Studies related to β-lactam antibiotics. Part 7. Facile formation of oxazolinoazetidinones from benzothiazolyldithioazetidinones and related reactions

Abstract

4β-(Benzothiazol-2-yldithio)azetidin-2-one (2a), derived from penicillin G sulphoxide ester (1a), is converted competitively into the oxazolinoazetidinone (3a) and 4α-(benzothiazol-2-ylthio)azetidinone (4a) upon treatment with triphenylphosphine at room temperature. Conversion of (3a) into (4a) is performed by heating with a large excess of 2-mercaptobenzothiazole in acetonitrile; reaction of (4a) with silver acetate regenerates (3a). The oxazolinoazetidinone (3b) having a 3-methylbut-3-enoic acid side-chain is easily obtained by reaction of the corresponding 4β-(benzothiazol-2-yldithio)azetidinone (2b) with triphenylphosphine. A one-pot synthesis of (3b) from penicillin G sulphoxide (1b) is achieved without isolation and purification of the intermediate dithioazetidinone (2b). 1-Dethia-1-oxa-5-epi-anhydropenicillin (9) is prepared by intramolecular thermal cyclisation of (3b) followed by base-catalysed isomerisation of the side-chain. Stereocontrolled substitution at position 5 of the oxazolinoazetidinone (3), leading to (4) and the azetidinone-lactone (8), is notable from the mechanistic point of view.