Stereoselective isomerisation of rel-(2R,4S,5R)-4-(3′,5′-dimethoxyphenyl)-2,5-dimethyl-1,3-dioxolane 7 with titanium tetrachloride affords rel-(1R,3R,4S)-4-hydroxy-6,8-dimethoxy-1,3-dimethylisochromane 19 and its C-1 epimer 20 in high yield. The former predominates at a reaction temperature of -78°C and the latter at -30°C. Similar isomerisation of the 1:1 mixture of rel-(2S,4R,5R)- and rel-(2R,4R,5R)-4-(3′,5′-dimethoxyphenyl)-2,5-dimethyl-1,3-dioxolanes 8 and 9 gives rel-(1R,3R,4R)-4-hydroxy-6,8-dimethoxy-1,3-dimethylisochromane 29 and its C-1 epimer 31, with the latter predominating at both -78 and -30°C. At 0°C, dioxolane 7 is isomerised to rel-(1S,1′R,3R)-1-(1′-hydroxyethyl)-4,6-dimethoxy-3-methyl-1,3- dihydroisobenzofuran 25 and its C-3 epimer 26 as the sole reaction products in a 10:1 ratio. Dioxolanes 8 and 9 are similarly converted into rel-(1R,1′R,3S)-1-(1′-hydroxyethyl)-4,6-dimethoxy-3-methyl-1,3- dihydroisobenzofuran 32 and its C-3 epimer 33. These furans probably arise through further isomerisation of the intermediate isochromanes at the higher reaction temperatures.
