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• Cyclic peptides often display improved metabolic stability, and in many cases, exhibit reduced polar surface area compared to linear peptides [1]. The incorporation of appropriate heterocyclic motifs into the structure of a cyclic peptide has the potential to enhance metabolic stability, increase potency and selectivity [2]. Many natural products possess tryptophan (Trp)-crosslinked macrocycle structures, such as stephanotic acid [3], chloropeptin Ⅱ [4], and celogentin C [5,6], which exhibit various biological activities, including anti-HIV, anti-inflammatory, and anti-fungal [7,8]. The traditional methods for synthesizing the Trp-crosslinked cyclic peptides could be divided into three categories: (a) Utilizing indole and its derivatives as starting materials, (b) transforming tryptophan, and (c) synthesizing the indole fragment via cross-coupling reactions (Fig. 1). However, these methods still have limitations that require further improvement. For example, in the synthesis of stephanotic acid methyl ester from indole derivatives involves racemization, resulting in the generation of cyclic peptides as racemic mixtures (Fig. 1a) [3]. Jia et al. employed protected 6-iodo-L-tryptophan as the indole-containing building block. Unfortunately, it requires five-step to synthesize 6-iodo-L-tryptophan, which leads to a decrease in synthetic efficiency (Fig. 1b) [9]. Larock annulation, an effective method for generating indoles, has been successfully utilized in the construction of Trp-crosslinked cyclic peptides [4,10-12]. However, a series of functional group interconversion steps are required, making these processes cumbersome (Fig. 1c). To overcome these limitations and improve the synthesis of these unique cyclic peptides, further research and innovative approaches are required.

  Figure 1

  

  Figure 1.  Synthesis of cyclic peptides with Trp crosslinks using traditional methods.

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  In recent years, the field of C-H functionalization has experienced rapid development [13-20]. Many strategies for site-selective functionalization of indole C-H bonds have been reported (Scheme 1a) [21-30]. However, these chemical strategies are primarily limited to straightforward indole and tryptophan derivatives. The late-stage modification of peptides using C-H functionalization has gained considerable attention due to its high atomic economy, convenient operation, and largely used for the cyclic peptide synthesis [31-34]. Therefore, developing conveniently installed and removal-traceless directing groups with mild reaction conditions for the direct late-stage modification of tryptophan-containing complex peptides are urgently needed. Trp-crosslinked cyclic peptides have been successfully constructed though C2 or C4 C-H activation of tryptophan (Scheme 1b) [32,35-37]. However, the construction of Trp(C7)-crosslinked cyclic peptides is more challenging and only a few successful cases have been reported [11,12]. Recently, Wang and our group have realized the construction of Trp-crosslinked cyclic peptides though C7 C-H activation of tryptophan, respectively [38,39]. The development of these methods opens up exciting opportunities for the efficient and selective modification of complex peptides, and it is expected to have a profound impact on the synthesis of biologically active cyclic peptides with enhanced properties. Further advancements in this field will undoubtedly expand the scope and applicability of C-H functionalization in peptide chemistry.

  Scheme 1

  

  Scheme 1.  Previous and present works for the construction of Trp-alkene-crosslinked cyclic peptides.

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  Heterocycle-alkene-braced cyclic peptides have been discovered in natural products, with some of them exhibiting unique biological activity [40,41]. For instance, cyclotheoneliazole A [41], a natural cyclic peptide, reported to be a potent elastase inhibitor and can alleviate acute lung injury. Given the pivotal role of indole in heterocycles, the development of convenient synthesis methods for Trp-alkene-crosslinked cyclic peptides holds great significance in obtaining novel and biologically active peptide macrocycles. In 2021, Ackermann and co-workers described the use of manganese-catalyzed alkyne hydroarylation raction for obtaining a series of cyclic peptides containing Trp(C2)-alkene crosslinks. This protocol was free of peptide racemization and highly tolerant to a variety of functional groups [42]. Here, we present a novel method for the rapid synthesis of E-configuration Trp(C7)-alkene-crosslinked cyclic peptides with potent anti-proliferative activities against cancer cells from simple linear peptide precursors through the merging of Rh(Ⅲ)-catalyzed pivaloyl (Piv)-directed late-stage C-H alkenylation and macrolactamization. This method overcomes the challenges posed by the large aromatic plane of cyclic peptide products and the unreactive C7 Trp site (Scheme 1c). Our notable findings include: (i) Completely E-configuration Trp(C7)-alkene-crosslinked cyclic peptides could be obtained by C-H alkenylation and the relay of macrolactamization, (ii) three kinds of cyclic peptides could be rapidly obtained by selecting rational designed acrylic esters based on different cyclization reaction sites, and (iii) directing group removal and macrolactamization could be combined into one step.

