Photochemical Chemoselective Alkylation of Tryptophan-Containing Peptides

Article abstract of DOI:10.1021/acs.orglett.0c03735

We report a photochemical method for the chemoselective radical functionalization of tryptophan (Trp)-containing peptides. The method exploits the photoactivity of an electron donor-acceptor complex generated between the tryptophan unit and pyridinium sal

Full text of DOI:10.1021/acs.orglett.0c03735

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Letter
Photochemical Chemoselective Alkylation of Tryptophan-
Containing Peptides
§
§
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Benjamin Laroche, Xinjun Tang, Gaetan Archer, Riccardo Di Sanza, and Paolo Melchiorre*
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ABSTRACT: We report a photochemical method for the chemoselective radical functionalization of tryptophan (Trp)-containing
peptides. The method exploits the photoactivity of an electron donor−acceptor complex generated between the tryptophan unit and
pyridinium salts. Irradiation with weak light (390 nm) generates radical intermediates right next to the targeted Trp amino acid,
facilitating a proximity-driven radical functionalization. This protocol exhibits high chemoselectivity for Trp residues over other
amino acids and tolerates biocompatible conditions.
compounds (the acceptor) can form colored EDA complexes
hotocatalysis is attracting increasing interest from the
Pchemistry community, mainly because of its operational through diffusion-controlled association. These new chemical
entities can then be electronically excited upon light
irradiation.
A photoinduced SET then affords a radical ion pair within
the solvent cage. Finally, radical recombination delivers the
product via a proximity-driven radical trap.
simplicity and the potential to promote radical processes under
mild conditions.1 Recent studies demonstrated that visible
light is also useful for promoting chemistry in complex
biological systems.2 Needed for these applications are reactions
that proceed under mild conditions while exhibiting high
functional group tolerance and compatibility in aqueous
environmentsall requirements that photochemistry and
radical reactivity excellently fulfill. For example, photochemical
methods were recently used for the selective peptide and
protein functionalization of natural amino acids by means of
radical processes.3 These strategies for protein bioconjugation4
can play a central role in the development of novel biologically
active protein conjugates for applications in biology and
medicine. The reported photoredox systems generally target
specific amino acids via redox activation based on single-
electron transfer (SET) manifolds.3 However, discriminating
amino acids on the basis of their redox properties can be
difficult, thus leading to undesired off-target modifications at
other residues.
We recently used the EDA complex strategy to promote the
C−H benzylation of 3-substituted indoles 1 (Figure 1b),6
which act as donors in EDA complex formation7 with electron-
deficient benzyl bromides 2. Notably, the indole moiety is the
characteristic structure of the canonical amino acid tryptophan
(Trp). Tryptophan is the rarest of all amino acids (only 1.3%
in occurrence), but it is present in about 90% of all proteins. A
photochemical method targeting this amino acid would
therefore considerably enrich the protein functionalization
toolbox. Previous strategies for Trp functionalization relied on
transition metal catalysts.8 Metal-free approaches were also
developed that mainly capitalized on radical reactivity
manifolds.9 Iridium-based photoredox catalysts have also
been used to promote radical functionalization of Trp.10
To achieve complete selectivity for specific amino acids, we
sought to design a strategy that uses visible light to generate
radicals only in close proximity of the targeted amino acid.
Specifically, we surmised that the photochemical activity of
transiently generated electron donor−acceptor (EDA) com-
plexes5 could serve to achieve this goal (Figure 1a). In this
strategy, electron-rich molecules (the donor) and electron-poor
Received: November 9, 2020
Published: January 5, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03735
© 2021 American Chemical Society
Org. Lett. 2021, 23, 285−289
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Scheme 1. Preliminary Studies: Reaction Performed Using
Equimolar Amounts of 1a and 2a
alkylated dipeptide 3a in 46% yield. A control experiment
established that the absence of light completely suppressed the
reactivity.
These initial studies indicated that our photochemical
strategy could secure the chemoselective functionalization of
the Trp unit under mild conditions and in an aqueous
environment. However, despite extensive efforts (detailed in
section B of the Supporting Information), we could not
increase the overall efficiency of the process using 2a as the
radical precursor.
We therefore evaluated other electron-poor compounds with
a known tendency to serve as acceptors for EDA complex
formation and as radical precursors (see section C5 in the
Supporting Information for details). In particular, using UV/vis
spectroscopic studies, we established that the glycine-derived
Katritzky pyridinium salt7b,13 4a could form a visible-light-
absorbing EDA complex upon aggregation with dipeptide 1a
(see inset in the figure of Table 1, measurement conducted in
DMA). We therefore evaluated if the photoactivity of this EDA
aggregate could drive the selective radical alkylation of Trp
within 1a.
