Azetidinone disulfides

Penicillin sulfoxides are converted on heating with trimethyl orthoacetate or excess ethyl 2-thioacetate into isothiazolin-3-ones. The azetidinone disulfide, formed when one equivalent of ethyl... 

In contrast to several other rearrangements of the penicillin sulfoxide, the reaction with 155 was also successful with the free acid (4) wherein 157 was isolated with no reported decarboxylation. Treatment of the acid (157) with sodium bicarbonate afforded a disproportionation-recombination reaction resulting in the azetidinone disulfide U58) and the benzthiazoyl disulfide (159). 

A utilization of the azetidinone disulfide as an intermediate in the synthesis of new (3-lactam structures was elegantly demonstrated in the synthesis of the penem (204) (Woodward, 1977). The disulfide (205) was converted to 206 which was the starting material for penems 204 and 207. The details of this synthesis are discussed in Volume 2, Chapter 5. 

When a mixture of stereoisomers of the disulfide 295 was kept at room temperature under argon at pH 9, the bicyclic azetidinone 296 was obtained in 76% yield <1999CCC190>. 

Woodward s Phosphorane Route. The first penem synthesis, shown in Figure 2, utilized an intramolecular Wittig reaction to form the [2,3] double bond of the thiazoline ring (84). Reductive acylation of the penicillin derived disulfide (44) gave the thioester (45). Ozonolysis of the latter provided the oxalimide (46) which on mild methanolysis gave the azetidinone (47). Well established methods were applied to convert (47) to the phosphorane (48) which underwent thermal cydization to the penem ester (49). Catalytic hydrogenation gave the penem acid [64370-39-4] (50) which was shown to possess antibacterial activity in spite of its rather limited stability. 

A final mention of Kamiya disulfides in penem synthesis relates to their use as intermediates for 4-chloroazetidinones these in turn can be converted to 4-thioesters [55]. However, chlorinolysis of azetidinone-4-sulfides and -disulfides finds its most important application in the 1,5-ring closure strategy to penems, so that it will be discussed at a later point in this review. 

The disulfide-enols 345 were converted to oxazoline-azetidinones 346 by intramolecular trapping of the azetinium cation [or of an intermediate 5-epiclavem 196] by the acylamino oxygen atom (various protocols trimethyl phosphite or triphenyl-phosphine treatment preferred). After mesylation, oxaz-oline cleavage with dry HCl afforded chloroazetidinones 347 with neat inversion of configuration, which underwent ring closure (H2S/TEA) to give the prescribed (5 R )-6-acylamino-2-methylpenems. 

Conversion of the disulfide (153) to an azetidinone thioether (153A) was achieved by treatment with triethylphosphite (Barton et al., 1971a). This conversion was proposed as proceeding through the pentavalent phosphorus intermediate (153B). 

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