Stereoselective isomerisations of 4-(2′,5′-dimethoxyphenyl)-2,5-dimethyl-1,3-dioxolanes and their 2′-chloro-5′-methoxyphenyl analogues. Temperature-dependent diastereoselective formation of isochromanes

Abstract

Stereoselective isomerisations of rel-(2R,4S,5R)-4-(2′,5′-dimethoxyphenyl)-2,5-dimethyl-1,3-dioxolane 1 and the 2∶1 epimeric mixture of rel-(2S,4R,5R)- and rel-(2R,4R,5R)-4-(2′,5′-dimethoxyphenyl)-2,5-dimethyl-1,3-dioxolanes 2 and 3 with titanium tetrachloride at –78 °C afford rel-(1R,3R,4S)- and rel-(1S,3R,4R)-4-hydroxy-5,8-dimethoxy-1,3-dimethylisochromanes 25 and 30, respectively. The yields are only moderate owing to the competing influence of the 2′-methoxy group in the starting dioxolanes, and are improved significantly when this group is replaced by a 2′-chloro substituent. rel-(2R,4S,5R)-4-(2′-Chloro-5′-methoxyphenyl)-2,5-dimethyl-1,3-dioxolane 13 under similar conditions is isomerised smoothly to rel-(1R,3R,4S)-5-chloro-4-hydroxy-8-methoxy-1,3-dimethylisochromane 34 as the sole reaction product. In contrast the C-2 epimers rel-(2R,4R,5R)- and rel-(2S,4R,5R)-4-(2′-chloro-5′-methoxyphenyl)-2,5-dimethyl-1,3-dioxolanes 14 and 15 each favour the formation of rel-(1R,3R,4R)-5-chloro-4-hydroxy-8-methoxy-1,3-dimethylisochromane 36 at –78 °C, while at –95 °C the 1S product 35 predominates. Dioxolane 14 isomerises more rapidly than its C-2 epimer 15, and both these reactions are under kinetic not thermodynamic control.