Macrocyclization of biaryl-bridged peptides through late-stage palladium-catalyzed C(sp2)-H Arylation

Article abstract of DOI:10.1021/acs.orglett.9b02945

Macrocyclic peptides are promising scaffolds of bioactive compounds and clinical therapeutics. Herein, we develop a strategy for the macrocyclization of biaryl-bridged peptides through late-stage Pd-catalyzed C(sp²)-H arylation. This method dis

Full text of DOI:10.1021/acs.orglett.9b02945

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Macrocyclization of Biaryl-Bridged Peptides through Late-Stage
Palladium-Catalyzed C(sp2)−H Arylation
Qingqing Bai, Zengbing Bai, and Huan Wang*
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center of Nanjing University, Jiangsu Key
Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093,
China
S
* Supporting Information
ABSTRACT: Macrocyclic peptides are promising scaffolds of bioactive
compounds and clinical therapeutics. Herein, we develop a strategy for the
macrocyclization of biaryl-bridged peptides through late-stage Pd-catalyzed
C(sp2)−H arylation. This method displays broad substrate scope and high
efficiency in the synthesis of peptide conjugates with various bioactive
molecules. Furthermore, we applied this method to prepare peptide
macrocycles with aryl−aryl cross-links. Our results show the effectiveness of backbone amide groups as directing groups in Pd-
catalyzed C−H functionalization of peptides.
eptides are a major class of biologically active compounds
with molecular weights poised between small molecules
P
and proteins. In particular, cyclic peptides with chemical
diversity and unique molecular topologies have attracted
attention from fields including medicinal chemistry and
chemical biology.1 Peptide macrocycles have shown high
potency and specificity as regulators of protein−protein
interactions, which are associated with numerous biological
processes and challenging to intervene with small molecules.2
In addition, conjugation of small molecule drugs to bioactive
peptides usually results in improved target specificity, which
further expands the application of peptides. Natural products
are rich sources of bioactive peptide macrocycles.3 For
example, arylomycins are broad-spectrum cyclic peptide
antibiotics with inhibitory activity toward type I signal
peptidase.4 The characteristic feature of arylomycins is 14-
membered, biaryl-bridged macrocyclic core formed between a
tyrosine and a 4-hydroxyphenylglycine residue (Figure 1A).
Recently, G0775, a synthetic arylomycin derivative, was
discovered with potent antibacterial activity against Gram-
negative pathogens through a systematic optimization of this
natural scaffold.5 The synthesis of cyclic peptides with
constrained biaryl-cross-links is chemically challenging, and
current strategies are limited to macrolactamization, cross-
coupling, and oxidative phenol coupling (Figure 1B).6−8
Recently, peptide functionalization by transition-metal-
catalyzed C−H activation has shown great potential in the
synthesis of cyclic peptides with diverse structures.9−11 Seminal
examples include peptide macrocyclization through tryptophan
(Trp) C(sp2)−H arylation at the C-2 position,12−14 β-C(sp3)−
H arylation,15,16 Mn-catalyzed C(sp2)−H alkynylation,17 as
well as δ-C(sp2)−H olefination of phenylalanine (Phe)18 and
N-terminal arylsulfonamides.19 Using proper directing groups,
Chen group developed methods to prepare cyclophane-braced
peptide macrocycles through Pd-catalyzed C−H activa-
tion.20,21 Our group have developed methods that utilizes
Figure 1. Macrocyclization of biaryl-bridged peptides via late-stage
Pa-catalyzed C−H activation. (A) Arylomycin and its bioactive
analogue G0775. (B) Macrocyclization of arylomycins through
macrolactamization and Cu-catalyzed C−H activation. (C) Back-
bone-directed macrocyclization of biaryl-bridged peptides through
late-stage Pd(II)-catalyzed C−H arylation.
amide bonds of peptide backbone as directing groups for
palladium catalyst to achieve site-selective macrocyclization of
peptides.22,23 Herein, we report a backbone-directed method
Received: August 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02945
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for arylation of peptidomimetics, as well as the synthesis of
biaryl-bridged cyclic peptides (Figure 1C). This method
displays broad substrate scope and are compatible with
bioactive molecules to generate corresponding peptide
conjugates. Furthermore, we applied this method for the
preparation of biaryl-bridged peptide macrocycles with
complex structures.
