Pd-Catalyzed Site-Selective C(sp2)-H Olefination and Alkynylation of Phenylalanine Residues in Peptides

Article abstract of DOI:10.1021/acs.orglett.9b00987

Pd-catalyzed site-selective C(sp²)-H olefination and alkynylation of phenylalanine residues in peptides are described. The amino acids within the peptides are used as native bidentate directing groups to facilitate C-H functionalization. This p

Full text of DOI:10.1021/acs.orglett.9b00987

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
2
Pd-Catalyzed Site-Selective C(sp )−H Olefination and Alkynylation
of Phenylalanine Residues in Peptides
†
,‡
Yong Zheng and Weibin Song*
†
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
‡
Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Stake Key Laboratory Cultivation Base for TCM Quality
and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
*
S Supporting Information
2
ABSTRACT: Pd-catalyzed site-selective C(sp )−H olefina-
tion and alkynylation of phenylalanine residues in peptides are
described. The amino acids within the peptides are used as
native bidentate directing groups to facilitate C−H function-
alization. This protocol would provide appealing strategies for
the postsynthetic modification of peptides.
eptides and peptidomimics are important pharmaceutically
Scheme 1. Pd-Catalyzed C−H Activation of Peptides without
the Installation of External Directing Groups
P
active molecules in drug discovery due to their high target
1
specificity and low toxicity. Consequently, a number of peptide-
1a
based drugs have been approved in the past few decades.
However, natural peptides often suffer from poor permeability
2
and metabolic stability. Furthermore, natural peptides lack
structural diversity due to the limitation of 20 proteinogenic
amino acids. To circumvent those disadvantages, several
strategies for peptide modification have been developed to
improve the pharmacokinetic properties and increase structural
3
diversity for structure−activity relationship (SAR) studies.
Among these, C−H functionalization has emerged as a
4
,5
promising tool for the postmodification of bioactive peptides.
2
For example, metal-catalyzed direct C(sp )−H functionalization
of tryptophan residues in peptides has been achieved. With the
aid of external directing groups, C(sp )−H functionalization of
6
3
7
peptides has also been reported.
Recently, C−H activation of peptides without installing
external directing groups became a particularly attractive
approach for the postsynthetic modification of peptides. For
example, Yu reported pioneering studies on site-selective
3
arylation, acetoxylation, and alkynylation of C(sp )−H bonds
of N-terminal amino acids in di-, tri-, and tetrapeptides (Scheme
8
1
). Amino acid moieties within peptides act as internal
bidentate directing groups to accelerate C−H activation,
which prevents the installation and removal of the directing
groups. Later, microcyclization of peptides was developed by
9
using peptide backbones as internal directing groups.
Pd-catalyzed directing group-assisted selective C−H olefina-
tion and alkynylation have received a considerable amount of
10,11
attention, as olefins and alkynes are versatile building blocks.
Incorporation of olefins and alkynes into peptides might
improve pharmacokinetic properties and biological activities.
Furthermore, alkyne groups in peptides also act as precursors for
Sonogashira coupling and click chemistry, which is used for the
residues in peptides without the installation of directing groups
are rare.
13
1
2
synthesis of labeled peptides and conjugates. However,
Received: March 20, 2019
examples of olefination and alkynylation of phenylalanine
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Previously, we reported a Pd-catalyzed intramolecular
Scheme 2. Substrate Scope for Olefination of Dipeptides
2
C(sp )−H amination of phenylalanine residues in dipeptides
1
4
(
Scheme 1). The amino acids within dipeptides were used as
internal directing groups. In a continuation of our efforts on
postsynthetic modification of phenylalanine residues in
peptides, we herein report a Pd-catalyzed site-selective
2
C(sp )−H olefination and alkynylation of phenylalanine
residues in peptides. This postsynthetic modification would
provide a powerful toolbox for accessing a series of olefinated
and alkynylated peptides for medicinal chemistry research.
To test these hypotheses, we initially started our C−H
olefination by treating dipeptide 1a with methyl acrylate. After
the optimization of reaction conditions (see the Supporting
Information for details), dipeptides containing various amino
acids at the N-terminus were examined (Scheme 2). The
dipeptides containing different Boc-L-amino acids proceeded
smoothly and afforded the mono- and diolefinated products in
moderate to good yields (2a−2g). Notably, both mono- and
diolefinated dipeptides were obtained without any epimeriza-
tion (2amono and 2a , respectively). For dipeptides bearing
di
methionine and serine, only diolefinated products (2h and 2i)
were formed, presumably because methylthio and acetoxyl also
acted as directing groups, which accelerated the C−H
olefination reaction. Furthermore, a dipeptide containing a
Boc-D-amino acid was also found to be a good substrate,
affording the desired mono- and diolefinated products (2jmono
and 2j , respectively) in 55% and 25% yields, respectively.
di
Different coupling partners were also surveyed. Styrene that
participated in this C−H olefination gave the desired mono- and
diolefinated products (2k
and 2k , respectively). Interest-
