The Development of Organometallic Methodologies For the Stereospecific Introduction of Cephalosporin Side Chains

A variety of 3-substituted cephems has become available via the coupling of 3-trifloxycephems with organostannanes, by a modified Stille coupling procedure that includes a new palladium ligand, tri(2-furyl)phosphine. A complementary cuprate coupling via the same intermediates is also described. A cheaper alternative to the triflates are the enol fluorosulfonates, which also undergo Stille and organocuprate couplings. A radically different approach to cephaosporins from penicillins involves a modification of the Morin rearrangement that involves the intermediacy of allenylazetidinones; these undergo chemoselective addition of cuprates to the allene central carbon, followed by rapid cyclization by intramolecular sulfenylation. The process was applied, i.a., to the efficient synthesis of the new oral antibiotic Cefprozil. 1. Introduction 2. The Stille Approach to Novel Cephalosporins 3. Other Cross-Coupling Approaches 4. The synthesis of Cephalosporins via Allenylazetidinones 5. Conclusion