Selective Photoredox Trifluoromethylation of Tryptophan-Containing Peptides

Article abstract of DOI:10.1002/ejoc.201901572

For application in drug discovery and biomedicine, it is crucial to develop new biocompatible methods to modify polypeptides. Herein, a visible-light-induced photoredox trifluoromethylation of tryptophan-containing peptides is reported. Under a mild, biocompatible, and straightforward condition, this strategy could incorporate the trifluoromethyl group into tryptophan residue with excellent chemo- and site-selectivity. The use of lower photocatalyst loading in 2 mol-% and cheap CF₃SO₂Na salt represents a great catalytic activity and economic CF₃ source. This direct trifluoromethylation strategy allows the ready study of fluorinated peptides exploiting ¹⁹F-NMR. Additionally, the development of this protocol enables the study of biochemical systems and potentially modulates the function of biomolecules. Careful mechanistic studies (Stern-Volmer fluorescence quenching, EPR, and radical inhibition/trapping experiments) indicate that the reaction would proceed with a radical–radical cross-coupling procedure.

Full text of DOI:10.1002/ejoc.201901572

A Journal of
Accepted Article
Title: Selective Photoredox Trifluoromethylation of Tryptophan-
containing Peptides
Authors: Bo Ding, Yue Weng, Yunqing Liu, Chunlan Song, Le Yin,
Jiafan Yuan, Yanrui Ren, Aiwen Lei, and Chien-Wei Chiang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901572
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901572
Supported by

10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
Selective Photoredox Trifluoromethylation of Tryptophan-
containing Peptides
Bo Ding,[a] Yue Weng,*[a][b] Yunqing Liu,[a] Chunlan Song,[a] Le Yin,[a] Jiafan Yuan,[a] Yanrui Ren,[a]
Aiwen Lei*[a] and Chien-Wei Chiang*[a]
Abstract: For application in drug discovery and biomedicine, it is
peptides with special properties and functions is attractive to
researchers. In addition, due to the high sensitivity, extreme
responsiveness to the local environment and broad chemical
shift range of the 19F-NMR, fluorinated peptides and proteins can
often be detected by 19F-NMR spectroscopy.10 Although fluorine-
containing biomolecules rarely exist in nature, the 19F-labeled
amino acids can be used to accelerate fluorine-containing drug
design, respond to fundamental biological problems and
illustrate the pharmacological mechanism.11 Furthermore,
fluorine-containing biomolecules could significantly support the
study of a living system and potentially modulate the function of
crucial to develop new biocompatible methods to modify
polypeptides.
Herein,
a
visible-light-induced
photoredox
trifluoromethylation of tryptophan-containing peptides is reported.
Under a mild, biocompatible, and straightforward condition, this
strategy could incorporate the trifluoromethyl group into tryptophan
residue with excellent chemo- and site-selectivity. The use of lower
photocatalyst loading in
2 mol% and cheap CF3SO2Na salt
represents a great catalytic activity and economic CF3 source. This
direct trifluoromethylation strategy allows the ready study of
fluorinated peptides exploiting 19F-NMR. Additionally, the
development of this protocol enables the study of biochemical
systems and potentially modulates the function of biomolecules.
Careful mechanistic studies (Stern-Volmer fluorescence quenching,
EPR, and radical inhibition/trapping experiments) indicate that the
reaction would proceed a radical-radical cross-coupling procedure.
biomolecules.12 Previously, the introduction of fluorine into
biomolecules, such as reports from Davis,6e,
Gouverneur,14
13
Parish and Krska,11 as well as others15 have provided numerous
useful trifluoromethyl synthons with unique properties.
Introduction
Since the exquisite target potency and selectivity of peptides
and proteins, a great interest in drug discovery has shifted to
modify biomolecules, taking on
a
significant role as
pharmaceuticals in the last decade.1 Consequently, it is crucial
to explore the possibility of biomolecular modification for
discovering new therapeutic drugs. The growing importance of
biomolecules has stimulated the chemistry field to develop new
biocompatible reactions for the functionalization and
bioconjugation of biomolecules.2 In a living system, tryptophan
(Trp) is the lowest abundance amino acid with a frequency of
about 1.4%,3 but around 90% of native proteins contain at least
one Trp residue in their sequence.4 Therefore, targeting Trp
residue as well as maintaining structural integrity is a promising
strategy for the modification of biomolecules due to its important
roles.5 Additionally, the C-2 position modification of the indole
group of Trp, such as arylation, alkynylation, and allylation, has
been recognized to be the most facile route of derivatization.6, 7
Within pharmaceutical chemistry, the incorporation of the
trifluoromethyl (CF3) group to medicinal molecules could
enhance the pharmacokinetic properties generally and improve
its surface hydrophobicity, among other benefits.8 Previously,
peptide-based drugs and probes have proven particularly useful
in biology.1, 9 Correspondingly, designing the fluorine-containing
Scheme 1. Trifluoromethylation of Trp residue.
According to the literature, methods of merging the CF3 group
into (hetero)aryl compounds through the radical process have
been reported.16 However, on account of the problem of N-H
interference, only
a
few studies have reported the
trifluoromethylation on Trp (Scheme 1a).6e, 15b, 17 Particularly, the
research of applying the radical trifluoromethylation to the Trp-
containing biomolecules, was reported by the Davis and co-
workers (Scheme 1b).6e Despite the utility of these approaches,
to date, the reports of applying visible-light-induced photoredox
catalytic trifluoromethylation to peptide substrates are still quite
rare.11, 15a Recently, photoredox catalysis has overcome several
problems in traditional organic synthesis. Therefore, this strategy
becomes a powerful tool for synthesizing complex molecules.3, 11,
[a] Bo Ding, Dr. Yue Weng, Yunqing Liu, Chunlan Song, Le Yin, Jiafan
Yuan, Yanrui Ren, Prof. Aiwen Lei, Prof. Chien-Wei Chiang
College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, P. R. China.
E-mail: cwchiang@whu.edu.cn; aiwenlei@whu.edu.cn;
wengyue@whu.edu.cn.
http://aiwenlei.whu.edu.cn/lawsys/
[b] TLS BL23A, National Synchrotron Radiation Research Center.
Hsinchu Science Park, Hsinchu, Taiwan, R. O. C.
Supporting information for this article is given via a link at the end of the
document.
18
Previously, our group has utilized photoredox catalysis for the
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10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
C-H bond activation of organic compounds towards C-C and C-
X bond generation.19 Consequently, we envisioned that a mild
and straightforward pathway to construct the fluorine-tagged
biomolecules would be attained by exploiting the photoredox
2a (Table 1, entry 2). However, using Ru(bpy)3(PF6)2 or Ir(ppy)3
as the photosensitizer delivered only trace amounts of the
corresponding product (Table 1, entries 3 and 4). After that, the
co-solvent effect was also explored. In comparison with CH3CN,
the co-solvent of DMSO displayed poor reactivity, but acetone
showed moderate yield (Table 1, entries 5 and 6). Moreover,
K2HPO4 was added to the reaction as the additive, resulting in a
poor transformation (Table 1, entry 7). In contrast, the weak acid
of HOAc had no effect on the formation of 2a (Table 1, entry 8).
