Chemoselective Peptide Backbone Diversification and Bioorthogonal Ligation by Ruthenium-Catalyzed C?H Activation/Annulation

Article abstract of DOI:10.1002/adsc.202100323

The field of peptide derivatization by metal-catalyzed C?H activation has been mostly directed to modify the side chains, but poor attention has been given to the peptide backbone. Here we report a ruthenium-catalyzed C?H activation/annulation process that can chemoselectively modify the peptide backbone producing functionalized isoquinolone scaffolds with high regioselectivity in a rapid and step-economical manner. This strategy is characterized by racemization-free conditions and the production of fluorescent peptides, and peptide conjugates to drugs, natural products and other peptide fragments, providing a chemical approach for the construction of novel peptide-pharmacophore conjugates. Mechanistic studies suggest that amide bonds of peptide backbone act as the bidentate directing group to promote the C?H activation/annulation process. This report provides an unprecedented example of peptide backbone diversification and bioorthogonal ligation exploiting the power of ruthenium-catalyzed C?H activation. (Figure presented.).

Full text of DOI:10.1002/adsc.202100323

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DOI: 10.1002/adsc.202100323
Very Important Publication
Chemoselective Peptide Backbone Diversification and
Bioorthogonal Ligation by Ruthenium-Catalyzed CÀ H
Activation/Annulation
Liangliang Song,a Gerardo M. Ojeda-Carralero,a, b Divyaakshar Parmar,a
David A. González-Martínez,b Luc Van Meervelt,c Johan Van der Eycken,d
Jan Goeman,d Daniel G. Rivera,b,* and Erik V. Van der Eyckena, e,*
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven Celestijnenlaan
200F, 3001, Leuven, Belgium
E-mail: erik.vandereycken@kuleuven.be
Center for Natural Product Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, Havana, Cuba
b
E-mail: dgr@fq.uh.cu
c
Biomolecular Architecture, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001, Leuven, Belgium
Laboratory for Organic and Bio-Organic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University,
d
Krijgslaan 281 (S.4), B-9000 Ghent, Belgium
Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya Street 6, Moscow, 117198, Russia
e
Manuscript received: March 14, 2021; Revised manuscript received: April 14, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100323
Abstract: The field of peptide derivatization by metal-catalyzed CÀ H activation has been mostly directed to
modify the side chains, but poor attention has been given to the peptide backbone. Here we report a
ruthenium-catalyzed CÀ H activation/annulation process that can chemoselectively modify the peptide
backbone producing functionalized isoquinolone scaffolds with high regioselectivity in a rapid and step-
economical manner. This strategy is characterized by racemization-free conditions and the production of
fluorescent peptides, and peptide conjugates to drugs, natural products and other peptide fragments, providing
a chemical approach for the construction of novel peptide-pharmacophore conjugates. Mechanistic studies
suggest that amide bonds of peptide backbone act as the bidentate directing group to promote the CÀ H
activation/annulation process. This report provides an unprecedented example of peptide backbone
diversification and bioorthogonal ligation exploiting the power of ruthenium-catalyzed CÀ H activation.
Keywords: Peptides; CÀ H Activation; Metal catalysis; Ruthenium; Annulation
Introduction
ing pharmacokinetics and enabling realtime tracking
under physiological conditions, respectively. However,
The chemo- and regioselective derivatization of pep- many of these covalent modifications are carried out at
tides is a key synthetic transformation in modern the peptide side chains and not tend to modify the
chemistry,[1–5] mainly because of its ability to fine- peptide backbone.
tuning structural features that help modulate physico-
On the other hand, the development of peptide
chemical and biological properties. Peptide conjuga- pharmaceuticals[14–17] very often focuses on derivatizing
tion to other bioactive molecules such as drugs, lipids, the peptide backbone seeking to modulate pharmaco-
carbohydrates and proteins are common derivatizations logical properties. Thus, the most common approaches
when seeking applications such as directed cancer are directed toward amide N-alkylation and backbone
therapy or vaccine development.[6–9] Similarly, ligation macro- and hetero-cyclization,[18–25] thus aiming at
to synthetic polymers (e.g., PEGs) and fluorescent tuning the bioactive conformation and/or improving
labels[10–13] are predominant modifications for improv-
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metabolic stability (i.e., resistance to peptidases) and they also show limitations such as a) the dependence
membrane permeability.[14–25]
on exogenous monodentate or bidentate auxiliaries,
When seeking chemoselective peptide derivatiza- which requires the multi-step introduction and subse-
tion, transition metal catalysis offers great opportuni- quent removal of the directing group, and b) the
ties for innovation and achieving the desired bioortho- predominance of one-step cross-coupling processes,
gonality in the process. Traditionally, alkyne-azide which restrains the structural complexity and diversity
dipolar cycloadditions[26–28] (metal-catalyzed or not) that can be achieved in the peptide structure.
