Postsynthetic Modification of Phenylalanine Containing Peptides by C-H Functionalization

Article abstract of DOI:10.1021/acs.orglett.8b03536

New methods for peptide modification are in high demand in drug discovery, chemical biology, and materials chemistry; methods that modify natural peptides are particularly attractive. A Pd-catalyzed, C-H functionalization protocol for the olefination of phenylalanine residues in peptides is reported, which is compatible with common amino acid protecting groups, and the scope of the styrene reaction partner is broad. Bidentate coordination of the peptide to the catalyst appears crucial for the success of the reaction.

Full text of DOI:10.1021/acs.orglett.8b03536

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Postsynthetic Modification of Phenylalanine Containing Peptides by
C−H Functionalization
Myles J. Terrey, Carole C. Perry, and Warren B. Cross*
Department of Chemistry and Forensic Science, School of Science and Technology, Nottingham Trent University, Clifton Lane,
Nottingham NG11 8NS, U.K.
S
* Supporting Information
ABSTRACT: New methods for peptide modification are in
high demand in drug discovery, chemical biology, and
materials chemistry; methods that modify natural peptides
are particularly attractive. A Pd-catalyzed, C−H functionaliza-
tion protocol for the olefination of phenylalanine residues in
peptides is reported, which is compatible with common amino
acid protecting groups, and the scope of the styrene reaction
partner is broad. Bidentate coordination of the peptide to the
catalyst appears crucial for the success of the reaction.
a
he chemical modification of peptides is critical to research
in chemical biology and biomedicine, finding applications
Table 1. Optimisation of the C−H Olefination
T
in advancing the understanding of biological function, the
diagnosis and treatment of disease, and the manufacture of new
materials.1,2 For example, peptides have been modified with tags
for the imaging of biological systems and with reporters for the
study of biological mechanism.3−7 In drug discovery, peptide
therapeutics are an attractive alternative to small molecule drugs,
often possessing higher target specificity.8,9 Native peptides
usually have poor pharmacological properties, but chemical
modification can greatly improve binding affinity to the target,
stability of the peptide, and cell penetration.10−13
Although a large number of methods have been developed for
the site-selective modification of peptides,2,14 these methods
commonly rely upon the reactions of heteroatoms within a side-
chain of the peptide, which are often important for biological
function,15,16 or upon the incorporation of non-natural amino
acids to facilitate the subsequent modification.17,18 Hence, new
methods for peptide modification that operate on the natural
peptide, and at sites other than heteroatoms, are highly
desirable. The postsynthetic modification of natural peptides
and peptidomimetics has been recently achieved through the
C−H functionalization of hydrophobic residues:19 reactions
have been reported that directly modify either tryptophan or
alanine resides.20−27 However, methods for the direct
modification of phenylalanine (Phe) residues in peptides are
lacking.2,28 Herein, we report a C−H olefination protocol for the
direct postsynthetic modification of Phe containing peptides;
very recently, a complementary method for the C−H olefination
of peptides has been communicated.29
equiv of
styrene
equiv of
AgOAc
time
yield
(%)
entry
solvent
T (°C) (h)
b
b
1
2
3
4
5
6
7
8
9
1
4
4
4
4
4
4
4
4
4
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
DCE/DMF
DCE/DMF
PhMe
DMF
MeCN
130
130
130
130
130
130
130
130
100
80
48
48
48
48
48
48
48
12
12
12
19
35
26
26
23
HFIP
trace
67
t-amylOH
t-amylOH
t-amylOH
t-amylOH
c
81
5
5
76
68
10
a
Full details of the optimization study are provided in the Supporting
b
c
Information. DCE/DMF = 15:1. The mono-olefinated peptide 2a′
was also isolated in 8% yield.
dichloroethane/DMF (15:1), gave the diolefinated peptide 2a
in 19% isolated yield, entry 1. In the 1H NMR spectrum for 2a,
the coupling constants for the alkene signals revealed that the
alkene was exclusively the trans geometry. Increasing the
number of equivalents of styrene increased the isolated yield
of 2a to 35%, entry 2; however, there was little benefit in using
more than 4 equiv of styrene in the reaction, see Supporting
Information. Next, we investigated the effect of the reaction
Inspired by previous research on the palladium-catalyzed
Fujiwara−Moritani (oxidative-Heck) reaction,28a,30 we began
by investigating the olefination of the model phenylalanine
containing dipeptide Ac-Gly-Phe-OMe (1a), Table 1. Treating
dipeptide 1a with an equimolar amount of styrene, Pd(OAc)2
(10 mol %) and AgOAc (2.5 equiv) at 130 °C in a mixture of 1,2-
Received: November 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03536
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of the N-Protecting Group for the C−H
Olefination of Gly−Phe Dipeptides
Scheme 3. Scope of the Amino Acid at the N-Terminus of
Dipeptides
Scheme 2. Scope of the Alkene for the C−H Olefination of
Model Dipeptide 1a
the nitrogen protecting group on the reaction, Scheme 1. This
study demonstrated the compatibility of protecting groups
commonly used in peptide synthesis. Although the original
acetyl protecting group gave the best yield, the use of the
carbamate protecting groups Boc, Fmoc, and Cbz also provided
the diolefinated peptide in moderate to good yields (52−71%).
