Functionalization of Sulfonamide-Containing Peptides through Late-Stage Palladium-Catalyzed C(sp3)-H Arylation

Article abstract of DOI:10.1021/acs.orglett.9b01953

Bioactive peptides are emerging as promising candidates of clinic therapeutics. Here, we report a method for late-stage functionalization of sulfonamide-containing peptides through Pd-catalyzed C(sp³)-H arylation. In this protocol, the backbone

Full text of DOI:10.1021/acs.orglett.9b01953

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Functionalization of Sulfonamide-Containing Peptides through
Late-Stage Palladium-Catalyzed C(sp3)−H Arylation
Qingqing Bai,† Jian Tang,‡ and Huan Wang*,†
†State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093, China
‡School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China
S
* Supporting Information
ABSTRACT: Bioactive peptides are emerging as promising
candidates of clinic therapeutics. Here, we report a method for late-
stage functionalization of sulfonamide-containing peptides through
Pd-catalyzed C(sp3)−H arylation. In this protocol, the backbones of
N-sulfonated peptides act as directing groups, which allows site-
specific arylation of benzylsulfonamide moiety. This chemistry
exhibits broad substrate scope and can be utilized to synthesize peptide−peptide and peptide−amino acid conjugates. Our
results highlight the potency of the backbone of peptidomimetics in promoting Pd-catalyzed functionalization.
eptides and peptidomimetics are rich sources of bioactive
peptidosulfonamides by Pd(II)-catalyzed late-stage C(sp3)−H
Pcompounds and drug candidates as well as important arylation. This strategy utilizes the combination of sulfonamide
molecular tools in chemical biology.1 Recently, protein−
and amide bonds as internal directing group and has broad
substrate scope. Furthermore, we applied this method for the
ligation of oligopeptides with amino acids to prepare peptide
conjugates with complex structures.
protein interactions (PPIs) have been identified in many
biological process; however, they are challenging to regulate
with small molecules. Peptides are proven as effective
regulators of PPI due to their unique capacity to interact
with protein surfaces.2 Furthermore, the development of
peptide−drug conjugates provides significantly expanded
chemical space for this class of compounds. Therefore, the
development of chemical methods to synthesize and modify
peptides to achieve structural diversity is important for their
application in medicinal chemistry. Aryl sulfonamides are
important pharmacophores, and their peptide conjugates are
often of diverse bioactivities, including anticoagulant and
inhibitor of bacterial peptidoglycan biosynthesis enzymes
(Figure 1a).3,4 Incorporation of sulfonamides in the backbone
of peptidomimetics often improves the proteolytic stability of
peptides, alters the overall peptide conformation, and improves
their pharmaceutical properties.5
We initiated our investigation by utilizing arylsulfonamide-
containing dipeptide 1a and iodobenzene 2a as substrates to
perform late-stage arylation (Table 1). Detailed optimization
studies revealed that the reaction proceeded most efficiently
with 4.0 equiv of iodobenzene 2a with the addition of 10 mol
t
% of Pd(OAc)2 and 3.0 equiv of AgOAc as oxidant in BuOH
at 100 °C for 20 h, affording di- and monoarylated products
3aa and 3aa′ in 76% yield with the ratio of di- and
monoarylated products to be 2:1 (entry 4). NMR character-
ization confirmed that arylation specifically occurred at the
benzylic C(sp3)−H positions (Figures S1−S3). Alteration of
oxidant from AgOAc to Ag2CO3 significantly decreased the
t
yield of the reaction (entry 1). When BuOH was used as the
reaction solvent, a higher ratio of diarylated product was
generated without affecting the reaction yield, in comparison
with reactions with DCE as the solvent (entries 2 and 4).
Similarly, the presence of basic or acid additives lowered the
reaction efficiency, presumably by interfering the coordination
between peptide backbone and Pd catalyst (entries 7−10).
Furthermore, when the amount of substrate 2a was increased
to 8 equiv, the total yield of arylation products was raised to
81%, and the ratio of di- and monoarylated products was
increased to 3:1 (entry 11).
Transition-metal-catalyzed C−H activation has emerged as a
highly efficient strategy in the functionalization of peptides and
peptidomimetics.6−15 For example, Yu and co-workers have
developed a method to achieve arylation of inert C(sp3)−H
bonds of N-terminal amino acids in oligopeptides (Figure
1b).16 Our group recently utilized Pd catalyst to perform late-
stage olefination of C(sp2)−H bonds of phenylalanine residues
in peptides (Figure 1b).17 These examples demonstrate that
amide bonds of peptide backbone coordinate efficiently with
palladium and facilitate the modification of peptide side chains
with high site selectivity. We envision that sulfonamide motifs
could participate in the coordination of transition-metal
catalysis and promote late-stage functionalization of sulfona-
mide-containing peptidomimetics (peptidosulfonamides).
Herein, we report the backbone-directed functionalization of
With the optimal reaction conditions in hand, we sought to
explore the generality of this protocol with respect to the aryl
iodides. Substrates bearing p- and m-methyl substitutions both
Received: June 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01953
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Scope of the arylation reaction of peptidosulfonamides with
respect to aryl iodides.
Figure 1. Pd-catalyzed late-stage C−H arylation of peptidosulfona-
mides: (a) bioactive peptidosulfonamides; (b) backbone-guided C−H
