Highly stereocontrolled synthesis of the 1β-methylcarbapenem key intermediate by the reformatsky reaction of 3-(2-bromopropionyl)-2-oxazolidone derivatives with a 4-acetoxy-2-azetidinone

The key synthetic intermediate (4) of 1β-methylcarbapenems (1-3) was efficiently synthesized by employing highly stereocontrolled Reformatsky reaction (C4-alkylation) of 3-(2-bromopropionyl)-2-oxazolidone derivatives (6) with (3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethylJ-2-azetidinone (5) in the presence of zinc dust followed by removal of 2-oxazolidone moieties. The best diastereoselectivity (β:α=95:5) could be realized by uses of sterically crowded achiral 2-oxazolidone derivatives such as 4,4-dimethyl-, 4,4,5,5-tetramethyl, and 4,4-dibutyl-5,5-pentamethylene-2-oxazolidone and higher reaction temperatures (refluxing tetrahydrofuran). The remarkable diastereoselectivities observed for the Reformatsky reactions could be explained by means of the weakly chelating transition state models.