Therefore, these results indicated that the basic system was not
favored in this reaction, and the acidic condition could keep the
generation of the product and inhibit the decomposition of the
indole ring under oxidative conditions.22 Moreover, control
experiments showed that no product could be found in the
absence of light, photocatalyst, or CF3SO2Na (Table 1, entries 9-
11). In addition, the yield was decreased to less than 5% by
using N2 or O2 instead of air (Table 1, entries 12 and 13). The
significant impact of air on the trifluoromethylation reaction,
which led us to realize that as a terminal oxidant, air would be
milder than O2, avoiding the over-oxidization of the reaction
intermediate.23
strategy. In addition, as
a
stable and inexpensive
trifluoromethylation reagent, Langlois reagent (CF3SO2Na) has
been wildly used as the CF3 source in the field of C-H
21
trifluoromethylation.20,
Herein, we reported the visible-light-
induced
trifluoromethylation on tryptophan-containing peptides with
CF3SO2Na. This protocol provided simple, mild, and
photocatalytic
procedure
to
perform
the
a
biocompatible condition for the generation of Trp-CF3 peptides
(Scheme 1c).
Results and Discussion
Our initial experimental efforts focused on the development of
reaction conditions for photocatalytic trifluoromethylation using
CF3SO2Na, as this would provide a mild and direct condition for
introducing the CF3 group into Trp residue. The screening of
photosensitizers and solvents was performed with CF3SO2Na
and Ac-Trp-CO2Me (1a) under the irradiation of blue LEDs at
room temperature. We found that using
2
mol% of
Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the photosensitizer and CH3CN
as solvent under air atmosphere, the desired product 2a could
be observed in 62% yield (Table 1, entry 1). Besides, for
applying to polypeptide substrates, the tolerance of the
photocatalytic conditions to mixed-aqueous systems is essential.
Encouragingly, carrying out the photoredox trifluoromethylation
of 1a in a 1 : 1 mixture of CH3CN : H2O also gave 51% yield of
Table 1. Optimization of the reaction conditions.[a]
Figure 1. The competition experiments of derivatized amino acids analog
revealed chemo- and site-selectivity toward 1a. (For details, see Supporting
Information). Blue columns represent the generation of Trp-CF3; Red columns
represent the generation of Cys-CF3, Phe-CF3, or/and Tyr-CF3.
With the optimized reaction conditions in hand, the residue
selectivity of this photocatalytic trifluoromethylation protocol was
studied. Various amino acid substrates, especially those with
active function groups, were tested by using the optimized
reaction conditions (see Supporting Information). According to
the evidence of 19F-NMR, high levels of trifluoromethylation
products were detected with Trp and cysteine (Cys) as
substrates. On the other hand, low levels of products from
tyrosine (Tyr) and phenylalanine (Phe) appeared as mixtures of
regioisomers. The trifluoromethylation could not occur on
histidine (His) residue. Notably, competition assays using
mixtures of equimolar Cys, Phe, Tyr, or/and His with Trp were
applied to assess residue-specific selectivity (Figure 1). The
results revealed that the selectivity favored achieving the
formation of Trp-CF3. The transformation of 1a was decreased
obviously when the mixture contained His residue, implying that
the His residue might inhibit the reaction process. These results
supported the photoredox trifluoromethylation on Trp was able to
achieve in chemo- and site-selective way.
Entry
1
Variation from standard conditions
CH3CN (2 mL), 4 h
Yield (%)
62 (60[b]
51 (52[b]
trace
trace
5
)
)
2
standard conditions
3
Ru(bpy)3(PF6)2 as the photosensitizer
Ir(ppy)3 as the photosensitizer
DMSO instead of CH3CN
acetone instead of CH3CN
added 1.0 equiv. K2HPO4
added 1.0 equiv. HOAc
no light
4
5
6
47
7
3
8
48
9
n.d.
trace
n.d.
4
10
11
12
13
no Ir photocatalyst
no CF3SO2Na
N2 instead of air
O2 instead of air
5
[a] Reaction conditions: 1a (0.20 mmol), CF3SO2Na (0.40 mmol),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%), CH3CN/H2O (1.5 mL/1.5 mL), air, 3 W
blue LEDs, room temperature, 12 h, 19F-NMR yield. n.d. = not detected;
dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; dtbbpy = 4, 4′-
di-tert-butyl-2,2′-bipyridine. [b] Isolated yield.
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10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
Table 2. Scope of selective trifluoromethylation of polypeptides.[a]
substrates, the results demonstrated the successful
trifluoromethylation of Trp residue as well (4j-4l).
To our delight, the photoredox trifluoromethylation of peptides
could also be tolerated to the mixed-aqueous environment.
While polypeptides were introduced to a 1 : 1 mixed-solvent of
CH3CN : H2O, the reaction could achieve the trifluoromethylation
of Trp in acceptable yields. Notably, these Trp-containing
polypeptides exhibited the excellent trifluoromethylation
selectivity on the Trp residue, which would provide the
opportunity to discover and explore the development of peptide
medicines.
Scheme 2. Gram-scale synthesis experiment.
Additionally, to further explore the utilities of this method, the
gram-scale synthesis experiment was implemented.
A
comparable yield of 63% (1.24 g) was attained when the model
reaction was conducted in 6 mmol (1.59 g) scale (Scheme 2).
This result indicated the potential of promising application in
preparative synthesis.
[a] Reaction conditions: peptide 3 (0.20 mmol), CF3SO2Na (0.40 mmol),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%), CH3CN (2 mL), air, 3 W blue LEDs,
room temperature, 4 h, isolated yield. dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)pyridine; dtbbpy
=
4, 4′-di-tert-butyl-2,2′-bipyridine. [b]
CH3CN/H2O (1.5 mL/1.5 mL) as solvent, 14 h, 19F-NMR yield.
Subsequently, we attempted to investigate the functional
group compatibility of this transformation by applying the
reaction to a range of polypeptides (Table 2). For example,
dipeptides containing relatively inert amino acid partners, such
as glycine, valine, and leucine, afforded the corresponding
products in moderate yields (4a-4c). Besides, when the readily
oxidizable methionine was applied as a dipeptide partner to test
the reactivity, this dipeptide also gave the desired product in 46%
yield (4d). Moreover, dipeptides with aromatic amino acids (Phe
and Tyr) as the neighboring amino acids showed good selective
trifluoromethylation at the Trp residue and provided the
corresponding products in the yields of 58% and 54%,
respectively (4e and 4f). For dipeptides 3g, 3h and 3i, the
adjacent amino acids containing unprotected alcohol or
carboxylic acid group would not interrupt the efficiency and
selectivity of the trifluoromethylation of Trp residue (4g-4i).
Furthermore, when other polypeptides were used as the
Figure 2. EPR spectroscopy. (For details, see Supporting Information).
To get more insight into the reaction mechanism, the
investigations of Stern-Volmer emission quenching experiments,
electron paramagnetic resonance (EPR) spectroscopy and
radical inhibition/trapping experiments have been performed.
The fluorescence intensity of the excited state of
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10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
Ir[dF(CF3)ppy]2(dtbbpy)PF6 could be linearly quenched by Ac-
Trp-CO2Me (1a) and CF3SO2Na individually in the analysis of
Stern-Volmer emission quenching studies (see Figure S6-S8 in
the Supporting Information). Noteworthy, 1a had a more obvious
quenching effect. In the EPR studies, under the irradiation of
blue LEDs, a signal of nitrogen radical of Trp could be detected
in the mixture of 1a and photocatalyst (g = 2.0060, AN = 10.1).
