Selective isomerization of 2,3-disubstituted butanediacetal esters and thioesters using lithium and sodium enolates: effects of bases and additives on stereoselectivity

The study concerned the stereoselective isomerisation of S2,S3-diethyl (<i>2R,3R,5R,6R</i>)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-dicarbotioate to the isomer S2, S3-diethyl (<i>2R,3S,5R,6R</i>)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-dicarbotioate via stable lithium and sodium enolates. For this purpose, enolate anions were generated using lithium diisopropylamide (LDA) and sodium isopropyl(trimethylsilyl)amide (NaPTA), using methanol as a proton source. Optimal stereoselectivity was achieved using 2.2 equivalents of LDA or NaPTA, yielding isomer ratios of 1:6.3 and 1:6.1, respectively, and good yields of 68% and 79%. The selectivity of the reaction was further increased in the presence of 10% (v/v) HMPA or six equivalents of LiCl in systems with LDA, indicating the important role of metal complexation. A symmetrical bis(silyl enol ether) with a Z,Z configuration of double bonds was isolated from the enolate formed during the reaction, confirming the ordered geometry of the system. The observed stereoselectivity is explained by the non-equivalence of the two possible enolates and the chelation-controlled desymmetrisation of the dienolate. Both NaPTA and LDA enabled selective isomerisation without additives, with NaPTA proving particularly effective for related butanediacetal derivatives containing thioesters, providing >90% cis isomer yield for the mixed ester-thioester substrate. These results show that NaPTA is an efficient and highly stereoselective base for the isomerisation of thioester-containing butanediacetals, expanding the possibilities of stereocontrolled enolate chemistry.