Figure 1. (a) Photochemical EDA complex strategy to generate
radicals. (b) Our previous work on EDA-complex-mediated C2
alkylation of indoles. (c) Proposed photochemical strategy to generate
radicals in close proximity of tryptophan and the resulting
chemoselective functionalization process; SET: single-electron trans-
fer; EWG: electron-withdrawing group.
The experiments were conducted in a DMA/water system
(4:1 ratio, 0.2 M) using 3 equiv of the Katritzky salt 4a, 2 equiv
of NaOAc as the base, and under illumination by a Kessil lamp
emitting at 390 nm, since this setup secured a more reliable
irradiation of the mixture. The reaction was complete after 4 h
to afford the C2 functionalized indole product 5a in 68% yield
Recently, there have been a few reports of photochemical
protocols that do not require the use of an exogenous
photoredox catalyst.11 In particular, a recent study11c exploited
the direct excitation of the indole nucleus within Trp residues
to elicit radical formation and selective functionalization.
However, this approach required irradiation with high-energy
light (λ = 302 nm).
a
Table 1. Optimization Studies
Here, we report the successful implementation of a visible-
light-driven EDA-complex-mediated radical functionalization
protocol for the selective modification of tryptophan in short
peptides (Figure 1c). The chemistry can be performed under
biocompatible conditions (aqueous solvent) and only requires
weak light (λ = 390 nm) as the activating factor. The protocol
exhibits high chemoselectivity for Trp residues over other
amino acids: this is because the underlying EDA complex
mechanism secures the generation of radicals right next to the
targeted Trp amino acid, thus facilitating a proximity-driven
radical functionalization. Overall, the process relies on a
biomimetic mechanism for it exploits the intrinsic tendency of
Trp to form photoactive charge transfer complexes in
biological systems.12
We started our investigations using the simplified dipeptide
Boc-Trp-Ala-OMe (1a) as the model donor substrate (Scheme
1). The choice of the electron-poor 2,4-dinitrobenzyl bromide
2a was informed by its ability to form EDA complexes with
indole frameworks.6 Since our aim was to develop a method
for the chemoselective functionalization of Trp under
biocompatible conditions, the experiments were conducted in
a water/CH3CN mixture (9:1) at ambient temperature. A
simple compact fluorescent light (CFL) bulb was used for
irradiation. These conditions secured the formation of the C-2
b
entry
deviation from standard conditions
% yield
1
2
3
4
5
6
7
none
75 (68)
in DMF/H2O (4:1)
in DMA
no NaOAc
no light
under air
1 mmol scale
70
35
60
0
<5
62 (55)
a
Reactions performed under an argon atmosphere on a 0.1 mmol
b
scale for 4 h using 3 equiv of 4a. Yield of 5a determined by 1H NMR
analysis of the crude mixture using 1,3,5-trimethoxybenzene as the
internal standard; yields of isolated 5a are reported in parentheses.
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(entry 1). The process could be performed in a different
aqueous system maintaining the same efficiency (DMF/water,
entry 2). Interestingly, promoting the reaction in pure DMA
afforded a lower yield (entry 3), highlighting the beneficial
effect of water. The reaction also proceeded in the absence of
base, although with a slightly lower efficiency (entry 4).
Control experiments demonstrated that the reaction requires
light14 and an argon atmosphere to perform well (entries 5 and
6). Conducting the model reaction on a 1 mmol scale only
slightly affected the process’ efficiency (5a formed in 55%
yield, entry 7), demonstrating the practical utility of the
method.
We then evaluated the synthetic potential of this strategy
under the optimized conditions described in Table 1, entry 1.
We examined the reactivity of different Trp-containing
dipeptides 1. We used the pyridinium salt 4b bearing a benzyl
substituent on the ester moiety, since this radical precursor
offered good reactivity and a more straightforward analysis of
the products (Figure 2).