Alternatively, when the radical spin trapping agent DMPO (5,5-
dimethyl-1-pyrroline N-oxide) was presented to the solution of
CF3SO2Na with photocatalyst, a significant signal of CF3 radical
According to the above observations and literature reports, a
plausible
reaction
mechanism
for
this
photoredox
trifluoromethylation of Trp was proposed (Scheme 4).3, 24 Firstly,
the excited state of the photosensitizer (II) would be generated
under the irradiation of the blue LEDs. Afterward, it performed
individually single-electron transfer (SET) oxidation with
CF3SO2Na and Trp (1a), and then produced the CF3 radical and
Trp radical cation species (IV). Subsequently, the reduced state
of the photosensitizer (III) was oxidized to its ground-state I and
completed the photoredox catalytic cycle. Meanwhile, the CF3
radical reacted directly with the Trp radical cation (IV) to form the
intermediate V. After facile deprotonation of the cation
intermediate V, the desired product (2a) could be obtained
eventually. On the other hand, based on the previous reports,6e,
21 we might not exclude the possibility of the CF3 radical addition
with the indole ring of Trp (see Figure S10 in the Supporting
Information).
could also be found with g value of 2.0066 (AN = 13.6 G, AH
=
16.2 G) (Figure 2). In addition, as DMPO was treated to the
model reaction system, we still could observe a CF3 radical
signal in EPR spectroscopy (see Figure S9 in the Supporting
Information).
To further confirm the formation of radical species and the
possibility of radical-radical coupling mechanism. Radical
inhibition/trapping experiments were conducted by adding the
external TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), 1,1-
diphenylethylene, and P(OEt)3 (triethyl phosphite), respectively.
When 2.0 equiv. of TEMPO was added to the reaction solution,
no corresponding product 2a was detected in the resulting
mixture (Scheme 3a). Accordingly, preliminary evidence of the
radical-involved reaction would be verified. In addition, as the
reaction mixture was treated with 1,1-diphenylethylene, an CF3
radical bound adduct 3,3,3-trifluoro-1,1-diphenylpropan-1-ol (5a)
could be identified. Nevertheless, the product 2a was still difficult
to obtain in this system (Scheme 3b). While P(OEt)3 was
introduced to the solution of 1a and photocatalyst, the
diethylphosphonate-bound tryptophan adduct (5b) could be
gained in 23% yield after the irradiation of blue LEDs (Scheme
3c). Therefore, based on the above mechanistic experiments,
we could suppose that the reaction was proceeded by the
radical-radical cross-coupling between Trp radical cation and
CF3 radical. Furthermore, light on/off experiments confirmed the
indispensability of visible light, suggesting that continuous
visible-light irradiation was necessary for the trifluoromethylation
of Trp residue. (see Figure S5 in the Supporting Information).
Scheme 4. Proposed mechanism.
Conclusions
In conclusion, we have introduced a visible-light-induced
photoredox method that allowed direct trifluoromethylation of Trp
and Trp-containing polypeptides without the prefunctionalization
under a mild, biocompatible, and straightforward condition. This
method offered a selective photoredox Trp bioconjugation
strategy, complementing previous reports of Cys and Lys
bioconjugation reactions. Furthermore, this protocol featured
excellent site- and chemo-selectivity, along with good catalytic
efficiency at photocatalyst loading as low as 2 mol%. The
evidence of Stern-Volmer emission quenching studies, EPR
spectroscopy and radical inhibition/trapping experiments could
demonstrate the reaction would proceed through a radical-
radical coupling procedure between the tryptophan radical cation
and CF3 radical. The value of this transformation was highlighted
via the trifluoromethylation of biologically peptides with
CF3SO2Na at room temperature under the easy-handle LED
irradiation.
Scheme 3. The radical inhibition/trapping experiments.
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10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
Hz, 1H), 7.18 - 7.08 (m, 2H), 7.03 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 7.8 Hz,
1H), 4.70 (td, J = 8.1, 5.4 Hz, 1H), 3.86 (d, J = 5.9 Hz, 2H), 3.64 (s, 3H),
3.27 (dd, J = 14.8, 5.4 Hz, 1H), 3.07 (dd, J = 14.8, 8.1 Hz, 1H), 1.83 (s,
3H). 13C NMR (101 MHz, CD3CN) δ 173.2, 171.1, 171.0, 137.2, 128.4,
124.5, 122.3, 119.7, 119.2, 112.2, 111.0, 54.6, 52.5, 41.6, 28.4, 22.9.
HRMS (ESI) calculated for C16H19N3O4, [M+Na]+, 340.1268, found
340.1265.
Experimental Section
General Information. All glassware was oven dried at 110 oC for hours
and cooled down under vacuum. All manipulations were carried out by
using standard Schlenk techniques. Unless otherwise noted, materials
were obtained from commercial suppliers and used without further
purification. The Ir[dF(CF3)ppy]2(dtbbpy)PF6 was prepared following
literature procedures.25 Thin layer chromatography (TLC) employed glass
0.25 mm silica gel plates. Flash chromatography columns were packed
with 200-300 mesh silica gel. Gradient flash chromatography was
conducted eluting with a continuous gradient from dichloromethane to the
ethyl acetate or methanol. All new compounds were characterized by
m.p., IR, 1H-NMR, 13C-NMR and HRMS. The known compounds were
characterized by 1H-NMR and 13C-NMR. The 1H-, 13C- and 19F-NMR
Ac-Trp-Val-OMe (3b):27 White solid. 1H NMR (400 MHz, DMSO-d6) δ
10.83 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.63 (d, J
= 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.06 (t, J =
7.3 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 4.69 (td, J = 8.7, 5.0 Hz, 1H), 4.21
(dd, J = 8.1, 6.4 Hz, 1H), 3.62 (s, 3H), 3.09 (dd, J = 14.7, 5.0 Hz, 1H),
2.91 (dd, J = 14.7, 9.1 Hz, 1H), 2.12 - 2.00 (m, 1H), 1.78 (s, 3H), 0.89
(dd, J = 9.4, 6.7 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 172.3, 172.0,
169.2, 136.1, 127.4, 123.6, 120.9, 118.6, 118.2, 111.3, 110.1, 57.5, 53.1,
51.7, 30.0, 27.8, 22.6, 19.0, 18.4. HRMS (ESI) calculated for C19H25N3O4,
[M+Na]+, 382.1737, found 382.1737.
1
spectra were recorded on a Bruker 400 MHz NMR spectrometer. For H-
NMR, chemical shifts (δ) were given in ppm relatives to the internal
standard (TMS at 0 ppm, DMSO-d6 at 2.50 ppm, CD3CN at 1.94 ppm,
Acetone-d6 at 2.05 ppm). Multiplicities are reported as follows: s = singlet,
d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet,
br = broad. Coupling constants are reported as a J value in Hertz (Hz).
The number of protons (n) for a given resonance is indicated as nH and
is based on spectral integration values. For 13C-NMR, chemical shifts (δ)
were reported in ppm using solvent as internal standard (CDCl3 at 77.16
ppm, DMSO-d6 at 39.52 ppm, CD3CN at 118.26 ppm, Acetone-d6 at
29.84 ppm). High resolution mass spectra (HRMS) were measured with a
Bruker UltiMate3000 & Compact instrument and accurate masses were
reported for the molecular ion + Hydrogen (M+H) or molecular ion +
Sodium (M+Na).