  We initiated our studies by choosing N-Piv-Boc-l-Trp-OMe (1a) and benzyl acrylate (2a) as the template substrates. Initially, a mixture of 1a (0.1 mmol) and 2a (0.3 mmol) was stirred at 80 ℃ in a sealed tube with DCE (1 mL) as the solvent for 12 h under air in the presence of catalyst (10 mol%), AgSbF₆ (20 mol%), and Cu(OAc)₂ (0.25 mmol) (Table 1, entries 1-4). Through the evaluation of various catalysts, we discovered that the desired product 3aa could be obtained in a 10% yield when [Cp*RhCl₂]₂ was introduced into the reaction system (Table 1, entry 1). The structure of 3aa was verified via NMR spectra, confirming the E-configuration connection of the alkenyl group to the indole moiety at the C7 position of tryptophan (see Supporting information for details). Subsequently, the influence of Ag salt was explored based on the above results (Table 1, entries 5 and 6). To our delight, AgNTf₂ was found to be an essential reagent, elevating the yield of 3aa to 49% upon replacing AgSbF₆ with AgNTf₂ (Table 1, entry 5). Further study revealed that the yield of 3aa could reach 69% by increasing the equivalent of 2a (4.5 equiv., Table 1, entry 7). Next, the influence of different solvents was examined. Solvent screening indicated that DCE was the best choice for this reaction (Table 1, entries 7-12). Additionally, extending the reaction time to 18 h did not lead to a further increase in yield (Table 1, entry 13). Ultimately, the optimal conditions for synthesizing 3aa were determined as follows: 1a (0.1 mmol), 2a (0.45 mmol), [Cp*RhCl₂]₂ (10 mol%), AgNTf₂ (20 mol%), Cu(OAc)₂ (0.25 mmol), in DCE (1 mL) stirred at 110 ℃ under air in a sealed tube for 12 h.

  Table 1

  

  Table 1.  Optimization of the reaction conditions.^a

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  After determining the optimal reaction conditions, we further investigated the scope of this reaction. The coupling of N-Piv-Boc-l-Trp-OMe (1a) with various acrylates were firstly examined. Trp (C7) alkenylation products could be obtained with medium to good yields when simple acrylates participated in this reaction (Scheme 2, 3aa-3ae, 49%-69%). 1a also reacted smoothly with acrylate-modified serine and serine-containing dipeptide (3af, 62%; 3ag, 40%). Different N-Piv installed tryptophan-containing dipeptides were synthesized, and they all reacted well with substrate 2a (3ba-3ka, 31%-75%). Notably, dipeptides containing unprotected asparagine, tryptophan, methionine, and methyl protected serine, as well as benzyl protected glutamic acid residue, successfully coupled with 2a under the optimal conditions (3ga-3ka, 31%-63%). Encouraged by these promising results, we further explored the potential application of this method for the alkenylation of tryptophan-containing tripeptides. Whether the N-Piv installed tryptophan residue was positioned at the N-terminus or C-terminus of the tripeptides, these tripeptides could react with the acrylate-modified serine 2f to obtain tetrapeptides containing the alkene-indole structure (3lf-3pf, 32%-62%).

  Scheme 2

  

  Scheme 2.  Rh(Ⅲ)-catalyzed alkenylation of Trp residues at the C7 position with Piv as the directing group. Reaction conditions: 1 (0.2 mmol), 2 (0.9 mmol), [Cp*RhCl₂]₂ (10 mol%), AgNTf₂ (20 mol%), Cu(OAc)₂ (0.5 mmol) in DCE (2 mL) under air at 110 ℃ for 12 h. NMR yield using 1,3,5-trimethoxybenzene as the internal standard. ^a Isolated yield.

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  The ligation of complex peptides randomly composed of tryptophan, leucine, phenylalanine, glycine, alanine, β-alanine, isoleucine, proline, protected glutamate, and protected aspartate with acrylates were further explored. To our delight, the determined optimal conditions remained effective for these Trp-containing tetrapeptides to hexapeptides (Scheme 3, 3qh-3th, 3ta, 3ui-3vi, 3wj-3yj, 39%-53%). The late-stage C-H alkenylation of these complex peptides served as a robust foundation, enabling the subsequent synthesis of a diverse array of cyclic peptides.

