HIGHLY STEREOCONTROLLED SYNTHESIS OF THE 1-BETA-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 1-beta-methylcarbapenems (1 approximately 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)ethyl]-2-azetidinone (5) in the presence of zinc dust followed by removal of 2-oxazolidone moieties. The best diastereoselectivity (beta:alpha = 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 tetrahydrofran). The remarkable diastereoselectivities observed for the Reformatsky reactions could be explained by means of the weakly chelating transition state models.