Rhodium(III)-Catalyzed C-H Alkenylation: Access to Maleimide-Decorated Tryptophan and Tryptophan-Containing Peptides

Decorated Tryptophan and Tryptophan-Containing Peptides

Letter

Rhodium(III)-Catalyzed C−H Alkenylation: Access to Maleimide-

Jingjing Peng, Chunpu Li, Mirzadavlat Khamrakulov, Jiang Wang,* and Hong Liu*

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00086

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sı Supporting Information

ABSTRACT: Maleimide is widely applied in many ﬁelds,

especially in antibody−drug conjugations and peptide drugs.

Herein, we develop a strategy for the C−H alkenylation of

tryptophan and tryptophan-containing peptides, providing a

synthetic route of decorating maleimide on peptides. The method

has a high tolerance of functional groups and protecting groups.

Furthermore, this method was applied to prepare peptide

conjugation with molecules such as drugs and ﬂuorescence probes.

Moreover, macrocyclic peptides were obtained via this reaction.

aleimide is a useful fragment in medicinal chemistry and

biochemistry. It is widely used for bioconjugation as a

Fluorescence-labeled maleimide can be easily decorated on

peptides containing cysteine. However, to conjugate the

maleimide moiety with biomolecules, biomolecules should

contain active reaction sites like cysteine, thiol, or other linkers.

It is important to develop a method to directly decorate

maleimide on biomolecules, especially peptides without cysteine

(Figure 1d).

Transition-metal-catalyzed C−H activation has provided an

eﬃcient route to decorate the maleimide moiety on various

organic molecules. Maleimide can be decorated on many useful

linker to link biomolecules and other molecules. Trastuzumab

emtansine (Kadcyla) is an ADC drug, which is approved by the

FDA for the treatment of HER2 positive breast cancer, using

maleimide to conjugate emtansine with trastuzumab (Figure

a). Albuvirtide, a long-acting anti-HIV peptide drug, which is

developed by Frontier Biotechnologies Inc., contains a

maleimide moiety (Figure 1b). The maleimide moiety can

bind with human serum albumin, thus improving the half-life of

the peptide. In addition, the maleimide moiety is commonly

used in biomolecule labeling as a linker (Figure 1 c).

scaﬀolds, such as benzene, 8-alkyl quinolines, N-sulfonylketi-

mines, 2-amino-1,4-naphthoquinones, and indoles, via this

C−H activation strategy, indicating that maleimide is a useful

moiety in organic chemistry. In recent years, methods to install

maleimide on the C-2 position of indoles have been extensively

explored, including using ruthenium, cobalt, and mangane-

se catalysts (Figure 2a). Maleimide can be used as alkylation

reagent and also alkenylation reagent in the latest reports via

rhodium and cobalt catalysts. Maleimide can be decorated

on the C-4 position of indoles with Heck-type products obtained

(

Figure 2b).

In the past few years, various transition-metal-catalyzed

modiﬁcations of peptides have been reported by the groups of

Lavilla and Albericio, Corey, Chen, Daugulis, Yu,

4−17

Ackermann,

Shi, James, Waser, and Fairlamb,

among others. Of all the reported literature, the Ackermann

group contributes a lot to the modiﬁcation of tryptophan and

tryptophan-containing peptides. Diaryliodonium salts as

arylation reagents for C-2 arylation were obtained via a noble-

Received: January 10, 2020

Figure 1. Application of maleimide and strategies to install maleimide

on biomolecules.

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Table 1. Optimization of the Rhodium(III)-Catalyzed C−H

a b

Alkenylation

catalyst

(5 mol %)

yield

(%)

entry

additive

solvent

[RhCp*Cl₂]₂Ag CO (30 mol %)

[RhCp*Cl₂]₂AgOAc (30 mol %)

DCE

[RhCp*Cl₂]₂Ag O (30 mol %)

[RhCp*Cl₂]₂Ag O (20 mol %) +

AgOAc (0.9 equiv)

[RhCp*Cl₂]₂Ag O (20 mol %) +

NMP

Figure 2. Transition-metal-catalyzed strategies to install maleimide on

indoles, tryptophan and tryptophan-containing peptides.

AgOAc (0.9 equiv)

[RhCp*Cl₂]₂Ag O (20 mol %) +

AgOAc (0.9 equiv)

14b,c

metal palladium catalyst.

However, palladium is expensive

[RhCp*Cl₂]₂Ag O (20 mol %) +

MeCN

AgOAc (0.9 equiv)

and toxic as a catalyst, whereas the use of less expensive and less-

toxic cobalt and manganese catalysts are a better choice for

^[^R^h^C^p^*^C^l2^]

Ag O (20 mol %) +

AgOAc (1.5 equiv)

peptide C−H activation. Alkynylation, cyanation, and

[RhCp*Cl

]

O (20 mol %) +

MeCN

allylation of tryptophan-containing peptides were reported.

