Stereoselective Synthesis of a Key Intermediate of Sanfetrinem by Means of a Chelated Tin(IV) Enolate

Abstract

(2S)-2-Methoxycyclohexanone [(2S)-6], reacts with the 4-acetoxyazetidinone 3a in the presence of SnCl4 and a tertiary amine base (such as N,N-diisopropylethylamine) to give the ketoazetidinone 5 (a key intermediate in the synthesis of the broad-spectrum antibiotic sanfetrinem 2a) with high yield and diastereoselectivity. Low-temperature NMR studies of the reaction indicated the formation of a 1:1 chelate complex 11 between SnCl4 and (2S)-6 which, on addition of the base is transformed into the highly reactive chelated tin enolate 12. The formation of compound 11 has been confirmed by single-crystal X-ray analysis. The high diastereoselectivity observed is believed to derive from an open transition state where the chelated SnCl4 amplifies the stereochemical influence of the methoxy group. This reaction offers considerable advantages over all existing syntheses of the ketoazetidinone 5 and is currently under evaluation for inclusion in the industrial synthesis of sanfetrinem.