Cu-Catalyzed Site-Selective C(sp2)-H Radical Trifluoromethylation of Tryptophan-Containing Peptides

Article abstract of DOI:10.1021/acs.orglett.0c00033

Site-selective functionalization of C-H bonds within a peptide framework poses a challenging task of paramount synthetic relevance. Herein, we report an operationally simple C(sp²)-H trifluoromethylation of tryptophan (Trp)-containing peptides. This fluorination technique is characterized by its chirality preservation, tolerance of functional groups, and scalability and exhibits chemoselectivity for Trp residues over other amino acid and heterocyclic units. As a result, it represents a sustainable tool toward the late-stage peptide modification and protein engineering.

Full text of DOI:10.1021/acs.orglett.0c00033

pubs.acs.org/OrgLett
Letter
Cu-Catalyzed Site-Selective C(sp2)−H Radical Trifluoromethylation
of Tryptophan-Containing Peptides
Itziar Guerrero and Arkaitz Correa*
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ABSTRACT: Site-selective functionalization of C−H bonds within a peptide
framework poses a challenging task of paramount synthetic relevance. Herein,
we report an operationally simple C(sp2)−H trifluoromethylation of
tryptophan (Trp)-containing peptides. This fluorination technique is
characterized by its chirality preservation, tolerance of functional groups,
and scalability and exhibits chemoselectivity for Trp residues over other
amino acid and heterocyclic units. As a result, it represents a sustainable tool
toward the late-stage peptide modification and protein engineering.
he straightforward chemical modification of biomolecules
remains an unmet challenge that has profound
permeability and its robustness toward oxidative metabolism.12
Although CF3 cross-coupling technologies have lately under-
gone an impressive development, C−H trifluoromethylation
reactions13 of peptides are rare. Merck laboratories have
disclosed the trifluoromethylation of tyrosine-containing
peptides under photoredox catalysis,14 and Li has used UV
light irradiation15 for the fluorination of a number of
heterocycles, including a couple of examples of Trp derivatives.
More recently, Langlois reagent (NaSO2CF3)16 has been used
for the modification of Trp-containing peptides under Ir-based
catalysis; likewise, Davis and co-workers reported the
trifluoromethylation of proteins such as melittin and
myoglobin with huge excess of oxidant (up to 25 equiv).17
Accordingly, we sought that trifluoromethylated oligopeptides
could be within reach by a more practical functionalization
event featuring base metal catalysis under mild reaction
conditions. Driven by the major breakthroughs in the field
by Baran18 and MacMillan,19 among others,20 we envisioned a
process harnessing the innate chemical reactivity21 of the
electron-rich indole motif to undergo site-specific incorpo-
ration of in situ formed electrophilic trifluoromethyl radicals.
As part of our interest in sustainable catalysis,5a,22,23 we report
herein the discovery of a new catalytic C−H trifluoromethy-
lation protocol, which features a previously unrecognized
opportunity in the field of sustainable late-stage peptide
modifications.
T
implications in chemical biology, proteomics, and drug
discovery.1 In this respect, the manipulation of native peptides
in a tailored fashion has received a great deal of attention given
the often improved biological activities and pharmacokinetics
of the resulting engineered biomolecules.2 The past decade has
witnessed the development of cutting-edge methods toward
the predictable activation of otherwise unreactive C−H bonds
as latent functional groups within peptide settings.3 The
functionalization of C(sp3)−H bonds has been extensively
studied;4 conversely, relatively few methods are available for
the parent C(sp2)−H functionalization of aromatic side chains
of peptides.5 As a result, the development of novel techniques
for the rapid diversification of aromatic amino acid residues
within a peptide framework constitutes a prime goal of utmost
interest in the drug discovery space.
Despite its low natural abundance in native proteins,
tryptophan (Trp) featuring the indole motif represents an
ideal platform for the design of postsynthetic transformations
of peptides. Ackermman,6 Fairlamb,7 and Albericio and
Lavilla8 have elegantly introduced C2-arylation, alkynylation,
and alkylation reactions of Trp-containing peptides.9 Although
of great importance, they are restricted to a reduced set of
reactions and mostly utilize expensive precious metals. In this
light, Ackermann has recently introduced C−H directed
allylation reactions of conveniently N-substituted-Trp deriva-
tives featuring cost-efficient cobalt10a and manganese10b
catalysis. Inspired by the emerging trends in sustainable
development,11 we envisioned that the use of earth-abundant
copper catalysts could offer new vistas in the field and hence
increase our synthetic toolbox for the introduction of other
coupling partners into Trp-containing peptides.