Ac-Trp-Leu-OMe (3c):6f White solid. 1H NMR (400 MHz, DMSO-d6) δ
10.82 (s, 1H), 8.42 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.63 (d, J
= 7.8 Hz, 1H), 7.32 (dt, J = 8.1, 0.9 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 7.10
- 7.03 (m, 1H), 7.02 - 6.95 (m, 1H), 4.59 (td, J = 8.8, 4.8 Hz, 1H), 4.37 -
4.28 (m, 1H), 3.61 (s, 3H), 3.10 (dd, J = 14.7, 4.7 Hz, 1H), 2.88 (dd, J =
14.7, 9.3 Hz, 1H), 1.76 (s, 3H), 1.68 - 1.54 (m, 2H), 1.54 - 1.45 (m, 1H),
0.90 (d, J = 6.3 Hz, 3H), 0.85 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 172.9, 172.1, 169.1, 136.1, 127.4, 123.6, 120.9, 118.6,
118.2, 111.3, 110.1, 53.0, 51.9, 50.3, 38.3, 27.8, 24.2, 22.8, 22.6, 21.4.
HRMS (ESI) calculated for C19H25N3O4, [M+Na]+, 396.1894, found
396.1889.
General Procedure for Synthesis protected amino acids 1a-1e.26 In
an oven-dried round-bottom flask (100 mL), L-amino acid (10 mmol) was
dissolved in anhydrous MeOH (40 mL). Stirred, cooled to 0 °C. Carefully
added SOCl2 (20 mmol) to the solution. The reaction mixture was then
warmed to room temperature and stirred overnight. The solvent was
removed by rotary evaporation to afford amino ester hydrochloride
residue. Without further purification, the residue and triethylamine (20
mmol) was added in anhydrous DCM (40 mL) and stirred for 15 min at
0 °C. Acetyl chloride (10 mmol) was added to the reaction solution
dropwise. Stirring was continued for 12 h while allowing the mixture to
warm up to room temperature. The reaction was washed with saturated
NaHCO3 solutions (50 mL × 2) and 10% HCl (50 mL × 1) to remove any
unreacted starting material. The combined organic extracts were dried
(anhydrous Na2SO4), filtered, and concentrated in vacuo. Then,
purification of the residue by column chromatography on silica gel
(dichloromethane/ethyl acetate) to afford corresponding protected amino
acid 1a-1e.
Ac-Trp-Met-OMe (3d):6f White solid. 1H NMR (400 MHz, CD3CN) δ 9.44
(s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.1
Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.14 - 7.08 (m, 2H)., 7.06 - 6.98 (m,
1H), 4.75 (td, J = 7.8, 5.6 Hz, 1H), 4.53 (td, J = 8.3, 4.8 Hz, 1H), 3.64 (s,
3H), 3.24 (dd, J = 14.7, 5.6 Hz, 1H), 3.08 (dd, J = 14.7, 7.8 Hz, 1H), 2.49
- 2.31 (m, 2H), 2.07 - 2.02 (m, 1H), 2.00 (s, 3H), 1.93 - 1.86 (m, 1H), 1.84
(s, 3H). 13C NMR (101 MHz, CD3CN) δ 173.0, 172.9, 171.2, 137.2, 128.3,
124.6, 122.2, 119.6, 119.2, 112.1, 110.8, 54.7, 52.7, 52.2, 31.5, 30.3,
28.4, 22.9, 15.1. HRMS (ESI) calculated for C19H25N3O4S, [M+Na]+,
414.1458, found 414.1452.
Ac-Trp-Phe-OMe (3e):6f White solid. 1H NMR (400 MHz, CD3CN ) δ 9.37
(s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.38 (dt, J = 8.2, 1.0 Hz, 1H), 7.29 - 7.21
(m, 3H), 7.17 (d, J = 7.8 Hz, 1H), 7.15 - 7.09 (m, 3H), 7.08 - 7.01 (m, 2H),
6.97 - 6.90 (m, 1H), 4.72 - 4.61 (m, 2H), 3.61 (s, 3H), 3.19 (dd, J = 14.8,
5.6 Hz, 1H), 3.10 - 2.98 (m, 2H), 2.93 (dd, J = 13.8, 7.7 Hz, 1H), 1.81 (s,
3H). 13C NMR (101 MHz, CD3CN) δ 172.5, 172.4, 171.1, 137.5, 137.2,
130.1, 129.2, 128.3, 127.6, 124.5, 122.3, 119.7, 119.2, 112.2, 110.9,
54.53, 54.47, 52.6, 37.9, 28.2, 22.8. HRMS (ESI) calculated for
C23H25N3O4, [M+Na]+, 430.1737, found 430.1735.
General Procedure for Synthesis of starting materials dipeptides 3a-
3f.26 In a round-bottomed flask (250 mL), equipped with a stir bar, N-
acetyl-L-tryptophan (5.0 mmol), HOBT (1-hydroxybenzotriazole) (7.5
mmol), HBTU (O-benzotriazole-N, N, N', N'-tetramethyl-uronium-
hexafluorophosphate) (7.5 mmol), dichloromethane (100 mL) and
triethylamine (6.0 mmol) were combined and added. The mixture was
stirred for 30 min at room temperature, and then, L-amino acids methyl
ester hydrochloride (5.0 mmol) and triethylamine (5.0 mmol) were added
to the solution. The reaction was stirred overnight. After regular workup,
the reaction mixture washed by saturated NaHCO3 solution (100 mL x 3),
2 M hydrochloric acid solution (100 mL x 3) and H2O (100 mL x 3). The
organic layers were combined, dried over Na2SO4, and concentrated.
The resulting crude product was purified by flash column
chromatography on silica gel (dichloromethane/ethyl acetate) to afford
corresponding dipeptides 3a-3f.
Ac-Trp-Tyr-OMe (3f):6c White solid. 1H NMR (400 MHz, CD3CN) δ 9.39
(s, 1H), 7.82 (br, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H),
7.18 - 7.09 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.95 -
6.89 (m, 2H), 6.73 - 6.66 (m, 2H), 4.69 (td, J = 7.9, 5.6 Hz, 1H), 4.59 (td,
J = 7.5, 5.7 Hz, 1H), 3.60 (s, 3H), 3.20 (dd, J = 14.8, 5.6 Hz, 1H), 3.04
(dd, J = 14.8, 8.0 Hz, 1H), 2.96 (dd, J = 13.9, 5.8 Hz, 1H), 2.84 (dd, J =
13.9, 7.4 Hz, 1H), 1.82 (s, 3H). 13C NMR (101 MHz, CD3CN) δ 172.54,
172.53, 171.6, 156.7, 137.2, 131.2, 128.3, 128.1, 124.5, 122.3, 119.7,
119.2, 116.0, 112.2, 110.8, 54.72, 54.68, 52.6, 37.1, 28.2, 22.8. HRMS
(ESI) calculated for C23H25N3O5, [M+Na]+, 446.1686, found 446.1684.
Ac-Trp-Gly-OMe (3a):15b White solid. 1H NMR (400 MHz, CD3CN) δ 9.36
(s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.26 (t, J = 5.8
General Procedure for Synthesis of starting materials dipeptides 3g-
3i.26 In a round bottomed flask (250 mL), equipped with a stir bar, N-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
acetyl-L-tryptophan (5.0 mmol), HOBT (7.5 mmol), HBTU (7.5 mmol),
dichloromethane (100 mL) and triethylamine (6.0 mmol) were combined
and added. The mixture was stirred for 30 min at room temperature, and
then, L-amino acids methyl ester hydrochloride (5.0 mmol) whose
residues are protected and triethylamine (5.0 mmol) were added to the
solution. The reaction was stirred overnight. After regular workup, the
reaction mixture washed by saturated NaHCO3 solution (100 mL x 3), 2
M hydrochloric acid solution (100 mL x 3) and H2O (100 mL x 3). The
organic layers were combined, dried over Na2SO4, and concentrated.
