Late‐Stage Peptide Macrocyclization by Palladium‐Catalyzed Site‐Selective C−H Olefination of Tryptophan

Abstract

Transition‐metal‐catalyzed C−H activation has shown potential in the functionalization of peptides with expanded structural diversity. Herein, the development of late‐stage peptide macrocyclization methods by palladium‐catalyzed site‐selective C(sp2)−H olefination of tryptophan residues at the C2 and C4 positions is reported. This strategy utilizes the peptide backbone as endogenous directing groups and provides access to peptide macrocycles with unique Trp–alkene crosslinks.

Recent Advances in Late‐Stage Construction of Stapled Peptides via C−H Activation

“…Recently, stapling reaction via olefination on the residue of Trp utilizing the same backbone‐assisted C(sp 2 )−H activation method was developed by Wang group [51] . In this work, stapled peptides with different sized rings were produced in moderate yields and the double bond in stapling product 18 a was further demonstrated as E ‐configuration through its coupling constant ( J ab =16.0 Hz) (Scheme 9).…”

“…Apart from utilizing the C‐2 position of Trp residue as a stapling site, a stapling strategy in the C‐4 position of Trp residues was developed by Wang group [51] . They recently reported an arene‐alkene crosslink stapling strategy in the C‐4 position of Trp residues through Pd‐catalyzed C(sp 2 )−H olefination employing trifyl (Tf) as DG.…”

Highly Efficient Cyclization Approach of Propargylated Peptides via Gold(I)-Mediated Sequential C–N, C–O, and C–C Bond Formation

“…This includes click chemistry, 7 alkene metathesis, 8 heteroatom coupling, 9 − 12 and more recently C–H activation. 13 , 14 However, some of these methods suffer from harsh conditions (e.g., reaction temperatures of 100 °C), 13 , 14 a requirement of long reaction times (24–48 h), 9 , 13 , 14 a requirement of sacrificial oxidants, 13 , 14 low yields, 13 , 14 and the necessity of protecting groups on the amino acid side chains, 10 − 14 which hamper the practical synthesis of the desired target.…”

A Peptide Stapling Strategy with Built‐In Fluorescence by Direct Late‐Stage C(sp2)−H Olefination of Tryptophan

“…During our manuscript submission, Wang′s group reported a C−H olefination method of the Trp residue by using the peptide backbone as a directing group. The group used this method to construct a macrocyclic peptide successfully [26] . However, this method requires high reaction temperatures and the Trp residue at the C‐terminal position, restricting its wide application.…”

“…The group used this method to constructamacro-cyclic peptides uccessfully. [26] However,t his method requires high reaction temperatures andt he Trpr esidue at the C-terminal position, restricting its wide application.I ns ummary,t he peptides tapling strategies based on the Trpr esidue modification are still under development. It also presents ac hallenge to develop ap ractical and regioselective methodology to construct stapled peptidesw ith improved fluorescent properties based on the Trpr esidue under mild conditions.…”