Next Article in Journal
Magnetic Nanomaterials as Catalysts for Syngas Production and Conversion
Next Article in Special Issue
A Second-Generation Palladacycle Architecture Bearing a N-Heterocyclic Carbene and Its Catalytic Behavior in Buchwald–Hartwig Amination Catalysis
Previous Article in Journal
Ni2P-Modified P-Doped Graphitic Carbon Nitride Hetero-Nanostructures for Efficient Photocatalytic Aqueous Cr(VI) Reduction
Previous Article in Special Issue
De Novo Synthesis of Polysubstituted 3-Hydroxypyridines Via “Anti-Wacker”-Type Cyclization
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Catalysts
Volume 13
Issue 2
10.3390/catal13020438
catalysts-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Transition-Metal-Catalyzed C–C Bond Macrocyclization via Intramolecular C–H Bond Activation

by
Xiao Wang
1,
Ming-Zhu Lu
2,3,* and
Teck-Peng Loh
1,2,3,*
1
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China
2
College of Advanced Interdisciplinary Science and Technology, Henan University of Technology, Zhengzhou 450001, China
3
School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore
*
Authors to whom correspondence should be addressed.
Catalysts 2023, 13(2), 438; https://doi.org/10.3390/catal13020438
Submission received: 17 January 2023 / Revised: 14 February 2023 / Accepted: 15 February 2023 / Published: 17 February 2023
(This article belongs to the Special Issue Theme Issue in Memory to Prof. Jiro Tsuji (1927–2022))
Browse Figures
Review Reports Versions Notes

Abstract

:
Macrocycles are commonly synthesized via late-stage macrolactamization and macrolactonization. Strategies involving C–C bond macrocyclization have been reported, and examples include the transition-metal-catalyzed ring-closing metathesis and coupling reactions. In this mini-review, we summarize the recent progress in the direct synthesis of polyketide and polypeptide macrocycles using a transition-metal-catalyzed C–H bond activation strategy. In the first part, rhodium-catalyzed alkene–alkene ring-closing coupling for polyketide synthesis is described. The second part summarizes the synthesis of polypeptide macrocycles. The activation of indolyl and aryl C(sp2)–H bonds followed by coupling with various coupling partners such as aryl halides, arylates, and alkynyl bromide is then documented. Moreover, transition-metal-catalyzed C–C bond macrocyclization reactions via alkyl C(sp3)–H bond activation are also included. We hope that this mini-review will inspire more researchers to explore new and broadly applicable strategies for C–C bond macrocyclization via intramolecular C–H activation.

1. Introduction

Macrocycles have been defined as cyclic molecules that contain 12 or more covalent connected atoms, which are featured widely in numerous biologically active natural products and pharmaceutically relevant molecules (Figure 1) [1,2]. Among them, polypeptide and polyketide macrocycles are the most common. For the synthesis of this important class of compounds, one of the crucial steps is the late-stage macrocyclization reaction [3,4,5,6,7,8,9,10]. As these precursors leading to the molecules may have different conformational structures, the key step involving intramolecular the macrocyclization reaction can been challenging. The common strategies reported so far include macrolactonization [11,12,13], macrolactamization [14,15,16], and macroaldolization [17,18,19] (Figure 2). Over the decades, transition-metal-catalyzed intramolecular coupling and ring-closing metathesis (RCM) have also been shown to be effective strategies for constructing large rings [20,21,22,23]. However, all of the reported methods have some disadvantages, such as the need to use expensive catalysts, difficulty in accessing the substrates, and difficulty in introducing alkene functionality with high selectivity. Furthermore, many of these methods are not atom-economical and sometimes produce substantial amounts of hazardous wastes that are difficult to treat.
In recent years, transition-metal-catalyzed C–H activation reactions have attracted increasing attention [24,25,26,27,28,29,30,31]. In contrast to the classical cross-coupling reactions, such as Suzuki coupling, Negishi coupling, and Stille coupling, the C–H bond functionalization coupling reactions do not need to use organometallic or organohalide reagents. Due to these remarkable advantages, the C–H bond functionalization reactions have been utilized widely in organic synthesis, and a large number of excellent reviews on this topic have also been reported [32,33,34,35,36,37,38,39,40,41,42,43]. While the intermolecular versions of metal-catalyzed, group-controlled C(sp2)–H for aryl groups and vinyl groups and C(sp3)–H for alkyl groups have been well studied, the application of the intramolecular version of macrocyclization to construct various macrocycles has remained relatively unexplored [44,45,46,47]. The lengthy synthesis of the precursors for the risky macrocyclization step may be one of the main reasons. In recent years, we have witnessed more activities in the polypeptide area as compared to polyketide synthesis. In this mini-review, we will mainly focus on the direct synthesis of polyketide and polypeptide macrocycles involving carbon–carbon-based cyclization reactions via intramolecular C–H bond macrocyclization reactions (Figure 2) [48].

2. Polyketide Macrocycles

Macrolides containing a diene moiety are found in many bioactive natural products such as vicenistatin [49,50,51], geldanamycin [52,53], and cyclamenol A [54]. Therefore, the development of robust methods to construct structurally diverse macrocycles via C–C bond macrocyclization containing a fixed configuration of the diene moiety can be challenging. Extending the reactions they developed for the intermolecular version [55], Loh’s group in 2018 first reported an efficient method to construct macrolactams containing diene functionality with high Z and E selectivity via an alkenyl sp2 C–H bond olefination using a Cp*Rh(III) catalyst (Figure 3) [56]. This strategy provides easy access to a wide variety of macrocodes with different ring sizes in an atom-economical manner. Mechanistically, this ring-closing alkene–alkene coupling reaction was proposed to proceed via a Z-olefinic vinylrohodium(III) intermediate of the acrylamide derivative (Figure 4). Initially, the anion exchange of the [RhCp*Cl2]2 catalyst with the NaBARF additive and Cu(OAc)2•H2O produced the highly reactive species A, which then selectively activated the Z-olefinic C(sp2)–H bond of acrylamides to generate the vinylrhodium(III) intermediate B. Subsequent coordination and further migratory insertion occurred smoothly to afford the intermediate D, which finally underwent facile β-H elimination to give the macrocycle product.
The intramolecular alkene–alkene ring cyclization reaction using the rhodium catalyst led to various macrocycles containing a versatile dienoate moiety. The conjugated moiety present in the resulting macrocycles is highly versatile and can be converted into many different functional groups, thereby allowing easy access to macrolides containing different functionalities (Figure 5). For example, the hydrogenation of the macrocyclization product in the presence of the Pd/C catalyst afforded the saturated alkane product. The treatment of the product with a copper catalyst with PhMe2Si-BPin furnished the 1,4-hydrosilylation product. On the other hand, reacting the product with the bis(pinacolato)diboron reagent led to the formation of the internal alkene product. Subjecting the product to nitromethane in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) led to the 1,4-Michael addition product. Overall, the versatility of the dienoate products allowed easy access to a wide variety of useful macrocycles that were not easily accessible using the reported methods.
In 2020, the Loh group further expanded their intramolecular ring-closing alkene–alkene coupling strategy to α,β-unsaturated ketone substrates (Figure 6) [57]. Under the same conditions, a wide variety of macrolactams of different ring sizes were synthesized in moderate to good yields (33−72%). Of note, the intramolecular coupling of the alkene substrate with no substitution at the α-position also proceeded smoothly to furnish the corresponding macrolactam at a 44% yield. Moreover, this protocol could afford more strained 12- and 13-membered ring macrolactams in satisfactory yields. The authors proposed an analogous catalytic mechanism to elucidate this Cp*Rh(III)-catalyzed alkenyl C(sp2)–H activation–macrocyclization pathway.

