Backbone-Enabled Directional Peptide Macrocyclization through Late-Stage Palladium-Catalyzed δ-C(sp2)?H Olefination

Article abstract of DOI:10.1002/anie.201807953

C?H activation methods for peptide macrocyclization have the potential to provide peptidomimetics and cyclic peptides with expanded structural diversity. Now, a highly versatile peptide macrocyclization strategy via late-stage palladium-catalyzed δ-C(sp

Full text of DOI:10.1002/anie.201807953

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Accepted Article
Title: Backbone-Enabled Directional Peptide Macrocyclization through
Late-Stage Palladium-Catalyzed δ-C(sp2)-H Olefination
Authors: Zengbing Bai, Chuangxu Cai, Zonglun Yu, and Huan Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807953
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10.1002/anie.201807953
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COMMUNICATION
Backbone-enabled Directional Peptide Macrocyclization through
Late-stage Palladium-catalyzed δ-C(sp2)-H Olefination
Zengbing Bai, Chuangxu Cai, Zonglun Yu and Huan Wang*[a]
Abstract: C-H activation methods for peptide macrocyclization have
the potential to provide peptidomimetics and cyclic peptides with
expanded structural diversity. Here, we report the development of a
highly versatile peptide macrocyclization strategy via late-stage
palladium-catalyzed δ-C(sp2)-H olefination of phenylalanine residues.
This protocol utilizes peptide backbone amides as internal directing
groups and allows facile macrocyclization of peptides in the “N-to-C”
direction. Combined with our previously developed β-C(sp3)-H
arylation method for peptide macrocyclization in the “C-to-N” direction,
we have obtained a pair of palladium-catalyzed reactions that are
directionally orthogonal, and demonstrate the first example of one-pot
synthesis of bicyclic peptides via Pd-catalyzed β-C(sp3)-H and δ-
C(sp2)-H activation.
Peptides and peptidomimetics have emerged as an
increasingly important class of therapeutics with high potency and
selectivity.[1] One major driving force for the growing interest of
these substances is their capability in regulating protein-protein
interactions (PPIs),[2] which have been identified in numerous
biological process and highly related to diseases. Compared with
native
peptides,
chemically
modified
peptides
and
peptidomimetics often display improved biological activities and
pharmacokinetics.[3] Therefore, it is highly desirable to develop
strategies for site-specific functionalization of peptides, among
which macrocyclization is one of the most prominent methods.
Compared to their acyclic counterparts, peptide macrocycles
usually have well-defined structures and drug-like properties.[4]
Classic methods to generate cyclic peptides include head-to-tail
lactamization,[5] internal disulfide[6] or thioether formation,[7] ring-
closing olefin metathesis (RCM)[8] and Cu-catalyzed cycloaddition
of azides to alkynes.[9] In addition, multicomponent-condensation
and SNAr substitution reactions have recently been successfully
applied to peptide macrocyclization.[10] Despite these advances,
chemical methods to construct cyclic peptides are still limited
compared with synthetic methods for small molecules.[11]
Transition metal catalyzed C-H activation has now become
a fundamental strategy to functionalize complex molecules.[12]
Recently, several elegant examples of late-stage site-selective C-
H functionalization of peptides using Pd catalyst have been
achieved, including β-C(sp3)-H arylation and alkynylation at the
N-terminal amino acid by Yu,[13] γ-C(sp3)-H carbonylation of
peptides by Carretero,[14] β-C(sp3)-H arylation and BODIPY
labelling of peptides using internal 1,2,3-triazole moieties as the
directing group by Ackermman.[15] As most methods follow a five-
membered palladacycle pathway during C-H activation, Shi and
Figure 1. Pd-catalyzed site-selective late-stage δ-C(sp2)-H functionalization
and macrocyclization of peptides enabled by peptide backbone.