Without further purification, the 50% TFA/DCM solution (40 mL) was
4.03 (m, 1H), 3.81 - 3.62 (m, 2H), 3.60 (s, 3H), 3.24 (d, J = 5.7 Hz, 2H),
1.42 (s, 9H), 1.21 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
173.9, 172.4, 169.2, 155.9, 136.2, 127.3, 123.9, 121.9, 119.3, 118.2,
111.6, 109.0, 80.5, 52.7, 52.6, 50.3, 42.8, 28.4, 27.3, 18.4. HRMS (ESI)
calculated for C22H30N4O6, [M+Na]+, 469.2058, found 469.2057.
Boc-Phe-Phe-Trp-OMe (3k): White solid. m.p. 48 - 51 ºC. IR (film)/cm-1
3292, 3061, 2930, 1743, 1648, 1517, 1456, 1383, 1250, 1169, 742, 700.
1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.67 (d, J = 5.8 Hz, 0.16H)
& 8.62 (d, J = 6.9 Hz, 0.78H), 8.11 (d, J = 7.7 Hz, 0.16H) & 8.03 (d, J =
8.0 Hz, 0.76H), 7.52 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.34 -
7.24 (m, 5H), 7.24 - 7.13 (m, 6H), 7.09 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.4
Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.79 - 4.65 (m, 1H), 4.60 (q, J = 7.1 Hz,
1H), 4.23 - 4.12 (m, 0.82H) & 4.12 - 3.99 (m, 0.25H), 3.57 (s, 3H), 3.22
(dd, J = 14.6, 6.3 Hz, 1H), 3.18 - 3.01 (m, 2H), 2.95 - 2.77 (m, 2H), 2.66
(dd, J = 13.8, 10.4 Hz, 1H), 1.29 (s, 7.80H) & 1.11 (s, 1.48H). 13C NMR
(101 MHz, DMSO-d6) δ 172.1, 171.5, 171.2, 155.2, 138.2, 137.5, 136.2,
129.5, 129.2, 128.1, 128.0, 127.2, 126.4, 126.2, 123.9, 121.1, 118.5,
118.1, 111.5, 109.2, 78.2, 55.9, 53.5, 53.3, 51.9, 37.9, 37.7, 28.2 & 27.8,
27.2. HRMS (ESI) calculated for C35H40N4O6, [M+Na]+, 635.2840, found
635.2836.
added dropwise and the mixture was stirred for 2-4
h at room
temperature. When the reaction finished, the reaction mixture was
concentrated in vacuo. The resulting crude product was purified by flash
column chromatography on silica gel (dichloromethane/ethyl acetate) to
afford corresponding dipeptides 3g-3i.
Ac-Trp-Thr-OMe (3g): Pale yellow solid. m.p. 63 - 66 ºC. IR (film)/cm-1
3298, 3060, 2928, 1742, 1653, 1541, 1438, 1206, 744. 1H NMR (400
MHz, DMSO-d6, diastereomer) δ 10.84 (s, 1H), 8.18 (d, J = 8.3 Hz,
0.82H) & 8.13 (d, J = 8.3 Hz, 0.18H), 8.09 (d, J = 8.3 Hz, 0.17H) & 8.02
(d, J = 8.6 Hz, 0.82H), 7.62 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H),
7.15 (d, J = 2.4 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H),
5.03 (d, J = 5.6 Hz, 0.20H) & 5.01 (d, J = 5.9 Hz, 0.76H), 4.69 (td, J =
8.8, 5.1 Hz, 1H), 4.33 (dd, J = 8.4, 3.4 Hz, 0.18H) & 4.29 (dd, J = 8.6, 3.3
Hz, 0.81H), 4.18 - 4.11 (m, 0.25H) & 4.11 - 4.02 (m, 0.80H), 3.64 (s,
2.27H) & 3.63 (s, 0.78H), 3.13 (dd, J = 15.0, 5.7 Hz, 1H), 2.91 (dd, J =
14.5, 9.2 Hz, 1H), 1.78 (s, 2.33H) & 1.77 (s, 0.72H), 1.07 (d, J = 6.4 Hz,
0.46H) & 0.95 (d, J = 6.4 Hz, 2.60H). 13C NMR (101 MHz, DMSO-d6,
diastereomer) δ 172.5 & 172.4, 171.12 & 171.08, 169.2, 136.1, 127.41 &
127.37, 123.6, 120.9, 118.5, 118.2, 111.3, 110.24 & 110.20, 66.4, 57.9 &
57.8, 53.5 & 53.3, 51.9, 28.1, 22.6, 20.1 & 20.0. HRMS (ESI) calculated
for C18H23N3O5, [M+H]+, 384.1530, found 384.1526.
Boc-Gly-Gly-Gly-Trp-OMe (3l): White solid. m.p. 72 - 75 ºC. IR
(film)/cm-1 3314, 3059, 2979, 2932, 1739, 1663, 1528, 1458, 1368, 1251,
1168, 741. 1H NMR (400 MHz, Acetone-d6) δ 7.54 (d, J = 7.8 Hz, 1H),
7.39 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.09 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H),
7.02 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 4.75 (t, J = 6.3 Hz, 1H), 3.92 (d, J =
3.1 Hz, 2H), 3.88 (s, 2H), 3.81 (s, 2H), 3.61 (s, 3H), 3.38 - 3.16 (m, 2H),
1.40 (s, 9H). 13C NMR (101 MHz, Acetone-d6) δ 172.9, 171.7, 170.6,
169.8, 157.2, 137.2, 128.2, 124.7, 122.0, 119.5, 118.9, 112.2, 110.1,
79.7, 53.9, 52.4, 44.6, 43.3, 43.0, 28.5, 28.0. HRMS (ESI) calculated for
C23H31N5O7, [M+Na]+, 512.2116, found 512.2115.
Ac-Trp-Asp-OMe (3h): Pale yellow solid. m.p. 52 - 55 ºC. IR (film)/cm-1
3316, 3059, 2954, 1732, 1647, 1539, 1437, 1229, 744. 1H NMR (400
MHz, DMSO-d6) δ 12.58 (br, 1H), 10.83 (s, 1H), 8.54 (d, J = 7.7 Hz, 1H),
8.11 (dd, J = 8.5, 3.1 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.9
Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.4
Hz, 1H), 4.78 - 4.45 (m, 2H), 3.62 (s, 3H), 3.13 (dd, J = 14.5, 4.6 Hz, 1H),
2.89 (dd, J = 14.4, 9.4 Hz, 1H), 2.75 (dd, J = 16.7, 5.9 Hz, 1H), 2.62 (dd,
J = 16.8, 6.8 Hz, 1H), 1.77 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
172.3, 172.0, 171.8, 169.6, 136.5, 127.8, 124.1, 121.3, 118.9, 118.6,
111.7, 110.5, 53.5, 52.6, 49.1, 36.2, 28.3, 23.0. HRMS (ESI) calculated
for C18H21N3O6, [M+Na]+, 398.1323, found 398.1316.
General Procedure for Photoredox Catalysis Trifluoromethylation of
1a. A solution of methyl N-acetyl-L-tryptophanate 1a (0.20 mmol),
CF3SO2Na (0.40 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%) in
CH3CN/H2O (1.5 mL/1.5 mL) was stirred under air atmosphere and
irradiated by 3 W blue LEDs for 12 h. When the reaction finished, the
reaction mixture was analyzed by 19F-NMR using α,α,α-trifluorotoluene
as an internal standard to determine solution yields. The solvent was
removed under reduced pressure by an aspirator. Then, the pure product
2a was obtained by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 3:1).
Methyl N-acetyl-2-trifluoromethyl-L-tryptophanate (2a):15b White solid.