3. Polypeptide Macrocycles

Peptide-based macrocycles have been shown to have a wide variety of biological activities [58]. Some important drugs such as the antibiotic vancomycin [59], anti-cancer agent octreotide [60], and immunosuppressant cyclosporine [61] contain a peptide macrocycle structure. Furthermore, in contrast to linear peptides, peptide macrocycles have improved properties in terms of cell penetration, stability, and selectivity. In recent years, cyclic peptides have also been used as the delivery systems in peptide–drug conjugates such as 177Lu-dotatate [62] and edotreotide gallium Ga-68 [63]. In addition to the amide bond formation strategy, the use of C–H bond functionalization strategies has gained tremendous attention in recent years due to their ability to construct many different stapled cyclopeptides. In this part of the review, we will divide them into 3 different categories: (1) in the first part, we will focus mainly on the sp2 C–H bond functionalization of indole C–H bond macrocyclization; (2) in the second part, we will focus mainly on the C–H bond functionalization of the aryl C(sp2)–H bond macrocyclization strategy; (3) in the final part, we will discuss the recent progress in the inert C(sp3)–H bond (both with and without a directing group) functionalization macrocyclization strategy.

3.1. C(sp2)–H Bond Functionalization of Indoles

The macrocyclization reactions involving C(sp2)–H bond activation can be grouped into 2 categories. The first group involves the sp2 C–H bond activation of the indole of Trp residues to couple with different coupling partners. With the assistance of microwave irradiation, James and co-workers in 2012 first developed a general palladium-catalyzed method to activate indole C–H bonds of tryptophan derivatives bearing aromatic iodide side chains for peptide macrocyclization through a Pd(0)/Pd(II) redox manifold, enabling the formation of diverse indole–aryl-bridged macrocycles (Figure 7) [64]. In the presence of 2-NO2-BzOH and AgBF4 additives, the macrocyclization reaction was typically finished within 30 min at 130 °C in dimethylacetamide (DMA), which could occur at a remarkably moderate concentration (30 mM). Both para- and meta-substituted aromatic iodides could be tolerated with the current protocol, generating a variety of 15- to 25-membered rings macrocyclization products in yields ranging from 40% to 75%. Of note, unprotected Tyr was also tolerated in this strategy.
Later, in 2015, Albericio, Lavilla, and their co-workers extended their Pd-catalyzed C–H activation–macrocyclization protocol, and further demonstrated the intramolecular C–H bond arylation of indoles of Trp residues at the C2 position with different aryl halides to construct structurally more complex and constrained cyclopeptides containing unique Trp(C4)–arene cross-links (Figure 8a) [65] This transformation was compatible with a series of unprotected amino acid units such as Arg, Gln, Asp, and Ser, which could be applied to both solution-phase and solid-phase peptide synthesis processes. Using this strategy, the authors were able to synthesize a double stapled bicyclic peptide in a 25% HPLC conversion process, which proved extremely difficult to prepare using previously reported methods. It should be noted that the competing intermolecular cyclodimerization associated with this strategy selectively generated cyclodimeric peptides. In order to obtain the determining factors in controlling the fate of the transformation, Lavilla et al. further carried out a systematic study of the intermolecular C–H bond arylation of Trp residues bearing iodinated aromatic side chains, and the results showed that linear peptides containing a meta- or para-iodophenylalanine unit at adjacent positions selectively afforded cyclic dimers instead of stapled peptides. Increasing the chain length of the residues remarkably resulted in the generation of peptide-based macrocycles (Figure 8b) [66].
In 2020, Liu and co-workers reported the activation of the C(sp2)–H bond of the N-protected indole at the C2 position with the assistance of the 2-pyridyl directing group enabled by Cp*Rh(III) catalysis. Under the typical reaction conditions of [RhCp*Cl2]2 (10 mol%), Ag2O (20 mol%), and AgOAc (1.5 equivalent) in CH3CN at 80 °C, the intramolecular C(sp2)–H bond coupling with a tethered maleimide moiety proceeded uneventfully to provide 3 examples of maleimide-decorated, tryptophan-based macrocyclic peptides in moderate yields (Figure 9) [67].
In an effort to achieve highly regioselective late-stage peptide macrocyclization, Wang et al. in 2020 utilized the peptide backbone as endogenous directing groups to promote site-selective peptide macrocyclization at Trp(C2) (Figure 10a) [68]. Using the combination of a Pd(OAc)2 (10 mol%) catalyst and AcOH (6.0 equivalent) additive under an O2 (1.0 atm) atmosphere in para-xylene at 100 °C, 12 examples of peptide-based macrocycles with unique Trp–alkene cross-links were documented in reasonable yields (20–42%). Under modified conditions, the authors were able to synthesize macrocyclic peptides containing unique Trp(C4)–alkene cross-links enabled by the palladium-catalyzed C(sp2)–H olefination at the C4 position of Trp residues bearing a TfNH-directing group (Figure 9a) [65]. More recently, the same group further extended this method to realize the rhodium(I)-catalyzed regioselective intramolecular C(sp2)–H bond alkylation of Trp residues bearing a N-PtBu2 directing group, providing efficient access to diverse peptide macrocycles with Trp(C7)-alkyl cross-links (Figure 10b) [69].
In 2017, The Ackerman group successfully utilized alkynyl bromide as an internal coupling partner for the cost-effective manganese(I)-catalyzed late-stage macrocyclization of 2-pym-protected indole of indole Trp residue, giving rise to a 21-membered, peptide-based macrocycle with aryl-alkyne cross-links at a 53% yield (Figure 11) [70].