  Scheme 3

  

  Scheme 3.  Synthesis of complex Trp-containing peptides. Reaction conditions: 1 (0.2 mmol), 2 (0.9 mmol), [Cp*RhCl₂]₂ (10 mol%), AgNTf₂ (20 mol%), Cu(OAc)₂ (0.5 mmol) in DCE (2 mL) under air at 110 ℃ for 12 h. Isolated yields.

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  Furthermore, a gram scale synthesis of 3ah was carried out with 64% isolated yield, further confirmed the practicality of this method (Scheme 4a). The conditions for deprotection and directing groups removal were examined. The directing group pivaloyl (Piv) of 3ah could be easily removed in the presence of triethylamine, and the addition of water being crucial for facilitating a smooth reaction, leading to the formation of the corresponding product 4ah in a yield of 99% (Scheme 4b). The protecting groups t-butyloxy carbonyl (Boc) and t-butyl (^tBu) of 3ah were effectively removed under acidic conditions without affecting the directing group, affording 4ah-2 in a yield of 99% (Scheme 4c). Moreover, the methyl ester group of 3ah could be selectively hydrolyzed with Me₃SnOH [43] as the base without affecting N-Piv, Boc, ^tBu, and most importantly, the acrylic ester moiety (Scheme 4d). The acid 4ah-3 could be obtained in a yield of 83%. The formation of the carboxylic acid group in 4ah-3 provides a suitable reaction site for further modification, enabling the synthesis of more complex and diverse cyclic peptides.

  Scheme 4

  

  Scheme 4.  Gram-scale synthesis, deprotection, and directing group removal studies of 3ah.

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  To obtain the Trp(C7)-alkene(E)-crosslinked cyclic peptides, we utilized a C-H alkenylation & macrolactamization strategy (Fig. 2). Starting from a linear peptide substrate, three different peptide macrocycles could be quickly obtained by selecting rational designed acrylic esters as alkenyl substrates and selecting different cyclization reaction sites, including the native C-terminus, N-terminus, and the glutamate/aspartate side chain. As shown in Fig. 2, a tert-butyl ester-containing fragment is introduced at the C7 position of tryptophan residue of linear peptide substrate by C-H alkenylation. After selective deprotection, the newly formed carboxylic acid undergoes macrolactamization with the N-terminal amino group to generate head-to-side chain cyclic peptide. Similarly, the side chain-to-tail cyclic peptide could be achieved using the allyl ester, which containing a Boc protected amino segment, in the C-H alkenylation step and relaying through macrolactamization. In addition, this strategy could also link the tryptophan side chain with the glutamate or aspartate side chain to obtain side chain-to-side chain cyclic peptide. It is worth noting that the directing group N-Piv could be removed during the condensation process using finely tuned conditions, resulting in products closely resemble natural cyclic peptides.

  Figure 2

  

  Figure 2.  Synthesis of Trp(C7)-alkene(E)-crosslinked peptide macrocycles via a C-H alkenylation and macrolactamization strategy.

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  We explored the possibility of constructing challenging Trp(C7)-alkene(E)-crosslinked cyclic peptides, focusing on 3qh, 3rh, 3th, 3ui, 3vi, 3xj and 3yj for cyclization investigation. Firstly, the protecting groups Boc and ^tBu were removed from 3yj under acidic conditions. The resulting intermediate was then stirred at room temperature for 18 h using 3-(diethoxyphosphoryloxy)-1, 2, 3-benzotrizin-4(3H)-one (DEPBT) [44-46] as the condensation agent, which has been confirmed to be an efficient condensation agent and has been successfully used in the total syntheses of various complex cyclic peptides. Subsequently, the side chain-to-tail 30-membered cyclic peptide 5yj was isolated in 33% yield (Scheme 5a). Moreover, the side chain-to-side chain 25-membered cyclic peptide 5xj could be obtained in 32% yield from the linear peptide 3xj (Scheme 5b). Finally, a series of head-to-side chain cyclic peptides with different structures and sizes (5qh, 5rh, 5th, 5ui, 5vi, 25-30 membered macrocycles, 28%-35% yield) were successfully synthesized using this strategy (Scheme 5c). These results demonstrate the effectiveness of our method in constructing challenging Trp(C7)-alkene(E)-crosslinked cyclic peptides with different ring sizes and topologies, providing a practical and efficient tool for the creation of structurally diverse cyclic peptides with potential applications in drug discovery and other biotechnological fields.

  Scheme 5

  

  Scheme 5.  C-H alkenylation & macrolactamization strategy for the construction of Trp(C7)-alkene(E)-crosslinked cyclic peptides. Conditions: (a) 3 (0.1 mmol), DCM/TFA 1:1 (10 mL), r.t., 4 h; (b) DEPBT (0.12 mmol), TEA (3 mmol), DCM/DMF/H₂O (10 mL/5 mL/0.5 mL), r.t., 18 h. Isolated yields.