[a]
Z.-B. Bai, Z.-L Yu, C.-X Cai, Prof. Dr. H. Wang
State Key Laboratory of Coordination Chemistry, Jiangsu Key
Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering
Nanjing University
No. 163 Xianlin Ave, Nanjing, China 210093
E-mail: wanghuan@nju.edu.cn
co-workers reported a unique example of selective δ-C(sp3)-H
alkylation of peptides through a kinetically less favored six-
membered palladacycle by utilizing PA as the directing group.[16]
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To achieve peptide macrocyclization, Albericio/Lavilla utilized Pd-
catalyzed C-2 arylation of the indole side chain of tryptophans
(Trp) by iodo-aryl amino acids to synthesize stapled peptides with
aryl-aryl crosslinks.[17] Noisier/Albericio and our group
independently developed an intramolecular β-C(sp3)-H arylation
method to construct peptide macrocycles containing βC-Ar
crosslinks.[18] In addition, a Mn-catalyzed C-H alkynylation method
is developed for late-stage peptide modification and
macrocyclization.[19] More recently, Chen and coworkers reported
a highly efficient and general strategy to prepare constrained
cyclic peptides using 8-aminoquinoline-directed intramolecular
arylation of C(sp3)-H bonds in the presence of Pd catalyst.[20] In
continuation of our studies on peptide macrocyclization,[21] we
herein report the late-stage Pd-catalyzed δ-C(sp2)-H olefination of
phenylalanine (Phe) residues enabled by peptide backbone, and
its application in synthesizing cyclic peptides with unique aryl-
alkene crosslinks. Our method utilizes peptide backbone amides
that are N-terminally to a Phe residue as internal directing groups
(Fig. 1B), and displays broad substrate scope including
unactivated alkenes. Furthermore, we show that peptide
macrocyclization achieved by this method follows the N-to-C
direction. Combined with the previously developed C-to-N peptide
macrocyclization through β-C(sp3)-H arylation, we have obtained
a pair of Pd-catalyzed peptide macrocyclization reactions that are
directionally orthogonal, and demonstrated the first example of
one-pot synthesis of bicyclic peptides using backbone-enabled β-
C(sp3)-H and δ-C(sp2)-H activation.
double bond was determined to be in E-configuration (Fig. S1-S2).
After detailed optimization, we finalized the reaction conditions for
the δ-C(sp2)-H olefination as follows: 10 mol% Pd(OAc)2, 3.0 eq.
AgOAc, with DCE as solvent at 80 ⁰C for 20 h (Table S1).
Figure 3. A). Two-fold C-H olefination for the homo-ligation of dipeptides; B).
Ligation of amino acids and peptides bearing Phe residues and alkenes. C).
Positional effect on the backbone-enabled Phe olefination.
With the optimized conditions in hand, we proceed to
evaluate the substrate scope of this peptide backbone-enabled
reaction (Fig. 2). Using dipeptide (1a) as the model substrate, we
first examined a variety of alkenes as olefination reagents.
Results showed that both acrylate methyl ester (2a) and acrylate
tert-butyl ester (2b) reacted with (1a) efficiently, yielding
corresponding products in 93% and 80% yields (entries 3aa and
3ab). Pent-1-en-3-one (2c) and N,N-dimethylacrylamide (2d)
were also good substrates, resulting in product (3ac) and (3ad) in
81% and 90% yields, respectively. Pd-catalyzed ortho-olefination
of arenes with unactivated alkenes is generally challenging.[22] To
our delight, substrate (1a) reacted smoothly with styrene (2e) and
3, 3-dimethylbut-1-ene (2g) in good yields (entries 3ae and 3ag).
Recently, Ackermann and co-workers developed a highly efficient
Figure 2. Pd-catalyzed olefination of Phe residues in dipeptide substrates
utilizing backbone amides as directing groups. The ratio of mono- and bi-
olefination products are shown in parentheses.
We initiated our investigation by employing a dipeptide
BocNH-Gly-Phe-COOBn (1a) as the model substrate and acrylate
methyl ester (2a) as the olefination reagent (Fig. 2). Preliminary
screenings led to the formation of mono-olefination product (3aa)
and di-olefination product (3aa’) in 93% yield (mono: di = 2.7: 1).