There was no evidence for C−H functionalization of the
aromatic C−H bonds in the Fmoc and CBz protecting groups.
Intriguingly, protecting the glycine nitrogen as the phthalimide
prevented any C−H functionalization of the peptide; in
combination with other experiments, this outcome proved
useful in delineating a mechanism for the reaction, vide infra.
With a view to future applications in chemical biology, we next
investigated the scope of the alkene. For the C−H olefination of
dipeptide 1a, we studied the reaction with a range of styrene
derivatives, Scheme 2. Electron-withdrawing (F−, Cl−, Br−,
F3C−, NC−, O2N−) and electron-donating substituents
(H3C−, MeO−) were compatible with the reaction; moreover,
the incorporation of halogen atoms potentially enables further
functionalization of the peptide.32 Alkenes possessing more
solvent on the yield of 2: conducting the reaction in toluene,
DMF, or acetonitrile resulted in very similar yields (23−26%,
entries 3−5). Hexafluoroisopropanol (HFIP), a solvent
previously used to good effect in C−H functionalizations,
including peptides,24,31 gave only a trace yield of 2a, entry 6. The
best solvent for the reaction proved to be tert-amyl alcohol; the
use of this solvent increased the yield of 2a to 67%, entry 7.
Alternative oxidants were investigated for the reaction, including
benzoquinone, Cu(OAc)2, and other silver salts, but none
proved to be as competent as AgOAc. However, the best yield of
2a was achieved by increasing the amount of AgOAc to 5 equiv
(81%, entry 8), when the reaction time could also be shortened
to 12 h. Under these higher-yielding conditions, we were also
able to isolate the mono-olefinated peptide 2a′ in 8% yield. It
was also possible to carry out the reaction at lower temperatures
(entries 9 and 10, 100, and 80 °C), but the yield was slightly
reduced.
Having determined the optimum conditions for the
olefination of dipeptide 1a, we next investigated the effect of
B
DOI: 10.1021/acs.orglett.8b03536
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. C−H Olefination of Tri- and Tetra-peptides
Scheme 5. Proposed Effect of Peptide Binding Mode on C−H
Activation
(4h) to determine if modification of Phe at the N-terminus was
possible in the absence of phenylalanine at the C-terminus, eq 1:
dipeptide 4h proved to be unaltered under the conditions of the
C−H olefination reaction.35
To evaluate the potential of the olefination reaction for the
modification of longer peptides, we surveyed the C−H
olefination of a range of tri- and tetra-peptides, Scheme 4. For
the tripeptides, diolefination occurred for phenylalanine
residues in the middle of the peptide chain or at the C-terminus
(8a, 8b), but not at the N-terminus (8c was not obtained).
Tetrapeptides with a Phe residue were also successfully modified
by the reaction (9a−c).
Why does the reaction not proceed when the phenylalanine
residue is at the N-terminus of the peptide? A key feature of the
peptide is that it can coordinate to the Pd-catalyst through amide
groups of the peptide backbone and hence facilitate the C−H
functionalization. As there is more than one amide group in the
peptide, several distinct coordination modes are possible. Prior
calculations have demonstrated that a bidentate directing group
can stabilize intermediates and transition states in C−H
activation.36 Here we propose that the peptide coordinates to
Pd through two nitrogen atoms, and when the Phe residue is not
at the N-terminus of the peptide, this coordination mode offers a
low energy pathway for C−H activation, Scheme 5a.37
In contrast, if the Phe residue is situated at the N-terminus,
bidentate coordination of the peptide means that C−H
activation is geometrically unfeasible at square planar Pd(II),
Scheme 5b. In this latter case, C−H activation can only proceed
through a monodentate intermediate. Presumably this higher
energy pathway is inaccessible under the reaction conditions.
In summary, we have developed an efficient peptide
modification protocol that employs the Fujiwara−Moritani
reaction to functionalize phenylalanine residues in peptides.
Specifically, Phe containing peptides have been modified by
reaction with styrene derivatives in the presence of Pd(OAc)2
extensive conjugation were also tolerated (4-phenylstyrene and
2-vinylnaphthalene); tailoring the extent of π-conjugation can
be important when modifying peptides for fluorescence
imaging.33
Next, we examined the scope of the amino acid at the N-
terminus of the dipeptide, Scheme 3. The aliphatic amino acids
Ala, Leu, Ile, and Val all proved amenable to the reaction (5a−
d), as was methionine (Met, 5e), which possesses a thioether
side-chain;34 isolated yields ranged from 60 to 76% for the
modification of these dipeptides. NMR and HPLC data
confirmed that the peptide was not racemized during the
reaction, see Supporting Information. The reaction did also
proceed with proline (Pro) as the adjacent residue, but the yield
was much lower (24%). The reduced yield in the synthesis of 5f
could be attributed to the tertiary amide group of proline, which
may be a less capable ligand for the Pd catalyst, or to the
conformational constraint imparted by the Pro residue.