mono
di
ingly, olefination of vinyl sulfone and allyl acetate with
dipeptides provided the mono-olefinated products (2l and
2
m) in 62% and 61% yields, respectively. A dipeptide containing
Cbz-glycine proceeded smoothly to give a mono-olefinated
product (2nmono) in 45% yield, along with a trace amount of a
diolefinated product (2n ). Next, the scope of substituents on
di
phenyl rings of dipeptides was studied. Both electron-donating
(
OAc) and electron-withdrawing (Cl, F, and NO ) groups on
2
the phenyl rings were compatible under the standard condition,
affording the desired olefinated products (2o−2s). Interestingly,
dipeptides with a NO2 group gave only mono-olefinated
products (2p and 2q). A substrate with a meta substituent was
olefinated at the less stericlly hindered ortho position (2s).
Tryptophan residues in dipeptides could also undergo
olefination under the standard conditions, affording the
olefinated products (2t and 2u). We further explored C−H
olefination of phenylalanine residues in tripeptides (Scheme 3).
For tripeptide 3a, only a diolefinated product (4a) was formed
probably because the tripeptide was chelated with palladium in a
tridentate manner, which accelerated the reaction. C−H
olefination of tripeptide 3b afforded 4b in 58% yield.
Having established the methodology for the C−H olefination
of peptides, we next explored the C−H alkynylation of peptides
(
see the Supporting Information for details of screening reaction
conditions). To our delight, with 10 mol % Pd(OAc) as a
2
catalyst, 2 equiv of K CO as a base, and 0.2 equiv of PivOH as
2
3
an additive, dipeptide 1a underwent alkynylation smoothly with
bromoethynyl)triisopropylsilane, giving the mono- and dia-
lkenylated products (5amono and 5a , respectively) in 52% and
a
Conditions: 1 (0.3 mmol), olefin (0.9 mmol), AgOAc (0.6 mmol),
(
Pd(OAc) (10 mol %), DCE (2 mL), 120 °C, 24 h. Isolated yields.
2
di
3
5% yields, respectively (Scheme 4). Alkynylated dipeptides (5b
and 5c) were also formed in good yields. C−H alkynylation of a
dipeptide with a NO substituent afforded only a monoalkeny-
lated product (5d) in 55% yield. Next, tripeptides were utilized
for this C−H alkynylation (Scheme 5). A dialkynylated
tripeptide (6a) was formed in 56% yield, along with a trace
amount of a monoalkynylated product under standard
2
B
DOI: 10.1021/acs.orglett.9b00987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Substrate Scope for Olefination of Tripeptides
Scheme 5. Substrate Scope for Alkynylation of Tripeptides
a
Conditions: 3 (0.3 mmol), olefin (0.9 mmol), AgOAc (0.6 mmol),
Pd(OAc) (10 mol %), DCE (2 mL), 120 °C, 24 h. Isolated yields.
2
a
Scheme 4. Substrate Scope for Alkynylation of Dipeptides
a
Conditions: 3 (0.3 mmol), (bromoethynyl)triisopropylsilane (0.9
mmol), K CO (0.6 mmol), PivOH (0.06 mmol), Pd(OAc) (10 mol
2
3
2
%
), DCE (2 mL), 120 °C, 24 h. Isolated yields.
Scheme 6. Plausible Mechanism
a
Conditions: 1 (0.3 mmol), (bromoethynyl)triisopropylsilane (0.9
mmol), K CO (0.6 mmol), PivOH (0.06 mmol), Pd(OAc) (10 mol
2
3
2
%), DCE (2 mL), 120 °C, 24 h. Isolated yields.
conditions. Tripeptides containing different amino acids (3b−
d) reacted smoothly with (bromoethynyl)triisopropylsilane to
3
provide the desired products (6b−6d) in moderate yields.
On the basis of the observations and literature reports
mentioned above, a plausible mechanism for this Pd-catalyzed
11k,l
C−H alkynylation reaction is depicted in Scheme 6.
C−H
alkynylation of dipeptides 7 and 9 did not take place under the
standard conditions because a bidentate palladium complex
could not be formed during the catalytic cycles. Dipeptide 1a
coordinates with Pd(OAc) to generate palladium complex I.
2
Complex I then undergoes C−H insertion to give intermediate
II. Next, oxidative addition to the TIPS-acetylene bromide
affords intermediate III. Reductive elimination affords alkyny-
lated product 3a. Finally, ligand exchange regenerates the Pd(II)
species to perpetuate the catalytic cycle.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00987.
In summary, we have developed Pd-catalyzed site-selective
2
C(sp )−H olefination and alkynylation of phenylalanine
Experimental procedures and spectroscopic data (PDF)
residues in the peptides. The amino acids within the peptides
are used as intrinsic bidentate directing groups to facilitate C−H
functionalization. This protocol would provide opportunities for
the postsynthetic modification of peptides, which is further used
in peptide-based drug research.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: songwbolin@163.com.
C
DOI: 10.1021/acs.orglett.9b00987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
Ge, H. Chem. - Eur. J. 2011, 17, 14371. (e) Yu, M.; Xie, Y.; Xie, C.;
Zhang, Y. Org. Lett. 2012, 14, 2164. (f) Gandeepan, P.; Cheng, C.-H. J.
Am. Chem. Soc. 2012, 134, 5738. (g) Meng, X.; Kim, S. Org. Lett. 2013,
15, 1910. (h) Wang, B.; Shen, C.; Yao, J.; Yin, H.; Zhang, Y. Org. Lett.
Weibin Song: 0000-0003-0925-3904
Notes
2
014, 16, 46. (i) Tang, R.-Y.; Li, G.; Yu, J.-Q. Nature 2014, 507, 215.
The authors declare no competing financial interest.
(j) Ye, X.; Shi, X. Org. Lett. 2014, 16, 4448. (k) He, C.; Gaunt, M. J.
Chem. Sci. 2017, 8, 3586. (l) Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. J.
ACKNOWLEDGMENTS
■
Am. Chem. Soc. 2014, 136, 13602.
2
The authors gratefully acknowledge the National Natural
Science Foundation of China (Grant 81602995) for financial
support.
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DOI: 10.1021/acs.orglett.9b00987
Org. Lett. XXXX, XXX, XXX−XXX