New Methods for the Synthesis of Spirocyclic Cephalosporin Analogues

Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin beta-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28-65%).

Automated summary

Spiro compounds with three-dimensional structures are attractive targets in drug discovery for enhancing protein interactions, solubility, and molecular modeling. A novel method has been developed for generating spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring, leading to selective formation of spiro-cephalosporins in moderate to good yields.