Considering that C−H activation has been successfully used in

peptide modiﬁcation and that maleimide is a useful linker in

medicinal chemistry, we begin to think if maleimide could be

directly decorated on tryptophan and tryptophan-containing

peptides and aﬀord Heck-type products via a transition-metal-

catalyzed C−H activation reaction (Figure 2c).

AgOAc (1.5 equiv)

Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), catalyst (5 mol

), additive, solvent (1 mL), 80 °C, 12 h, Ar. Isolated yield. DCE

2 mL). 2 h.

(

investigating a variety of N-substituted maleimide derivatives

Scheme 1). Thus, the rhodium(III) catalyst proved to be

compatible with various alkyl functionalities in maleimide,

(

To test our hypothesis, we chose tryptophan 1a and

maleimide 2a as the model substrates. We initiated our studies

by exploring reaction conditions for the rhodium(III)-catalyzed

C−H alkenylation (Table 1). Diﬀerent kinds of Ag additives

were explored (entries 1−3). When Ag CO was used, 3a can be

including primary alkyl 2b (76%), secondary alkyls 2c−2e (42,

a,b

Scheme 1. Scope of the Maleimide Derivatives

obtained in 40% yield (entry 1), whereas AgOAc and Ag O

shared similar yields (49 and 44%, respectively, entries 2 and 3).

The yield of 3a could slightly improve when the concentration of

a increases to 0.2 M (entry 4). To investigate the role of the

silver additive, 10 mol % of Ag O was replaced with 0.9 equiv of

AgOAc, and the yield continued to improve to 55% (entry 5).

Various metals such as cobalt, manganese, ruthenium, and

iridium were explored, but no product was obtained (see the

Supporting Information, Table S1 ), indicating the importance of

the rhodium catalyst. To further optimize the reaction, diﬀerent

solvents were selected (entries 6−8 and Table S1 ). MeCN was

the best solvent for the titled transformation, resulting in 76%

yield of 3a (entry 8). To further improve the product yield, we

tried to increase the amount of AgOAc additive (entry 9).

Finally, reaction time was also investigated (entry 10). It was

shown that shortening the reaction time had no eﬀect on this

reaction. To investigate the role of a 2-pyridine directing group,

two control experiments were designed. When 1a was replaced

with Ac-Trp-OMe (S1a ) and Ac-Trp(Ph)-OMe (S1b) (see the

Supporting Information , brief mechanistic investigation), no

product could be obtained, thus indicating that the 2-pyridine

directing group was crucial in this reaction. In summary, we

ﬁnally chose tryptophan 1a and maleimide 2a in the presence of

[

RhCp*Cl ] catalyst and Ag O and AgOAc as additives in 1 mL

2 2 2

of acetonitrile as the best reaction condition.

Reaction conditions: 1a (0.2 mmol), 2b−2o (0.6 mmol),

[RhCp*Cl ] (5 mol %), Ag O (20 mol %), AgOAc (1.5 equiv),

With the optimal conditions for the rhodium(III)-catalyzed

C−H alkenylation identiﬁed, we examined its versatility by ﬁrst

MeCN (1 mL), 80 °C, 2 h, Ar. Isolated yield.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

a,b

7, and 53%, respectively), tertiary alkyl 2f (75%), and

Scheme 2. Scope of the Tryptophan-Containing Peptides

quaternary alkyl 2g (83%), resulting in good yields of desired

products. Substituted aryl groups in maleimide were also

investigated. Electron-rich substitutions (2h, 2i, and 2j)

provided yields (76, 72, and 80%, respectively) better than

those with electron-deﬁcient substitutions 2k−2n (57, 64, 32,

and 54%, respectively). In addition to alkyl and aryl groups in

maleimide, heteroaromatic pyridine was also compatible with

the reaction condition, leading to the formation of respective

product 3o in 58% yield. Studies of potential racemization

showed that the chiral center was not racemized during the C−

H alkenylation process (see Supporting Information for detailed

information).

Subsequently, the universality of the rhodium(III)-catalyzed

C−H alkenylation strategy was investigated for the diversiﬁca-

tion of dipeptides, which provided an eﬃcient route to

synthesize a broad range of maleimide-decorated dipeptides

(

Scheme 2).

