Studies related to penicillins. Part 17. Reactions of (2S)-3-mercapto-3-methyl-2-{(1S,5R)-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl}-butanoates

Abstract

Methyl (2S)-2-{(1S,5R)-3-benzyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl}-3-mercapto-3-methylbutanoate (4a) reacts with toluene-p-sulphonic acid monohydrate to give (2S,3S)-1-[(1S)-2-mercapto-1-methoxycarbonyl-2-methylpropyl]-4-oxo-3-phenylacetamidoazetidin-2-yl 3-[(1S)-2-mercapto-1-methoxycarbonyl-2-methylpropyl]amino-2-phenylacetamidoacrylate (7). With anhydrous toluene-p-sulphonic acid, the mercaptobutanoate (4a) affords methyl 5,5-dimethyl-2-thiazoline-4-carboxylate (16).

The mercaptobutanoate (4a) is converted into a mixture of methyl benzylpenicillenate (18), methyl benzyl-5-epi-penicillinate (6a), and the thiazepinone (11a) with zinc acetate in boiling benzene. A corresponding reaction, to give the epi-penicillinate (6d) and the thiazepinone (11c), occurs with p-nitrobenzyl (2S)-3-mercapto-3-methyl-2-{(1S,5R)-7-oxo-3-phenoxymethyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl}butanoate (20a). Hydrogenolysis of the derivative (6d) in the presence of sodium hydrogen carbonate yields sodium phenoxymethyl-5-epi-penicillinate (6e), which is devoid of antimicrobial activity.

Acetic acid reacts with the mercaptobutanoate (4a) to give methyl (2S)-[(2S,3S)-2-acetoxy-4-oxo-3-phenyl-acetamidoazetidin-1-yl]-3-mercapto-3-methylbutanoate (9a). Analogous reactions, affording the chloroazetidinone (9b) and the trifluoroacetoxyazetidinone (9c), occur with hydrogen chloride and trifluoroacetic acid.

The mercaptobutanoate (4a) is transformed into (2S,6S,7S)-2-methoxycarbonyl-3,3-dimethyl-8-oxo-7-phenylacetamido-5-oxa-4-thia-1-azabicyclo[4.2.0]octane 4-oxide (24a) by m-chloroperbenzoic acid. Hydrogenolysis of the 2-p-nitrobenzyloxycarbonyl analogue of (24a) in the presence of sodium hydrogen carbonate yields the salt (24c), which shows no significant biological activity.