We commenced our studies by exploring the radical
trifluoromethylation of N-Ac-Trp-OMe (1a) with the Langlois
reagent as the model reaction (see Table 1). The method
developed by Baran18c featured the use of bench-stable
Received: January 3, 2020
The incorporation of a CF3 group into a given biomolecule
can dramatically modify its physical and biological properties,
thereby resulting in the enhancement of the cellular membrane
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© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
important to note that exclusion of air was not required, and
the reaction tube was simply sealed with a plastic cap to
prevent solvent evaporation, which constitutes an additional
bonus in terms of operational simplicity. HPLC analysis
verified that the reaction took place with preservation of the α-
center chirality,24 and crystallographic analysis of 2a confirmed
that the absolute stereochemistry was identical to that of the
starting Trp residue.24 Notably, the process could be
performed in gram-scale with a remarkable 75% yield, thus
highlighting the synthetic utility and robustness of our radical
functionalization method.
Table 1. Cu-Catalyzed C−H Trifluoromethylation of 1a
b
entry
change from standard conditions
2a (%)
c
1
none
78 (75)
2
without (NH4)2S2O8
0
52
30
76
78
36
30
60
79
61
0
With the optimized conditions in hand, we next examined
our oxidative alkylation in the challenging setting of peptides.
Notably, a number of Trp-containing dipeptides were
selectively trifluoromethylated in the C2 position of the Trp
residue in the presence of Phe (2b,l−m), Gly (2c,i), Ser (2d),
Thr (2e), Leu (2f,j), Asp (2g), Ala (2h), Val (2k), Pro (2n),
Ile (2o), Sar (2p), Lys (2q), Met (2r), and Tyr (2s) units
(Scheme 1). Of tremendous importance is the tolerance of
oxidizable protic free-hydroxyl groups of Ser- and Thr-
containing dipeptides (2d and 2e, respectively) as well as
thioether of Met-containing peptide 2r.25 Importantly, a wide
range of N-protecting groups boded well, and peptides
protected with Boc-, Ac-, Fmoc-, Cbz-, and even Ts-groups
smoothly underwent the corresponding radical trifluorome-
thylation reaction. The success of the method did not rely on a
specific situation of the Trp along the peptide sequence and
was applicable to Trp residues located at both the N- and C-
terminal positions. We next evaluated the robustness of the
trifluoromethylation technique for the late-stage diversification
of more complex oligopeptides. In this respect, it efficiently
provided tripeptides 2t and 2u in 79% and 68% yields. Other
related tripeptides (2v,w) were obtained in moderate yields.