Classical amine protecting group protected peptides, such as

Boc-Phe-Trp(2-py)-OMe (4a), Cbz-Leu-Trp(2-py)-OMe

4b), and Ac-Gly-Trp(2-py)-OMe (4c), and acid protecting

group protected peptides, such as Boc-Trp(2-py)-Gly-OBn

(

4d) and Boc-Trp(2-py)-Ala-O Bu (4e), were all tolerant of the

C−H alkenylation process in good yields ranging from 48 to

5%. However, the 2,2,4,6,7-pentamethyldihydrobenzofuran-5-

sulfonyl (Pbf) group for arginine Boc-Arg(Pbf)-Trp(2-py)-

OMe (4f) could only aﬀord product in moderate yield (38%).

Notably, free carboxamide Boc-Gln-Trp(2-py)-OMe (4g), OH-

free Thr peptide Boc-Trp(2-py)-Thr-OMe (4h), and sulfur-

containing peptide Boc-Trp(2-py)-Met-OMe (4i) were ob-

tained with medium to good levels of yields (range from 45 to

7%), indicating the compatibility with protic functional groups

via the rhodium(III)-catalyzed C−H activation reaction. On the

other hand, peptides containing unnatural amino acids and β-

amino acids were explored to identify the versatility of

rhodium(III) catalyst in the C−H activation reaction. We

were pleased to observe the chemoselective C−H alkenylation

of dipeptides containing unnatural amino acids (4k and 4l) and

β-amino acid (4m) with yields ranging from 30 to 52%, even

though dipeptides contained thiazole.

Encouraged by the eﬃcacy of C−H alkenylation in

dipeptides, we explored the rhodium(III)-catalyzed C−H

activation strategy toward the late-stage modiﬁcation of

tryptophan-containing complex peptides (Scheme 2). Indeed,

a broad range of tripeptides delivered the desired products with

moderate levels of yields (29−64%) when tryptophan was at the

C-terminal of peptide chain 5n (30%), at the N-terminal of

peptide chains 5o−5r (36, 64, 37, and 40%, respectively), or in

the middle of peptide chains 5s and 5t (29 and 36%). Notably,

NH-free tryptophan-containing peptides (5q and 5r) were also

tolerated by the rhodium(III)-catalyzed C−H activation,

indicating the outstanding chemoselectivity ensured by the

directing-group-induced chelation assistance. Tryptophan-con-

taining tetrapeptides Boc-Ala-Phe-Gly-Trp(2-py)-OMe (4u),

Boc-Trp(2-py)-Val-Val-Gly-OEt (4v), Boc-Trp(2-py)-Ile-Asp-

Reaction conditions: 4a−4z (0.2 mmol), 2a (0.6 mmol),

RhCp*Cl ] (5 mol %), Ag O (20 mol %), AgOAc (1.5 equiv),

[

MeCN (1−2 mL), 80 °C, 2 h, Ar. Isolated yield.

reﬂected by complete tolerance of complex peptides containing

protected lysine, aspartate, glutamic acid, threonine, serine, and

methionine.

It should be mentioned that gram-scale reactions of 1a and 2a

proceeded smoothly to give 3a without negative eﬀects on the

reaction eﬃciency (Scheme 3a). The synthetic application of the

C−H alkenylation reaction was demonstrated by removal of the

pyridyl motif without reduction of the double bond in

(

OBn)-Gly-OBn (4w), and Boc-Trp(2-py)-Glu(OBn)-Leu-

Met-OMe (4x) could also be transformed into desired products

33, 66, 38, and 35%, respectively), whereas more complicated

maleimide in the presence of Pd(OH) /C and ammonium

formate (Scheme 3b). To expand our application, dipeptide

derivative 5e was chosen for complete deprotection. After

sequential removal of the directing group and protecting group,

the maleimide-decorated dipeptide 7b can be obtained in good

yield (Scheme 3c).

After establishing a robust method for the C−H alkenylation

on peptides, we focused on complexity-increasing trans-

(

pentapeptide Boc-Gly-Ser(OBn)-Thr(OBn)-Ile-Trp(2-py)-

OMe (4y) and hexapeptide Boc-Trp(2-py)-Ala-Leu-Val-Gly-

Phe-OMe (4z) were compatible with this transformative C−H

alkenylation reaction, with 46 and 59% corresponding products

obtained. The chemoselectivity of the C−H transformation was

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 3. Gram-Scale Synthesis and Removal of the

Directing Group and Protecting Groups

can be linked with metronidazole via maleimide in 31% yield. In

addition, the rhodium(III) catalysis method was shown to be

tolerant of a maleimide-linked amino acid such as Gly-OBn,

which was an eﬃcient synthetic route for delivering amino acid

conjugation product with good levels of site-selectivity (Scheme

c). Tryptophan 9a and maleimide-linked Gly-OBn 2r can be

conjugated in 73% yield. Maleimide-decorated tryptophan can

potentially react with thiols such as cysteine. So it may be

interesting if maleimide-decorated tryptophan and cysteine can

be linked together via Michael addition. We indeed obtained the

addition product 11a with a desirable yield (Scheme 4d).

