Acid‐Catalyzed Cycloaddition of Guanines with TMOP: A Unified Strategy for Synthesizing Tricyclic Acyclovir Analogues and M 1 G‐Containing Oligonucleotides

This article describes an efficient acid-catalyzed cyclization strategy for constructing the tricyclic pyrimido1,2-apurin-10(3H)-one scaffold via the reaction of guanine derivatives with 1,1,3,3-tetramethoxypropane (TMOP) catalyzed by 2,4,5-trifluorobenzoic acid. The method features mild conditions, eliminates the need for hydroxyl protection, and exhibits excellent functional-group tolerance, making it applicable to the late-stage structural diversification of various nucleosides, nucleotides, and oligonucleotides. Using the antiviral drug acyclovir and an azide-containing guanosine derivative as model substrates, we successfully synthesized a tricyclic acyclovir analogue in 81% yield and an M1G-containing oligonucleotide in 40% yield. This protocol provides a general, convenient, and efficient experimental approach for synthesizing this class of potentially bioactive tricyclic nucleoside analogues. © 2026 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of tricyclic acyclovir analogue Basic Protocol 2: Synthesis of M1G-containing oligonucleotide.