Guanidine Additive Enabled Intermolecular ortho‐Phthalaldehyde‐Amine‐Thiol Three‐Component Reactions for Modular Constructions.

Recently, ortho‐phthalaldehyde (OPA) is experiencing a renascence for the modification of proteins and peptides through OPA‐amine two‐component reactions for bioconjugation and intramolecular OPA‐amine‐thiol three‐component reactions for cyclization. Historically, small thiol molecules were used in large excess to allow for the intermolecular OPA‐amine‐thiol reaction forming 1‐thio‐isoindole derivatives. In this study, we discovered that guanidine could serve as an effective additive to switch the intermolecular OPA‐amine‐thiol three‐component reaction to a stoichiometric process and enable the modular construction of peptide‐peptide, and peptide‐drug conjugate structures. Thus, 12 model peptide‐peptide conjugates have been synthesized from unprotected peptides featuring all proteinogenic residues. Besides, 6 peptide‐drug conjugates have been prepared in one step, with excellent conversions and isolated yields. In addition, a conjugate product has been further functionalized by utilizing a premodified OPA derivative, demonstrating the versatility and flexibility of this reaction. [ABSTRACT FROM AUTHOR]