3.2. C(sp2)–H Bond Functionalization of Arenes

Besides the above-mentioned examples of C(sp2)–H bond functionalization of indole of tryptophan, the intramolecular macrocyclization reactions via transition-metal-catalyzed C(sp2)–H bond functionalization of simple arenes have also been investigated in recent years. In 2019, Wang and colleagues elaborated a general backbone-directed approach to fabricate macrocycle peptides with biaryl cross-links via the palladium-catalyzed intramolecular ortho-C(sp2)–H arylation of short peptides with tethered aromatic iodide side chains (Figure 12) [71]. The N-terminal benzamides of the peptide backbone act as efficient directing groups in this strategy, which significantly facilitate this site-specific arylation process. Under the reaction conditions, biaryl-bridged cyclic peptides with different ring sizes were synthesized in reasonable yields (20–40%). Moreover, this protocol was also applicable to the intermolecular ortho-C(sp2)–H arylation of various oligopeptides, furnishing a series of biaryl-linked products in good yields.
In a subsequent study, Chen and co-workers disclosed a versatile approach for the synthesis of diverse cyclophane-braced macrocycle peptides through the efficient picolinamide-directed intramolecular aromatic γ- and δ-C(sp2)–H arylation of readily accessible linear peptide precursors with aryl iodides (Figure 13) [72]. The judicious choice of silver additive was found to be critical for high efficiency. The intramolecular aromatic C(sp2)–H arylation reactions occurred smoothly in the presence of the Pd(CH3CN)4(BF4)2 (10 mol%) catalyst and 1.5 equivalent of AgOBz additive at 130 °C. Under modified conditions of Pd(OAc)2 and AgOAc in hexafluoroisopropanol (HFIP), the alkenyl counterparts were also compatible with the C–H sources for this approach, giving rise to the corresponding aryl–vinyl C(sp2)-linked peptide-based macrocycles in moderate yields. However, a remarkable 1:1 mixture of γ- and δ-arylated products was observed for the alkenyl C(sp2)–H arylation of a smaller ring size. Mechanistically, the reaction was suggested to occur via Pd(II)-catalyzed C(sp2)–H activation to produce a putative palladacycle species. The subsequent oxidative addition (OA) with tethered aryl iodides generated the key Pd(IV) intermediate, which finally underwent reductive elimination (RE) to afford the C–H activation–macrocyclization product.
The Wang group in 2018 reported the straightforward synthesis of macrocycle peptides with unique aryl–vinyl cross-links via the late-stage palladium-catalyzed δ-C(sp2)–H olefination of phenylalanine (Phe) residues (Figure 14) [73]. The peptide backbone amides were readily employed as internal directing groups to facilitate the macrocyclization of peptides in the N-to-C direction. This macrocyclization protocol tolerated a broad range of short peptides, generating a variety of peptide-based macrocycles of different sizes and shapes. Both activated and unbaised aliphatic alkenes were viable coupling partners for this macrocyclization. Moreover, the authors also demonstrated the utility of this protocol via the synthesis of a structurally constrained bicyclic peptide via the one-pot macrocyclization of β-C(sp2)–H arylation and δ-C(sp2)–H olefination reactions.
In the same year, Wang and co-workers also reported a peptide-guided C(sp2)–H activation method for the late-stage macrocyclization of various sulfonamide-containing peptides via intramolecular ortho-directed C(sp2)–H alkenylation, which was significantly facilitated by the internal peptide backbone (Figure 15) [74]. Using the N-sulfonated peptides as endogenous directing groups, this macrocyclization protocol featured a broad substrate scope and tolerated both activated acrylates and unbaised aliphatic alkenes, giving rise to a series of bioactive peptidosulfonamide macrocycles with aryl–alkene cross-links over a 34–72% yield range. As an extension of this approach, the same group in 2019 further achieved the macrocyclization reaction of peptidoarylacetamides under identical conditions (Figure 16) [75].
Subsequently, Wang and colleagues continued their versatile macrocyclization strategy [76], and further accomplished an efficient late-stage macrocyclization reaction of various bioactive oxazole-containing peptides through the intramolecular palladium-catalyzed δ-C(sp2)–H olefination (Figure 17a) [77]. In this report, the oxazole motifs in the peptide backbones acted as endogenous directing groups to promote this ortho-C(sp2)–H olefination reactions. The resulting oxazole-containing cyclic peptides bearing aryl–alkene cross-links showed strong cytotoxicity toward cancer cells. Quite recently, Wang et al. further expanded to report on the late-stage modification and macrocyclization of diverse thiazole-containing peptides, generating a series of 21–25 membered bioactive peptide-based macrocycles in 35–59% yields (Figure 17b) [78].

3.3. C(sp3)–H Bond Functionalization

In recent years, there has been much interest in the development of stapled peptides, including polypeptide macrocycles, for drug discovery. Simultaneously, the construction of C–C cross-linked stapled peptides using the C–H activation coupling strategies has also emerged as an attractive strategy for peptide-based macrocycles synthesis. Although there are many reports on the intermolecular C(sp3)–H bond functionalization of amino acids and peptides [79,80,81], the intramolecular version of C(sp3)–H bond functionalization for polypeptide macrocycles synthesis is still very rare. Inspired by Yu’s backbone-assisted inert C(sp3)–H activation strategy for the late-stage derivatization of various short peptides [82], Albericio, Noisier, and co-workers in 2017 elegantly established an efficient palladium-catalyzed C(sp3)–H activation method without relying on any external directing group for peptide stapling (Figure 18) [83]. Unprecedentedly, this process allowed the linkage between N-terminal alanine (Ala) and C-terminal phenyl alanine (Phe) residues. The role of the solvent was found to be crucial for this peptide macrocyclization process, and using t-BuOH as the co-solvent they significantly suppressed the unwanted side reactions. Under the optimized reaction conditions, the intramolecular C(sp3)–H arylation of N-terminal Ala with meta-iodinated Phe proceeded smoothly with good to excellent conversion rates, and a wide variety of cyclic hydrocarbon cross-linked polypeptides bearing different ring sizes macrocycles were synthesized in modest yields. Moreover, this strategy is also compatible with solid-phase peptide synthesis, enabling the rapid synthesis of new peptide motifs.
Almost at the same time, Wang and co-workers also demonstrated an analogous macrocyclization via the intramolecular β-C(sp3)–H arylation of amino acids at the N-terminus of the peptides, which could proceed smoothly in both solution-phase and solid-phase peptide synthesis approaches (Figure 19) [84]. In this protocol, 1,2-dichloroethane (DCE) was used as the solvent to achieve remarkable efficiency. This approach tolerated a broad scope of peptide substrates, including tetra- and pentapeptides, delivering a diverse variety of polypeptide macrocycles bearing Cβ–Ar cross-links between the β-carbon of amino acids and the aromatic ring of Phe/Trp, with satisfactory diastereoselectivity. Successfully, the authors applied this macrocyclization methodology to the total synthesis of the key fragment in the bioactive natural product celogentin C.
Through the assistance of 8-aminoquinoline (AQ) as the bidentate directing group [85], Chen et al. in 2018 developed a broadly applicable strategy for the efficient synthesis of cyclophane-braced peptide macrocycles from readily accessible linear peptide precursors via the exo-type intramolecular β-C(sp3)–H macrocyclization of diverse alkyl appendants bearing iodinated aromatic side chains or tethered aryl iodides (Figure 20) [86]. The choice of ortho-phenyl benzoic acid (oPBA) as the efficacious additive significantly promoted this AQ-directed intramolecular β methylene C(sp3)–H arylation reaction. Both protected and unprotected amino acid units were compatible with this macrocyclization strategy. Various cyclophane-braced peptide macrocycles of different sizes and shapes were synthesized in moderate to good yields. However, the amide-linked AQ auxiliary was found to be difficult to remove from the peptide macrocycles in this case. Mechanistically, this AQ-directed intramolecular macrocyclization process was proposed to occur through a concerted metalation–deprotonation (CMD) catalytic mechanism. With the assistance of the carboxylate ligand, the reversible β-C(sp3)–H palladation produced a chelation-stabilized five-membered alkylpalladium(II) species. Subsequently, this putative palladacycle intermediate underwent intramolecular oxidative addition and reductive elimination to afford the expected peptide macrocycles.
By taking advantage of readily accessible and removable N,N-bidentate picolinamide (PA) auxiliaries, Chen and co-workers in 2019 also described the efficient Pd-catalyzed intramolecular remote γ-C(sp3)–H arylation of diverse N-terminal aliphatic amino acid units via Pd(II)/Pd(IV) catalysis (Figure 21a) [87]. This reaction tolerates γ-C(sp3)–H bonds at both methyl and methylene positions of peptide substrates. Unprotected peptides bearing diverse free polar side chains were proven to be compatible substrates for this PA-directed C(sp3)–H macrocyclization protocol, and the cyclization reaction occurred smoothly with high efficiency. Through the typical combination of a Pd(MeCN)4(BF4)2 catalyst and AgOAc additive, 30 examples of this transformation were documented with reasonable yields up to 80%. Encouraged by this success, the same group further elaborated on the efficient synthesis of cyclophane-braced peptide macrocycles via the palladium(II)-catalyzed, AQ-directed endo-type intramolecular β methyl C(sp3)–H arylation reaction with tethered aryl iodides, giving rise to a broad range of cyclic peptides featuring different ring sizes in satisfactory yields (Figure 21b) [88].

