Tyrosine-Specific Modification via a Dearomatization-Rearomatization Strategy: Access to Azobenzene Functionalized Peptides

Article abstract of DOI:10.1021/acs.orglett.1c01013

Azobenzene functionalized peptides are of great importance in photoresponsive biosystems and photopharmacology. Herein, we report an efficient approach to prepare azobenzene functionalized peptides through late-stage modification of tyrosine-containing peptides using a dearomatization-rearomatization strategy. This approach shows good chemoselectivity and site selectivity as well as sensitive group tolerance to various peptides. This method enriches the postsynthetic modification toolbox of peptides and has great potential to be applied in medicinal chemistry and chemical biology.

Full text of DOI:10.1021/acs.orglett.1c01013

pubs.acs.org/OrgLett
Letter
Tyrosine-Specific Modification via a Dearomatization−
Rearomatization Strategy: Access to Azobenzene Functionalized
Peptides
Pengxin Wang,∥ Yulian Cheng,∥ Chunlei Wu, Yimin Zhou, Zhehong Cheng, Hongchang Li, Rui Wang,*
Wu Su,* and Lijing Fang*
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ABSTRACT: Azobenzene functionalized peptides are of great
importance in photoresponsive biosystems and photopharmacology.
Herein, we report an efficient approach to prepare azobenzene
functionalized peptides through late-stage modification of tyrosine-
containing peptides using a dearomatization−rearomatization strat-
egy. This approach shows good chemoselectivity and site selectivity
as well as sensitive group tolerance to various peptides. This method
enriches the postsynthetic modification toolbox of peptides and has
great potential to be applied in medicinal chemistry and chemical
biology.
n recent years, peptides have emerged as powerful scaffolds
rearomatization of the quinonoidal spirolactone intermediates
with arylhydrazines in the presence of a catalytic amount of
ceric ammonium nitrate led to azobenzene−alanine amino
acids.8 Inspired by our works on developing asymmetric
dearomatization of naphthols9 and the previous works on
tyrosine modifications, we are curious about whether the
dearomatization−rearomatization method could be applied to
the site-specific modification of complex peptides at the
aromatic side chain of the Tyr residue. Taking advantage of the
4-hydroxylcyclohexadienone (Int A) intermediate obtained in
the hypervalent iodine(III)-mediated oxidative dearomative
step, we anticipate that modification at the C4 site could be
realized by a subsequent rearomative step mediated by phenyl
hydrazine via a hydrazone intermediate (Int B), affording the
azobenzene functionalized peptides10 (Scheme 1). Herein, we
report such a novel dearomatization−rearomatization strategy
to form azobenzene functionalized peptides and demonstrate
the utility of it in the site-selective late-stage modification of
peptides in mild conditions compatible with various amino
acids via a two-step one-pot procedure.
1
Iin both pharmacology and chemical biology. Along with
the increasing interest in application of peptides as potential
therapeutics, targeting ligands, and molecular probes, there has
been a growing demand for direct functionalization of these
structurally complex molecules. Late-stage chemical modifica-
tion of a specific amino acid residue in peptides under mild,
water-compatible, and easy-to-handle conditions has attracted
much attention due to its convenience in achieving structural
diversity, enabling rapid conjugation and labeling of peptides.2
Although lysine and cysteine are the most commonly
functionalized amino acids, chemoselective modification of
alanine, phenylalanine, tryptophan, and histidine has been
developed.3 Presently, tyrosine (Tyr) is also considered to be
an attractive residue for site-specific peptide functionalization
due to its low natural abundance in bioactive peptides. Several
elegant methods have emerged for Tyr modification, such as
Pd-catalyzed cross-coupling reaction, O-functionalization,
photochemical catalysis, electrochemistry, ene-type reactions,
etc.4 Despite the success achieved in C3 or O-modification of
the Tyr side chain, little attention has been focused toward C1,
C2, and C4 modification at the phenol motif.5 Therefore,
efficient methods that can modify these undeveloped sites of
Tyr residue are required for the enrichment of peptide
scaffolds.