1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.32
(d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 6.27
(d, J = 8.1 Hz, 1H), 4.98 (dt, J = 8.2, 6.3 Hz, 1H), 3.65 (s, 3H), 3.49 - 3.32
(m 2H), 1.94 (s, 3H). 19F NMR (377 MHz, CDCl3) δ -57.71. 13C NMR (101
MHz, CDCl3) δ 172.3, 170.3, 135.6, 127.3, 124.9, 122.8 (q, JC-F = 36.8
Hz), 122.0 (q, JC-F = 269.8 Hz), 120.8, 119.9, 112.2, 111.7 (q, JC-F = 2.6
Hz), 52.8, 52.6, 27.0, 23.0. HRMS (ESI) calculated for C15H15F3N2O3,
[M+Na]+, 351.0927, found 351.0924.
Fmoc-Ser-Trp-OMe (3i): White solid. m.p. 79 - 81 ºC. IR (film)/cm-1 3327,
3062, 2952, 1724, 1666, 1525, 1450, 1232, 759, 740. 1H NMR (400 MHz,
CD3CN) δ 9.33 (s, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.68 - 7.58 (m, 2H), 7.52
(d, J = 7.9 Hz, 1H), 7.42 - 7.32 (m, 4H), 7.32 - 7.23 (m, 2H), 7.16 - 7.08
(m, 2H), 7.04 (t, J = 7.3 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 4.80 (dt, J =
7.7, 6.0 Hz, 1H), 4.35 - 4.24 (m, 3H), 4.18 (t, J = 7.0 Hz, 1H), 3.87 - 3.68
(m, 2H), 3.58 (s, 3H), 3.43 (br, 1H), 3.33 - 3.19 (m, 2H). 13C NMR (101
MHz, CD3CN) δ 172.9, 171.3, 157.2, 144.83, 144.76, 141.9, 137.1,
128.5, 128.2, 127.9, 126.0, 124.8, 122.4, 120.8, 119.9, 119.1, 112.3,
110.0, 67.5, 63.0, 57.3, 54.1, 52.7, 47.7, 27.9. HRMS (ESI) calculated for
C30H29N3O6, [M+Na]+, 550.1949, found 550.1949.
Methyl N-acetyl-S-trifluoromethyl-L-cysteinate (2e)：15a White solid.
1H NMR (400 MHz, CDCl3) δ 6.84 (d, J = 7.4 Hz, 1H), 4.82 (dt, J = 7.1,
5.0 Hz, 1H), 3.73 (s, 3H), 3.43 (dd, J = 14.3, 4.8 Hz, 1H), 3.27 (dd, J =
14.3, 5.2 Hz, 1H), 2.00 (s, 3H). 19F NMR (377 MHz, CDCl3) δ -41.06. 13
C
General Procedure for Synthesis of starting materials peptides 3j-
3l.26 Refer to the synthesis method of 3a-3f.
NMR (101 MHz, CDCl3) δ 170.4, 170.1, 130.5 (q, JC-F =307.4 Hz), 53.0,
51.8, 31.5, 22.8.
Boc-Ala-Gly-Trp-OMe (3j): White solid. m.p. 74 - 76 ºC. IR (film)/cm-1
3309, 3057, 2978, 2931, 1736, 1663, 1522, 1457, 1367, 1249, 1166, 744.
1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.28
(d, J = 8.0 Hz, 1H), 7.20 - 7.08 (m, 3H), 7.05 (t, J = 7.3 Hz, 1H), 6.97 (d, J
= 2.0 Hz, 1H), 5.45 (d, J = 6.8 Hz, 1H), 4.77 (q, J = 6.3 Hz, 1H), 4.19 -
General procedure for trifluoromethylation of di-, tri- and
tetrapeptides. A solution of peptide 3 (0.20 mmol), CF3SO2Na (0.40
mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%) in CH3CN (2 mL) was
stirred under air atmosphere and irradiated by 3 W blue LEDs for 4 h.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
When the reaction finished, the solvent was removed under reduced
pressure by an aspirator. Then, the product was obtained by flash
column chromatography on silica gel (dichloromethane/ethyl acetate) to
afford corresponding trifluoromethylation of peptide 4.
MHz, CD3CN) δ -58.12. 13C NMR (101 MHz, CD3CN) δ 172.2, 171.5,
170.6, 137.5, 136.6, 130.2, 129.2, 128.0, 127.7, 125.5, 123.1 (q, JC-F
=
269.3 Hz), 123.0 (q, JC-F = 36.7 Hz), 121.22, 121.18, 113.9 (q, JC-F = 2.8
Hz), 112.9, 54.6, 54.4, 52.6, 38.2, 27.4, 22.8. HRMS (ESI) calculated for
C24H24F3N3O4, [M+Na]+, 498.1611, found 498.1616.
Ac-Trp(CF3)-Gly-OMe (4a):15b White solid. 1H NMR (400 MHz, CD3CN) δ
10.18 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.29 (t, J
= 7.6 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 6.0 Hz, 1H), 6.93 (d, J
= 8.6 Hz, 1H), 4.71 (td, J = 8.2, 5.8 Hz, 1H), 3.81 (qd, J = 17.7, 5.9 Hz,
2H), 3.63 (s, 3H), 3.41 (dd, J = 14.5, 5.7 Hz, 1H), 3.18 (dd, J = 14.4, 8.1
Hz, 1H), 1.79 (s, 3H). 19F NMR (377 MHz, CD3CN) δ -58.10. 13C NMR
(101 MHz, CD3CN) δ 172.2, 170.84, 170.79, 136.6, 128.0, 125.4, 123.1
(q, JC-F = 269.3 Hz), 123.0 (q, JC-F = 36.6 Hz), 121.14, 121.11, 113.9 (q,
JC-F = 2.7 Hz), 112.9, 54.5, 52.5, 41.5, 27.6, 22.8. HRMS (ESI) calculated
for C17H18F3N3O4, [M+Na]+, 408.1142, found 408.1141.
Ac-Trp(CF3)-Tyr-OMe (4f): White solid. m.p. 102 - 104 ºC. IR (film)/cm-1
3296, 2956, 1740, 1654, 1517, 1445, 1229, 1166, 1118, 844, 749. 1H
NMR (400 MHz, CD3CN) δ 10.01 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.43
(d, J = 8.3 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.19 - 7.10 (m, 2H), 6.95 - 6.89
(m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.69 - 6.62 (m,
2H), 4.68 - 4.60 (m, 1H), 4.55 - 4.48 (m, 1H), 3.57 (s, 3H), 3.36 - 3.28 (m,
1H), 3.17 - 3.08 (m, 1H), 2.93 (dd, J = 13.9, 5.7 Hz, 1H), 2.82 (dd, J =
13.9, 7.2 Hz, 1H), 1.77 (s, 3H). 19F NMR (377 MHz, CD3CN) δ -58.11. 13
C
NMR (101 MHz, CD3CN) δ 172.3, 171.4, 170.8, 156.7, 136.6, 131.3,
128.3, 128.0, 125.5, 123.1 (q, JC-F = 269.3 Hz), 123.0 (q, JC-F = 36.6 Hz),
121.22, 121.16, 115.9, 113.9 (q, JC-F = 2.9 Hz), 112.9, 54.65, 54.62, 52.6,
37.3, 27.4, 22.8. HRMS (ESI) calculated for C24H24F3N3O5, [M+Na]+,
514.1560, found 514.1560.