Cyclic peptides have been widely used in medicinal chemistry

due to their unique stability against enzymatic degradation.

Thus, an eﬃcient synthetic route to these key structural motifs is

still in high demand. Encouraged by the unique robustness of

our method, we explored the utility of the intramolecular and

intermolecular C−H activation toward tryptophan-based

macrocycles. Thus, unbiased amino acid derivative 12a was

successfully cyclized to provide the 18-membered macrocycle

3a in 50% yield (Scheme 5a); while cutting the length of the

formations with diﬀerent molecular architectures. The rhodium-

Scheme 5. Synthesis of Macrocycles via C−H Activation

(

III) catalyst proved to be eﬀective for conjugating peptides

through C−H activation with ﬂuorescence probes (Scheme 4a)

Scheme 4. Transformative C−H Fusion with Diﬀerent

Molecules

maleimide linker of substrate, we cannot obtain the desired 15-

membered macrocycle; however, a dimer macrocycle 13b can be

obtained in 32% yield (Scheme 5b). The structure of 13b is

determined by X-ray. In addition, the larger 20-membered

macrocycle 13c is also tolerated in our method (Scheme 5c),

indicating it a useful route for macrocycle synthesis.

In summary, we developed a new rhodium(III)-catalyzed C−

H alkenylation strategy toward maleimide-decorated peptides.

Maleimide-decorated peptides can be obtained under mild and

epimerization-free reaction condition. Classical protecting

groups and heteroatom-containing functional groups were

fully tolerated, thus indicating the robustness of the C−H

and drug molecules (Scheme 4b). The ﬂuorescence probe could

be linked to tryptophan via a maleimide linker, which was a

potential way to label the amino acid. The labeled tryptophan

derivative 8a could be obtained in 87% yield. The C−H

transformation with 2q was mirrored by the tolerance of a N-

containing heteroring, thus providing a synthetic route for

conjugating peptides with small molecular drugs. Dipeptide 4c

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Chen, B.; Liu, B.; Li, X.; Jiang, H. An albumin-conjugated peptide

Letter

activation reaction. Our ﬁndings further highlight the unique

practical application of rhodium(III)-catalyzed C−H activation

for peptide conjugation with a ﬂuorescence probe, drug

molecule, and amino acid derivative as well as the synthesis of

macrocyclic peptides.

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ASSOCIATED CONTENT

sı Supporting Information

■

(

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.0c00086.

Integrin Expression. J. Nucl. Med. 2006, 46, 1172−1180.

Detailed experimental procedures, reaction development,

studies on potential racemization, and characterization

data for all compounds (PDF)

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Maleimides. Asian J. Org. Chem. 2018, 7, 1338 −1342. (c) Chen, X.;

Ren, J.; Xie, H.; Sun, W.; Sun, M.; Wu, B. Cobalt(III)-catalyzed 1,4-

addition of C −H bonds of oximes to maleimides. Org. Chem. Front.

CCDC 1961640 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge via

www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_

request@ccdc.cam.ac.uk , or by contacting The Cambridge

Crystallographic Data Centre, 12 Union Road, Cambridge

CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

■

320 −1324. (f) Sherikar, M. S.; Prabhu, K. R. Weak Coordinating

Corresponding Authors

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Switchable Decarboxylative Heck-Type and [4 + 1] Annulation

Reactions with Maleimides. Org. Lett. 2019, 21 , 4525 −4530.

Jiang Wang − State Key Laboratory of Drug Research, Shanghai

Institute of Materia Medica, Chinese Academy of Sciences,

Shanghai 201203, China; University of Chinese Academy of

Sciences, Beijing 100049, China; orcid.org/0000-0003-

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Hong Liu − State Key Laboratory of Drug Research, Shanghai

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Authors

Jingjing Peng − State Key Laboratory of Drug Research, Shanghai

(6) Reddy, K. N.; Krishna Rao, M. V.; Sridhar, B.; Reddy, B. V. S.

Institute of Materia Medica, Chinese Academy of Sciences,

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Chunpu Li − State Key Laboratory of Drug Research, Shanghai

Institute of Materia Medica, Chinese Academy of Sciences,

Shanghai 201203, China; University of Chinese Academy of

Sciences, Beijing 100049, China

Mirzadavlat Khamrakulov − State Key Laboratory of Drug

Research, Shanghai Institute of Materia Medica, Chinese

Academy of Sciences, Shanghai 201203, China; University of

Chinese Academy of Sciences, Beijing 100049, China

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Complete contact information is available at:

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Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We are grateful to the National Natural Science Foundation of

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