The N-protecting group in 1 could be swapped from Boc to
Fmoc maintaining a useful reactivity (adducts 5b and 5c). N-
Boc protected dipeptides bearing a large variety of amino
acidic residues were selectively alkylated at the C2 carbon of
the Trp unit (products 5d−5n). Substrates containing a
secondary amine and an ester moiety reacted smoothly to
afford the corresponding products 5h and 5i in good yields. A
dipeptide containing a histidine residue could be selectively
functionalized at the indole moiety, albeit with a low yield
(adduct 5j isolated in 20% yield). The protocol also tolerated
oxidizable functionalities, including the hydroxyl groups within
Ser- and Thr-containing dipeptides (products 5k and 5l,
respectively) and the thioether unit of methionine (adduct
5m). The dipeptide Boc-Trp-Trp-OMe, bearing two indole
units, could be efficiently difunctionalized using an excess (6
equiv) of radical precursor 4b (product 5n). In all experiments,
the method’s mild conditions ensured the stereochemical
integrity of the amino acidic residues (a single diastereomer
was consistently formed). In addition, glycine residues
remained untouched in all cases (e.g., product 5o), which
stands in contrast to a recently reported EDA-complex-based
photochemical functionalization method with pyridinium
salts.15 As a limitation of the system, unprotected amino
acidic residues, such as a fully unprotected tryptophan and the
dipeptide Boc-Trp-Asp-OH, did not react under the optimized
conditions. Also a cysteine-containing dipeptide was not
amenable to this functionalization protocol (see Figure S4,
section H in the Supporting Information, which includes a list
of moderately successful and unsuccessful substrates).
In addition to dipeptides, this method was expanded to
include the chemoselective functionalization of more complex
Trp-containing oligopeptides. A tripeptide (Boc-Gly-Gly-Trp-
OMe) and a tetrapeptide (Boc-Gly-Gly-Trp-Leu-OMe) both
offered good reactivity, affording the corresponding products
5p and 5q in 41% and 51% yield, respectively. Overall, the
method secured the selective functionalization of Trp
independently of its position along the peptide sequence, e.g.
Trp located at both the N- and C-terminal positions (products
5o and 5p) or within the peptide sequence (adduct 5q).
We then evaluated the radical precursors 4 suitable for this
photochemical method, using dipeptide Boc-Trp-Ala-OMe 1a
as the model substrate (Figure 3). The pyridinium salts 4 were
readily prepared from amino acid precursors.13
Figure 2. Photochemical chemoselective alkylation: scope of the Trp-
containing peptides. Reactions performed on a 0.1 mmol scale using 3
equiv of 4b. Yields of the isolated products 5 are reported below each
entry (average of two runs per substrate). aUsing 6 equiv of 4b and 4
equiv of NaOAc.
A primary radical precursor derived from CF3-containing
glycinate afforded a good yield (product 6a). Secondary radical
precursors could also be used to alkylate the Trp unit (adducts
6b−6j), although the newly generated stereogenic center could
not be controlled (diastereomeric ratio of about 1:1). A variety
of functional groups were used to adorn the Trp unit within
the final products. Specifically, Katritzky salts derived from
phenylalanine and tyrosine showed good reactivity, affording
the corresponding products 6e−6g. The use of methionine and
Cbz-lysine-derived Katritzky salts allowed a thio and amino
moiety to be installed in adducts 6i−6j, respectively, albeit
with moderate reactivity. A pyridinium salt bearing an N-
cyclohexyl moiety, which would generate a nucleophilic alkyl
radical, remained completely unreacted.16
In summary, we have developed a photochemical method
for the alkylation of tryptophan-containing peptides. The
protocol exhibits high chemoselectivity for Trp residues over
other amino acids, tolerates biocompatible conditions, and
only requires weak light as the activating factor. The availability
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03735
Author Contributions
§B.L. and X.T. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by Agencia Estatal de
■
́
Investigacion (PID2019-106278GB-I00 and CTQ2016-
75520-P), the AGAUR (Grant 2017 SGR 981), and the
European Research Council (ERC-2015-CoG 681840 -
CATA-LUX). X.T. thanks the European Union Horizon
2020 program for a fellowship (PROBIST - H2020-MSCA-
COFUND-2016 n.754510). We thank Miss Sara Kopf (ICIQ)
and Dr. Sara Cuadros (ICIQ) for preliminary investigations
and Dr. Noemí Cabello (ICIQ) for support with High
Resolution Mass Spectrometry measurements.
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ASSOCIATED CONTENT
* Supporting Information
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sı
(6) Kandukuri, S. R.; Bahamonde, A.; Chatterjee, I.; Jurberg, I. D.;
The Supporting Information is available free of charge at
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Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
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́
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Paolo Melchiorre − ICIQ − Institute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain; ICREA, 08010 Barcelona, Spain;
orcid.org/0000-0001-8722-4602; Email: pmelchiorre@
iciq.es
Authors
Benjamin Laroche − ICIQ − Institute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
Xinjun Tang − ICIQ − Institute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
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Gaetan Archer − ICIQ − Institute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
Riccardo Di Sanza − ICIQ − Institute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
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