functionalization of peptides; (c) backbone-directed functionalization
of peptidosulfonamides by Pd(II)-catalyzed late-stage C(sp3)−H
arylation.
a,b
Table 1. Optimization of the Reaction Conditions
c
entry
oxidant
solvent
additive
yield (%) (di/mono)
1
2
3
Ag2CO3
AgOAc
Cu(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
DCE
DCE
DCE
32 (1:1)
71 (1:1)
trace
76 (2:1)
66 (1:2)
nr
45 (2:3)
42 (di)
22 (1:1)
72 (2:1)
81 (3:1)
4
tBuOH
DCM
DMF
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
5
6
7
NaOAc
tBuOK
o-PBA
PivOH
Figure 3. Scope of the arylation reaction of peptidosulfonamides with
8
t
respect to oligopeptides. (a) Solvent: BuOH. (b) Solvent: DCE.
9
10
d
11
efficiently, affording product 3ad in 83% isolated yield
dominantly with diarylated product. Substrates 2e and 2f
with fluoro- and trifluoromethyl groups at the para-position
were both well tolerated and underwent arylation smoothly
(Figure 2, 3ae and 3af). Naphthalene iodide was proven to be
good substrate in this chemistry to yield product 3ag in 66%
yield. However, ortho-substituted aryl iodides often lead to low
reaction yields, presumably due to the steric hindrance.18,19
Overall, our results demonstrate that various para- and meta-
substituted aryl iodide compounds are well accepted as aryl
donors in this protocol.
a
Reaction conditions: 1a (0.05 mmol), 2a (4 equiv), Pd(OAc)2 (10
mol %), oxidant (3 equiv), additive (2 equiv) in solvent (1 mL) at
b
100 °C for 20 h. Full details of the optimization study are provided
c
in the Supporting Information. 1H NMR yields are determined by
d
using 1,3,5-trimethoxybenzene as the internal standard. 2a (8 equiv)
was used.
reacted with dipeptide 1a smoothly by generating correspond-
ing products in good yields (Figure 2, 3ab and 3ac). Substrate
2d with a para-butyl substitution reacted with 1a highly
B
DOI: 10.1021/acs.orglett.9b01953
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
derivatives (Figure 4). Using iodobenzene-derivatized phenyl-
alanine 2h and serine 2i as substrates, ligation reactions with
dipeptides 1c and 1l were successfully achieved specifically at
the benzyl carbon of dipeptide substrates by generating
conjugates 3ch and 3li in good yields. Moreover, both iodo
dipeptides 2j and 2k reacted efficiently with dipeptide 1e
under standard reaction conditions by producing conjugates
3ej and 3ek in 49% and 38% isolated yields. These results
demonstrated the potential of this chemistry in the direct
preparation of peptide conjugates with complex structures in a
site-specific manner.
In summary, we report a general functionalization of
peptidosulfonamides at the N-terminus via Pd-catalyzed
C(sp3)−H activation. The potency of peptide backbone as a
directing group is demonstrated by the site-specific arylation.
The increasing importance of bioactive peptidomimetics
containing benzosulfonamide motifs should render this
method attractive for synthetic and medicinal chemistry.
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.9b01953.
Figure 4. Ligation of peptides and amino acid derivative through Pd-
catalyzed C(sp3)−H arylation. Reaction conditions: (a) 1a (0.05
mmol), 2y (2 equiv), Pd(OAc)2 (10 mol %), AgOAc (3 equiv) in
DCE (1 mL) at 100 °C for 20 h; (b) 1a (0.05 mmol), 2y (2 equiv),
Pd(OAc)2 (20 mol %), AgOAc (3 equiv) in tBuOH (1 mL) at 100 °C
for 20 h.
1
Experimental procedures and H and 13C NMR spectra
for all new compounds (PDF)
AUTHOR INFORMATION
■
Next, the substrate scope of this chemistry with various
peptide sequences was examined using iodobenzene as a
substrate (Figure 3). We synthesized dipeptide 2b with an N-
terminal D-tLeu residue and subjected it to standard reaction
conditions. The results showed that substrate 2b reacted
efficiently with iodobenzene to yield product 3ba in 78% yield
with a mono/di substitution ratio of 1:1. In comparison with
the reaction of substrate 2a, the chirality of the N-terminal
residue does not significantly affect the reaction efficiency.
Dipeptide substrates with Leu, Val, Ile, and Phe residues at the
N-terminus are all converted to the corresponding arylated
products in good yields (Figure 3, 3ca−3fa). However, when
the second amino acid directly attached to the reactive
sulfonamide carrying bulky side chains, such as Val and Leu,
the reaction yields were significantly decreased. Furthermore,
three tripeptide derivatives were synthesized with sequences of
tLeu-Gly-Val, Ile-Gly-Phe, and Ile-Gly-Ala and subjected to
reactions with 2a. The results showed that all three substrates
reacted efficiently (entries 3ia−3ka), further demonstrating
the versatility of this protocol.
To address the potential epimerization issue during the
reaction, substrates 1g and 1h with dipeptides of Leu-(L-Ala)
and Leu-(D-Ala), respectively, were synthesized and were
subjected to reactions with iodobenzene 2a under standard
conditions. The stereochemistry of the resulting products 3ga
and 3ha, both mono- and diarylation products, were analyzed
by directly injecting crude reaction mixtures in reversed-phase
high-performance liquid chromatography (RP-HPLC). Both
reaction mixtures gave distinct retention times, indicating that
the stereochemical integrity was fully retained without
epimerization (Figure S4).
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 work is supported by NSF of China (Grant Nos.
21778030 and 21861142005 to H.W.), the start-up fund from
the State Key Laboratory of Coordination Chemistry, and the
Fundamental Research Funds for the Central Universities
(Grant Nos. 14380138 and 14380131 to H.W.).
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DOI: 10.1021/acs.orglett.9b01953
Org. Lett. XXXX, XXX, XXX−XXX