Synthesis of functionalized (-)-Epigallocatechin gallates by amidomethylation with amidomethyl 2-alkynylbenzoates and its application to the synthesis of 18F-labled labled EGCG

In this study, we report a gold-catalyzed electrophilic aromatic substitution of protected (-)-epigallocatechin gallates (EGCG) with amidomethyl 2-alkynylbenzoates. Treatment of the amidomethyl 2-alkynylbenzoates with (Ph3P)AuOTf provided N-acyl imines under neutral conditions. The N-acyl imines underwent electrophilic aromatic substitution of EGCG at the electron-rich 8 and 6 positions of the A ring. This method facilitated direct modification of a protected EGCG to produce EGCG derivatives containing a (2,2-dimethyl-1,3-dioxan-5-yl)methyl sulfonyloxy group on the A ring, serving as synthetic precursors for 18F-labeled EGCGs. Importantly, the introduction of the radiohalogen labeling unit at the A ring of EGCG did not diminish their cytotoxicity against U266 cells compared to EGCG. Finally, we successfully synthesized a 18F-labeled EGCG via 18F-fluorination of the precursors followed by acidic deprotection.