NMR analysis of product (3aa) revealed that the olefination
occured selectively at the δC position of the Phe residue, and the
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Ru-catalyzed method allowing fluorescent labelling of peptides.[23]
Encouraged by the success of intermolecular olefination of
Phe-containing dipeptides, we further explore the applicability of
our method in generating cyclic peptides with unique aryl-alkene
crosslinks, which are found in a number of natural products
including cyclopeptide alkaloids (Fig. S4).[24] We started with a
tripeptide substrate (6a) containing an acrylate-modified Ser
residue (Fig. 4, Fig. S4). Under standard conditions, substrate
(6a) reacted efficiently with full conversion, yielding a 15-
membered cyclic peptide (7a). Tetrapeptides (6b) and (6c)
cyclized with increased efficiency, affording 18-membered
macrocycle (7b) and (7c) in 55% and 40% isolated yields,
respectively. Positioning Ala and Leu residues at the third position
to the C-terminus has no impact on macrocyclization (entries 7d
or 7e). Introduction of Pro residue in substrate (6f) facilitated the
macrocyclization, affording product (7f) in 58% yield. When
methyl protected Tyr was incorporated into the tetrapeptide
substrate (6g), intramolecular δ-C(sp2)-H olefination of Tyr
occured selectively to yield macrocycle (7g) in good yield,
demonstrating the versatility of this method. Next, we expanded
the substrate scope to pentapeptide (6h) and hexapeptide (6i),
leading to 21- and 24-membered macrocycles (7h) and (7i),
respectively, in good yields. Structural analysis by NMR revealed
that the olefination reaction occurred at the δ-C(sp2) position of
Phe residue, and the resulting double bond is in E-configuration
in the resulting cyclic peptides (Fig. S5-S6). Next, we challenged
our macrocyclization method with unactivated alkenes. A pent-4-
enoic acid was conjugated to the side chain of Ser at the N-
terminus in substrate (6j), and treatment of substrate (6j) under
standard condition led to the successful production of a 17-
membered cyclic peptide (7j) in 52% yield, demonstrating the
potency of this backbone-enabled macrocyclization method. It is
noteworthy that no branched olefination product was observed
during the macrocyclization of (6j). Finally, we applied our method
to the synthesis of a bioactive cyclic RGD sequence, which
provided a 26-membered peptide macrocycle (7k) in 42% yield.
Together, these results demonstrated that the backbone-enable
macrocyclization strategy is highly efficient in generating cyclic
peptides of various sizes and sequences.
Our approach successfully install
a
fluorescent 4-(4-
vinylphenyl)pyrene (2f) onto dipeptide in 69% yield (entries 3af).
Next, we evaluated the impact of dipeptide sequences on the
reaction. The protocol is also compatible with dipeptides
containing N-terminal Ala, Ile and t-Leu (entries 3ba-3da), as well
as protected amino acids (entry 3ea). No racemization was
observed during reaction (Scheme S1). Together, these results
showed that the backbone amides are effective directing groups
to facilitate the site-selective δ-C(sp2)-H olefination of the Phe
residue.
Furthermore, the robustness of this olefination method
leads to two-fold C-H olefination for the homo-ligation of dipeptide
(1a) with bis-functional alkenes (4a) and (4b), delivering tetra-
peptides (5aa) and (5ab) in high yields (Fig. 3A). This result
prompted us to utilize this reaction in site-selective ligation of
amino acids and peptides to Phe-containing oligopeptides.
Alkene-modified serine (4c) and dipeptide (4d) both reacted
efficiently with substrate (1a) (Fig. 3B), demonstrating the
potential of this chemistry in the direct preparation of peptide
conjugates with complex structures in a site-specific manner.
Next, we evaluated whether the position of Phe residue in
an oligopeptide would affect the efficiency of the olefination
reaction. Three tripeptide substrates (1f-1h) were therefore
synthesized with Phe residue incorporated at the C-, N-terminus
or the middle position, and treated with acrylate butyl ester (2b).
Results showed that only tripeptide (1f) was olefinated by acrylate
tert-butyl ester (2b) efficiently, whereas substrates (1g) and (1h)
was unreactive under standard conditions, indicating that two
amide bonds N-terminally to the Phe residue are required to
enable this reaction. The reaction of substrate (1h) fails most
likely because for C-terminal amides to facilitate δ-C-H olefination
of Phe, a kinetically unfavored seven-member palladacycle need
to be formed (Fig. S3). In contrast, two amide bonds that are N-
terminally to the Phe residue in substrate (1f) could activate the
δ-C-H bond by generating a six-membered palladacycle, allowing
the reaction to proceed smoothly (Fig. S3).
18
18
18
18
18
15
21
24
18
17
26
Figure 4. Peptide macrocyclization via late-stage Pd-catalyzed δ-C(sp2)-H olefination of phenylalanine
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Enzymatic macrocyclization of peptide natural products is
often a directional process, which endows highly controlled and
regioselective formation of complex ring topologies.[25] The
positional effect of backbone-enabled Phe olefination in peptides
(Fig. 3C) raises the possibility that the backbone-enabled
macrocyclization reaction is directional. Therefore, we
synthesized tripeptide (6b’) containing the same amino acid
composition as peptide (6b), but in reverse order (Fig. 5A).
Results showed that peptide (6b) cyclized smoothly to yield
macrocycle (7b) (Fig. 4, Fig. 5), whereas peptide (6b’) was
completely unreactive under standard conditions. Similarly,
substrates (6c’) and (6f’), the reverse peptide sequences of
substrates (6c) and (6f), are also unreactive under standard
reaction conditions. These results indicate that the backbone-
enabled peptide macrocyclization via Pd-catalyzed olefination of
Phe residues can only proceed in the “N-to-C” direction, where
the alkene group is N-terminally to the target Phe. The failure of
“C-to-N” macrocyclization of peptide (6b’) is presumably due to
the requirement of generating a kinetically unfavored seven-
membered palladacycle for δ-C-H activation of Phe (Fig. S7).
Previously, Noisier/Albericio and our group have independently
developed a Pd-catalyzed β-C(sp3)-H arylation method for
peptide macrocyclization,[18a, 18b] and our recent studies indicated
that this macrocyclization method follows the “C-to-N” direction,
in which the iodophenylalanine (I-Phe) is required to be C-
terminally to the target Ala residue (Fig. 5A). We propose that
such directionality is also determined by the formation of
palladacycle intermediates during C-H activation. Following the
“C-to-N” direction, the reaction generates a five-membered
palladacycle, whereas a kinetically unfavored four-membered
palladacycle intermediate is generated when following the “N-to-
C” direction (Fig. S7). Thus, the backbone-enabled peptide
macrocyclization via β-C(sp3)-H and δ-C(sp2)-H activation are
directionally orthogonal.
Structurally constrained bicyclic peptides have emerged as
an important type of bioactive compounds;[26] however, methods
to achieved regioselective synthesis of these compounds are
rare.[27] One-pot synthesis of bicyclic peptides are particularly
challenging because it generally requires two chemically
orthognal reactions for the formation of two ring structures.[27d] We
envisioned that peptide macrocyclization through β-C(sp3)-H
arylation and δ-C(sp2)-H olefination as a pair of directionally
orthogonal cyclization reactions (Fig. 5A) may allow one-pot
synthesis of bicyclic peptides with high regioselectivity. To
examine this hypothesis, we synthesized substrate 9a containing
an N-terminal Ala and meta-I-Phe as one pair of reacting groups,
as well as a C-terminal Phe and alkene-modified Ser as a second
pair (Fig. 5B). Treatment of peptide 9a under optimized conditions
generated a bicyclic product 10a in 35% isolated yield. NMR
analysis indicated that the formation of the two rings are highly
controlled in 10a, and solely generated from the β-C(sp3)-H
arylation of the N-terminal Ala and δ-C(sp2)-H olefination of the C-
terminal Phe (Fig. 5B). This result demonstrates that the Pd-
catalyzed C-H activation enabled by peptide backbone is a robust
strategy in the preparation of complex peptide macrocycles.
Figure 5. One-pot synthesis of bicyclic peptides through directionally orthogonal
Pd-catalyzed macrocyclization.A) peptide macrocyclization via β-C(sp3)-H and
δ-C(sp2)-H activation are directionally orthogonal; B) One-pot synthesis of
bicyclic peptides using Pd-catalyzed C-H activation.
In conclusion, we have developed a highly versatile late-
stage peptide macrocyclization strategy through palladium-
catalyzed δ-C(sp2)-H olefination of phenylalanine residues that
are facilitated by the peptide backbone. This method is efficient in
peptide modification, ligation and generation of peptide
macrocycles of various sizes and sequences. Furthermore, we
demonstrate that the backbone-enabled peptide macrocyclization
via δ-C(sp2)-H olefination follows the N-to-C direction, whereas
peptide macrocyclization via β-C(sp3)-H arylation follows the C-
to-N direction, providing a pair of reactions that are directionally
orthogonal. Such a pair of reactions is applied in the one-pot
synthesis of a bicyclic peptide with high regioselectivity. With
rational design, the backbone-enabled C-H activation method
holds great potential in generating peptide macrocycles of
complex topology and related studies are undergoing in our
labarotory.
Acknowledgements
This work was supported by the 1000-Youth Talents Plan, NSF of
China (Grant 21778030), NSF of Jiangsu Province (Grant
BK20160640), the Fundamental Research Funds for the Central
Universities (Grant 14380138 and 14380131).
Keywords: cyclic peptide • macrocycle • macrocyclization •
palladium catalysis• C-H activation
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This article is protected by copyright. All rights reserved.

10.1002/anie.201807953
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
A highly versatile late-stage
Zengbing Bai, Chuangxu Cai, Zonglun Yu and Huan
Wang*
peptide macrocyclization strategy
through palladium-catalyzed δ-
C(sp2)-H olefination of
phenylalanine residues has been
developed. The backbone-enabled
macrocyclization follows the N-to-
C direction and allows the one-pot
synthesis of a bicyclic peptide.
Backbone-enabled Directional Peptide
Macrocyclization through Late-stage Palladium-
catalyzed δ-C(sp2)-H Olefination
This article is protected by copyright. All rights reserved.