For the reaction of the peptide Ac-Phe-Phe-OMe (4g), we
were interested to see if olefination would take place on both
phenylalanine residues. From this reaction of 4g, the modified
peptide 5g was obtained, in which only the phenylalanine
residue at the C-terminus had undergone C−H olefination.
Consequently, we prepared the dipeptide Ac-Phe-Gly-OMe
C
DOI: 10.1021/acs.orglett.8b03536
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Letter
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catalyst and AgOAc; good yields of the diolefinated peptide were
achieved at a temperature of 80 °C, but the best yields were
obtained at 130 °C. This protocol is complementary to
previously reported methods for the C−H functionalization of
tryptophan and alanine residues. A range of styrene derivatives
were used in the reaction, and several of these can enable further
chemistry to be carried out on the modified peptide. The
chemistry we describe offers new opportunities for the
development of peptide pharmaceuticals or for application in
chemical biology; we are currently pursuing applications in these
areas.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03536.
(11) Lau, Y. H.; de Andrade, P.; Wu, Y.; Spring, D. R. Peptide Stapling
Techniques Based on Different Macrocyclisation Chemistries. Chem.
Soc. Rev. 2015, 44 (1), 91−102.
Detailed experimental procedures, reaction development,
mechanistic studies, and characterization data for all new
compounds (PDF)
(12) Chang, Y. S.; Graves, B.; Guerlavais, V.; Tovar, C.; Packman, K.;
To, K.-H.; Olson, K. A.; Kesavan, K.; Gangurde, P.; Mukherjee, A.;
Baker, T.; Darlak, K.; Elkin, C.; Filipovic, Z.; Qureshi, F. Z.; Cai, H.;
Berry, P.; Feyfant, E.; Shi, X. E.; Horstick, J.; Annis, D. A.; Manning, A.
M.; Fotouhi, N.; Nash, H.; Vassilev, L. T.; Sawyer, T. K. Stapled α-
Helical Peptide Drug Development: a Potent Dual Inhibitor of MDM2
and MDMX for P53-Dependent Cancer Therapy. Proc. Natl. Acad. Sci.
U. S. A. 2013, 110 (36), E3445−E3454.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: warren.cross@ntu.ac.uk.
ORCID
(13) White, C. J.; Yudin, A. K. Contemporary Strategies for Peptide
Macrocyclization. Nat. Chem. 2011, 3 (7), 509−524.
(14) Stephanopoulos, N.; Francis, M. B. Choosing an Effective
Protein Bioconjugation strategy. Nat. Chem. Biol. 2011, 7 (12), 876−
884.
(15) Lee, H. G.; Lautrette, G.; Pentelute, B. L.; Buchwald, S. L.
Palladium-Mediated Arylation of Lysine in Unprotected Peptides.
Angew. Chem., Int. Ed. 2017, 56 (12), 3177−3181.
(16) Cheng, W.-M.; Lu, X.; Shi, J.; Liu, L. Selective modification of
natural nucleophilic residues in peptides and proteins using
arylpalladium complexes. Org. Chem. Front. 2018, 5 (21), 3186−3193.
(17) Lang, K.; Chin, J. W. Cellular Incorporation of Unnatural Amino
Acids and Bioorthogonal Labeling of Proteins. Chem. Rev. 2014, 114
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Carole C. Perry: 0000-0003-1517-468X
Warren B. Cross: 0000-0001-6277-400X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Nottingham Trent University
(NTU) through a studentship for M.J.T. We thank Anna
Vilanova Garcia and Arnau Rodriguez Rubio (both at NTU, on
́
an Erasmus+ scholarship from University Rovira i Virgili, Spain)
for carrying out some preliminary investigations, Nigel Mould
(NTU) for carrying out the HPLC experiments, Ashley Holmes
(NTU) for assisting with the 1 mmol scale reaction, and the
EPSRC UK National Mass Spectrometry Facility at Swansea
University for carrying out high resolution mass spectrometry.
(18) Cheruku, P.; Huang, J.-H.; Yen, H.-J.; Iyer, R. S.; Rector, K. D.;
Martinez, J. S.; Wang, H.-L. Tyrosine-Derived Stimuli Responsive,
Fluorescent Amino Acids. Chem. Sci. 2015, 6 (2), 1150−1158.
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the Synthesis of Amino Acids and Peptides. Chem. Rev. 2014, 114 (18),
8775−8806. (b) Wang, W.; Lorion, M. M.; Shah, J.; Kapdi, A. R.;
Ackermann, L. Late-Stage Peptide Diversification by Position-Selective
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(20) (a) Williams, T. J.; Reay, A. J.; Whitwood, A. C.; Fairlamb, I. J. S.
A Mild and Selective Pd-Mediated Methodology for the Synthesis of
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feasible, as are alternative protonation states of the peptide, but this
proposal is consistent with experimental evidence: either N-
methylation of the Phe residue or phthaloyl protection of the
neighboring residue render the reaction ineffective; see Supporting
Information for attempted modification of 4h and 4i.
E
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