Late Stage Phosphotyrosine Mimetic Functionalization of Peptides Employing Metallaphotoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.1c01200

Access to phosphotyrosine (pTyr) mimetics requires multistep syntheses, and therefore late stage incorporation of these mimetics into peptides is not feasible. Here, we develop and employ metallaphotoredox catalysis using 4-halogenated phenylalanine to afford a variety of protected pTyr mimetics in one step. This methodology was shown to be tolerant of common protecting groups and applicable to the late stage pTyr mimetic modification of protected and unprotected peptides, and peptides of biological relevance.

Full text of DOI:10.1021/acs.orglett.1c01200

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Letter
Late Stage Phosphotyrosine Mimetic Functionalization of Peptides
Employing Metallaphotoredox Catalysis
Hao Chen, Runyu Mao, Martin Brzozowski, Nghi H. Nguyen,* and Brad E. Sleebs*
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ABSTRACT: Access to phosphotyrosine (pTyr) mimetics requires multistep syntheses, and therefore late stage incorporation of
these mimetics into peptides is not feasible. Here, we develop and employ metallaphotoredox catalysis using 4-halogenated
phenylalanine to afford a variety of protected pTyr mimetics in one step. This methodology was shown to be tolerant of common
protecting groups and applicable to the late stage pTyr mimetic modification of protected and unprotected peptides, and peptides of
biological relevance.
yrosine phosphorylation is a reversible post-translational
Tmodification that underpins signal transduction pathways
controlling a wide range of biological processes including cell
differentiation, proliferation, and apoptosis.1,2 A number of
peptides and peptidomimetics that contain phosphotyrosine
(pTyr) have been designed to modulate dysregulated signaling
transductions for disease treatment.3−5 Their application in
drug discovery, however, has been limited, as the pTyr
phosphate group is rapidly cleaved by phosphatases in the cell.
To combat this drawback, many pTyr mimetics have been
designed that are resistant to cellular enzyme hydrolysis.6
Methods to generate pTyr mimetic building blocks require
multistep syntheses (Scheme 1) and then require incorpo-
ration into functionalized peptides or peptidomimetics most
often by solid phase peptide synthesis (SPPS).7,8 A common
example of a pTyr mimetic is the 4-phosphonomethyl
phenylalanine (Pmp) which has been used in peptides
designed to target the Src homology 2 (SH2) domains of
Grb2 and PI 3-kinase, and protein tyrosine phosphatases.8−10
The para-carboxymethyl phenylalanine (pCMF) is another
monocharged pTyr mimetic that has been incorporated into a
peptide to target the SH2 domain of Lck.11
solution phase methods and high consumption of amino acid
building blocks. It is also challenging to synthesize peptides
with nonproteinogenic modifications on a large scale by SPPS,
due to the complexity of synthesis or high cost of purchasing
nonproteinogenic amino acids. To address this problem, late-
stage modification of peptides has emerged as a valuable
strategy for the design and synthesis of peptidomimetics by
introducing diverse chemical functionalities onto the peptide
chain directly.13−18
Traditional methods of pTyr mimetic synthesis require
multiple steps and harsh conditions (Scheme 1) and therefore
are not suitable for late-stage peptide modification.7,8 Recent
developments in photoredox cross-coupling methods have
enabled the formation of C(sp3)−C(sp2) bonds in one step
under mild conditions,19−25 allowing their application to late-
stage peptide functionalization.26 Relevant to the synthesis of
pTyr mimetics, the MacMillan group recently described an
efficient dual photoredox/nickel-catalyzed strategy for the
Received: April 8, 2021
Published: May 24, 2021
SPPS is a powerful and convenient technique to synthesize
peptides or peptidomimetics by building a peptide chain
iteratively on solid support.12 Despite its convenience, SPPS
still has inherent limitations, such as low yield relative to
https://doi.org/10.1021/acs.orglett.1c01200
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4244−4249
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a
Scheme 1. Traditional Methods of pTyr Mimetic Synthesis
Table 1. Reaction Optimization
and Related C(sp3)−C(sp2) Photochemical Reactions
reductant/
b
d
entry
photocatalyst
base
solvent conversion
1
2
3
4
5
6
7
8
9
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
DIPEA
Et3N
HE
HE/DIPEA
HE/Et3N
HE/DIPEA
HE/DIPEA
HE/DIPEA
HE/DIPEA
HE/DIPEA
DMA
DMA
DMA
DMA
DMA
DMF
NMP
MeCN
DMSO
DMF
21
26
12
78
64
86 (73)
72
70
59
76
10
[Ir(dF(CF3)ppy)2
(dtbbpy)]·PF6
11
12
13
−
HE/DIPEA
−
HE/DIPEA
DMF
DMF
DMF
24
0
0
4CzIPN
4CzIPN
c
a
Reaction conditions: NiBr2·DME (10 mol %), 4,4′-dtbbpy (15 mol
%), PC (2.5 mol %), reductant (6 equiv), solvent (0.1 M), blue LED,
b
c
d
16 h, rt. Mixed reductant system (3 equiv/3 equiv). No light.