Remarkably, the innate trifluoromethylation of oligopeptides of
high structural complexity was illustrated by the efficient
assembly of trifluoromethylated tetra- and pentapeptides 2x
and 2y in good yields. Our trifluoromethylation manifold could
occur not only at Trp units located at N- and C-terminal
positions but also within peptides bearing Trp units in inner
positions (2w and 2x). It must be highlighted that the use of a
copper catalyst did not result in the presence of significant
amounts of metal impurities within the trifluoromethylated
peptides, and ICP-MS analysis of some representative samples
verified that amounts lower than 4 ppb remained in certain
samples.24 In this regard, the metal-free reaction conditions
which provided 2a in 65% yield were applied for a number of
Trp-containing peptides (Scheme 1); however, the Cu-
catalyzed protocol afforded comparatively higher yields in all
cases, thus illustrating the clear benefits derived from the use of
a Cu catalyst in this transformation. The chemoselectivity of
the method was further illustrated by the C2-selective
trifluoromethylation of a wide range of diversely substituted
Trp derivatives 3a−q. As shown in Scheme 2, a variety of
sensitive functional groups were accommodated such as
tetrahydrofuryl ring (4c), aliphatic carboxamides (4j,k), or
alkyl cyano groups (4h,i). One of the most notable aspects of
using ammonium persulfate as the oxidant was the full
tolerance to commonly oxidizable C(sp3)−H in adjacent
positions of oxygen26 (4d) or nitrile groups27 (4h,i). Likewise,
the predictable nature of the present innate trifluoromethyla-
tion was underpinned by the inherent reactivity of the indole
ring to undergo preferential C−H trifluoromethylation in the
presence of 1,2,3-triazoles (4f) or pyridines (4d,e), which have
3
4
without Cu(OAc) under Ar
without Cu(OAc)
5
6
Cu(OAc)2 instead of Cu(OAc)
50 mol % of Cu(OAc)
7
8
9
10
11
12
13
14
15
CoBr2 instead of Cu(OAc)
AgOTf instead of Cu(OAc)
Na2S2O8 instead of (NH4)2S2O8
under Ar
at rt instead of 40 °C
at rt instead of 40 °C without Cu(OAc)
NaSO2CF3 (2.0 equiv)
49
26
65
NaSO2CF3 (1.0 equiv)
without Cu(OAc), (NH4)2S2O8 (4 equiv), 60 °C
a
Reaction conditions: 1a (0.25 mmol), NaSO2CF3 (0.75 mmol),
Cu(OAc) (10 mol %), (NH4)2S2O8 (0.50 mmol) in DMSO (0.125
M) at 40 °C for 24 h under air. Yield of isolated product after
column chromatography. Experiment performed with 1.0 g of 1a.
b
c
NaSO2CF3 as the surrogate for gaseous CF3I and was found
efficient for the innate trifluoromethylation of a vast array of
heterocycles including melatonin, which contained the indole
ring.
However, its application18c to the functionalization of 1a
provided the target product 2a in just 21% yield, hence
showing the subtleties of the modification of the Trp residue.
After considerable experimentation,24 we found that the
combination of Cu(OAc) (10 mol %), NaSO2CF3 as the
trifluoromethyl source, and (NH4)2S2O8 as the oxidant in
DMSO as the solvent at 40 °C under air provided the best
results, giving rise to 2a in 78% yield (entry 1). Control
experiments in the absence of either oxidant (entry 2) or
copper catalyst (entries 3, 4, and 12) underpinned their critical
role in the radical trifluoromethylation. Despite the crucial role
of Cu(OAc) at room temperature, at 40 °C the reaction can
also occur to some extent in its absence (entries 11 and 12).
Moreover, whereas the presence of air seemed to enhance the
reactivity of the copper catalyst, the parent metal-free process
took place in lower yields under an air atmosphere (entries 3
and 4). Intrigued by this experimental finding, we performed a
number of experiments to critically analyze the role of the
copper source. Increasing the catalyst loading did not result in
higher yields of 2a (entry 6), and while Cu(OAc)2 proved to
be equally efficient to Cu(OAc) (entry 5), other copper, cobalt
(entry 7), or silver sources (entry 8) were shown
comparatively less active catalysts.24 Further experiments
enabled a metal-free synthesis of 2a in 65% yield (entry
15),24 although higher temperature and huge excess of oxidant
were required. The nature of the solvent had a profound effect
in the reaction outcome, and the best results were obtained in
DMSO. Importantly, inexpensive (NH4)2S2O8 was the oxidant
of choice and provided higher yields than commonly used tert-
butyl hydroperoxide or related hazardous peroxides.24 It is
B
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a b
,
Scheme 1. Cu-Catalyzed C(sp2)−H Trifluoromethylation of Trp-Containing Oligopeptides
a
b
c
d
As for Table 1, entry 1. Yield of isolated product after column chromatography, average of at least two independent runs. 48 h. Reaction
conditions: 1 (0.25 mmol), NaSO2CF3 (0.75 mmol), (NH4)2S2O8 (1.0 mmol) in DMSO (0.125 M) at 60 °C for 24 h under air.
been efficiently trifluoromethylated by related radical techni-
ques.18−20 Importantly, a primary amine (4a) or carboxylic
acids (4l,m), which are prevalent motifs in native peptides,
could be also accommodated. Furthermore, the compatibility
of the process in structurally more intricate contexts was
demonstrated by using Trp derivatives bearing biologically
relevant molecules and active pharmaceuticals, including those
derived from fatty acids (palmitic and oleic acid, 4o and 4p,
respectively), ibuprofen (4n), and aspirine (4q).
