Synthesis, structural and conformational studies of Z- and E-isomers of fluorinated C-6 isobutenyl N-methyl thymine derivatives

A new series of conformationally restricted pyrimidine derivatives bearing C-6 isobutenyl side-chain (2–9) has been prepared. The novel fluoroalkenyl pyrimidine nucleoside mimetic 3 as model compound for development of tracer molecule in positron emission tomography (PET) was synthesized by fluorination reaction of methoxytritylated pyrimidine derivative using diethylaminosulfur trifluoride (DAST). Conversion of one hydroxyl group to methoxytritylated, fluorinated, mesylated and acetylated pyrimidine derivatives (2, 3, 5–7 and 9) afforded a mixture of Z- and E-isomers in which Z-isomers were predominant. Conformational study of 1, and its fluorinated structural congeners 3 and 4 by the use of NOE experiments revealed predominant conformation of compounds where vinyl H-1′ proton is spatially close to N-1 methyl and H-3′b methylene protons and on the other hand H-3′a methylene protons are close to C-5 methyl protons. The stereostructure of 1,3-dihydroxyisobutenyl N-methyl thymine 1 was unambiguously confirmed by X-ray crystal structure analysis.

Graphical abstractSyntheses of fluorinated C-6 isobutenyl substituted N-methyl thymines are reported. The conformational study of Z- and E-isomer of monofluorinated derivative as model compound for development of PET tracer is also presented.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Syntheses of fluorinated C-6 isobutenyl substituted N-methyl thymines. ► Mixture of Z- and E-isomers in which Z-isomers were predominant. ► The conformational studies by the use of NOE experiments were performed. ► Monofluorinated pyrimidine derivative as model compound for development of PET tracer. ► X-ray crystal structure analysis of 1,3-dihydroxyisobutenyl N-methyl thymine.