Azetidinyl thioester

Insertion of carbenoid species into the azetidinone N-H bond is the most straightforward route to 2-oxocarbapenams, and thence to the vast majority of carbapenem antibiotics [186]. Unfortunately, synthesis of the 2-oxopenam 281a (R" = Me) from diazomalonic azetidinyl thioester 323 was abortive [172,187]. The prescribed carbene was generated (rhodium acetate dimer or hv), but it underwent Wolff rearrangement to a ketene. 

In the original formulation [81a], DBN and a slight molar excess of AgN03 in MeCN solution were used. Depletion of the starting penicillanic ester was followed by tic and, when complete, obtained silver azetidinyl mercaptides 126 were in situ treated with acyl chlorides to afford thioesters 127 these in turn were oxidized at the butenoate double bond to give lH-4-thioesters 128, key intermediates of Woodward s original phosphorane-thioester cyclization route to penems [1, 48], or ozonized to the iV-oxalo compounds 129, immediate penem precursors by a newly discovered reductive dicarbonyl coupling [82]. 

The Hatfield protocol was used for the synthesis of 6p-acylamino-2-methylpenems, where a natural penicillin is the substrate and acetic anhydride is the reagent isobutyric anhydride was also employed with success [48]. In particular, esters of penicillin V sulfoxide and its 6a-methoxy and 6a-methyl derivatives 138a c were converted to the corresponding azetidinyl-4-thio-esters of formula 137, isomerized to the conjugated AT-butenoates of general formula 127, and thence oxidatively cleaved to 1 if-4-thioesters 139a c [48, 87, 88] without problems, apart from the competing formation of thiazoline-azetidin-ones 140. 

---