It is particularly noteworthy that azobenzene functionalized
peptides formed in this strategy are of great potential as
photoswitches in biological systems.11 As the most popular
Received: March 26, 2021
Published: May 19, 2021
Dearomatization of phenol derivatives is an important way
for the synthesis of complex molecules from simple and cheap
aromatic compounds.6 Cyclohexadienones including quino-
noidal spiro compounds formed by oxidation of the phenol
group of tyrosine derivatives have been used as building blocks
in organic synthesis.7 As reported by John and co-workers,
https://doi.org/10.1021/acs.orglett.1c01013
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4137−4141
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Letter
Scheme 1. Late-Stage Modification of Tyr-Containing
Peptides through a Dearomatization−Rearomatization
Sequence
Scheme 2. Scope of Dipeptides
Table 1. Screening of Reaction Conditions
Step 1
Step 2
Solvent
(MeCN/
H2O)
Equiv of
PhI(OAc)2
a
b
Entry
Time
T
Time Yield
1
2
3
4
5
6
7
1.1
1.2
1.5
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.2
1.2
1.2
1/1
1/1
1/1
1/1
3/1
9/1
1/1
1/1
1/1
1/1
1/1
1/3
H2O
1.5 h
1.5 h
1.5 h
5 min
5 min
5 min
1 h
1 h
1 h
1 h
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C−rt
0 °C−rt
0 °C−rt
0 °C−rt
0 °C−rt
0 °C−rt
0 °C−rt
12 h
12 h
12 h
12 h
12 h
12 h
1.5 h
1.5 h
1.5 h
3.5 h
3.5 h
3.5 h
3.5 h
52%
52%
33%
54%
38%
17%
50%
56%
54%
64%
66%
40%
44%
a
To a solution of 4 (0.10 mmol) in MeCN/H2O (1/1, 1.0 mL) was
added PhI(OAc)2 (1.2 equiv) at 0 °C. The mixture was stirred at rt
for 0.5 h before a solution of phenyl hydrazine (2a, 2.0 equiv) in
MeCN/H2O (1/1, 1 mL) was added at 0 °C. Then the reaction was
kept stirring at rt for 3.5 h. The ratio of cis- and trans-isomers was
determined by isolated yield. The ratio of cis- and trans-isomers was
c
b
8
9
c
cd
,
c e
,
determined by HPLC.
10
11
12
13
c ef
,
,
0.5 h
0.5 h
0.5 h
c ef
,
,
current work proved to be efficient to form an azobenzene
linker at the C4 site of the Tyr residue via direct
functionalization of the peptides.
c ef
,
,
a
To a solution of 1a (0.10 mmol) in MeCN/H2O (1/1, 1.0 mL) was
We initiated our study by utilizing Ac-Tyr-OMe (1a) as the
model substrate, PhI(OAc)2 as the oxidant, phenyl hydrazine
(2a) as the rearomative reagent, and a mixure of MeCN/H2O
as the solvent (Table 1). The reaction of Ac-Tyr-OMe (1a)
with PhI(OAc)2 (1.1 or 1.2 equiv) proceeded smoothly in
MeCN/H2O (v/v, 1:1) to form the hydroxyl substituted
cyclohexadienone intermediate (1a′), which reacted with
phenyl hydrazine (2a, 1.2 equiv) in the presence of
Ce(NH4)2(NO3)6 (10 mol %) to reestablish the aromaticity,14
affording azobenzene 3a in 52% yield (entries 1 and 2). To be
noted, azobenzene 3a was obtained as a mixture of cis- and
trans-isomers, in which the thermodynamically more stable
trans-isomer is the major product.8 When the amount of
PhI(OAc)2 was increased from 1.2 to 1.5 equiv, the total yield
of 3a significantly decreased from 52% to 33% (entry 3). The
ratio of MeCN/H2O also affected the reaction remarkably, as
increasing the ratio of MeCN resulted in the decrease of the
total yield (entries 4−6). Although the reaction could be
performed with less MeCN or without MeCN, the yields were
also lower due to the poor water solubility of 1a (entries 11−
13). Interestingly, a comparable yield was obtained when the
reaction was carried out without the addition of Ce-
(NH4)2(NO3)6 (entries 7 and 8), indicating that Ce-
added PhI(OAc)2 (1.1 equiv) at 0 °C. After a specific period of time,
phenyl hydrazine (2a, 1.2 equiv) and Ce(NH4)2(NO3)6 (10 mol %)
b
c
were added to the mixture at 0 °C. Isolated yield. Without
d
e
Ce(NH4)2(NO3)6. Phenyl hydrazine (2a, 1.5 equiv). Phenyl
hydrazine (2a, 2.0 equiv). To a mixture of step 1 was added a
f
solution of phenyl hydrazine (2a, 2.0 equiv) in CH3CN/H2O (1/1, 1
mL) at 0 °C, and the reaction was stirred at rt for 3.5 h.