%
conversion was determined by LCMS using acetophenone as the
internal standard. The value within parentheses refers to the isolated
yield. TFA = trifluoroacetamide.
S1), reactions without reductant or light source did not afford
any product (entries 12 and 13).
We then applied the optimized conditions (Table 1, entry
6), to explore the reaction scope with common N- and C-
terminal protecting groups on the 4-iodo substituted Phe
substrate 4 to access the pCMF mimetic scaffold 5 (Scheme
2). Universally applied N-terminal protecting groups including
Cbz, Fmoc, and Boc (5a, 5c and 5e) were all well tolerated
(>70% yields) when the C-terminus was protected as a methyl
ester. The method was also tolerant of unprotected N-terminal
amino esters with 5f isolated in a 45% yield. In addition, N-
cross-coupling of α-chloro carbonyls with aryl halides (Scheme
1).27 Later, Mao et al. also reported a dual-catalyzed C(sp3)−
C(sp2) reductive cross-coupling method using 2,4,5,6-tetra-
(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as the photo-
catalyst (PC) and Hantzsch ester (HE) as the reductant using
α-chloro esters and aryl iodides (Scheme 1).28 However, both
of these methods have not been applied to single amino acids
or late stage peptide modification. Herein, we report on an
adaptation of the photoredox/nickel-catalyzed C(sp3)−C(sp2)
cross-coupling methodology to synthesize pTyr mimetic
building blocks and pTyr mimetic modified peptides by late
stage functionalization.
Scheme 2. Reaction Scope with a Variety of Common N-
a
and C-Terminal Protecting Groups
Our study began with the synthesis of the pCMF pTyr
mimetic using N- and C-protected 4-iodo substituted phenyl-
alanine 1 and tert-butyl chloroacetate 2 as model substrates.
Inspired by Mao’s work,28 we chose 4CzIPN and DMA as the
starting PC and solvent. Mixtures of different bases and
reductants were screened (entries 1−5) (Table 1), and the
combination of HE and DIPEA gave the protected pCMF
mimetic 3 with the highest rate of conversion (entry 4, 78%).
Next, several commonly used solvents including NMP, DMSO,
MeCN, and DMF (entries 6−9) were evaluated. Of the
solvents trialed, DMF was shown to give the best conversion
(entry 6, 86%), and the product (3) was isolated in a 73%
yield. The iridium photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]·
PF6 was also tested (entry 10), and it delivered similar
conversion compared to 4CzIPN. Given 4CzIPN was easier to
access in our laboratory, we selected this PC for the remainder
of this study. Interestingly, reactions in the absence of PC still
provided the product because HE itself was likely participating
as the PC (entry 11), consistent with previously reported
observations.29 In line with our mechanistic hypothesis (Figure
a
Isolated yields are reported.
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protected substrates with no carboxylic acid protection were
also converted into the desired products (>50%, 5b and 5d),
demonstrating the utility of this method to afford building
blocks than can be directly applied to solution phase synthesis
or SPPS. Furthermore, no epimerization was observed under
the reaction conditions (Figure S2), further highlighting the
applicability of this protocol in peptide research.
optimized conditions (Table 1, entry 6) were applied to the
model dipeptide (8a), a complex mixture of products was
observed by LCMS together with low conversion to the
desired product 9a. The major byproduct in the mixture had a
mass associated with DMF participating in the reaction. Aryl
halides are known to afford amino carbonylation products
under Ni-catalysis conditions,30,31 providing precedence for the
observed DMF coupled byproduct. Notably, the amino
carbonylation product was not observed in the initial screening
experiments (Table 1), indicating there was a competing side
reaction when peptide substrates were used. To circumvent
this competing pathway when using DMF as solvent, we
sought a new solvent system that was compatible with
photoredox conditions and provided adequate solubility of
peptide substrates. A mixture of DMSO and MeCN (1:1) was
found to be a suitable replacement for DMF and delivered 9a
in a 70% yield (Scheme 4).