4. Conclusions

In summary, we have witnessed a surge in the use of intramolecular C–H bond activation–macrocyclization reactions to construct polypeptide macrocycles, and to a lesser extent polyketide macrocycles. Despite the remarkable advantages of using C–H activation strategies for the straightforward synthesis of diverse polyketide and polypeptide macrocycles, it is not yet possible to completely avoid the use of substrates bearing alkene or aryl iodide functionalities for the C–H bond activation–macrocyclization reactions. The application of the C–H bond macrocyclization strategy is still an untapped territory, and strategies utilizing transition-metal-free electrocatalytic photoredox C–H bond activation remain to be tested. Most of the reported strategies utilize the aryl C(sp2)–H activation methods to construct macrocycles. Sporadic examples utilizing alkenyl C(sp2)–H bond and alkyl C(sp3)–H bond activation methods have also emerged in recent years. With the surge in activities related to C–H bond activation, more reports utilizing C–H activation strategies for macrocyclization can be envisaged in this fascinating field.

Author Contributions

X.W.: Literature collection and manuscript writing. M.-Z.L.: Literature collection, manuscript writing. and funding acquisition; T.-P.L.: Content design, manuscript revision, project administration, and funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (no. 22101095) and the “Innovation and Entrepreneurship Talents Plan” of Jiangsu Province (M.-Z. Lu). We also acknowledge the financial support from the Distinguished University Professor grant (Nanyang Technological University); the AcRF Tier 1 grants from the Ministry of Education of Singapore (RG11/20 and RT14/20); and the Agency for Science, Technology, and Research (A*STAR) under its MTC Individual Research Grants (M21K2c0114).