Ac-Trp(CF3)-Val-OMe (4b): White solid. m.p. 96 - 98 ºC. IR (film)/cm-1
3281, 3077, 2966, 1743, 1651, 1543, 1438, 1215, 1165, 1118, 748. 1H
NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.10 (t, J = 8.1 Hz, 2H), 7.81
(d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.10
(t, J = 7.4 Hz, 1H), 4.70 (q, J = 7.4 Hz, 1H), 4.29 - 4.11 (m, 1H), 3.55 (s,
3H), 3.27 (dd, J = 14.2, 5.8 Hz, 1H), 3.09 (dd, J = 13.9, 7.4 Hz, 1H), 2.04
- 1.91 (m, 1H), 1.77 (s, 3H), 0.83 (dd, J = 6.8, 5.6 Hz, 6H). 19F NMR (377
MHz, DMSO-d6) δ -56.20. 13C NMR (101 MHz, DMSO-d6) δ 171.7, 171.2,
Ac-Trp(CF3)-Thr-OMe (4g): White solid. m.p. 94 - 97 ºC. IR (film)/cm-1
3292, 2925, 1740, 1649, 1523, 1437, 1383, 1212, 1163, 1116, 745. 1H
NMR (400 MHz, DMSO-d6, diastereomers) δ 11.95 (s, 1H), 8.25 (d, J =
8.9 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.41 (d, J =
8.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.92 (d, J =
6.2 Hz, 0.83H) & 4.88 (d, J = 6.2 Hz, 0.12H), 4.73 (q, J = 7.8 Hz, 1H),
4.15 (dd, J = 8.3, 3.1 Hz, 0.87H) & 4.09 (dd, J = 8.3, 3.1 Hz, 0.21H), 4.05
- 3.94 (m, 1H), 3.62 (s, 2.53H) & 3.61 (s, 0.48H), 3.27 (dd, J = 14.3, 6.2
Hz, 1H), 3.08 (dd, J = 14.0, 7.6 Hz, 1H), 1.78 (s, 0.64H) & 1.77 (s,
2.36H), 0.73 (d, J = 6.4 Hz, 2.56H) & 0.64 (d, J = 6.4 Hz, 0.37H). 19F
NMR (377 MHz, DMSO-d6, diastereomers) δ -56.16 & -56.19. 13C NMR
(101 MHz, DMSO-d6, diastereomers) δ 171.6, 171.0, 169.2, 135.8, 127.1,
124.3, 122.4 (q, JC-F = 270.0 Hz), 121.7 (q, JC-F = 36.2 Hz), 120.7, 119.9,
112.9 (q, JC-F = 2.9 Hz), 112.2, 66.22 & 66.17, 58.0, 53.9, 52.0, 27.3, 22.6
& 22.5, 19.6 & 19.4. HRMS (ESI) calculated for C19H22F3N3O5, [M+Na]+,
452.1404, found 452.1404.
169.2, 135.8, 127.2, 124.2, 122.4 (q, JC-F = 269.7 Hz), 121.8 (q, JC-F
=
36.4 Hz), 120.7, 119.8, 112.8 (q, JC-F = 2.7 Hz), 112.2, 57.4, 53.7, 51.7,
30.4, 27.2, 22.6, 18.9, 18.4. HRMS (ESI) calculated for C20H24F3N3O4,
[M+Na]+, 450.1611, found 450.1609.
Ac-Trp(CF3)-Leu-OMe (4c):White solid. m.p. 211 - 213 ºC. IR (film)/cm-1
3283, 3077, 2958, 1740, 1650, 1545, 1439, 1386, 1211, 1163, 1117, 747.
1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H),
8.05 (d, J = 8.9 Hz, 0.54H) & 7.99 (d, J = 9.0 Hz, 0.12H), 7.83 (d, J = 8.1
Hz, 0.82H) & 7.77 (d, J = 8.3 Hz, 0.15H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 (t,
J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.75 - 4.57 (m, 0.88H) & 4.57 -
4.47 (m, 0.15H), 4.42 - 4.25 (m, 1H), 3.61 (s, 0.44H) & 3.55 (s, 2.60H),
3.28 (dd, J = 14.2, 5.1 Hz, 1H), 3.05 (dd, J = 14.1, 8.3 Hz, 1H), 1.73 (s,
3H), 1.65 - 1.40 (m, 3H), 0.84 (dd, J = 12.8, 6.2 Hz, 6H). 19F NMR (377
MHz, DMSO-d6) δ -56.15. 13C NMR (101 MHz, DMSO-d6) δ 172.73 &
172.71, 171.1 & 171.0, 169.1 & 169.0, 135.8, 127.2, 124.2, 122.4 (q, JC-F
= 269.7 Hz), 121.8 (q, JC-F = 35.4 Hz), 120.7, 119.8, 112.9 (q, JC-F = 2.8
Hz), 112.2, 53.5 & 53.4, 51.9 & 51.8, 50.3 & 50.2, 40.0, 27.2, 24.22 &
24.17, 22.84 & 22.80, 22.60 & 22.56, 21.53 & 21.47. HRMS (ESI)
calculated for C21H26F3N3O4, [M+Na]+, 464.1768, found 464.1760.
Ac-Trp(CF3)-Asp-OMe(4h): Pale yellow solid. m.p. 81 - 84 ºC. IR
(film)/cm-1 3408, 2990, 1712, 1661, 1400, 1273, 1165, 1119, 752. 1H
NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.13
(d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.26
(t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 4.66 - 4.53 (m, 2H), 3.56 (s,
3H), 3.28 (dd, J = 14.5, 4.7 Hz, 1H), 3.02 (dd, J = 14.5, 8.9 Hz, 1H), 2.70
(dd, J = 16.8, 6.2 Hz, 1H), 2.56 (dd, J = 16.8, 6.3 Hz, 1H), 1.69 (s, 3H).
19F NMR (377 MHz, DMSO-d6) δ -56.13. 13C NMR (101 MHz, DMSO-d6)
δ 171.7, 171.2, 170.9, 169.0, 135.7, 127.1, 124.2, 122.3 (q, JC-F = 270.0
Hz), 121.6 (q, JC-F = 36.2 Hz), 120.6, 119.8, 113.0 (q, JC-F = 2.9 Hz),
112.2, 53.5, 52.2, 48.6, 35.8, 27.0, 22.5. HRMS (ESI) calculated for
C19H20F3N3O6, [M+Na]+, 466.1196, found 466.1193.
Ac-Trp(CF3)-Met-OMe (4d):White solid. m.p. 151 - 153 ºC. IR (film)/cm-1
3284, 2924, 1742, 1652, 1523, 1439, 1386, 1213, 1166, 1118, 748. 1H
NMR (400 MHz, CD3CN) δ 10.02 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.44
(d, J = 8.3 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.19 - 7.12 (m, 1H), 6.90 (d, J =
8.0 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 4.67 (td, J = 8.1, 6.4 Hz, 1H), 4.47
(td, J = 8.3, 4.8 Hz, 1H), 3.59 (s, 3H), 3.41 - 3.32 (m, 1H), 3.23 - 3.14 (m,
1H), 2.45 - 2.32 (m, 2H), 2.01 (s, 3H), 2.00 - 195 (m, 1H), 1.89 - 1.81 (m,
1H), 1.79 (s, 3H). 19F NMR (377 MHz, CD3CN) δ -58.10. 13C NMR (101
MHz, CD3CN) δ 172.6, 171.8, 170.6, 136.6, 128.0, 125.5, 123.14 (q, JC-F
= 269.3 Hz), 123.05 (q, JC-F = 36.6 Hz), 121.2, 121.3, 113.9 (q, JC-F = 2.8
Hz), 112.9, 54.6, 52.7, 52.1, 31.9, 30.3, 27.5, 22.9, 15.1. HRMS (ESI)
calculated for C20H24F3N3O4S, [M+Na]+, 482.1332, found 482.1334.