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  Next, we determined the effects of the selected linear peptides and cyclic peptides on the proliferation of HCC1806 cells (human breast cancer cells). Cyclic peptides 5rh and 5vi exhibited significant anti-proliferative activity with 97% and 99% inhibition rate at 30 µmol/L, respectively (Fig. 3). The IC₅₀ value of 5vi was further determined to be 15.44 µmol/L (see Supporting Information for details). These results indicated that compounds 5vi and 5rh exhibit potent anti-proliferative activity against cancer cells.

  Figure 3

  

  Figure 3.  Anticancer activity of select compounds against HCC1806 cells at 30 µmol/L, n = 2/group. ^***P < 0.001, A.U., arbitrary units. HCC1806 cells were treated with vehicle control (0.3% DMSO).

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  In summary, we have provided an efficient method for the construction of cyclic peptides with unique Trp(C7)-alkene(E)-crosslinks, starting from easily accessible linear peptide precursors, through the merging of Rh(Ⅲ)-catalyzed Piv-directed late-stage C-H alkenylation and macrolactamization. This method exhibits mild reaction conditions, traceless removal of the directing group, and high configuration selectivity. Three kinds of cyclic peptides could be quickly obtained by selecting rational designed acrylic esters based on different cyclization reaction sites. 25- to 30-membered cyclic peptides were successfully constructed using this method, and cyclic peptides 5rh and 5vi exhibited potent anti-proliferative activity against cancer cells. Our findings laid a solid foundation for subsequent research of these compounds in the field of medicinal chemistry and pharmacology. Moreover, this method also has significant reference value for synthesizing cyclic peptides with other C7-modified Trp crosslinks.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  We gratefully acknowledge the National Key R&D Program of China (No. 2022YFA1302900 to H. Liu), National Natural Science Foundation of China (Nos. 82130105, 22337003 and 82121005 to H. Liu; and Nos. 22177124, 82322063 to J. Wang), Program of Shanghai Academic Research Leader (No. 23XD1460300 to J. Wang), the Lingang Laboratory (No. LG-GG-202204-02 to J. Wang) for supporting this work. We would like to acknowledge Shanghai Highline Therapeutics. Inc for their assistance in the biological activity assay.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2023.109408.

  
  
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• 

  Figure 1  Synthesis of cyclic peptides with Trp crosslinks using traditional methods.

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  Scheme 1  Previous and present works for the construction of Trp-alkene-crosslinked cyclic peptides.

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  Scheme 2  Rh(Ⅲ)-catalyzed alkenylation of Trp residues at the C7 position with Piv as the directing group. Reaction conditions: 1 (0.2 mmol), 2 (0.9 mmol), [Cp*RhCl₂]₂ (10 mol%), AgNTf₂ (20 mol%), Cu(OAc)₂ (0.5 mmol) in DCE (2 mL) under air at 110 ℃ for 12 h. NMR yield using 1,3,5-trimethoxybenzene as the internal standard. ^a Isolated yield.

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  Scheme 3  Synthesis of complex Trp-containing peptides. Reaction conditions: 1 (0.2 mmol), 2 (0.9 mmol), [Cp*RhCl₂]₂ (10 mol%), AgNTf₂ (20 mol%), Cu(OAc)₂ (0.5 mmol) in DCE (2 mL) under air at 110 ℃ for 12 h. Isolated yields.

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  Scheme 4  Gram-scale synthesis, deprotection, and directing group removal studies of 3ah.

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  Figure 2  Synthesis of Trp(C7)-alkene(E)-crosslinked peptide macrocycles via a C-H alkenylation and macrolactamization strategy.

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  Scheme 5  C-H alkenylation & macrolactamization strategy for the construction of Trp(C7)-alkene(E)-crosslinked cyclic peptides. Conditions: (a) 3 (0.1 mmol), DCM/TFA 1:1 (10 mL), r.t., 4 h; (b) DEPBT (0.12 mmol), TEA (3 mmol), DCM/DMF/H₂O (10 mL/5 mL/0.5 mL), r.t., 18 h. Isolated yields.

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  Figure 3  Anticancer activity of select compounds against HCC1806 cells at 30 µmol/L, n = 2/group. ^***P < 0.001, A.U., arbitrary units. HCC1806 cells were treated with vehicle control (0.3% DMSO).

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  Table 1.  Optimization of the reaction conditions.^a

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•