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Gibson, S.E.; Lecci, C. Amino acid derived macrocycles—An area driven by synthesis or application? Angew. Chem. Int. Ed. 2006, 45, 1364–1377. [Google Scholar] [CrossRef]
  2. Yudin, A.K. Macrocycles: Lessons from the distant past, recent developments, and future directions. Chem. Sci. 2015, 6, 30–49. [Google Scholar] [CrossRef] [Green Version]
  3. Wessjohann, L.; Rivera, D.G.; Vercillo, O.E. Multiple multicomponent macrocyclizations (MiBs): A strategic development toward macrocycle diversity. Chem. Rev. 2009, 109, 796–814. [Google Scholar] [CrossRef]
  4. White, C.J.; Yudin, A.K. Contemporary strategies for peptide macrocyclization. Nat. Chem. 2011, 3, 509–524. [Google Scholar] [CrossRef]
  5. Martí-Centelles, V.; Pandey, M.D.; Burguete, M.I.; Luis, S.V. Macrocyclization reactions: The importance of conformational, configurational, and template-induced preorganization. Chem. Rev. 2015, 115, 8736–8834. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Wu, J.; Tang, J.; Chen, H.; He, Y.; Wang, H.; Yao, H. Recent developments in peptide macrocyclization. Tetrahedron Lett. 2018, 59, 325–333. [Google Scholar] [CrossRef]
  7. Mortensen, K.T.; Osberger, T.J.; King, T.A.; Sore, H.F.; Spring, D.R. Strategies for the diversity-oriented synthesis of macrocycles. Chem. Rev. 2019, 119, 10288–10317. [Google Scholar] [CrossRef]
  8. Reguera, L.; Rivera, D.G. Multicomponent reaction toolbox for peptide macrocyclization and stapling. Chem. Rev. 2019, 119, 9836–9860. [Google Scholar] [CrossRef] [PubMed]
  9. Zheng, K.; Hong, R. Stereoconfining macrocyclizations in the total synthesis of natural products. Nat. Prod. Rep. 2019, 36, 1546–1575. [Google Scholar] [CrossRef]
  10. Rivera, D.G.; Ojeda-Carralero, G.M.; Reguera, L.; Van der Eycken, E.V. Peptide macrocyclization by transition metal catalysis. Chem. Soc. Rev. 2020, 49, 2039–2059. [Google Scholar] [CrossRef]
  11. Parenty, A.; Moreau, X.; Campagne, J.-M. Macrolactonizations in the total synthesis of natural products. Chem. Rev. 2006, 106, 911–939. [Google Scholar] [CrossRef]
  12. Li, Y.; Yin, X.; Dai, M. Catalytic macrolactonizations for natural product synthesis. Nat. Prod. Rep. 2017, 34, 1185–1192. [Google Scholar] [CrossRef] [PubMed]
  13. Yang, M.; Wang, X.; Zhao, J. Ynamide-mediated macrolactonization. ACS Catal. 2020, 10, 5230–5235. [Google Scholar] [CrossRef]
  14. Ishihara, K.; Kuroki, Y.; Hanaki, N.; Ohara, S.; Yamamoto, H. Antimony-templated macrolactamization of tetraamino esters. facile synthesis of macrocyclic spermine alkaloids, (±)-buchnerine, (±)-verbacine, (±)-verbaskine, and (±)-verbascenine. J. Am. Chem. Soc. 1996, 118, 1569–1570. [Google Scholar] [CrossRef]
  15. Doi, T.; Kamioka, S.; Shimazu, S.; Takahashi, T. A synthesis of RGD model cyclic peptide by palladium-catalyzed carbonylative macrolactamization. Org. Lett. 2008, 10, 817–819. [Google Scholar] [CrossRef] [PubMed]
  16. Lim, N.-K.; Linghu, X.; Wong, N.; Zhang, H.; Sowell, C.G.; Gosselin, F. Macrolactamization approaches to arylomycin antibiotics core. Org. Lett. 2019, 21, 147–151. [Google Scholar] [CrossRef] [PubMed]
  17. Hayward, C.M.; Yohannes, D.; Danishefsky, S.M. Total synthesis of rapamycin via a novel titanium-mediated aldol macrocyclization reaction. J. Am. Chem. Soc. 1993, 115, 9345–9346. [Google Scholar] [CrossRef]
  18. Wessjohann, L.A.; Scheid, G.O.; Eichelberger, U.; Umbreen, S. Total synthesis of epothilone D: The nerol/macroaldolization approach. J. Org. Chem. 2013, 78, 10588–10595. [Google Scholar] [CrossRef]
  19. Abramite, J.A.; Sammakia, T. Application of the intramolecular Yamamoto vinylogous aldol reaction to the synthesis of macrolides. Org. Lett. 2007, 9, 2103–2106. [Google Scholar] [CrossRef]
  20. Gradillas, A.; Pérez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products: Reaction conditions and limitations. Angew. Chem. Int. Ed. 2006, 45, 6086–6101. [Google Scholar] [CrossRef]
  21. Denmark, S.E.; Muhuhi, J.M. Development of a general, sequential, ring-closing metathesis/intramolecular cross-coupling reaction for the synthesis of polyunsaturated macrolactones. J. Am. Chem. Soc. 2010, 132, 11768–11778. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Yu, M.; Wang, C.; Kyle, A.F.; Jakubec, P.; Dixon, D.; Schrock, R.R.; Hoveyda, A.H. Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis. Nature 2011, 479, 88–93. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Lecourt, C.; Dhambri, S.; Allievi, L.; Sanogo, Y.; Zeghbib, N.; Othman, R.B.; Lannou, M.-I.; Sorin, G.; Ardisson, J. Natural products and ring-closing metathesis: Synthesis of sterically congested olefins. Nat. Prod. Rep. 2018, 35, 105–124. [Google Scholar] [CrossRef]
  24. Gensch, T.; Hopkinson, M.N.; Glorius, F.; Wencel-Delord, J. Mild metal-catalyzed C–H activation: Examples and concepts. Chem. Soc. Rev. 2016, 45, 2900–2936. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. He, J.; Wasa, M.; Chan, K.S.L.; Shao, Q.; Yu, J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds. Chem. Rev. 2017, 117, 8754–8786. [Google Scholar] [CrossRef]
  26. Loup, J.; Dhawa, U.; Pesciaioli, F.; Wencel-Delord, J.; Ackermann, L. Enantioselective C–H activation with earth-abundant 3d transition metals. Angew. Chem. Int. Ed. 2019, 58, 12803–12818. [Google Scholar] [CrossRef] [PubMed]
  27. Woźniak, L.; Tan, J.-F.; Nguyen, Q.-H.; Madron du Vigne, A.; Smal, V.; Cao, Y.-X.; Cramer, N. Catalytic enantioselective functionalizations of C–H bonds by chiral iridium complexes. Chem. Rev. 2020, 120, 10516–10543. [Google Scholar] [CrossRef]
  28. Liu, B.; Romine, A.M.; Rubel, C.Z.; Engle, K.M.; Shi, B.-F. Transition-metal-catalyzed, coordination-assisted functionalization of nonactivated C(sp3)–H bonds. Chem. Rev. 2021, 121, 14957–15074. [Google Scholar] [CrossRef]
  29. Murali, K.; Machado, L.A.; Carvalho, R.L.; Pedrosa, L.F.; Mukherjee, R.; da Silva Júnior, E.N.; Maiti, D. Decoding directing groups and their pivotal role in C–H activation. Chem. Eur. J. 2021, 27, 12453–12508. [Google Scholar] [CrossRef]
  30. Carvalho, R.L.; Almeida, R.G.; Murali, K.; Machado, L.A.; Pedrosa, L.F.; Dolui, P.; Maiti, D.; da Silva Júnior, E.N. Removal and modification of directing groups used in metal-catalyzed C–H functionalization: The magical step of conversion into ‘conventional’ functional groups. Org. Biomol. Chem. 2021, 19, 525–547. [Google Scholar] [CrossRef]