light-responsive ligands, azobenzene and its derivatives readily
isomerize from trans to cis forms under irradiation at 300−380
nm, whereas the interconversion may be reversed at wave-
lengths >400 nm. The reversible trans−cis isomerization of
azobenzene upon UV-blue light irradiation has opened the way
to numerous applications in peptide engineering, which can
induce the secondary structural changes of peptides and thus
affect their binding affinity to the target.12 To introduce an
azobenzene moiety, chemical approaches mainly rely on
incorporation of the azobenzene amino acids during peptide
chain assembly or site-specific modification of peptides by the
use of mono- or bifunctional azobenzene derivatives carrying
residue-specific reacting groups. Different from the diazonium-
mediated modification at the C3 site of the Tyr residue,13 the
dearomatization−rearomatization strategy developed in the
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Scheme 3. Scope of Complex Bioactive Peptides
Scheme 4. Direct Conjugation of Two Bioactive Peptides
a
To a solution of 6a (0.005 mmol) in MeCN/H2O (1/1, 0.2 mL) was
added PhI(OAc)2 (1.2 equiv) at 0 °C. The mixture was stirred at rt
for 45 min before a solution of 11 (2.0 equiv) and DIEA (3.0 equiv)
in MeCN/H2O (1:1, 20 μL) was added. Then the reaction was stirred
b
at rt for 3 h. Isolated yield.
a
To a solution of 6 (0.005 mmol) in MeCN/H2O (1/1, 0.2 mL) was
5f′, the cis- and trans-isomers could exchange under UV/blue
LED irradiation.
added PhI(OAc)2 (1.2 equiv) at 0 °C. The mixture was stirred at rt
for 0.5 h before phenyl hydrazine (2, 10.0 equiv) was added. Then the
reaction was kept stirring at rt for 3.5 h. Isolated yield. Phenyl
hydrazine (2a, 4.0 equiv). Phenyl hydrazine (2a, 2.0 equiv).
We further examined the compatibility of this protocol with
unprotected and structurally more complex peptides (Scheme
3). To our delight, cyclopentapeptide (6a), containing an Arg-
Gly-Asp (RGD) motif, which is an important peptide sequence
commonly used in targeted therapy since it can specifically
bind to integrin receptor on the cell surface,16 could be well
decorated with 2a at the Tyr residue to give the major trans-
isomer 7a in 55% yield. Analysis of the crude reaction mixture
indicated that a small amount of nonreacted tyrosine-
containing peptide 6a, the corresponding 4-hydroxylcyclo-
hexadienone intermediate, as well as some unknown by-
products were present in the crude products. Tetrapeptide 6b,
a lysosome sorting peptide bearing the Tyr residue at the N-
terminus,17 could also be functionalized, affording 7b (trans-
isomer) in 51% yield. To further explore the scope of this
strategy, hexapeptide 6c was designed to contain different
kinds of amino acid residues, while without any protection at
both the N- and C-terminus. The reaction of hexapeptide 6c
with both phenyl hydrazine (2a) and m-ethynyl-phenyl
hydrazine (2c) proceeded smoothly, furnishing 7c and 7d in
moderate yields as the trans-isomers. Modification of Tat (6e),
a cell penetrating peptide which contains 11 amino acid
residues, was also accomplished via this method, providing
trans-isomer 7e in 47% isolated yield. To be noted, increasing
the amount of phenyl hydrazine from 2 to 10 equiv led to
better conversion of complex peptides. In all cases, the
azobenzene functionalized peptides could be easily separated
from the starting peptides by semipreparative RP-HPLC.
Hexapeptide 7d, tagged with m-ethynyl-substituted azoben-
b
c
d
(NH4)2(NO3)6 is not required for the rearomatization step.
The effects of reaction time, reaction temperature, and the
amount of phenyl hydrazine were further evaluated (entries 9−
11). Although a small amount of the dimeric tyrosine 1a15 was
detected as the byproduct, 3a could be obtained in an overall
yield of 66% through the two-step one-pot sequence under the
optimized conditions (entry 11). The method proved to be
compatible with various substituted phenyl hydrazines 2,
providing a mixture of cis- and trans-azobenzenes 3 in 58−70%
yields (Scheme S1 in Supporting Information). In general,
phenyl hydrazines bearing electron-donating groups generated
the corresponding products in higher yields compared with
electron-withdrawing groups.
Encouraged by this result, we next evaluated the
compatibility of the reaction with a series of dipeptides 4a−
h (Scheme 2). Under the optimal conditions, a number of Boc-
or Fmoc-protected dipeptides bearing various sensitive groups
(4a−4g) were selectively modified with phenyl hydrazine (2a),
indicating a broad functional group tolerance of the reaction.
The corresponding products 5a−5g were obtained in 46−63%
isolated yields with a cis/trans ratio ranging between 1:9 and
1:3 depending on the second amino acid of the dipeptide.
