Penem sulfone

Methylene penems constitute good /3-lactamase inhibitors as their hydrolytic metabolism leads to the formation of 1,4-thiazepines, strengthening the thus-formed acyl-enzyme complex link (see Sections 2.03.6.9 and 2.03.12.4). However, compared to penams, penem sulfones are not as good /3-lactamase inhibitors as their half-lives of hydrolysis are too short, making them labile under physiological conditions <1997BML2217>. 

Pfaendler s study deals with the preparation of both penem sulfoxides 43 and sulfones 45 from 42 using the required amounts of OT-chloroperbenzoic acid (MCPBA) as depicted in Scheme 25. In a second step, 43 and 45 were converted into their respective potassium salts 44 and 46. However, catalytic hydrogenation on 45a resulted in product decomposition, as 46a was too labile to be isolated <1997BML2217>. 

While 1,2-cleavage of penams by base-promoted P-elimination requires activation with thiophiles, penam sulfones readily react with DBN to give azetidinone sulfinic acids by an ElcB mechanism [98]. Stoodley et al., who discovered this reaction, also developed the sulfinic acid chemistry necessary for application to penem synthesis, namely the conversion of the ring-opened products into either 4-alkylsulfonyl- or 4-acyldithioazetidinone derivatives. 

Similar rearrangements were observed on related substrates in the preparation of bis-norpenicillins [188a]. Competition from the sulfur atom in the nucleophilic intramolecular attack of the nitrogen atom to the carbenoid species could be repressed by oxidation to the sulfoxide or sulfone derivatives [188]. Unfortunately, these findings were of no use in penem synthesis. 

FIGURE 8.5 Structures of /3-lactamase inhibitors ciavulanic acid, penicillanic acid sulfone(s), carba-penem(s), 6/8-halopenam(s), and sulfenimine(s). 

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