  31. Sinha, S.K.; Guin, S.; Maiti, S.; Biswas, J.P.; Porey, S.; Maiti, D. Toolbox for distal C–H bond functionalizations in organic molecules. Chem. Rev. 2022, 122, 5682–5841. [Google Scholar] [CrossRef] [PubMed]
  32. Sambiagio, C.; Schönbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M.F.; Wencel-Delord, J.; Besset, T.; et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603–6743. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Sauermann, N.; Meyer, T.H.; Qiu, Y.; Ackermann, L. Electrocatalytic C–H activation. ACS Catal. 2018, 8, 7086–7103. [Google Scholar] [CrossRef]
  34. Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition metals for C–H activation. Chem. Rev. 2019, 119, 2192–2452. [Google Scholar] [CrossRef] [PubMed]
  35. Stepek, I.A.; Itami, K. Recent advances in C–H activation for the synthesis of π-extended materials. ACS Mater. Lett. 2020, 2, 951–974. [Google Scholar] [CrossRef]
  36. Achar, T.K.; Maiti, S.; Jana, S.; Maiti, D. Transition metal catalyzed enantioselective C(sp2)–H bond functionalization. ACS Catal. 2020, 10, 13748–13793. [Google Scholar] [CrossRef]
  37. Meng, G.; Lam NY, S.; Lucas, E.L.; Saint-Denis, T.G.; Verma, P.; Chekshin, N.; Yu, J.-Q. Achieving site-selectivity for C–H activation processes based on distance and geometry: A carpenter’s approach. J. Am. Chem. Soc. 2020, 142, 10571–10591. [Google Scholar] [CrossRef]
  38. Zhang, Q.; Shi, B.-F. 2-(Pyridin-2-yl)isopropyl (PIP) amine: An enabling directing group for divergent and asymmetric functionalization of unactivated methylene C(sp3)–H bonds. Acc. Chem. Res. 2021, 54, 2750–2763. [Google Scholar] [CrossRef]
  39. Lam NY, S.; Wu, K.; Yu, J.-Q. Advancing the logic of chemical synthesis: C–H activation as strategic and tactical disconnections for C–C bond construction. Angew. Chem. Int. Ed. 2021, 60, 15767–15790. [Google Scholar] [CrossRef]
  40. Kharitonov, V.B.; Muratov, D.V.; Loginov, D.A. Cyclopentadienyl complexes of group 9 metals in the total synthesis of natural products. Coord. Chem. Rev. 2022, 471, 214744. [Google Scholar] [CrossRef]
  41. Mandal, D.; Roychowdhury, S.; Biswas, J.P.; Maiti, S.; Maiti, D. Transition-metal-catalyzed C–H bond alkylation using olefins: Recent advances and mechanistic aspects. Chem. Soc. Rev. 2022, 51, 7358–7426. [Google Scholar] [CrossRef] [PubMed]
  42. Lucas, E.L.; Lam NY, S.; Zhuang, Z.; Chan HS, S.; Strassfeld, D.A.; Yu, J.-Q. Palladium-catalyzed enantioselective β-C(sp3)–H activation reactions of aliphatic acids: A retrosynthetic surrogate for enolate alkylation and conjugate addition. Acc. Chem. Res. 2022, 55, 537–550. [Google Scholar] [CrossRef] [PubMed]
  43. Lu, M.-Z.; Goh, J.; Maraswami, M.; Jia, Z.; Tian, J.-S.; Loh, T.-P. Recent advances in alkenyl sp2 C–H and C–F bond functionalizations: Scope, mechanism, and applications. Chem. Rev. 2022, 122, 17479–17646. [Google Scholar] [CrossRef]
  44. Sengupta, S.; Mehta, G. Late stage modification of peptides via C–H activation reactions. Tetrahedron Lett. 2017, 58, 1357–1372. [Google Scholar] [CrossRef]
  45. Lu, X.; He, S.-J.; Cheng, W.-M.; Shi, J. Transition-metal-catalyzed C–H functionalization for late-stage modification of peptides and proteins. Chin Chem Lett. 2018, 29, 1001–1008. [Google Scholar] [CrossRef]
  46. Wang, W.; Lorion, M.M.; Shah, J.; Kapdi, A.R.; Ackermann, L. Late-stage peptide diversification by position-selective C–H activation. Angew. Chem. Int. Ed. 2018, 57, 14700–14717. [Google Scholar] [CrossRef]
  47. Tong, H.-R.; Li, B.; Li, G.; He, G.; Chen, G. Postassembly modifications of peptides via metal-catalyzed C–H functionalization. CCS Chem. 2020, 2, 1797–1820. [Google Scholar] [CrossRef]
  48. Sengupta, S.; Mehta, G. Macrocyclization via C–H functionalization: A new paradigm in macrocycle synthesis. Org. Biomol. Chem. 2020, 18, 1851–1876. [Google Scholar] [CrossRef]
  49. Minami, A.; Eguchi, T. Substrate flexibility of vicenisaminyltransferase vinC involved in the biosynthesis of vicenistatin. J. Am. Chem. Soc. 2007, 129, 5102–5107. [Google Scholar] [CrossRef]
  50. Shinohara, Y.; Kudo, F.; Eguchi, T. A natural protecting group strategy to carry an amino acid starter unit in the biosynthesis of macrolactam polyketide antibiotics. J. Am. Chem. Soc. 2011, 133, 18134–18137. [Google Scholar] [CrossRef]
  51. Miyanaga, A.; Iwasawa, S.; Shinohara, Y.; Kudo, F.; Eguchi, T. Structure-based analysis of the molecular interactions between acyltransferase and acyl carrier protein in vicenistatin biosynthesis. PNAS 2016, 113, 1802–1807. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Qin, H.-L.; Panek, J.S. Total synthesis of the Hsp90 inhibitor geldanamycin. Org. Lett. 2008, 10, 2477–2479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Hilton, M.J.; Brackett, C.M.; Mercado, B.Q.; Blagg BS, J.; Miller, S.J. Catalysis-enabled access to cryptic geldanamycin oxides. ACS Cent. Sci. 2020, 6, 426–435. [Google Scholar] [CrossRef]
  54. Nazare, M.; Waldmann, H. Synthesis of the (9S,18R) diastereomer of cyclamenol A. Angew. Chem. Int. Ed. 2000, 39, 1125–1128. [Google Scholar] [CrossRef]
  55. Zhang, J.; Loh, T.-P. Ruthenium- and rhodium-catalyzed cross-coupling reaction of acrylamides with alkenes: Efficient access to (Z,E)-dienamides. Chem. Commun. 2012, 48, 11232–11234. [Google Scholar] [CrossRef] [PubMed]
  56. Jiang, B.; Zhao, M.; Li, S.-S.; Xu, Y.-H.; Loh, T.-P. Macrolide synthesis through intramolecular oxidative cross-coupling of alkenes. Angew. Chem. Int. Ed. 2018, 57, 555–559. [Google Scholar] [CrossRef]
  57. Maraswami, M.; Goh, J.; Loh, T.-P. Macrolactam synthesis via ring-closing alkene-alkene cross-coupling reactions. Org. Lett. 2020, 22, 9724–9728. [Google Scholar] [CrossRef]
  58. Driggers, E.M.; Hale, S.P.; Lee, J.; Terrett, N.K. The exploration of macrocycles for drug discovery—An underexploited structural class. Nat. Rev. Drug Discovery 2008, 7, 608–624. [Google Scholar] [CrossRef]
  59. Shchelik, I.S.; Gademann, K. Thiol- and disulfide-containing vancomycin derivatives against bacterial resistance and biofilm formation. ACS Med. Chem. Lett. 2021, 12, 1898–1904. [Google Scholar] [CrossRef]
  60. Lelle, M.; Kaloyanova, S.; Freidel, C.; Theodoropoulou, M.; Musheev, M.; Niehrs, C.; Stalla, G.; Peneva, K. Octreotide-mediated tumor-targeted drug delivery via a cleavable doxorubicin–peptide conjugate. Mol. Pharm. 2015, 12, 4290–4300. [Google Scholar] [CrossRef]
  61. Peruzzi, M.T.; Gallou, F.; Lee, S.J.; Gagné, M.R. Site selective amide reduction of cyclosporine A enables diverse derivation of an important cyclic peptide. Org. Lett. 2019, 21, 3451–3455. [Google Scholar] [CrossRef]
