Azetidinone sulfenic acid

The thermal equilibration between penam sulfoxides and azetidinone-4-sulfenic acids 109 opens the way to a number of methodologies for obtaining azetidinone 4-thioesters. The oldest one, discovered in 1970 by Hatfield et al. [86], simply involves heating of the penam sulfoxide with a carboxylic anhydride and trimethyl phosphite thioesters 137 are obtained through a mechanism representable by the formation and collapse of penta-coordinate phosphorous intermediate 135. 

Several new examples of the known transformation of penicillin sulfoxides into isothiazolones, through the corresponding azetidinone sulfenic acid, have been reported <1998TL6983>. 

Reactions of Azetidinone Sulfenic Acids with Halogenating Reagents. Conjugate Addition Reactions of Azetidinone Sulfenic Acids. Reaction of Azetidinone Sulfenic Acids with Enol Ethers. 

Reactions of Azetidinone Sulfenic Acid with Phosphorus Reagents. 

The existence of an equilibrium between penicillin sulfoxide and the azetidinone sulfenic acid was first explored in 1969 and further substantiated by several groups (Cooper and Spry, 1972). The intermediate, however, had never itself been isolated. Indeed, an isolable sulfenic acid was a rare entity. Chou and co-workers (1974) observed that a mixture was obtained after an ethyl acetate solution of the sulfoxide (17) was refluxed and rapidly cooled. Separation, by fractional crystallization, yielded the starting sulfoxide (17) and a second compound identified as the sulfenic acid (19). Cyclization of 19 to the sulfoxide occurred readily (/1/2 3 hr at 38°C in chloroform). NMR data indicated that the structure of the sulfenic acid was best represented by isomer a rather than iso mer b. 

An alternate method of preparing the azetidinone sulfenic acid was developed by initially trapping the sulfenic acid as its trimethylsilyl ester (32) (Chou et al., 1976). Careful cleavage of the trimethylsilyl protecting group with methanol afforded the sulfenic acid (31) (Chou et al., 1974). 

III. Reactions of Azetidinone Sulfenic Acids with Halogenating Reagents... 

V. Reaction of Azetidinone Sulfenic Acids with Enol Ethers... 

Instead, cyclization occurred between a sulfenic acid at azetidinone C4 and an alkyne moiety at nitrogen [206]. The ( )-2-alkylidenepenams 374 were selectively obtained by thermolysis of appropriate 4-rert-butylthioazetidinone precursors, through the intermediacy of transient sulfenic acids 373. The high stereoselectivity of the reaction is suggestive of a pericyclic ring closure. Sulfoxide reduction of 374 was achieved with PBZ3 in DMF. 

The sulfenic acid was reported to react with certain thioamides in which the thioamide reacted as a thioimine to produce azetidinone-4-iminodisulfides. This represented a bimolecular analogy of the previous reaction. However, no further details are available on this reaction or the products (Micetich, 1976c). 

Other azetidinone derivatives useful for the synthesis of new p-lactam structures have been prepared by variations in the reaction of a trialkyl-phosphite with the sulfenic acid derived from a penicillin sulfoxide. 

Similarly, sulfenimino-P-lactam 205 [107] reacted with diazomethane to give y-lactam 206 by methylene insertion into the C-6/C-7 azetidinone bond (Scheme 58). A spiro-aziridine intermediate was probably formed [106]. Sulfen-amide cleavage initiated by triphenylphosphine followed by acylation and ester deprotection led to the acid 207 which does not have any significant antimicrobial or p-lactamase inhibitory activity [106]. 

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