Collectively, the Cu-catalyzed C−H trifluoromethylation of
enantiomerically pure Trp-containing peptides proceeded with
excellent site- and chemoselectivity, and it represents a
prototypical example of innate modification in which the
incorporation of the electrophilic radical species is biased by
the innate reactivity of the indole ring. In order to gain some
insights into the reaction mechanism, we carried out several
control experiments with 1a as the model system. We found
that the trifluoromethylation of 1a was suppressed in the
presence of radical traps such as TEMPO and BHT, which
revealed that a radical pathway may be operative (Scheme 3).
In particular, the performance of the process in the presence of
diphenylethylene resulted in the isolation of compound 5 in
10% yield, and not even traces of product 2a were detected.
Accordingly, the intermediacy of electrophilic trifluoromethyl
radical species was reasonably assumed to be a plausible
scenario. On the basis of the above results and previous
reports,17 a reaction mechanism is proposed in Scheme 3. The
reaction would start with the Cu(I)-assisted redox decom-
position of peroxydisulfate ion28 to provide the sulfate radical
anion SO4•−, which is a very strong one-electron oxidant. The
latter would react with CF3SO2 to deliver CF3SO2 , which
would further release SO2 and the active trifluoromethyl radical
species. The indole ring of the Trp residue 1 would next
undergo an electrophilic aromatic substitution at the C2
position, followed by reoxidation of the resulting radical
intermediate IntA to the corresponding carbocation IntB.17,18
Eventually, aromatization of the indole moiety would afford
the targeted product 2. It must be commented that the group
of Baran18c has observed that traces of metal impurities often
remain in the commercially available Langlois reagent; the
latter may initiate the corresponding persulfate cleavage toward
the production of the transient trifluoromethyl radical species
when performing the process in the absence of the copper
catalyst.29
−
•
C
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Scheme 2. Cu-Catalyzed C(sp2)−H Trifluoromethylation of
Scheme 3. Control Experiments and Mechanism Proposal
a b
,
Trp Derivatives
anticipate that our Cu-catalyzed trifluoromethylation process
could become a new platform for the introduction of
metabolism blocking fluoroalkyl groups in a late-stage fashion
of utmost importance in the field of bioconjugation, thus
providing access to new peptide entities beyond those found in
native proteins.
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00033.
Experimental procedures, syntheses, and character-
ization of all new compounds, and tables with details
of several optimization studies (PDF)
Accession Codes
CCDC 1952460 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
■
Corresponding Author
Arkaitz Correa − University of the Basque Country (UPV/
EHU), Department of Organic Chemistry I, Joxe Mari Korta
́
R&D Center 20018 Donostia-San Sebastian, Spain;
orcid.org/0000-0002-9004-3842; Email: arkaitz.correa@
ehu.eus
a
b
As for Table 1, entry 1. Yield of isolated product after column
chromatography, average of at least two independent runs.
Author
Itziar Guerrero − University of the Basque Country (UPV/
In summary, we have developed a practical radical
trifluoromethylation of Trp-containing oligopeptides with the
readily available Langlois reagent. The mildness of the reaction
conditions, advantageous use of nonprecious first row copper
catalyst, inexpensive persulfate oxidant, avoidance of chlori-
nated solvents, and performance under open-air conditions
provide the method attractive features to greatly enhance the
sustainability in late-stage drug development. Therefore, we
EHU), Department of Organic Chemistry I, Joxe Mari Korta
́
R&D Center 20018 Donostia-San Sebastian, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00033
Notes
The authors declare no competing financial interest.
D
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Letter
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ACKNOWLEDGMENTS
■
We are grateful to MINECO (RTI2018-093721-B-I00) and
the Basque Government (IT1033-16) for financial support.
I.G. thanks the Basque Government for a predoctoral
fellowship. We are thankful for technical and human support
provided by SGIker of UPV/EHU and European funding
(ERDF and ESF). Cost-CHAOS action (CA15106) is also
acknowledged.
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