  62. Banerjee, S.; Pillai, M.R.; Knapp, F.F. Lutetium-177 therapeutic radiopharmaceuticals: Linking chemistry, radiochemistry, and practical applications. Chem. Rev. 2015, 115, 2934–2974. [Google Scholar] [CrossRef] [PubMed]
  63. Patel, T.K.; Adhikari, N.; Amin, S.A.; Biswas, S.; Jha, T.; Ghosh, B. Small molecule drug conjugates (SMDCs): An emerging strategy for anticancer drug design and discovery. N. J. Chem. 2021, 45, 5291–5321. [Google Scholar] [CrossRef]
  64. Dong, H.; Limberakis, C.; Liras, S.; Price, D.; James, K. Peptidic macrocyclization via palladium-catalyzed chemoselective indole C-2 arylation. Chem. Commun. 2012, 48, 11644–11646. [Google Scholar] [CrossRef]
  65. Mendive-Tapia, L.; Preciado, S.; García, J.; Ramón, R.; Kielland, N.; Albericio, F.; Lavilla, R. New peptide architectures through C-H activation stapling between tryptophan-phenylalanine/tyrosine residues. Nat. Commun. 2015, 6, 7160–7169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Mendive-Tapia, L.; Bertran, A.; García, J.; Acosta, G.; Albericio, F.; Lavilla, R. Constrained cyclopeptides: Biaryl formation through Pd-catalyzed C-H activation in peptides-structural control of the cyclization vs. cyclodimerization outcome. Chem.–Eur. J. 2016, 22, 13114–13119. [Google Scholar] [CrossRef] [PubMed]
  67. Peng, J.; Li, C.; Khamrakulov, M.; Wang, J.; Liu, H. Rhodium(III)-catalyzed C–H alkenylation: Access to maleimide-decorated tryptophan and tryptophan-containing peptides. Org. Lett. 2020, 22, 1535–1541. [Google Scholar] [CrossRef]
  68. Bai, Z.; Cai, C.; Sheng, W.; Ren, Y.; Wang, H. Late-stage peptide macrocyclization by palladium-catalyzed site-selective C–H olefination of tryptophan. Angew. Chem. Int. Ed. 2020, 59, 14686–14692. [Google Scholar] [CrossRef]
  69. Liu, L.; Fan, X.; Wang, B.; Deng, H.; Wang, T.; Zheng, J.; Chen, J.; Shi, Z.; Wang, H. PIII-Directed late-stage ligation and macrocyclization of peptides with olefins by rhodium catalysis. Angew. Chem. Int. Ed. 2022, 61, e202206177. [Google Scholar]
  70. Ruan, Z.; Sauermann, N.; Manoni, E.; Ackermann, L. Manganese-catalyzed C–H alkynylation: Expedient peptide synthesis and modification. Angew. Chem. Int. Ed. 2017, 56, 3172–3176. [Google Scholar] [CrossRef]
  71. Bai, Q.; Bai, Z.; Wang, H. Macrocyclization of biaryl-bridged peptides through late-stage palladium-catalyzed C(sp2)–H arylation. Org. Lett. 2019, 21, 8225–8228. [Google Scholar] [CrossRef] [PubMed]
  72. Han, B.; Li, B.; Qi, L.; Yang, P.; He, G.; Chen, G. Construction of cyclophane-braced peptide macrocycles via palladium-catalyzed picolinamide-directed intramolecular C(sp2)–H arylation. Org. Lett. 2020, 22, 6879–6883. [Google Scholar] [CrossRef] [PubMed]
  73. Bai, Z.; Cai, C.; Yu, Z.; Wang, H. Backbone-enabled directional peptide macrocyclization through late-stage palladium-catalyzed δ-C(sp2)–H olefination. Angew. Chem. Int. Ed. 2018, 57, 13912–13916. [Google Scholar] [CrossRef] [PubMed]
  74. Tang, J.; Chen, H.; He, Y.; Sheng, W.; Bai, Q.; Wang, H. Peptide-guided functionalization and macrocyclization of bioactive peptidosulfonamides by Pd(II)-catalyzed late-stage C–H activation. Nat. Commun. 2018, 9, 3383–3390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Tang, J.; Wu, J.; Liu, S.; Yao, H.; Wang, H. Macrocyclization of peptidoarylacetamides with self-assembly properties through late-stage palladium-catalyzed C(sp2) –H olefination. Sci. Adv. 2019, 5, eaaw0323. [Google Scholar]
  76. Bai, Z.; Wang, H. Backbone-enabled peptide macrocyclization through late-stage palladium-catalyzed C–H activation. Synlett 2020, 31, 199–204. [Google Scholar] [CrossRef]
  77. Liu, S.; Cai, C.; Bai, Z.; Sheng, W.; Tan, J.; Wang, H. Late-stage macrocyclization of bioactive peptides with internal oxazole motifs via palladium-catalyzed C–H olefination. Org. Lett. 2021, 23, 2933–2937. [Google Scholar] [CrossRef]
  78. Cai, C.; Wang, F.; Xiao, X.; Sheng, W.; Liu, S.; Chen, J.; Zheng, J.; Xie, R.; Bai, Z.; Wang, H. Macrocyclization of bioactive peptides with internal thiazole motifs via palladium-catalyzed C–H olefination. Chem. Commun. 2022, 58, 4861–4864. [Google Scholar] [CrossRef]
  79. Noisier, A.F.M.; Brimble, M.A. C–H functionalization in the synthesis of amino acids and peptides. Chem. Rev. 2014, 114, 8775–8806. [Google Scholar] [CrossRef]
  80. He, G.; Wang, B.; Nack, W.A.; Chen, G. Syntheses and transformations of α-amino acids via palladium-catalyzed auxiliary-directed sp3 C–H functionalization. Acc. Chem. Res. 2016, 49, 635–645. [Google Scholar] [CrossRef]
  81. Brandhofer, T.; Mancheño, O.G. Site-selective C–H bond activation/functionalization of alpha-amino acids and peptide-like derivatives. Eur. J. Org. Chem. 2018, 2018, 6050–6067. [Google Scholar] [CrossRef]
  82. Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. Site-selective C(sp3)–H functionalization of di-, tri-, and tetrapeptides at the N-terminus. J. Am. Chem. Soc. 2014, 136, 16940–16946. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Noisier AF, M.; García, J.; Ionuţ, I.A.; Albericio, F. Stapled peptides by late-stage C(sp3)–H activation. Angew. Chem. Int. Ed. 2017, 56, 314–318. [Google Scholar] [CrossRef] [PubMed]
  84. Tang, J.; He, Y.; Chen, H.; Sheng, W.; Wang, H. Synthesis of bioactive and stabilized cyclic peptides by macrocyclization using C(sp3)–H activation. Chem. Sci. 2017, 8, 4565–4570. [Google Scholar] [CrossRef] [Green Version]
  85. Daugulis, O.; Roane, J.; Tran, L.D. Bidentate, monoanionic auxiliary-directed functionalization of carbon–Hydrogen bonds. Acc. Chem. Res. 2015, 48, 1053–1064. [Google Scholar] [CrossRef] [Green Version]
  86. Zhang, X.; Lu, G.; Sun, M.; Mahankali, M.; Ma, Y.; Zhang, M.; Hua, W.; Hu, Y.; Wang, Q.; Chen, J.; et al. A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp3 C–H arylation. Nat. Chem. 2018, 10, 540–548. [Google Scholar] [CrossRef]
  87. Li, B.; Li, X.; Han, B.; Chen, Z.; Zhang, X.; He, G.; Chen, G. Construction of natural-product-like cyclophane-braced peptide macrocycles via sp3 C–H arylation. J. Am. Chem. Soc. 2019, 141, 9401–9407. [Google Scholar] [CrossRef]
  88. Li, X.; Qi, L.; Li, B.; Zhao, Z.; He, G.; Chen, G. Synthesis of cyclophane-braced peptide macrocycles via palladium-catalyzed intramolecular C(sp3)–H arylation of N-methyl alanine at C-termini. Org. Lett. 2020, 22, 6209–6213. [Google Scholar] [CrossRef]
Catalysts 13 00438 g001 550
Figure 1. Representative examples of bioactive macrocyclic natural products.
