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

Abstract

<p>Recently, ortho-phthalaldehyde (OPA) is experiencing a renascence for the modification of<br>proteins and peptides through OPA-amine two-component reactions for bioconjugation and intramolecular<br>OPA-amine-thiol three-component reactions for cyclization. Historically, small thiol molecules were used in<br>large excess to allow for the intermolecular OPA-aminethiol reaction forming 1-thio-isoindole derivatives. In<br>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.<br></p>