Acid-Catalyzed Cycloaddition of Guanines with TMOP: A Unified Strategy for Synthesizing Tricyclic Acyclovir Analogues and M1G-Containing Oligonucleotides

This article describes an efficient acid-catalyzed cyclization strategy for constructing the tricyclic pyrimido[1,2-a]purin-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 M 1 G-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 M 1 G-containing oligonucleotide