Abstract

Recently, ortho-phthalaldehyde (OPA) is gaining a renascence for modifying proteins and peptides, via OPA-amine two-component reaction for bioconjugation1 and intramolecular OPA-amine-thiol three-component reaction for cyclization2-3. 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 report, we discovered that guanidine could serve as an effective additive to switch the intermolecular OPA-amine-thiol three-component reactions to a stoichiometric process and enable the modular construction of peptide-peptide, and peptide-drug structures. In addition, the conjugate products could be further functionalized by utilizing the pre-modified OPA derivatives, demonstrating the versatility and flexibility of this reaction.

Reference:

1. Tung, C. L., Wong, C. T., Fung, E. Y. & Li, X. Org. Lett, 2016, 18, 2600–2603.
2. Todorovic, M. et al. Angew. Chem., Int. Ed. 2019, 58, 14120–14124.
3. Zhang, Y., Zhang, Q., Wong, C. T. T. & Li, X. J. Am. Chem. Soc. 2020, 141, 12274–12279.