We next explored the scope of the methodology to access a
variety of protected pTyr mimetics (Scheme 3). The pTyr
a
Scheme 3. Access to Various pTyr Mimetics
Scheme 4. Late-Stage Modification of Side Chain Protected
a
Peptides
a
b
Isolated yields are reported. 4a used unless otherwise noted. 4-
Bromo substituted 6 was used as the starting material.
mimetics 7a and 7b with α-mono- methyl and fluoro
substitution were isolated as a mixture of α-benzylic epimers
(Figure S3) in yields of 88% and 65% respectively, while the
yield of sulfonyl product 7c was moderate (38%). Of note, low
conversion to Pmp products 7d and 7e (<20%) was observed
using 4-iodo substituted 4a starting material. A high degree of
dehalogenation was observed in the reaction; however, when
4-bromo substituted Phe (6) was utilized as the starting
material the Pmp pTyr mimetics, 7d and 7e, were isolated in
78% and 35% yields. We also attempted to apply the
methodology to generate α,α-disubstituted Pmp mimetics
7f−h using either 4a or 6 as the starting material, but in all
cases no conversion to the desired product was detected. We
hypothesized the products 7f−h were not formed because the
α,α-disubstituted methanephosphonates are too sterically
encumbered. Nevertheless, the methodology was applicable
to afford the protected form of the commonly used pCMF and
Pmp pTyr mimetics. Chloroacetic acid was also trialed as the
radical precursor in an attempt to directly access the
unprotected Pmp mimetic 7i, but no product was detected
by LCMS.
a
Isolated yields are reported. Peptide with Phe(4-iodo) used unless
b
c
otherwise noted. 4-Bromo substituted peptide was used. 10 equiv of
H2O were added.
The optimized solvent conditions were then applied to a
selection of peptide substrates with diverse protected side
chain functionality to demonstrate the broad applicability of
the protocol. The amino acid protection groups and
functionalities such as Met, Ser(OtBu), Glu(OtBu), Tyr-
(OtBu), Trp(N-Boc), and Arg(N-Pbf) were well tolerated and
the products 9b−9f were isolated in 43−65% yields,
highlighting the chemoselectivity of this method. The
methodology, however, was incompatible with a peptide
incorporating His(N-Trt). We also applied this method to
access the peptides modified with the Pmp mimetic, affording
We next sought to apply the conditions developed for late-
stage incorporation of the pCMF mimetic 5 directly into side
chain protected peptides containing 4-iodo-Phe. When the
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the Pmp derivative 9g in 38% yield. Notably, no α-center
epimerization was observed under the reaction conditions with
peptides 9a−9c (Figure S4).
We then applied the methodology to peptides without side
chain protection. A trial reaction on the tripeptide Ac-Glu-
Phe(4-iodo)-Ser-NH2 10a with unprotected hydroxyl and
carboxyl functionality afforded 11a in 45% isolated yield
(Scheme 5). Encouraged by this result, the methodology was
(amino acids 756−760). gp130 is reported to preferentially
bind to SOCS3.32 Deprotection of 11c and 11e with TFA and
TMSI, respectively, were performed to generate carboxylic and
phosphonic acid products, 12b and 12c (Table 2, Figure S5).
In addition, a peptide with the same sequence but modified
with pTyr (12a) was synthesized by SPPS as a control.
Table 2. IC50 μM (SD) Values of pTyr Mimetic Containing
a
Peptides against SOCS SH2 Domain Proteins
Scheme 5. Late-Stage Modification of Side Chain
a
Peptide
CIS
SOCS1
SOCS2
SOCS3
Unprotected Peptides
12a
12b
12c
1.8 (0.12)
>50
3.6 (1.7)
0.77 (0.15)
>50
31 (15)
8.4 (2.1)
>50
15 (4.4)
3.8 (0.75)
>50
38 (17)
a
Values reported are averages and SDs for n = 3 competitive SPR
experiments.
The biochemical activity of peptides 12a−c was measured
using gp130 and JAK1 phosphopeptides as the substrates in a
competition SPR assay with SOCS3 and CIS, SOCS1 and 2
proteins respectively (Table 2, Figure S5). The results show
the pTyr peptide 12a exhibited the highest binding affinity to
SOCS1 (IC50 0.77 μM) followed by CIS, SOCS3, and SOCS2
with IC50 values of 1.8, 3.8, and 8.4 μM respectively.
Significantly lower activity was observed for pCMF mimetic
peptide 12b with IC50 values >50 μM against all SOCS
proteins tested. This is consistent with previous data
suggesting pCMF is significantly less active than the pTyr
substrate itself.33 Compared to the pTyr peptide 12a, the Pmp
mimetic peptide 12c exhibited a 2-fold loss in potency against
CIS (IC50 3.6 μM) and SOCS2 (IC50 15 μM), and an
approximate 10-fold and 20-fold reduction in activity against
SOCS3 (IC50 38 μM) and SOCS1 (IC50 31 μM). The overall
reduction in activity shown by the Pmp mimetic (12c) versus
the surrogate pTyr peptide (12a) is consistent with previous
observations against SH2 domain proteins.8 Overall, the Pmp
mimetic was found to be more suitable than pCMF for
targeting SH2 domain proteins and could be applied as a pTyr
mimetic in future studies to avoid hydrolysis by cellular
phosphatases.
a
Isolated yields are reported. Peptide with Phe(4-iodo) used unless
b
c
otherwise noted. Peptide with Phe(4-iodo) was used. Requires 6
equiv of DIPEA and 26 h reaction time.
