L-Leu-L-Cys-OMe was conducted in flow.
When attempting the arylation of N-Boc-L-Trp-L-Cys-OMe, we
found the presence of indole to be incompatible with the in situ
diazonium formation.[25] However, when pre-formed diazonium
salt was added to N-Boc-L-Trp-L-Cys-OMe, the corresponding
arylated derivative 10a was obtained in 39% yield. Finally, N-Boc-
L-Phe-L-Cys-OMe afforded the corresponding arylated derivative
11a in 55% yield.
In order to further demonstrate the utility of our methodology, we
focused our attention on performing our arylation strategy on
more complex peptide substrates. However, we anticipated that
the in situ formation of diazonium salts might be incompatible with
the delicate nature of peptides and proteins. Keen to adapt our
protocol to biologically relevant reaction conditions, we tested the
possibility of employing pre-made diazonium salts and aqueous
phosphate buffer (pH = 8) for our cysteine arylation. Thus, we
applied our arylation protocol under these mild reaction conditions
on peptide 12, which was used upon resin cleavage without
further purification. In the presence of para-F benzenediazonium
salt tetrafluoroborate or para-OCF3 benzenediazonium
tetrafluoroborate, full conversion to the desired products 13 and
14 was achieved within 30 minutes as detected by LC/MS
(Scheme 3). Notably, no selectivity issues were observed in
presence of lysine and serine residues, and no organic solvent
was required, thus demonstrating the excellent compatibility of
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10.1002/anie.201706700
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COMMUNICATION
Scheme 1: Arylation of cysteine-containing dipeptides in batcha and flowb: aReaction conditions for dipeptide arylation in batch are the same as for the arylation
of N-Ac-L-cysteine-OMe but on 0.25 mmol scale. bReaction conditions for dipeptide arylation in flow are the same as for the arylation of N-Ac-L-cysteine-OMe but
on a 1 mmol scale. cFor Trp-Cys pre-made 4-tBu benzenediazonium tetrafluoroborate was used. d150 seconds residence time.
22b]
intermediates.[20a,
An array of arylated cysteine derivatives
decorated with a broad range of substituents was obtained in
moderate to good yields (17 examples, 28-79%). The
implementation of a microflow reactor afforded faster reaction
times and increased yields (30 to 150 seconds residence time, 11
examples, 45-89% yield). Moreover, a diverse set of cysteine
containing dipeptides was arylated successfully in batch and in
flow (12 examples, 32-86% yield). The reaction was easily scaled-
up, affording more than one gram of the arylated cysteine
derivative within 2 hours of total operation time. Finally, in
biologically relevant conditions, a model peptide containing
additional nucleophilic side chains was selectively converted to its
Cys-arylated derivative within 30 minutes. Taking into account the
simplicity of our reaction conditions (atmospheric conditions,
visible light irradiation, short reaction time), we believe that our
procedure will be appealing to chemical biologists for post
translational chemical modification of cysteine.
Scheme 2: Arylation of a cysteine-containing peptide: 1 eq of crude peptide
12 (0.47 μmol), 10 eq diazonium salt, 1 mol% Eosin Y in 1 mL PBS buffer (pH
= 8), white CFL, 30 min reaction time.
Acknowledgements
The authors would like to thank Mark van den Bosch for the
preparation of diazonium salts. C.B and T.N acknowledge the
European Union for a Marie Curie ITN Grant (Photo4Future,
Grant No. 641861). Further financial support for this work was
provided by a VIDI grant (T.N., SensPhotoFlow, No. 14150).
S.B.G thanks Flanders Innovation & Entrepreneurship for funding.
Financial support from BOF-UGent and IOF-UGent is further
gratefully acknowledged.
our protocol with other common post translational modification
methods involving these residues.
In conclusion, we reported a one-pot protocol for cysteine
arylation via visible light photoredox generation of aryl radicals
from their corresponding diazonium salts. In situ formation of
diazonium salts starting from readily available anilines reduces
the risks associated with the handling of potentially explosive
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COMMUNICATION
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Keywords: cysteine arylation • continuous flow • photoredox
catalysis • diazonium salts • visible light
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10.1002/anie.201706700
Angewandte Chemie International Edition
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Entry for the Table of Contents
Cecilia Bottecchia[a], Maarten Rubens[a], Smita B. Gunnoo[b], Volker Hessel[a], Annemieke Madder[b]
and Timothy Noёl*[a]
Page No. – Page No.
Visible Light-Mediated Selective Arylation of Cysteine in Batch and Flow
A mild visible light-mediated strategy for cysteine arylation is presented. The method relies on the use of Eosin Y as metal-free
photocatalyst and aryldiazonium salts as arylating agents. The batch and flow protocol described herein afforded a series of arylated
cysteine derivatives and arylated cysteine containing dipeptides. The method was also applied to the chemoselective arylation of a
model peptide in biocompatible reaction conditions.
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