Stereoselective and Scalable Synthesis of Potent Antibiotic RSC-435830 Through a Key Intermediate C2 (<i>S</i>)-Methylcephalosporin

Cephalosporins are valuable antibiotics for clinical treatment of infectious diseases. RSC-435830 is a cephalosporin-containing antibiotic with a unique C2 (S)-methylcephalosporin structure. It was a synthetic challenge to construct a chiral methyl group at the C-2 position on the cephalosporin scaffold. We report herein two routes for the stereoselective and scalable synthesis of C2 (S)-methylcephalosporin 4, a key intermediate of RSC-435830, that has advanced to phase I clinical trials. The first route focused on stereoselective isomerization of the double bond on the cephalosporin structure without significant changes from the initial synthetic route. For the second route, we set an alternative starting material and then optimized a Mannich-type reaction followed by stereoselective reduction, to enable shortening of the reaction steps from the first route. This culminated in the synthesis of several hundred grams of the key intermediate 4 leading to RSC-435830.