"Ligand-Controlled Stereodivergent a-Vinylation and a-Arylation of Peptide Backbones"
Today we are sharing a research article led by Professor Gong Hegui's team, published in the Journal of the American Chemical Society. This study, for the first time, developed a nickel-catalyzed reductive cross-coupling strategy that enables ligand-controlled, stereodivergent vinylation and arylation of the internal α-carbon within peptide backbones. Using readily available racemic α-tosyl glycine (TsG) units as key electrophiles, this work overcomes the bottleneck of difficult stereocontrol in traditional peptide modification, providing a powerful new tool for the late-stage precise functionalization of peptide therapeutics.
01 Research Background
Peptides containing unnatural chiral α-amino acids are widely used in drug development, biomaterials, and asymmetric synthesis, but their synthesis remains challenging. Traditional methods relying on pre-assembling unnatural amino acids carry risks of racemization, involve tedious steps, and are costly. In contrast, late-stage modification strategies for peptides are more efficient; however, existing methods predominantly focus on side-chain modifications, while stereoselective modification of the internal α-carbon of the peptide backbone remains extremely difficult. Traditional techniques like Barton-type radical additions or nucleophilic substitution of α-halogenated peptides lack stereoselectivity, and strategies like Rh-catalyzed hydrogenation cannot achieve α-vinylation/arylation or stereodivergent control. Furthermore, although transition metal-catalyzed C-C coupling chemistry is well-established for synthesizing unnatural amino acids, it has never been successfully applied to modify internal sites within peptide backbones, primarily due to challenges in stereocontrol arising from substrate reactivity, stability, and the complexity of peptide structures (Figure 1). Therefore, developing a general and efficient catalytic platform for the stereoselective C(sp²) functionalization of the peptide backbone α-carbon is urgently needed.
Figure 1. (a,b) Methods for the carbofunctionalization of peptide backbone internal α-carbons.
02 Innovative Highlights
- First example of stereodivergent C–C coupling at internal α-carbons of peptide backbones: This is the first application of a Ni-catalyzed reductive cross-coupling strategy to peptide backbone modification. Using robust racemic TsG units as electrophiles reacting with alkenyl/aryl triflates or halides, it enables the efficient synthesis of α-vinyl/aryl peptides, filling a significant technological gap in the field.
- Ligand-dominated stereocontrol: Through the rational design of chiral bisimidazoline (BiIm) ligands (e.g., (R,R)-L1-L4), the catalyst exerts absolute control over the stereoselectivity, allowing the programmable synthesis of peptide diastereomers (dr up to >90:1), breaking the limitation of substrate chirality dependency in traditional methods.
- Broad substrate compatibility and application potential: Successfully modified various complex backbones, from dipeptides to decapeptides and cyclic pentapeptides, including those containing sensitive residues (e.g., proline) and biologically active fragments (e.g., an intermediate of a Pasireotide analog), demonstrating excellent functional group tolerance and synthetic utility.
03 Results and Discussion
3.1 Reaction Optimization and Mechanistic Exploration
Using N-Bz-protected racemic α-TsG-L-Ala methyl ester (1a) and cyclohexenyl triflate (2) as a model reaction, systematic screening identified optimal conditions (Method A): (R,R)-BiIm ligand L1, Ni(BF₄)₂·6H₂O as catalyst, Zn as reductant, MgCl₂/TBAI as additives, in a DMA/DME/1,4-dioxane mixed solvent. These conditions afforded product 3a in 74% yield and 49:1 dr via a stereoconvergent process; the α-carbon configuration was confirmed as R by single-crystal X-ray diffraction. Control experiments indicated the indispensability of MgCl₂ (activates Zn for reducing Ni salts) and the ligand. Mechanistic studies, involving radical trapping (reaction inhibited by TEMPO, adduct 68 isolated) and characterization of Ni intermediates, propose a pathway: the peptidyl radical (P·) is generated via single-electron reduction of an in-situ formed iodide or iminium species from TsG, which is then captured by an Ar(L)NiIIX species to form a key NiIII intermediate, yielding the product after reductive elimination (Figure 2) .
Figure 2. Reaction optimization and scope for Csp²-electrophiles coupling with N-terminal peptides.
3.2 Scope of Alkenyl/Aryl Electrophiles
Method A is applicable to various alkenyl triflates and aryl halides. Cyclic alkenes (e.g., those containing gem-dimethyl, difluoro, or heteroatom substituents, 5-9), sterically hindered linear alkenes (13-16), and styrenyl bromides (19-22) all coupled in good yields (22-68%) and high dr (>15:1). Aryl bromides (e.g., indole, pyridine derivatives 23-28) and bioactive molecules (e.g., analog of the lipid-lowering drug clofibric acid, 27) were also successfully incorporated, with reactive sites like the 4-bromophenyl group (28) retained for further functionalization.
3.3 Peptide Substrate Generality and Complex Modifications
The study systematically evaluated the compatibility with different peptide backbones. Replacing the L-Ala residue in dipeptides with various amino acids (e.g., residues containing thioether, ether chain, alkyl side chains) (29-36) maintained high coupling efficiency (yields 40-68%) and excellent dr (>20:1). A tripeptide (e.g., Boc-L-Val-TsG-L-Val-OMe 1c) with (R,R)-L2 ligand gave 40 (dr>90:1), while N-terminal D-amino acids (e.g., 1d-1e) required matched (S,S)-L2 ligand for high selectivity (41-42, dr>20:1), highlighting the critical role of stereochemical matching between the ligand and the N-terminal chirality. The strategy was further extended to tetrapeptides (63), pentapeptides (64), even a decapeptide (65), and modification of a cyclic pentapeptide (Val-TsG-Pro-Phe-D-Ala 1m) (66, dr 10:1), demonstrating its adaptability to higher-order peptide structures (Figure 3).
Figure 3. Scope of the internal TsG-peptides.
3.4 Synthetic Application Demonstration
The practical value of the method was highlighted by preparing a key tripeptide intermediate (67) for an analog of Pasireotide (an FDA-approved drug for acromegaly). This synthesis involved a novel three-component reaction to construct an α-sulfonylthioglycinate (a-TTG), followed by HATU coupling and mCPBA oxidation to give the sulfonyl precursor 1n, which finally coupled with PhBr to afford 67 in 34% yield and >90:1 dr, avoiding racemization issues common in traditional amide condensation (Figure 4).
Figure 4. Preparation of a key intermediate to an analogue of pasireotide.
04 Conclusion and Future Perspectives
This study successfully developed a Ni/chiral BiIm-catalyzed reductive cross-coupling platform enabling the stereodivergent C(sp²) functionalization of internal α-carbons in peptide backbones. Its core innovation lies in utilizing readily available, stable TsG units as versatile electrophiles, achieving high stereoselectivity through ligand control, and demonstrating compatibility with linear, cyclic, and long-chain peptides. This strategy not only avoids racemization problems inherent in traditional peptide assembly, providing a new pathway for the late-stage precise diversification of peptide libraries, but also holds promise for promoting innovative applications of transition metal catalysis in peptide modification, facilitating the development of novel biotherapeutic agents and peptide-based functional materials. Future research directions may focus on extending the coupling to C(sp³) electrophiles, developing modifications for more challenging protein backbones, and advancing the industrial application of this technology in peptide drug production.
Original Article:
Hu J, Su S, Zhang H, An H, Chen Y, Gong H. Ligand-Controlled Stereodivergent α-Vinylation and α-Arylation of Peptide Backbones. J Am Chem Soc. 2025 Oct 22;147(42):38475-38483.