and palladium-catalyzed cross-couplings[29–31] have
Herein we report a ruthenium-catalyzed CÀ H
been the most widely employed methods for the activation/annulation[21,24,53] as a versatile procedure for
bioorthogonal peptide derivatization – including cycli- the structural diversification and bioorthogonal ligation
zation – and ligation to other molecules or labels of structurally complex peptides (Scheme 1C). Interest-
(Scheme 1A,B). Although classical reactions and ing features of our approach are a) the chemo-
cross-couplings have been employed for the chemo- selectivity of the CÀ H activation/annulation at the
selective diversification and bioorthogonal ligation of benzoylated N-terminal residue in the presence of other
peptides, they largely rely on prefunctionalizations, aromatic (Phe, Trp) and functionalized (Lys, Met, Ser)
leading to lengthy synthetic procedures and undesired amino acids, b) the racemization-free CÀ H activation/
byproducts as well as the racemization of the peptidic annulation for the efficient synthesis of fluorescent
scaffold. Recently, this field has been moving towards peptides, c) the utilization of the peptide backbone as
approaches focusing on transition metal-catalyzed bidentate directing group, d) the bioorthogonal ligation
CÀ H activation processes in an atom- and step- to amino acids, other peptides, drugs and natural
economical manner.[32–36] A variety of elegant transition products in an efficient way, and e) the rapid access to
metal-catalyzed methods have been successfully em- dimeric peptide-drug conjugates through twofold CÀ H
ployed in the late-stage derivatization of peptides, activation/annulation.
including CÀ H arylation,[37–43] alkynylation,[44,45]
olefination,[46,47] allylation[48,49] and alkylation.[50–52] De-
Results and Discussion
spite the indisputable advances, in addition to being
used mostly for the modification of the side chains, Assessment of the chemoselectivity and substrate
scope. As shown in Table 1, our study on peptide CÀ H
activation/annulation was initiated using standard
reaction conditions[21,24,53] with dipeptide 1–1, bearing a
D-Ala residue, and the commercially available diphe-
nylacetylene 2–1. To our delight, 1–1 was fully
consumed in just 1 h and the annulation product 3–1
was obtained in 92% yield.[54] A dipeptide bearing an
L-Ala residue worked equally well, giving product 3–2
in 95% yield in 1 h. Then symmetrical diaryl- and
dialkyl-substituted alkynes were utilized, leading to
products (3–3 to 3–7) in 52–82% yield. We were
pleased to observe that unsymmetrical disubstituted
alkynes (3–8 to 3–10) and especially dialkyl-substi-
tuted alkynes (3–11), were well tolerated to yield the
desired products (23–86%) with excellent regioselec-
tivity in the annulation process. Dipeptides with
various benzamides, such as naphthalene, pyrene,
benzofuran, indole and acrylamide reacted smoothly to
deliver the desired products (3–12 to 3–16) in 81–92%.
To address the influence of the peptide sequence on
the reaction outcome, a variety of dipeptides having
functionalized amino acids were evaluated. Thus,
dipeptides bearing a free C-terminal carboxylic group
(Val, 3–18), a deprotected indole (Trp, 3–20), a free
hydroxyl (Ser, 3–21), a Boc-protected amine (Lys, 3–
24) and a thioether (Met, 3–22) afforded the isoquino-
lone-decorated peptides (3-17 to 3–24) in 45–93%.
This approach also displayed the capability to efficient
synthesis of decorated peptide involving both α- and β-
amino acids (3–25). These examples proved the
Scheme 1. Metal-catalyzed chemoselective approaches for the
peptide derivatization (e.g., labeling) and ligation to drugs or
other bioactive molecules.
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Table 1. Evaluation of the substrate scope and chemoselectivity of the ruthenium-catalyzed CÀ H activation/annulation of N-
terminal benzoyl peptides.[a]
[a] 1 (0.3 mmol), 2 (0.36 mmol), [Ru(p-cymene)Cl2]2 (0.015 mmol), NaOAc (0.15 mmol), Cu(OAc)2 (0.6 mmol) and t-AmOH
°
(3.0 mL), 120 C, 1 h.
[b] 2 h.
[c] t-AmOH/DMF (1:1).
[d] 12 h.
[e] t-AmOH/DMF (3:1). The regioisomeric ratios are shown in parenthesis.
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excellent chemoselectivity of this ruthenium-catalyzed strates, which again included Ser (3–36 and 3–40), Trp
CÀ H activation/annulation strategy and its potential for (3-43) and Pro (3–37) residues, as well as several
the derivatization of more complex architectures.
others having Phe at different positions. In none of the
We were also interested in evaluating the efficacy cases did we detect side reactions involving the
of this process with peptides having an N-alkylated modification of the peptide side chains, thus proving
amide in the second position. To achieve this, we broad substrate scope and excellent functional-group
employed the Ugi four-component reaction to assem- tolerance regardless the peptide length and sequence. It
ble peptides having N-alkylated amides[55,56] and these is particularly noteworthy that the racemization of
compounds were submitted to the ruthenium(II)-cata- peptidic backbone did not occur under the standard
lyzed reaction to furnish the isoquinolone-peptide conditions from NMR spectra.
hybrids 3–26 to 3–30 in good to excellent yields. The
After proving the success of this CÀ H activation/
good results obtained in the synthesis of these annulation strategy in the chemoselective derivatiza-
compounds – especially 3–28 that includes a sterically tion of varied peptide sequences, we were encouraged
congested N-benzyl α-disubstituted residue – confirm to further investigate the bioorthogonal ligation of
the robustness of this protocol.
peptides to α- and β-amino acids, other peptides, drugs
In this initial assessment of the annulation reaction, and bioactive natural products. As depicted in Table 2,
we also carried out the derivatization of dipeptides besides the variation of the peptide sequence, two
derived from the commercial drugs probenecid and additional diversification sites are available at the
bexarotene, resulting in the chimeric products 3–33 isoquinolone ring, thus enabling to use either the
(76%) and 3–34 (68%). Finally, we derivatized a substituted phenyl ring or the aliphatic tail for the
number of tri-, tetra-, penta- and hexapeptide sub- ligation to the molecule of interest. In this sense, the
Table 2. Peptide ligation to drugs, other peptides and natural products by ruthenium-catalyzed CÀ H activation/annulation.[a]
[a] 1 (0.3 mmol), 2 (0.36 mmol), [Ru(p-cymene)Cl2]2 (0.015 mmol), NaOAc (0.15 mmol), Cu(OAc)2 (0.6 mmol) and t-AmOH
°
(3.0 mL), 120 C, 1 h.
[b] The regioisomeric ratios are shown in parenthesis.
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short dipeptide N-benzoyl-Gly-Ala-OMe was subjected peptide
derivatives.
Figure 1
illustrates
the
to a variety of annulation/ligation procedures using the fluorescence spectra of selective decorated peptides
alkyne functionalized peptides, the drugs febuxostat, with maximum emission wavelengths ranging from
memantine, mexiletine and the natural product deriva- 392 to 479 nm. This proves the capacity of this
tive dehydrocholic acid. To our delight, all these covalent modification to modulate the electronic
substrates were efficiently ligated to the peptide properties of decorated peptides at the same time that
forming the isoquinolone scaffold and leading to the medicinally relevant moieties are attached to the
hybrids 3–44 to 3–52 in good to excellent yields.
peptide backbone.
Subsequently, the bioorthogonal ligation of diverse
Scheme 2 shows a final synthetic approach in
oligopeptides to the alkynyl dipeptide Val-Gly-OMe which we investigate the possibility to accomplish a
was examined, furnishing the conjugated peptides 3– double CÀ H activation/annulation process leading to
53 to 3–62 in excellent yields, with complete chemo- biaryl and biaryl-ether dimeric peptide conjugates. The
selectivity regarding the peptide side chains. The good syntheses of the chimeric polyheterocyclic-peptide-
regioselectivity of the annulation process when using drug conjugates 5–1 and 5–2 in good yields confirmed
asymmetric alkynes bearing an aliphatic and aromatic the robustness of this ruthenium(II)-catalyzed proce-
substituent validates our hypothesis that the two dure to generate molecular complexity in a short
appendages are equally useful diversification points of sequence. As proven, the rigid bisisoquinolone cores
the isoquinolone-peptide hybrid. Finally, the drug resulting from this dual approach can be used not only
febuxostat was conjugated to a complex hexapeptide to for the assembly of multimeric drugs, but also for the
render the conjugate 3–63 in a very good yield.
multimerization of longer bioactive peptide chains.
Due to the formation of the pyridone moiety
Mechanistic studies. One of the positive aspects
conjugated to other aromatic rings, we envisioned that that we noted during the CÀ H activation/annulation
this could be a useful method for accessing fluorescent process with peptides is that the reaction proceeds in a
much shorter time as compared with simpler benza-
mides not having the peptidic backbone. This implies
that the peptide backbone assists the CÀ H activation/
annulation reaction participating as a bidentate ligand,
something impossible, for example, in simpler N-alkyl
benzamides. As a result, we sought to carry out
comparative experiments under the standard conditions
used in this work (i.e., 5 mol% of [Ru(p-cymene)Cl2]2,
°
additives, 120 C, 1 h) to gain more mechanistic
insights into the ruthenium-catalyzed CÀ H activation/
annulation reaction. As shown in Scheme 3, N-meth-
ylbenzamide (6–1) was initially submitted to the
standard conditions with diphenylacetylene 2–1, result-
ing in the annulation product (7-1) and the unreacted
substrate in 34% and 57% yield respectively. In
parallel, methyl benzoylglycinate (6–2) furnished the
Figure 1. Fluorescent properties of some isoquinolone-peptide
hybrids 3.
Scheme 2. Synthesis of multimeric peptide-drug conjugates by double ruthenium-catalyzed CÀ H activation/annulation.
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Scheme 3. Control experiments using standard conditions
°
(5 mol% [Ru(p-cymene)Cl2]2, additives, 120 C, 1 h).
Scheme 4. Proposed mechanism based on experimental evi-
dence.
annulated product 7–2 in 46% yield under the same
standard conditions, with a 48% yield recovery of the
unreacted substrate. On the other hand, a significant tides and functionalized alkynes, affording N-terminal
improvement was observed in the reaction of benzoyl- isoquinolone-decorated peptides with good to excellent
glycine (6–3), which led to the corresponding product regioselectivity in a rapid and step-economical manner.
7–3 in almost full conversion and 72% yield. Nonethe- Through the chelating assistance of amide bonds of the
less, the efficiency of this transformation for the peptide backbone – i.e., bidentate directing group –
dipeptidic 1–1 is superior to all previous examples, very complex annulation products are obtained in high
showing full conversion into product 3–1 just after 1 h, yield, including peptide conjugates to drugs, bioactive
with an isolated yield of 92%.
natural products and other peptide fragments. Some
These results confirm that the peptide backbone decorated peptides are analyzed for their fluorescent
serves as a bidentate directing group promoting the properties, showing that this type of backbone hetero-
ruthenium-catalyzed CÀ H activation/annulation[57] annulation might be useful for labeling/tracking strat-
even to a greater extent than a terminal carboxylate. egies in peptide chemistry. Finally, this straightforward
Based on these results and previous reports, we CÀ H activation/annulation, implemented in a twofold
proposed a plausible mechanism for this transforma- manner, allows for the rapid access to dimeric peptide-
tion (Scheme 4). Initially, the ruthenium(II) catalyst drug conjugates, a strategy that shows promise for the
coordinates to the NH-deprotonated 1–1, resulting in a multimerization of peptide therapeutics. Overall, we
bidentate coordinated intermediate A. Subsequently, A have demonstrated that this robust and versatile CÀ H
undergoes C(sp2)-H bond cleavage to deliver the activation/annulation method can be implemented for
intermediate B. Alkyne insertion into intermediate B the derivatization of complex peptides and their
generates intermediate C, which then undergoes reduc- bioorthogonal ligation to drugs or other biomolecules.
tive elimination to render the product 3–1. The
resulting ruthenium(0) is next reoxidized by Cu(OAc)2
to regenerate the ruthenium(II) species that enters into
Experimental Section
In a seal capped flask equipped with a stirring bar, the peptide
(0.3 mmol), alkyne (0.36 mmol), Cu(OAc)2 (0.6 mmol), NaOAc
(0.15 mmol), [Ru(p-cymene)Cl2]2 (0.015 mmol) and 3 mL of t-
AmOH were added. The reaction mixture was put in an oil bath
the next catalytic cycle.
Conclusion
°
and heated at 120 C for 1 h. After the reaction completion
We have developed a versatile and efficient procedure
for the chemoselective and racemization-free diversifi-
cation of the peptide backbone of amino acids such as
Ser, Met, Phe, and Trp. This bioorthogonal derivatiza-
tion strategy relies on a ruthenium(II)-catalyzed CÀ H
activation/annulation reaction between N-benzoyl pep-
(TLC checked), the mixture was diluted with 25 mL of DCM
and filtered over a pad of Celite. The remaining organics were
dried over anhydrous Na2SO4. Then, the organic phase was
concentrated in vacuum and the crude was purified by a silica
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gel column chromatography (n-heptane/ethyl acetate or DCM/
MeOH) to afford the product.
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Acknowledgements
LVM thanks the Hercules Foundation for supporting the
purchase of the diffractometer through project AKUL/09/0035.
We acknowledge the FWO [Fund for Scientific Research-
Flanders (Belgium)], the Research Council of KU Leuven
(BOF), VLIR-UOS (Flemish-Cuban project CU2018-
TEA458A101) for financial support. D. G. R. is grateful to KU
Leuven for a visiting scientist fellowship. This paper has been
supported by the RUDN University Strategic Academic Leader-
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