Fmoc-Ser-Trp(CF3)-OMe (4i):White solid. m.p. 91 - 93 ºC. IR (film)/cm-1
3308, 3066, 2954, 1717, 1666, 1521, 1450, 1229, 1165, 1118, 741. 1H
NMR (400 MHz, CD3CN) δ 9.97 (s, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.71 (d,
J = 8.1 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.48 - 7.38 (m, 3H), 7.37 - 7.27 (m,
3H), 7.27 - 7.21 (m, 1H), 7.19 - 7.11 (m, 1H), 5.91 (d, J = 8.0 Hz, 1H),
4.74 (q, J = 7.3 Hz, 1H), 4.33 (d, J = 7.5 Hz, 2H), 4.22 (t, J = 7.1 Hz, 1H),
4.16 - 4.07 (m, 1H), 3.70 - 3.56 (m, 2H), 3.54 (s, 3H), 3.42 - 327 (m, 2H),
3.22 (br, 1H). 19F NMR (377 MHz, CD3CN) δ -58.31. 13C NMR (101 MHz,
CD3CN) δ 172.4, 171.0, 157.0, 145.0, 144.9, 142.0, 136.6, 128.6, 128.0,
127.9, 126.1, 125.7, 123.05 (q, JC-F = 269.2 Hz), 123.04 (q, JC-F = 36.8
Hz), 121.5, 120.9, 120.9, 113.2 (q, JC-F = 2.7 Hz), 113.0, 67.4, 62.9, 57.2,
54.1, 52.8, 47.9, 27.4. HRMS (ESI) calculated for C31H28F3N3O6,
[M+Na]+, 618.1822, found 618.1833.
Ac-Trp(CF3)-Phe-OMe (4e):White solid. m.p. 174 - 176 ºC. IR (film)/cm-1
3292, 3065, 2954, 1740, 1651, 1524, 1444, 1386, 1215, 1165, 1118, 744,
702. 1H NMR (400 MHz, CD3CN) δ 10.00 (s, 1H), 7.72 (d, J = 8.1 Hz,
1H), 7.43 (d, J = 8.3 Hz, 1H), 7.32 - 7.20 (m, 4H), 7.17 - 7.09 (m, 3H),
6.83 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 4.69 - 4.53 (m, 2H),
3.57 (s, 3H), 3.36 - 3.27 (m, 1H), 3.16 - 3.08 (m, 1H), 3.04 (dd, J = 13.6,
5.8 Hz, 1H), 2.91 (dd, J = 13.8, 7.3 Hz, 1H), 1.76 (s, 3H). 19F NMR (377
Boc-Ala-Gly-Trp(CF3)-OMe (4j): White solid. m.p. 86 - 89 ºC. IR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
(film)/cm-1 3296, 3066, 2981, 1740, 1662, 1524, 1455, 1369, 1251, 1165,
1119, 743. 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.61 (d, J = 8.0 Hz,
1H), 7.32 (d, J = 8.2 Hz, 1H), 7.27 - 7.17 (m, 2H), 7.16 -7.03 (m, 2H),
5.36 (d, J = 7.3 Hz, 1H), 4.88 (q, J = 7.0 Hz, 1H), 4.13 (q, J = 7.5 Hz, 1H),
3.85 (dd, J = 17.2, 5.5 Hz, 1H), 3.78 - 3.66 (m, 1H), 3.59 (s, 3H), 3.42 (dd,
J = 14.7, 6.6 Hz, 1H), 3.32 (dd, J = 14.7, 6.7 Hz, 1H), 1.41 (s, 9H), 1.27
(d, J = 6.9 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ -57.74. 13C NMR (101
MHz, CDCl3) δ 173.5, 171.9, 168.8, 155.7, 135.6, 127.2, 124.8, 122.8 (q,
JC-F = 37.4 Hz), 122.0 (q, JC-F = 269.7 Hz), 120.7, 119.8, 112.3, 111.7 (q,
JC-F = 2.8 Hz), 80.3, 53.0, 52.5, 50.3, 42.8, 28.3, 26.9, 18.54. HRMS (ESI)
calculated for C23H29F3N4O6, [M+Na]+, 537.1931, found 537.1929.
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21701127, 21520102003, 21390402), the
Hubei Province Natural Science Foundation of China
(2017CFB152, 2017CFA010), the Fundamental Research
Funds for the Central Universities (213413000050), and the
Scientific Research Foun-dation of Wuhan University
(413100043, 413100021). The Pro-gram of Introducing Talents
of Discipline to Universities of China (111 Program) is also
appreciated.
Boc-Phe-Phe-Trp(CF3)-OMe (4k): White solid. m.p. 167 - 169 ºC. IR
(film)/cm-1 3290, 3064, 2929, 1736, 1644, 1497, 1453, 1248, 1158, 1111,
742, 697. 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.82 (d, J = 7.4
Hz, 0.18H) & 8.77 (d, J = 7.4 Hz, 0.70H), 8.05 (d, J = 7.7 Hz, 0.15H) &
7.97 (d, J = 8.2 Hz, 0.74H), 7.71 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz,
1H), 7.32 - 7.22 (m, 6H), 7.22 - 7.11 (m, 6H), 6.94 (d, J = 8.7 Hz, 1H),
4.71 - 4.60 (m, 1H), 4.59 - 4.49 (m, 1H), 4.19 - 4.08 (m, 0.86H) & 4.08 -
4.00 (m, 0.18H), 3.43 (s, 3H), 3.36 - 3.20 (m, 2H), 3.01 (dd, J = 13.9, 4.9
Hz, 1H), 2.91 - 2.78 (m, 2H), 2.66 (dd, J = 13.6, 10.7 Hz, 1H), 1.28 (s,
7.75H) & 1.11 (s, 1.44H). 19F NMR (377 MHz, DMSO-d6) δ -56.55. 13C
NMR (101 MHz, DMSO-d6) δ 171.43, 171.40, 170.9, 155.2, 138.2, 137.4,
135.7, 129.4, 129.2, 128.1, 128.0, 126.7, 126.4, 126.2, 124.5, 122.2 (q,
JC-F = 269.7 Hz), 121.6 (q, JC-F = 36.4 Hz), 120.2, 119.9, 112.4, 111.8 (q,
JC-F = 2.8 Hz), 78.2, 56.0, 53.4, 51.8, 37.9, 37.5, 28.1 & 27.8, 26.5.
HRMS (ESI) calculated for C36H39F3N4O6, [M+Na]+, 703.2714, found
703.2713.
Keywords: Photoredox • Trifluoromethylation • Tryptophan •
Peptide • chemo- and site-selectivity
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10.1002/ejoc.201901572
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Late-Stage Trifluoromethyl Labeling
of Peptides*
Bo Ding,[a] Yue Weng,*[a][b] Yunqing Liu,[a]
Chunlan Song,[a] Le Yin,[a] Jiafan Yuan,[a]
Yanrui Ren,[a] Aiwen Lei*[a] and Chien-
Wei Chiang*[a]
Visible-light-induced photoredox Trp bioconjugation of peptides with excellent
Visible-light-induced photoredox Trp bioconjugation of peptides with excellent
selectivity in a mild and straightforward condition can be achieved.
Page No. – Page No.
Selective Photoredox
Trifluoromethylation of Tryptophan-
containing Peptides
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.