We initiated our studies with dipeptide 1a bearing N-
terminal benzamide group and 1-iodo-4-methylbenzene 2a as
model substrates (Table 1). Detailed optimization of reaction
a,b
Table 1. Optimization of the Reaction Conditions
c
T
time
(h)
yield
entry
additives
solvent (°C)
(%)
d
1
2
3
4
5
AgOAc (2.0 equiv)
AgOAc (2.0 equiv)
Ag2CO3 (1.0 equiv)
Ag2CO3 (1.0 equiv)
Ag2CO3 (1.0 equiv) + Na2CO3 PhCF3
(2.0 equiv)
DCE
100
100
100
120
120
16
16
16
16
24
6
PhCF3
PhCF3
PhCF3
22
30
47
59
6
7
NMe4Cl (2.0 equiv) + Na2CO3 PhCF3
(3.0 equiv)
120
120
24
24
34
e
NMe4Cl (3.0 equiv) + KOAc
(4.0 equiv)
PhCF3
67
Figure 2. Substrate scope with respect to iodobenzene derivatives of
the arylation of dipeptide 1o. Reaction yields represent isolated yields.
a
Reaction conditions: 1a (0.1 mmol), 2a (2.0 equiv), Pd(OAc)2 (10
b
mol %), and additives in solvent (1 mL). Optimization studies are
c
provided in the Supporting Information. Reaction yields were
determined by 1H NMR using 1,2-dibromoethane as the internal
para- and meta-substituted aryl iodide compounds are well
tolerated by this method.
d
e
standard. 1a (0.05 mmol). 2a (3 equiv).
We next explored the substrate scope of this chemistry with
N-terminal benzamides of peptide substrates using iodoben-
zene 2a as the aryl donor (Figure 3). Peptide substrate 1j
reacted with 2a efficiently by generating mono- and diarylated
products in 40% and 43% yields, respectively (entry 3ja). Halo
substitutions on the N-terminal benzamides of dipeptide
substrates are tolerated in this reaction, resulting in the
corresponding products in moderate to good yields (entries
3la−3na). Substrates containing meta-methyl substitutions
were arylated at the ortho-position exclusively (entries 3oa and
3ra), whereas para-methylated dipeptide 1p generated both
mono- and diarylated products in moderate yields (entry 3pa).
Notably, when the methyl substitution is at the ortho-position,
arylation at C(sp2)−H and C(sp3)−H were both observed
(entries 3qa and 3qa′), further demonstrating the versatility of
this reaction. In addition, methoxyl-substituted and N-
naphthamide-protected substrates (1s and 1t) were both
good substrates for this chemistry. Overall, our results showed
that this method is compatible with peptide substrates with
various N-terminal benzamide groups.
To address the impact of peptide sequences to the reaction,
a variety of dipeptide substrates with an N-terminal o-
chlorobenzamide group were synthesized and subjected to
reaction with iodobenzene 2a (Figure 4). The results showed
that incorporation of hydrophobic amino acids at the N-
terminus of peptide substrates, such as tLeu, Leu, Ile, and Val,
does not affect their reaction with 2a, resulting in the
corresponding products in moderate to good yields (entries
3aa−3da). However, dipeptide 1e containing a Gly residue at
the N-terminus exhibited lower reaction efficiency (entry 3ea).
conditions led to the standard conditions as follows: 3.0 equiv
of substrate 2a, 10 mol % of Pd(OAc)2 as the catalyst, 3.0
equiv of NMe4Cl, and 4.0 equiv of KOAc in trifluorotoluene
(PhCF3) at 120 °C for 24 h, affording ortho-arylated product
3aa in 67% yield (Table 1, entry 7). Alteration of additives and
solvents decreased the yield of the reaction significantly
(entries 1−5).
First, we evaluated the substrate scope of the arylation
method toward the aryl iodides (Figure 2). Using dipeptide 1o
as a substrate, iodobenzene, p-iodomethylbenzene, and m-
iodomethylbenzene all reacted efficiently by generating the
corresponding products in high isolated yields (Figure 2, 3oa−
3oc). Substrate 2d and 2e with p-butyl and dimethyl
substitutions, respectively, both reacted with 1o in excellent
yields (entries 3od and 3oe). Substitution of a methoxyl group
at the para- and meta-positions does not affect the reaction
yields (entries 3of and 3og). Chloro and fluoro substitutions
are also well-tolerated in this protocol (entries 3oh and 3oi).