In conclusion, a visible light photoredox/nickel-catalyzed
cross-coupling method has been developed to access a variety
of pTyr mimetics. The one-step protocol developed is a
significant improvement on existing multistep methods
(Scheme 1) to synthesize pTyr mimetic building blocks. The
method is compatible with a variety of common peptide
protecting groups and unprotected amino acid side chain
functional groups underscoring the chemoselectivity observed.
More importantly, this method is applicable to late stage
modification of peptides with or without side chain protection.
The chemistry developed here is a viable method for accessing
biologically important tool peptides and substrates incorporat-
ing pTyr mimetics.
further expanded to peptides with carboxyl, hydroxyl, amino,
indole, and phenolic side chain functionalities, providing
pCMF mimetic peptides, 11b, 11c, and 11d, and the Pmp
mimetic peptide 11e in moderate yields (31−42%) after
preparative HPLC purification. Peptides trialed with an
unprotected histidine showed no conversion to the product.
We also performed the reaction on a decapeptide including
Gln, Pro, Lys, Tyr, Asp, Glu, and Val. The decapeptide
displayed diminished reactivity relative to tri- and pentapep-
tides but still provided the pCMF mimetic peptide 11f in a
28% yield after preparative LC purification.
To demonstrate the biological relevance of the photo-
chemical inclusion of pTyr mimetics into peptides, we assessed
several deprotected peptide products against a selection of
SH2 domain proteins that recognize pTyr post-translationally
modified motifs. Four SH2 domain proteins from the
suppressor of the cytokine signaling (SOCS) family, CIS,
SOCS 1, 2, and 3, were selected to biochemically evaluate the
deprotected forms of the pCMF and Pmp mimetic peptides,
11c and 11e, derived from the pTyr glycoprotein 130 (gp130)
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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Experimental details, characterization data and spectra
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AUTHOR INFORMATION
■
Corresponding Authors
Nghi H. Nguyen − The Walter and Eliza Hall Institute of
Medical Research, Parkville, Victoria 3052, Australia;
Department of Medical Biology, The University of Melbourne,
Parkville, Victoria 3010, Australia; Email: nguyen.n@
wehi.edu.au
Brad E. Sleebs − The Walter and Eliza Hall Institute of
Medical Research, Parkville, Victoria 3052, Australia;
Department of Medical Biology, The University of Melbourne,
Parkville, Victoria 3010, Australia; orcid.org/0000-0001-
9117-1048; Email: sleebs@wehi.edu.au
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Authors
Hao Chen − The Walter and Eliza Hall Institute of Medical
Research, Parkville, Victoria 3052, Australia; Department of
Medical Biology, The University of Melbourne, Parkville,
Victoria 3010, Australia
Runyu Mao − The Walter and Eliza Hall Institute of Medical
Research, Parkville, Victoria 3052, Australia; Department of
Medical Biology, The University of Melbourne, Parkville,
Victoria 3010, Australia
Martin Brzozowski − The Walter and Eliza Hall Institute of
Medical Research, Parkville, Victoria 3052, Australia;
Department of Medical Biology, The University of
Melbourne, Parkville, Victoria 3010, Australia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01200
Notes
(16) Chen, X.; Ye, F.; Luo, X.; Liu, X.; Zhao, J.; Wang, S.; Zhou, Q.;
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Drury, W. J., 3rd; Valeur, E.; Malins, L. R.; Gopalakrishnan, R. Late-
stage functionalization of histidine in unprotected peptides. Angew.
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Wang, R.; Xu, Z. Visible-light-promoted C(sp(3))-H alkylation by
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J. D.; Caron, S.; Weix, D. J. New ligands for nickel catalysis from
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(21) Amani, J.; Sodagar, E.; Molander, G. A. Visible light photoredox
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the University of Melbourne
Research Scholarship to H.C. and R. M., the Australian Cancer
Research Foundation, and the Victorian State Government
Operational Infrastructure Support. B.E.S. is a Corin Fellow.
We thank A/Prof. Sandra Nicholson, A/Prof. Jeffery Babon,
and Dr. Christoph Grohmann from The Walter and Eliza Hall
Institute for helpful discussions and Wilhemus Kersten from
The Walter and Eliza Hall Institute for acquisition of HPLC
analytical data.
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