Dipeptide 4h containing an indole group could be selectively
functionalized at the phenol moiety to form 5h, albeit with a
low yield. As demonstrated in the photoisomerization of 5f and
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Letter
zene, could further react with biotin-PEG3-azide (8) via click
chemistry to generate biotin labeled peptide 9.
Chinese Academy of Sciences, Shenzhen, Guangdong 518055,
China
This protocol also proved to be efficient for direct
conjugation of peptides with different bioactivities, offering
unique azobenzene linked bifunctional peptides (Scheme 4).
Using standard solid-phase peptide synthesis (SPPS), a free
phenyl hydrazine group could be conveniently introduced to
the N-terminus of ETWW (10), a major-groove-specific
nuclear-localizing, cell-penetrating tetrapeptide,18 generating
phenyl hydrazine substituted ETWW (11). Since ETWW
peptide 11 was obtained as the trifluoroacetate salt, pretreat-
ment of it with 3 equiv of DIEA was carried out before it was
used to react with cyclopeptide 6a in the coupling reaction. As
expected, azobenzene functionalized peptide 12 was isolated in
good yield as the trans-isomer.
In summary, we have developed a dearomatization−
rearomatization strategy for chemoselective and site-selective
modification of Tyr-containing peptides under mild conditions,
providing azobenzene functionalized peptides which are of
great importance in photoresponsive biosystems and photo-
pharmacology. As demonstrated by using a wide range of
peptides, this approach shows good compatibility with various
amino acid residues and different peptide lengths. This method
enriches the postsynthetic modification toolbox of peptides
and has great potential to be applied in medicinal chemistry
and chemical biology.
Yulian Cheng − Guangdong Key Laboratory of Nanomedicine,
Institute of Biomedicine and Biotechnology, Shenzhen
Institute of Advanced Technology, Chinese Academy of
Sciences, Shenzhen, Guangdong 518055, China; Nano
Science and Technology Institute, University of Science and
Technology of China, Suzhou 215123, Jiangsu, China
Chunlei Wu − Guangdong Key Laboratory of Nanomedicine,
Institute of Biomedicine and Biotechnology, Shenzhen
Institute of Advanced Technology, Chinese Academy of
Sciences, Shenzhen, Guangdong 518055, China
Yimin Zhou − Guangdong Key Laboratory of Nanomedicine,
Institute of Biomedicine and Biotechnology, Shenzhen
Institute of Advanced Technology, Chinese Academy of
Sciences, Shenzhen, Guangdong 518055, China
Zhehong Cheng − Guangdong Key Laboratory of
Nanomedicine, Institute of Biomedicine and Biotechnology,
Shenzhen Institute of Advanced Technology, Chinese
Academy of Sciences, Shenzhen, Guangdong 518055, China
Hongchang Li − Guangdong Key Laboratory of
Nanomedicine, Institute of Biomedicine and Biotechnology,
Shenzhen Institute of Advanced Technology, Chinese
Academy of Sciences, Shenzhen, Guangdong 518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01013
ASSOCIATED CONTENT
Author Contributions
∥P.W. and Y.C. contributed equally.
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01013.
Notes
The authors declare no competing financial interest.
Experimental details and characterization data for all
new compounds (PDF)
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21778068, 21977111, and
22007096), the Shenzhen Science and Technology Innovation
Commission (Grant No. JCYJ20170818153538196 and
JCYJ20170413165916608), and the Natural Science Founda-
tion of Guangdong Province (Grant Nos. 2019A1515012073
and 2018B030308001). The authors appreciate Peking
University Shenzhen Graduate School for the assistance of
Mass facility.
AUTHOR INFORMATION
Corresponding Authors
■
Rui Wang − Key Laboratory of Preclinical Study for New
Drugs of Gansu Province, Institute of Drug Design &
Synthesis, School of Basic Medical Sciences, Lanzhou
University, Lanzhou 730000, Gansu, China; orcid.org/
0000-0002-4719-9921; Email: wangrui@lzu.edu.cn
Wu Su − Guangdong Key Laboratory of Nanomedicine,
Institute of Biomedicine and Biotechnology, Shenzhen
Institute of Advanced Technology, Chinese Academy of
Sciences, Shenzhen, Guangdong 518055, China;
orcid.org/0000-0001-9958-3434; Email: wu.su@
siat.ac.cn
Lijing Fang − Guangdong Key Laboratory of Nanomedicine,
Institute of Biomedicine and Biotechnology, Shenzhen
Institute of Advanced Technology, Chinese Academy of
Sciences, Shenzhen, Guangdong 518055, China;
orcid.org/0000-0001-7355-3923; Email: lj.fang@
siat.ac.cn
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