Substrates with electron-withdrawing groups, such as trifluor-
omethyl and nitro groups, led to high reaction yields (entries
3oj and 3ok). Finally, iodonaphthalene 2l was shown to be an
excellent substrate in this chemistry to yield product 3ol in
94% yield. In addition, detailed NMR analysis revealed that the
arylation occurs at the ortho-position (Supporting Information
section 5). However, when ortho-substituted aryl iodides are
employed as substrates, reaction yields are generally low. We
reasoned that the steric hindrance at the ortho-position
decreases reaction efficiency. Together, our results show that
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substrates have little impact on their arylation (entries 3ha and
3ia). Furthermore, we examined our method on tripeptide and
tetrapeptide substrates 1u and 1v, respectively. The results
showed that both substrates are modified efficiently by yielding
corresponding products (entries 3ua and 3va). Thus, this
method demonstrates good substrate scope regarding peptides
of various sequence and length.
The success of this method on peptide arylation prompted
us to further explore its applicability in the synthesis of
complex peptide derivatives. First, we synthesized iodobenzene
derivatives of bioactive molecules containing a hydroxyl group,
including (−)-menthol, cholesterol, and diacetone-D-galactose.
Under optimized conditions, these derivatives were efficiently
conjugated to peptide substrate 1o in good yields (Figure 5A),
Figure 3. Scope of the arylation reaction with respect to N-terminal
benzamides of peptide substrates.
Figure 5. Pd-catalyzed C−H activation to build complex peptide
derivatives. (A) Ligation of peptides with bioactive molecules. (B)
Macrocyclization of biaryl-bridged cyclic peptides.
demonstrating the versatility of this method. Furthermore, we
challenged this method in the construction of peptide
macrocycles with biaryl-cross-links (Figure 5B). We first
prepared precursor pentapeptide 4a by incorporating iodo-
benzene-modified Ser. Under the optimized conditions,
substrate 4a underwent macrocyclization smoothly through
ortho-arylation, affording the 24-membered macrocycle 5a in
with 80% conversion, as determined by HPLC analysis of the
crude reaction mixture (Figure S5), and 40% isolated yield.
Finally, the macrocyclization of peptides 4b−4f were
examined. Gratifyingly, all substrates cyclized smoothly, and
corresponding products were purified in reasonable yields
(entries 5b−5f). Thus, this peptide arylation method is
efficient in the synthesis of peptide conjugates and macrocycles
with unique biaryl cross-links.
Figure 4. Scope of the arylation reaction with various oligopeptides.
In contrast, incorporation of Phe and protected Lys residues at
the N-terminus resulted in good arylation efficiency (entries
3fa and 3ga). Substrates 1h and 1i both reacted efficiently
although the chirality of their C-terminal amino acids is
different, indicating that D- or L-amino acids in peptide
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To sum up, we have developed a versatile method for the
modification and macrocyclization of short peptides with N-
terminal benzamide groups via Pd-catalyzed C(sp2)−H
arylation. Amide groups of the peptide backbone behave as
directing groups and facilitate the Pd-catalyzed and site-specific
arylation. Moreover, our protocol allows direct conjugation of
bioactive molecules to peptide substrates as well as direct
preparation of peptide macrocycles with aryl−aryl bridges.
This chemistry serves as a valuable addition to the chemical
toolbox in synthesizing peptide derivatives with complex
architectures.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02945.
Experimental procedures and H and 13C NMR spectra
for all new compounds (PDF)
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wanghuan@nju.edu.cn.
ORCID
Huan Wang: 0000-0003-1585-6760
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study is financially supported by NSF of China (Grant
Nos. 21778030 and 21922703 to H.W.) and the Fundamental
Research Funds for the Central Universities (Grant Nos.
14380138 and 14380131 to H.W.).
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Peptide-guided functionalization and macrocyclization of bioactive
peptidosulfonamides by Pd(II)-catalyzed late-stage C-H activation.
Nat. Commun. 2018, 9, 3383.
(20) Li, B.; Li, X.; Han, B.; Chen, Z.; Zhang, X.; He, G.; Chen, G.
Construction of Natural-Product-Like Cyclophane-Braced Peptide
Macrocycles via sp(3) C-H Arylation. J. Am. Chem. Soc. 2019, 141,
9401−9407.
(21) Zhang, X.; Lu, G.; Sun, M.; Mahankali, M.; Ma, Y.; Zhang, M.;
Hua, W.; Hu, Y.; Wang, Q.; Chen, J.; He, G.; Qi, X.; Shen, W.; Liu,
P.; Chen, G. A general strategy for synthesis of cyclophane-braced
peptide macrocycles via palladium-catalysed intramolecular sp(3) C-
H arylation. Nat. Chem. 2018, 10, 540−548.
(22) Tan, J.; Wu, J.; Liu, S.; Yao, H.; Wang, H. Macrocyclization of
peptidoarylacetamides with self-assembly properties through late-
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(23) Bai, Q.; Tang, J.; Wang, H. Functionalization of Sulfonamide-
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D
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