FUKSOVÁ, M., HRUBÁ, K., HORÁK, A., DE DOBBELEER, Corinne, ROBIETTE, R., POSPÍŠIL, Jiří. Modular Synthesis of Dihydropyranones through Cyclization and Organometallic Functionalization. European Journal of Organic Chemistry. 2025, 28(48), e202500848. ISSN 1434-193X. E-ISSN 1099-0690

Dihydropyranones are key structural motifs in biologically active polyketides. We report a reproducible and scalable method for synthesizing 3-methoxy-4,5-dihydropyran-2-ones (MeO-DHP-2-ones) via base-promoted cyclization of hydroxy alkynes. Mechanistic and computational studies revealed that water content and reaction time critically influence lactonization efficiency. Two optimized protocols – using potassium carbonate (K2CO3) or in situ generated sodium methoxide (MeONa) – enabled consistent yields across multiple substrates. Cyclization in deuterated methanol provided deuterium-enriched DHP-2-one scaffolds with high isotopic incorporation, valuable for mechanistic and medicinal applications. The transformation of DHP-2-ones into 4,5-dihydropyran-4-ones (DHP-4-ones) was achieved via organometallic addition followed by a tailored workup involving aqueous hydrochloric acid and boron trifluoride diethyl etherate (BF3·OEt2). This protocol proved robust and scalable, compatible with both organolithium and organomagnesium reagents, although the latter afforded lower yields. Mechanistic analysis highlighted key steps including hemiacetal formation, oxonium activation, and controlled hydrolysis. The methodology enables multigram-scale preparation of both DHP-2-one and DHP-4-one scaffolds and provides a streamlined route toward spiroacetal precursors.