Figure 1. Representative examples of bioactive macrocyclic natural products.
Catalysts 13 00438 g001
Catalysts 13 00438 g002 550
Figure 2. General strategies for the direct synthesis of macrocycles.
Figure 2. General strategies for the direct synthesis of macrocycles.
Catalysts 13 00438 g002
Catalysts 13 00438 g003 550
Figure 3. Macrolide synthesis via Cp*Rh(III)-catalyzed intramolecular oxidative cross-coupling of alkenes [56].
Figure 3. Macrolide synthesis via Cp*Rh(III)-catalyzed intramolecular oxidative cross-coupling of alkenes [56].
Catalysts 13 00438 g003
Catalysts 13 00438 g004 550
Figure 4. Proposed mechanism for the Cp*Rh(III)-catalyzed intramolecular alkenyl sp2 C–H activation–macrocyclization [56].
Figure 4. Proposed mechanism for the Cp*Rh(III)-catalyzed intramolecular alkenyl sp2 C–H activation–macrocyclization [56].
Catalysts 13 00438 g004
Catalysts 13 00438 g005 550
Figure 5. Synthetic derivatization of the cross-coupling macrocycle product [56].
Figure 5. Synthetic derivatization of the cross-coupling macrocycle product [56].
Catalysts 13 00438 g005
Catalysts 13 00438 g006 550
Figure 6. Macrolactam synthesis via Cp*Rh(III)-catalyzed intramolecular ring-closing alkene−alkene cross-couplings [57].
Figure 6. Macrolactam synthesis via Cp*Rh(III)-catalyzed intramolecular ring-closing alkene−alkene cross-couplings [57].
Catalysts 13 00438 g006
Catalysts 13 00438 g007 550
Figure 7. Synthesis of cyclic peptides via palladium-catalyzed intramolecular indole C-2 C–H bond arylation [64].
Figure 7. Synthesis of cyclic peptides via palladium-catalyzed intramolecular indole C-2 C–H bond arylation [64].
Catalysts 13 00438 g007
Catalysts 13 00438 g008 550
Figure 8. Synthesis of stapled peptides via palladium-catalyzed intramolecular C(sp2)–H bond arylation [65,66].
Figure 8. Synthesis of stapled peptides via palladium-catalyzed intramolecular C(sp2)–H bond arylation [65,66].
Catalysts 13 00438 g008
Catalysts 13 00438 g009 550
Figure 9. Synthesis of maleimide-decorated peptide macrocycles via the Cp*Rh(III)-catalyzed intramolecular C(sp2)–H alkenylation of tryptophan [67].
Figure 9. Synthesis of maleimide-decorated peptide macrocycles via the Cp*Rh(III)-catalyzed intramolecular C(sp2)–H alkenylation of tryptophan [67].
Catalysts 13 00438 g009
Catalysts 13 00438 g010 550
Figure 10. Peptide macrocyclizations via site-selective intramolecular C(sp2)–H bond functionalization of tryptophan [68,69].
Figure 10. Peptide macrocyclizations via site-selective intramolecular C(sp2)–H bond functionalization of tryptophan [68,69].
Catalysts 13 00438 g010
Catalysts 13 00438 g011 550
Figure 11. Peptide macrocyclization via manganese-catalyzed intramolecular C(sp2)–H alkynylation [70].
Figure 11. Peptide macrocyclization via manganese-catalyzed intramolecular C(sp2)–H alkynylation [70].
Catalysts 13 00438 g011
Catalysts 13 00438 g012 550
Figure 12. Macrocyclization of biaryl-bridged cyclic peptides via palladium-catalyzed intramolecular C(sp2)–H bond activation [71].
Figure 12. Macrocyclization of biaryl-bridged cyclic peptides via palladium-catalyzed intramolecular C(sp2)–H bond activation [71].
Catalysts 13 00438 g012
Catalysts 13 00438 g013 550
Figure 13. Synthesis of cyclophane-braced peptide macrocycles through palladium-catalyzed intramolecular vinyl and aryl C(sp2)–H arylation [72].
Figure 13. Synthesis of cyclophane-braced peptide macrocycles through palladium-catalyzed intramolecular vinyl and aryl C(sp2)–H arylation [72].
Catalysts 13 00438 g013
Catalysts 13 00438 g014 550
Figure 14. Peptide macrocyclization via Pd(II)-catalyzed intramolecular δ-C(sp2)–H olefination of phenylalanines [73].
Figure 14. Peptide macrocyclization via Pd(II)-catalyzed intramolecular δ-C(sp2)–H olefination of phenylalanines [73].
Catalysts 13 00438 g014
Catalysts 13 00438 g015 550
Figure 15. Macrocyclization of peptidosulfonamides via palladium(II)-catalyzed intramolecular C(sp2)–H bond olefination [74].
Figure 15. Macrocyclization of peptidosulfonamides via palladium(II)-catalyzed intramolecular C(sp2)–H bond olefination [74].
Catalysts 13 00438 g015
Catalysts 13 00438 g016 550
Figure 16. Macrocyclization via Pd(II)-catalyzed intramolecular C(sp2)–H olefination of peptidoarylacetamides [75].
Figure 16. Macrocyclization via Pd(II)-catalyzed intramolecular C(sp2)–H olefination of peptidoarylacetamides [75].
Catalysts 13 00438 g016
Catalysts 13 00438 g017 550
Figure 17. Late-stage macrocyclization via intramolecular δ-C(sp2)–H bond olefination of oxazole-and thiazole-containing peptides [77,78].
Figure 17. Late-stage macrocyclization via intramolecular δ-C(sp2)–H bond olefination of oxazole-and thiazole-containing peptides [77,78].
Catalysts 13 00438 g017
Catalysts 13 00438 g018 550
Figure 18. Stapled peptides obtained via Pd(II)-catalyzed intramolecular C(sp3)–H arylation [83].
Figure 18. Stapled peptides obtained via Pd(II)-catalyzed intramolecular C(sp3)–H arylation [83].
Catalysts 13 00438 g018
Catalysts 13 00438 g019 550
Figure 19. Synthesis of peptide macrocycles via palladium(II)-catalyzed intramolecular C(sp3)–H arylation [84].
Figure 19. Synthesis of peptide macrocycles via palladium(II)-catalyzed intramolecular C(sp3)–H arylation [84].
Catalysts 13 00438 g019
Catalysts 13 00438 g020 550
Figure 20. Synthesis of cyclophane-braced peptide macrocycles via palladium-catalyzed intramolecular C(sp3)–H arylation [86].
Figure 20. Synthesis of cyclophane-braced peptide macrocycles via palladium-catalyzed intramolecular C(sp3)–H arylation [86].
Catalysts 13 00438 g020
Catalysts 13 00438 g021 550
Figure 21. Synthesis of cyclophane-braced peptide macrocycles via intramolecular C(sp3)–H arylation [87,88].
Figure 21. Synthesis of cyclophane-braced peptide macrocycles via intramolecular C(sp3)–H arylation [87,88].
Catalysts 13 00438 g021
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wang, X.; Lu, M.-Z.; Loh, T.-P. Transition-Metal-Catalyzed C–C Bond Macrocyclization via Intramolecular C–H Bond Activation. Catalysts 2023, 13, 438. https://doi.org/10.3390/catal13020438

AMA Style

Wang X, Lu M-Z, Loh T-P. Transition-Metal-Catalyzed C–C Bond Macrocyclization via Intramolecular C–H Bond Activation. Catalysts. 2023; 13(2):438. https://doi.org/10.3390/catal13020438

Chicago/Turabian Style

Wang, Xiao, Ming-Zhu Lu, and Teck-Peng Loh. 2023. "Transition-Metal-Catalyzed C–C Bond Macrocyclization via Intramolecular C–H Bond Activation" Catalysts 13, no. 2: 438. https://doi.org/10.3390/catal13020438

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop